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 .
Application Status
The amended claims filed March 18, 2026 with the response to the non-final Office Action are acknowledged. Claims 1, 4-7, 10-12, 15, 19, 23, and 25 have been amended. Claims 2-3, 16, 18, 20-21, 24, and 26-28 are canceled.
Claims 1, 4-15, 17, 19, 22-23, and 25 are pending and under examination herein.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). The certification of the English translation of the foreign priority document, filed March 18, 2026, is accepted by the Examiner. Applicant is entitled to the foreign priority date of the CN202011249960.3 application filed on November 10, 2020.
Notice Regarding Non-Compliant Claim Amendments
It is noted that claims 8-9, 13, 17, and 22, which were annotated as “(Currently Amended)” in the amended claims filed May 10, 2023, are now annotated as “(Original)” in the amended claims filed March 18, 2026.
In the interest of compact prosecution, these claims will be examined herein.
Applicant is advised to follow the rules set forth in MPEP § 714 in future amendment submissions.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). The sequence disclosure is located on page 29 (Example 1, second paragraph) of the specification as filed on March 18, 2026, and corresponds to a glycine-serine peptide linker “(G4S)3”.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
WITHDRAWN OBJECTIONS AND REJECTIONS
All prior grounds of objection to the specification are withdrawn in view of Applicant's amendments to the disclosure.
All prior grounds of objection and/or rejection to claims 2-3, 16, 18, 20-21, 24, and 26-28 are rendered moot by the cancelation of the claims.
The prior grounds of objection to claims 1 and 10 are withdrawn in view of Applicant's amendments thereto.
The prior grounds of rejection of claims 6-7, 10-12, 15, 17, 19, and 25 under 35 U.S.C. 112(b) are withdrawn in view of Applicant's claim amendments.
The rejection of claims 4-5 under 35 U.S.C. § 112(a) for failing to comply with the written description requirement is withdrawn in view of Applicant's amendments to said claims.
The rejection of claims 1, 5-8, 10, 13-15, 17, 19, 22-23, and 25 under 35 U.S.C. § 102 as being anticipated by H. Yang (US 2023/0192903 A1) is withdrawn in view of Applicant's amendment to claim 1 to incorporate the limitations previously set forth in claim 2 (now canceled).
MAINTAINED REJECTIONS & NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Claim Rejections - 35 USC § 112(b)
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.
Claims 10-12, 15, 17, 19, 22-23, and 25 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. This is a new rejection necessitated by claim amendment.
Claim 10 newly depends from claim 9 instead of claim 1, altering the scope of the claim. Claim 10 recites “The bispecific antibody according to claim 9, having a structure of linking an anti-CD3 scFv at a C-terminus of the heavy or light chain of a full-length anti-CD18.2 antibody”. The claim is indefinite because it is unclear whether “an anti-CD3 scFv” and “a full-length anti-CLDN18.2 antibody” are intended to refer to those specifically set forth in claim 9 (in which case, the claim should recite “the anti-CD3 scFv” and “the full-length anti-CLDN18.2 antibody” to have proper antecedent basis to these limitations) or whether the claim is referring to one or more separate members than those recited in the earlier claims.
Claim 11 newly depends from claim 10 instead of claim 1, altering the scope of the claim. Claim 11 does not remedy the deficiencies set forth above for claim 10. Furthermore, claim 11 recites that the bispecific antibody of claim 10 has a structure “of fusing the anti-CD3 scFv to the C-terminus of each of the two light chains of the full-length anti-CLDN18.2 antibody to form two homologous light chains and two homologous heavy chains”, but it is not apparent how a single anti-CD3 scFv (as implied by “the anti-CD3 scFv”) can be simultaneously attached to two light chains and subsequently form two identical homologous light chains. Accordingly, claim 11 is further indefinite.
Even taking into consideration that the “two homologous light chains … each have a sequence as set forth in in SEQ ID NO: 2”, which appears to comprise the anti-CLDN18.2 VL comprising the amino acid sequence of instant SEQ ID NO: 5, a GGGGS linker, and the anti-CD3 comprising the amino acid sequence of instant SEQ ID NO: 8, the prior claim does not expressly recite that the bispecific antibody comprises two anti-CD3 scFvs or antigen-binding domains. The claim should be amended to clarify what is considered to be the invention.
