Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on 23 January 2026. Claims 1, 3, 4, 6, 8 – 14, and 29 – 40 are currently pending. Claims 1, 4, 6, 8, 9, 10, 11, 12, 13, 14, 29, 30, 31, 32, 35, 36, 37, and 39 have been amended and claim 40 has been newly added in the Applicant’s amendment filed 23 January 2026. Claims 2, 5, 7, and 15 - 28 have been canceled in the Applicant’s amendment filed 23 January 2026.
Applicant's election, with traverse, in the reply filed 31 July, 2025, 2025 of Group I, claims 1 – 13 (claims 5 and 7 now canceled) , directed to a binding moiety that specifically binds to Claudin 18.2; and the following election of Species, without traverse, was acknowledged:
Sequence election of CDR1 set forth in Seq ID No:5, CDR2 set forth in Seq ID No: 21, CDR3 set forth in Seq ID No. 36, the set of CDR sequences correspond to the VHH sequence set forth in Seq ID No: 50 (referring to instant claims 3,5, and 8), and this set of CDR sequences correspond to the CAR sequence set forth in Seq ID No: 65 (referring to instant claim 31; See Applicants’ remarks at page 1). Note that claim 2 subpart (xiii) recites “ a CDR1, a CDR2, and a CDR3 having the amino acid sequences of the CDR1, CDR2, and CDR3, respectively, as set forth in SEQ ID NO:50;” and claim 5 recites “ further comprising one or more FR regions as set forth in …SEQ ID NO:50”.
Claims 14 - 39 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. (Claims 15 – 28 have now been canceled).
Please note: Claims 6 – 13 were previously withdrawn for being improper multiple dependent claims. Claims 6 – 13 have been rejoined, and will be examined on the merits.
The restriction requirement was deemed proper and was therefore made FINAL.
The claims were examined insofar as they read on the elected species.
Therefore, claims 1, 3, 4, 6, 8 – 13, and 40 are under consideration to which the following grounds of rejection are applicable. Claims 1, 3, 11-13, and 40 are independent claims.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on December 31, 2025, and January 23, 2026 has been considered. An initialed copy of the IDS accompanies this Office Action.
Priority
The present application filed 17 June, 2022, is a 35 U.S.C. 371 national stage filing of International Application No. PCT/CN2020/139143, filed 24 December, 2020, which claims the benefit of Chinese PCTCN2019129095, filed 27 December, 2019.
Therefore, the earliest priority date is 27 December, 2019.
Maintained Objections/Rejections
Claim Rejection - 35 USC § 112(a) Scope of Enablement
The rejection of claims 1, 3 and 4 is maintained, and claims 6, 8 – 13, and 40 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the Specification, while being enabling for
An anti- Claudinl8.2 single-domain antibody, comprising framework regions and complementarity determining regions (CDRs), wherein the CDRs comprise CDRI, CDR2, and CDR3 , respectively, in sequence (e.g., FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4), corresponding to the CDR1, CDR2, and CDR3 identified with a SEQ ID NO in claim 1 subparts (1)-(14) and new claim 40, subparts (1) – (14), and their corresponding full length amino acids sequence of Seq IDs No: 38 – 51, and 77 – 85 comprising said claim 1 subparts (1)-(14) as recited in claim 3,
does not reasonably provide enablement for any binding moieties that do not comprise framework regions where the CDRI, CDR2, and CDR3 are located in any order t and does not reasonably provide enablement for any binding moieties that have less than 100% sequence alignment to the amino acids sequence of Seq IDs No: 38 – 51, and 77 – 85. This rejection has been modified as necessitated by the response filed January 23, 2026.
The Specification does not enable any person skill in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The claims, when given the broadest possible interpretation, encompasses a binding moiety that specifically binds to Claudin18.2, comprising a single domain antibody or antigen binding fragment thereof comprising a CDR1, CDR2, and CDR3. The Specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
Nature of invention. The invention encompasses a binding moiety that specifically binds to Claudin18.2, comprising a single domain antibody or antigen binding fragment thereof comprising a CDR1, CDR2, and CDR3 that is set forth in a sequences Seq IDs No: 38 – 51, and 77 – 85 as recited in claim 3, wherein claim 1 teaches the Seq IDs of CDR1, CDR2, and CDR3.
Scope of the invention. The invention encompasses a composition, a binding moiety, that binds to Claudin18.2, which can be used for treating a Claudin18.2 expressing tumor or cancer.
