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
The Amendment filed on 08May2026 is acknowledged in which claim(s) 1-26, 31, 34, 36-37, 39, 45, 48-49, 52-53, 55-64, 66-68, and 70-146 were canceled by Applicant.
Applicant’s election without traverse of Group I and species of (a) an antigen binding domain comprising a VH comprising HCDR1-3 of SEQ ID NOs: 1-3, respectively and a VL comprising LCDR1-3 of SEQ ID NOs: 4-6, respectively, (b) an IgG4 hinge/spacer, (c) a CD28 transmembrane domain, (d) an intracellular CD28 costimulatory domain and an intracellular CD3 zeta domain, and Applicant further self-elected (e.g., without Office Requirement) (i) a dominant-negative TGFB receptor Type II (dnTGFBRII) optional armoring molecule, (ii) a cleavable peptide linker linking the armoring molecule and the CAR, in the reply filed on 08May2026 is acknowledged.
The separate species of antigen binding domain comprising HCDR1-3 and LCDR1-3 sequences are rejoined herein by the Examiner.
Claim(s) 65 and 69 is/are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08May2026.
Claim(s) 27-30, 32-33, 35, 38, 40-44, 46-47, 50-51, and 54 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., xCELLigence, FlowJo, GraphPad, FACSymphony, QuickCal, FACSAria, ExPERT GTx), 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 Objections
Claim(s) 40 is/are objected to because of the following informalities: ‘variants’ thereof is grammatically incorrect. Appropriate correction is requested.
Claim Rejections - 35 USC § 112 (b)
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) 30, 32-33, 35, 40, 51 is/are 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.
Regarding claim(s) 40, 51, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(h)(II). It is unclear if the limitation(s) following the phrase are limitation(s) or merely provided as an example. For the purposes of compact prosecution, the limitations following the phrase are not considered part of the claimed invention. This rejection may be overcome by amending claim(s) 40, 51 to remove “optional” limitations and/or the phrase “optionally”.
Regarding claim(s) 30, 32, recite(s) “…selected from...” followed by a list of transmembrane domains joined by an “or” in line(s) 3-4 or claim(s) 30, which renders the claims indefinite. Specifically, because the group members are recited in the alternative ("or"), it is unclear which members are part of the claimed grouping. See MPEP 2173.05(h) for examples of proper Markush formats: "…e.g., alternatives may be set forth as "a material selected from the group consisting of A, B, and C"…". For the purposes of compact prosecution, the joining word is considered to be “and” for claim(s) 30 and 32. This rejection can be overcome by amending claim(s) 30 to replace the “or” joining the list of transmembrane domains with an “and”. Claim(s) 32 can overcome this rejection by amending claim(s) 30 as described above.
Claim(s) 33, 35 recite(s) the limitation "the one or more intracellular domains" in line(s) 1-2 of claim(s) 33. There is insufficient antecedent basis for this limitation in the claim. Specifically, claim(s) 33 depends from claim(s) 27, which does not recite that the CAR comprises one or more intracellular domains. For the purposes of compact prosecution, claim(s) 33 is/are considered to recite “wherein the CAR comprises one of more intracellular domains”. This rejection can be overcome by amending claim(s) 33 as recited above or to otherwise provide proper antecedent basis. Claim(s) 35 can overcome this rejection by amending claim(s) 33 as described above.
Claim Rejections - 35 USC § 112 (a) – written description
Claim(s) 27-30, 32-33, 35, 38, 40, 42-44, 46-47, 51, 54 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) 27-30, 32-33, 35, 38, 40, 42-44, 46-47, 51, 54 are drawn to a chimeric antigen receptor (CAR) that binds CLDN18.2 antigen.
Breadth of Claims
The invention as disclosed in claim(s) 27 (and claim(s) 28-30, 32-33, 35, 38, 40, 42-44, 46-47, 51) and 54 are drawn to a mix and match of heavy and light chain CDRs. Specifically, the inventions as disclosed in claim(s) 27 (and claim(s) 28-30, 32-33, 35, 38, 40, 42-44, 46-47, 51) and 54 recite(s) “…wherein the VH comprises a CDR1…selected from SEQ ID NO: 1, 11, 21, 31, and 41; a CDR2…selected from SEQ ID NO: 2, 12, 22, 32, and 42; and a CDR3…selected from SEQ ID NO: 3 13, 23, 33, and 43; and wherein the VL comprises a CDR1…selected from SEQ ID NO: 4, 14, 24, 34, and 44; a CDR2…selected from SEQ ID NO: 5, 15, 25, 35, and 45; and a CDR3…selected from SEQ ID NO: 6, 16, 26, 36, and 46…” in line(s) 4-11. These claims read that one would be able to mix and match HCDR3 and LCDR3 sequences and arrive at an antibody or CAR that binds to CLDN18.2 antigen. However, according to Applicant’s disclosure there are specific SEQ ID pairings for each anti-CLDN18.2 antibody clone (see summary table below). One of ordinary skill in the art would understand that to mix and match CDRs between antibodies and/or antigen binding domains thereof (e.g., in a CAR), the HCDR1-3 and LCDR1-3 sequences must be identical. Each of the HCDR1, HCDR2, LCDR1, and LCDR2 sequences are identical between disclosed anti-CLDN18.2 clones. However, HCDR3 and LCDR3 sequences are not identical between all disclosed anti-CLDN18.2 clones. The example alignment below of the anti-CLDN18.2 clones shows that instant claimed HCDR3 and LCDR3 both have different sequences and therefore cannot be mixed and matched (e.g., no support for anti-CLDN18.2 Ab with HCDR3 and LCDR3 of SEQ ID NOs: 3, 16, respectively):
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Scope of Disclosed Species
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The CLDN18.2-directed CAR(s) and/or antigen binding fragments thereof in the Applicant disclosure (see summary table above for details) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the CLDN18.2-directed CAR(s) and/or antigen binding fragments thereof that the applicant was in possession of at the time of filing.