Claim 12 newly depends from claim 9 instead of claim 1, altering the scope of the claim. Claim 12 recites “The bispecific antibody according to claim 9, having a structure of fusing an anti-CD3 scFv to a C-terminus of one heavy chain of a full-length anti-CD18.2 antibody”. The claim is indefinite because it is unclear whether “an anti-CD3 scFv” and “a full-length anti-CLDN18.2 antibody” are intended to refer to those specifically set forth in claim 9 (in which case, the claim should recite “the anti-CD3 scFv” and “the full-length anti-CLDN18.2 antibody” to have proper antecedent basis to these limitations) or whether the claim is referring to one or more separate members than those recited in the earlier claims.
Regarding claims 15, 19, 23, and 25, the phrases “optionally”, “preferably”, and “more preferably” render the claims indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). Examples and preferences in a claim may lead to confusion over the intended scope of the claim. The description of examples or preferences is properly set forth in the specification rather than the claims. In addition, it is noted that the claim recites “eukaryotic cells” and “mammalian cells” as separate alternatives in lines 3-4, but later refers to mammalian cells as a type of eukaryotic cells in lines 6-7.
Claim 17, which depends from claim 15, is similarly rejected.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 12 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 12 newly depends from claim 9. Claim 9 requires that the full-length anti-CLDN18.2 antibody has a heavy chain sequence as set forth in instant SEQ ID NO: 1. Claim 12 recites that “the heavy chain containing the scFv has a sequence as set forth in SEQ ID NO: 3” and that “the heavy chain without the scFv has a sequence as set forth in SEQ ID NO: 4”. However, the amino acid sequences of instant SEQ ID NO: 3 and SEQ ID NO: 4 do not contain a portion thereof having 100% sequence identity to instant SEQ ID NO: 1. See alignments below. Accordingly, claim 12 fails to include all of the limitations of the claim from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Alignment between SEQ ID NO: 3 (“Qy”) and SEQ ID NO: 1 (“Db”)
PNG
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746
620
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Alignment between SEQ ID NO: 4 (“Qy”) and SEQ ID NO: 1 (“Db”):
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media_image2.png
738
610
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Greyscale
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
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.
(1)
Claims 1, 4, 6-8, 13-15, 17, 19, 22-23, and 25 are rejected under 35 U.S.C. § 103 as being unpatentable over H. Yang (US 2023/0192903 A1; cited in PTO-892 mailed December 18, 2025) in view of Y. Yang (US 2022/0411492 A1, English language equivalent of WO 2020/228806 A1 (cited in IDS); PCT filing date: May 15, 2020). This is a maintained rejection that has been updated due to Applicant's claim amendments.
The applied reference of US 2022/0411492 A1 (“Y. Yang”) may have a common inventor (Yingying Yang) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
H. Yang discloses bispecific antibodies against CLDN18.2 and CD3 (e.g., Abstract). H. Yang teaches that the bispecific antibodies of the invention have two specific antigen-binding sites enabling simultaneous binding of an immune cell surface antigen (CD3) and a tumor cell specific antigen (CLDN18.2), effectively bridging tumor cells and immune cells and promoting killing of the tumor cells by the immune cells (e.g., ¶ 0005). H. Yang discloses an embodiment in which the bispecific antibody comprises an anti-CD3 binding domain comprising a VH having the amino acid sequence of SEQ ID NO: 10 (which comprises the instantly claimed HCDRs comprising the amino acid sequences of instant SEQ ID NO: 17, 18, and 19, respectively) and a VL having the amino acid sequence of SEQ ID NO: 11 (which comprises the instantly claimed LCDRs comprising the amino acid sequences of SEQ ID NO: 20, 21, and 22, respectively) (e.g., ¶ 0006), relevant to claim 1. The VH and VL disclosed by H. Yang shares 93.6% sequence identity to the instantly claimed VH having an amino acid sequence of instant SEQ ID NO: 6 and 95.3% sequence identity to the instantly claimed VL having an amino acid sequence of instant SEQ ID NO: 7. The sequence alignments between the instantly claimed VH and VL (“Qy”) and those of H. Yang (“Db”) are provided in the non-final Office Action mailed December 18, 2025.
Relevant to claim 6, H. Yang teaches an embodiment in which the antigen-binding domain specific for CLDN18.2 is in the form of a Fab fragment and the antigen-binding domain specific for CD3 is in the form of an scFv (e.g., Items 8 and 9, ¶ 0006; claims 8-9). Relevant to claim 7, H. Yang teaches that the Fc domain is wildtype or mutant Fc domain (e.g., ¶ 0006-0008). Relevant to claim 8, H. Yang teaches an embodiment in which an anti-CD3 scFv is linked to the C-terminus of a heavy chain of a full-length anti-CDLN18.2 antibody (e.g., Figure 4).