Number of working examples and guidance. In the instant case, Applicant provides one relevant working example. In example 1, the as-Filed Specification teaches the generation of Anti-Claudin 18.2 antibodies, wherein camels were immunized a phage-display library was constructed to identify anti-Claudin18.2 VHH leads (Paragraph [0494]). The as-Filed Specification describes the method of cell line construction, animal immunization and immune response assay, and VHH phage display library construction, and teaches that the clones with high binding capacities were selected and sequenced, wherein the CDR and VHH sequences are summarized in Table 2, attached below (Paragraph [0506]).
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As seen in this table, the VHH domain is associated with a particular CDR1, CDR2, and CDR3. Any
other sequence combination of CDR1, CDR2, and CDR3 cannot be used to yield an effective VHH domain or anti- Claudinl8.2 single-domain antibody. Further, no other variations of the VHH sequences are taught in the as-Filed Specification.
State of the art. Although the field of antibodies comprising CDRs is highly developed,
binding moieties that comprise CDRs that specifically bind to Claudin18.2 is not highly developed. The art must therefore be considered to be poorly developed.
Unpredictability of the art. Before the effective filing date of the claimed invention, it was
known that amino acid substitutions in antibody-antigen interfaces play a role in affinity maturation of antibody responses, wherein single amino acid sequence changes can lower the affinity of the antibody, as evidenced by Colman (Colman PM. Res Immunol. 1994 Jan;145(1):33-6. doi: 10.1016/s0923-2494(94)80039-1. PMID: 7516563.) (first page).
Further, it was known in the art that the study of the amino acid sequence and a structural analysis can elucidate the amino acid residues and 3D conformation involved the specificity of inhibition (Paragraph [0131]), It was known in the art that The SH2 domain of Grb14 is 81% similar to Grb7 on the amino acid level but Grb14 does not bind ErbB2, indicating that the peptides are specific for Grb7 only, as evidenced by Pero et al. (US 20030105000 A1, published June 5, 2003) (Paragraph [0255]).
Additionally, it was known in the art that changing the lysine 132 to a glutamic acid residue in a heparin binding growth factor causes a reduction of affinity for the heparin binding growth factors for the immobilized heparin, as evidenced by Burgess et al. (Burgess WH. Et al. J Cell Biol. 1990 Nov;111(5 Pt 1):2129-38. doi: 10.1083/jcb.111.5.2129. PMID: 1699952; PMCID: PMC2116333.) (Abstract).
Amount of Experimentation Required. Given the unpredictability of the art, and
The role of a single amino acid in lowering the affinity of an amino acid, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention to determine the CDRs and the full length sequence (comprising the CDRs and the FRs of the binding moiety that can be used in a binding moiety that specifically binds to Claudin18.2.
Response to Arguments as they apply to rejection of claims 3, 4, 6, and 8 - 13 under 35 USC § 103
Applicant’s arguments filed 23 January, 2025 have been fully considered but they are not persuasive. Applicant essentially asserts (a) a person of ordinary skill in the art would have known how to generate a single domain antibody based on the disclosure of Table 2 without undue experimentation (pg. 2, last paragraph).
Regarding (a), Applicant’s arguments are not found persuasive. While one of ordinary skill in the art would be able to generate a single domain antibody that has 100% sequence alignment to Seq ID Nos: 38 – 51 and 77 – 85 based on the disclosure of Table 2, one of ordinary skill would not have been able to generate a functional binding moiety that is less than 100% identical. It has not been clarified which amino acids are necessary for the binding to Claudin 18.2. For example, patent US 10538572 B2 (published January 21, 2020) teaches that the “polynucleotide encoding the V.sub.α domain is at least 80% identical to the nucleotide sequence of SEQ ID NO 78, 128 or 80” (claim 1). This patent pertains to the CDRS that are separated by framework regions. However, it has been made part of the record that variation in the polynucleotide sequence as compared to a reference sequence does not alter the amino acids sequences of the recited CDRs (pg. 16 of the remarks filed on August 7, 2019). Thus, in this instance, it has been made clear that the variations do not change the amino acid sequence. However, in the instant application, it is still unclear whether the variability in the amino acid sequence of the will allow for functional binding to Claudin 18.2.
New Objections/Rejections
Claim Rejection - 35 USC § 112(b)
Claim 4 is newly 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 4 is indefinite for the recitation of “the CDR1, CDR2, or CDR3 are determined according to….. or a combination thereof” in lines 1 – 4. It is unclear how the CDRs are being determined by these numbering schemes when the CDRs are already encompassed in the sequences. As shown in Table 2, Seq ID No. 3 comprises Seq ID No: 1 (aka CDR1), Seq ID No: 12 (aka CDR2), and Seq ID No: 24 (aka CDR3). Thus, the metes and bounds of the claim cannot be determined.
Conclusion
Claims 1, 3, 4, 6, and 8 - 13 and 40 remain rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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