State of the Prior Art
At the time of filing, antibody and/or CAR(s) antigen binding domain functionality was/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, ¶ 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, ¶ 3].
At the time of filing, WO 2019/174617 A1 (hereinafter “WO617”) taught CLDN18.2-directed CAR(s) were recognized in the art [e.g., abstract; ¶ 17]. WO617 taught various separate species of CLDN18.2-directed CAR(s) [e.g., abstract; ¶ 17-18, 113-138, 226-240]. Therefore, the prior art demonstrates that the binding of CLDN18.2 antigen is possible by various CLDN18.2-directed CARs. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in CLND18.2-directed CAR(s) that would allow prediction of CDR residues that specifically bind to CLDN18.2 antigen.
Thus, making changes to the one or more of the six CDR sequence(s) (e.g., mixing and matching of CDRs from different clones) of a CAR antigen binding domain sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such changes 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 (e.g., mixed and matched) and still result in a CAR that binds CLDN18.2 antigen. 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) 27 and 54 would need to recite the 6 CDRs sets (e.g., HCDR1-3 and LCDR1-3) for each clone in the CAR(s) that bind CLDN18.2 antigen, without mixing and matching of CDRs between clone(s). Claim(s) 28-30, 32-33, 35, 38, 40, 42-44, 46-47, 51 can overcome this rejection by amending claim(s) 27 as recited above.
Allowable Subject Matter
Claim(s) 41, 50 is/are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Specifically, claim(s) 41 and 50 are drawn to a CLDN18.2 directed CAR construct comprising HCDR1-3 of SEQ ID NOs: 1-3, respectively, and LCDR1-3 of SEQ ID NOs: 4-6, respectively (see table below for details). Briefly, a sequence search of the prior art returned no 100% matches to the required HCDR1-3 sequences (see closest prior art alignment below), and therefore cannot return a 100% sequence identity match to either of the instant claimed CAR constructs.
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Alignment of anti-CLDN18.2 clone 008LYG_D08 HCDR1-3 (SEQ ID NOs: 1-3, respectively) with WO2017189724-A1 (Anti-GDF15 antibody heavy chain variable region, SEQ ID 194):
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Free From the Prior Art
During the course of examination, the CLDN18.2-directed CAR construct(s) comprising an antigen binding domain comprising HCDR1-3 and LCDR1-3 of any one of anti-CLDN18.2 clone(s) “008LYG_D08”, “008LY1_D04”, “ZP1I16_D05”, “008M0G_G03”, or “ZP1I18_B08” (see summary table below for sequence details), was/were found to be nonobvious in view of the closest prior art. Briefly, a sequence search of the prior art returned no 100% matches to any of the disclosed anti-CLDN18.2 clones’ HCDR1-3 sequences (see closest prior art alignments below), and therefore cannot return a 100% match to any of the 6 CDR set(s), VH/VL set(s), scFv(s), or CAR constructs of the instant claimed invention.
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For alignment of clone “008LYG_D08” HCDR1-3, see ‘allowable subject matter’ above.
Alignment of anti-CLDN18.2 clone “008LY1_D04” HCDR1-3 (SEQ ID NOs: 11-13, respectively) with EP3919126-A1 (Anti-Spike RBD mAb YU505-A05 VH domain, SEQ 944):
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Alignment of anti-CLDN18.2 clone “ZP1I16_D05” HCDR21-23 (SEQ ID NOs: 21-23, respectively) with WO2017189724-A1 (Anti-GDF15 antibody heavy chain variable region, SEQ ID 194):
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Alignment of anti-CLDN18.2 clone “008M0G_G03” HCDR1-3 (SEQ ID NOs: 31-33, respectively) with WO2011020783-A2 (Human anti-tenascin C A2 domain antibody VH region, SEQ ID 7):
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Alignment of anti-CLDN18.2 clone “ZP1I18_B08” HCDR1-3 (SEQ ID NOs: 41-43, respectively) with WO2017189724-A1 (Anti-GDF15 antibody heavy chain variable region, SEQ ID 194):
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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
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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