Relevant to claims 13-15 and 17, H. Yang discloses nucleic acids, vectors, and host cells encoding the bispecific antibody of the invention, and use of the same in a method of preparation (e.g., ¶ 0006; Examples 1-2).
Relevant to claims 19 and 22, H. Yang discloses pharmaceutical compositions and kits comprising a bispecific antibody of the invention (e.g., ¶ 0006, claim 18).
Relevant to claim 25, H. Yang discloses a method of treating cancers such as gastric cancer or pancreatic cancer, which H. Yang teaches are associated with expression of CLDN18.2, that comprises administering a therapeutically effective amount of a pharmaceutical composition comprising the bispecific antibody to a subject (e.g., ¶ 0004-0006; claim 21). Upon administration of said pharmaceutical composition to a subject, the CLDN18.2-expressing tumor cells of said subject would be expected to be contacted by the bispecific antibody, further relevant to claim 23.
However, H. Yang does not expressly teach an anti-CLDN18.2 antibody or antigen-binding fragment thereof comprising the combination of heavy chain CDRs having the amino acid sequences of instant SEQ ID NOs: 11, 12, and 13, respectively, and the light chain CDRs having the amino acid sequences of instant SEQ ID NOs: 14, 15, and 16, respectively, or an anti-CLDN18.2 binding domain comprising the VH and VL amino acid sequences of instant SEQ ID NOs: 23 and 24, respectively.
Y. Yang discloses antibodies and antigen-binding fragments thereof comprising an antigen-binding domain specific for CLDN18.2, which have utility in treating cancers such as gastric cancer or pancreatic cancer (e.g., Abstract; claims 25-26). Relevant to claim 1, Y. Yang discloses an anti-CLDN18.2 antibody or antigen-binding fragment thereof that comprises a combination of heavy chain CDRs comprising the amino acid sequences of SEQ ID NO: 71, 72, and 73, respectively (which share 100% sequence identity to instant SEQ ID NO: 11, 12, and 13, respectively) and light chain CDRs comprising the amino acid sequences of SEQ ID NO: 112, 93, and 107, respectively (which share 100% sequence identity to instant SEQ ID NO: 14, 15, and 16, respectively) (e.g., claims 1-4; ¶ 0005-0012). Relevant to claim 4, Y. Yang further discloses an anti-CLDN18.2 antibody or antigen-binding fragment thereof, “hu299B2-S32A-3”, that comprises a VH having the amino acid sequence of SEQ ID NO: 120 (which shares 100% sequence identity to instant SEQ ID NO: 23) and a VL having an amino acid sequence of SEQ ID NO: 124 (which shares 100% sequence identity to instant SEQ ID NO: 24) (e.g., ¶ 0015-0018; Examples 7-8). Y. Yang further provides bispecific antibodies comprising an anti-CLDN18.2 antibody or antigen-binding fragment thereof (e.g., ¶ 0024; claims 16-17).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the bispecific anti-CLDN18.2/CD3 disclosed by H. Yang by substituting into the anti-CLDN18.2 antigen-binding domain the antigen-binding domain taught by Y. Yang. The skilled artisan would have been motivated to do so because the anti-CLDN18.2 antibodies and antigen-binding fragments thereof have utility in treating CLDN18.2-expressing cancers such as gastric cancer, and are amenable for use in bispecific antibody constructs. There would have been a reasonable expectation of success because the skilled artisan would recognize that the two anti-CLDN18.2 antibodies are functional equivalents that are useful for achieving the same purpose.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Response to Arguments
Applicant's arguments filed March 18, 2026 have been fully considered but they are not persuasive.
Applicant submits that while H. Yang does disclose a bispecific anti-CLDN18.2/CD3 antibody, it does not provide for the bispecific of the instantly claimed invention, having the combinations of anti-CLDN18.2 and anti-CD3 CDRs set forth in claim 1, and states that “there is absolutely no teaching or suggestion to employ the specific CDR sequence combination (SEQ ID NOs: 11-22) defined in Claim 1 of the present invention”. Applicant further states that while Y. Yang “discloses a monoclonal antibody with a specific antigen-binding domain against CLDN18.2”, the reference “does not explicitly teach its use for developing a bispecific antibody”. Remarks at page 104-105. Applicant further submits that one of ordinary skill in the art would not have had any reason to modify the bispecific antibody taught by H. Yang to comprise the anti-CLDN18.2 antigen-binding domain CDRs taught by Y. Yang, with any reasonable expectation that the combination would address the technical problem addressed by the present invention. Remarks at pages 104-106. Applicant submits that the instantly claimed bispecific antibody exhibits unexpected technical effects, including high affinity and selectivity for CLDN18.2 and potent anti-tumor activity.
In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In contrast to Applicant's assertions, Y. Yang does in fact expressly teach embodiments of a bispecific antibody having an anti-CLDN18.2 antigen-binding domain of the invention (e.g., ¶ 0024; claims 16-17). Furthermore, one of ordinary skill in the art would have been motivated to use the anti-CLDN18.2 antigen-binding domain set forth by Y. Yang in the bispecific construct of H. Yang because Y. Yang teaches that the hu299B2-S32A-3 clone exhibits an EC50 of 0.399 nM against HEK293-hCLDN18.2 cells and does not bind to CLDN18.1 (e.g., Example 8; Tables 11 and 12), thus demonstrating high affinity.
With respect to Applicant's arguments regarding unexpected technical effect, it is submitted that the cited references teach that antibodies comprising each individual antigen-binding domain similarly show that they show strong anti-tumor activity and affinity for their respective antigens, which would have motivated one of ordinary skill in the art to try using them in a bispecific antibody construct. However, it is also noted that the hu299B2-S32A-3 clone taught by Y. Yang (which shares identical anti-CLDN18.2 CDRs to those instantly claimed) is reported to show stronger affinity (i.e., an EC50 of 0.399 nM against HEK293-hCLDN18.2 cells, as set forth above) than when used in the instantly claimed bispecific construct.
For these reasons, the rejection is maintained.
(2)
Claims 1, 5, and 91 are rejected under 35 U.S.C. § 103 as being unpatentable over H. Yang (US 2023/0192903 A1; supra) in view of Y. Yang (US 2022/0411492 A1; supra) as applied to claims 1, 4, 6-8, 10, 13-15, 17, 19, 22-23, and 25 above, further in view of Kurtzman (US 2023/0374130 A1; earliest priority date: July 30, 2019). This is a new rejection necessitated in part by Applicant's claim amendments to claim 5.
The applied reference of US 2023/0374130 A1 (Kurtzman) may have a common inventor (Shihao Chen) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The teachings of H. Yang are recited in the 35 U.S.C. § 103 rejection above.
While H. Yang does disclose an anti-CD3 antigen-binding domain comprising the heavy chain and light chain CDRs set forth in claim 1, H. Yang does not disclose an anti-CD3 antigen-binding domain comprising a VH having 100% sequence identity to instant SEQ ID NO: 6 and a VL comprising 100% sequence identity to instant SEQ ID NO: 7.
The teachings of Y. Yang are set forth above.
Kurtzman discloses multispecific antibodies comprising an anti-CD3 antigen-binding domain (e.g., Abstract). Exemplary anti-CD3 antigen-binding domains comprise heavy chain CDRs having the amino acid sequences of SEQ ID NOs: 2, 4, and 14, respectively (which share 100% sequence identity to the instant SEQ ID NOs: 17-19, respectively) and light chain CDRs having the amino acid sequences of SEQ ID NOs: 17, 20, and 23 (which share 100% sequence identity to instant SEQ ID NOs: 20-22, respectively) (e.g., Tables 1-2 at pages 14-19), pertinent to claim 1. Pertinent to claim 5, Kurtzman discloses exemplary anti-CD3 antigen-binding domains such as 160C9, which comprises a VH having the amino acid sequence of SEQ ID NO: 55 (which shares 100% sequence identity to instant SEQ ID NO: 6) and a VL having the amino acid sequence of SEQ ID NO: 107 (which shares 100% sequence identity to instant SEQ ID NO: 7) (e.g., Table 5 at page 21; Table 6 at page 23). Kurtzman teaches that bispecific antibodies comprising the 160C9 anti-CD3 antigen-binding domain show strong potentiation of CD4+ and CD8+ T cells (e.g., Example 8, ¶ 0181; Figure 9).
In view of the further teachings of Kurtzman, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the bispecific anti-CLDN18.2/CD3 disclosed by H. Yang by substituting into the anti-CD3 antigen-binding domain the antigen-binding domain taught by Kurtzman. The skilled artisan would have been motivated to do so because said anti-CD3 antigen-binding domain would be expected to share similar binding affinity to that of Y. Yang (by virtue of having the same CDRs) and because Kurtzman teaches that the 160C9 clone potentiates the proliferation of CD4+ and CD8+ T cells in the tumor microenvironment. There would have been a reasonable expectation of success because the skilled artisan would recognize that the two anti-CD3 antigen-binding domains are functional equivalents that are useful for achieving the same desired purpose.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
(3)
Claims 1 and 9-10 are rejected under 35 U.S.C. § 103 as being unpatentable over H. Yang (US 2023/0192903 A1; supra) in view of Y. Yang (US 2022/0411492 A1; supra) and Kurtzman (US 2023/0374130 A1; supra) as applied to claims 1, 5, and 9 above, further in view of Shitara (U.S. Patent No. 8,883,981; published November 11, 2014), Uniprot (Uniprot Accession No. P01834 “IGKC_HUMAN”, Sequence Last Updated March 15, 2017 v2), and Wang (Protein Cell (2018) 9(1): 63-73).
The teachings of H. Yang are recited in the 35 U.S.C. § 103 rejection above. As set forth above, H. Yang teaches an embodiment in which an anti-CD3 scFv is linked to the C-terminus of a heavy chain of a full-length anti-CDLN18.2 antibody (e.g., Figure 4), pertinent to claims 9-10. See also claim 8 of H. Yang. H. Yang teaches that the Fc domain can be selected from an IgG1, IgG2, IgG3, and IgG4 subtype (e.g., claim 8).
However, H. Yang does not expressly teach that the anti-CLDN18.2 antigen-binding domain comprises a heavy chain amino acid sequence as set forth in instant SEQ ID NO: 1, a light chain amino acid sequence as set forth in instant SEQ ID NO: 5, and an anti-CD3 binding domain (scFv) comprising the amino acid sequence of instant SEQ ID NO: 8.
The teachings of Y. Yang and Kurtzman are recited above. Kurtzman further discloses an scFv of the anti-CD3 160C9 clone, comprising the amino acid sequence of SEQ ID NO: 160, arranged in the order VH-linker-VL, which comprises said VH having the amino acid sequence of SEQ ID NO: 55, a “GGGGSGGGGSGGGGS” linker, an alanine residue “A”, and said VL having the amino acid sequence of SEQ ID NO: 107 (e.g., Table 7 at page 26). By reversing the orientation of the VH and VL domains to (A-)VL-linker-VH (with the alanine residue at the front), one would arrive at an scFv having the amino acid sequence of instant SEQ ID NO: 8 (which is set forth in claim 9).
Shitara teaches that the IgG1 Fc domain (CH1, CH2, CH3) comprises an amino acid sequence of SEQ ID NO: 76, which shares 99.4% sequence similarity to residues 121-450 of instant SEQ ID NO: 1, wherein the two sequences differ by the addition of the substitutions L234A and L235A. Wang teaches that these mutations in the IgG1 Fc reduce binding to FcγR and C1q, which reduce effector function of the antibody (e.g., Table 1). By combining the anti-CLDN18.2 VH taught by Y. Yang (corresponding to residues 1-120 of instant SEQ ID NO: 1), the IgG1 Fc domain taught by Shitara (corresponding to residues 121-450 of instant SEQ ID NO: 1), and incorporating the Fc mutations of L234A and L235A to modulate antibody effector function as taught by Wang, one would arrive at an anti-CLDN18.2 heavy chain comprising the amino acid sequence of instant SEQ ID NO: 1, further relevant to claim 9.
Uniprot recites the amino acid sequence of the human Ig kappa (κ) constant region sequence, which shares 100% sequence similarity to residues 114-220 of instant SEQ ID NO: 5. By combining the anti-CLDN18.2 VL of Y. Yang (which shares 100% sequence similarity to residues 1-113 of instant SEQ ID NO: 5) and the human Ig κ constant region taught by Uniprot, one would arrive at an anti-CLDN18.2 light chain comprising the full amino acid sequence of instant SEQ ID NO: 5, further relevant to claim 9.
Based on the further teachings of Shitara, Wang, and Uniprot, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a bispecific anti-CLDN18.2/CD3 antibody comprising an anti-CLDN18.2 heavy chain having the amino acid sequence of instant SEQ ID NO: 1, an anti-CLDN18.2 light chain having the amino acid sequence of instant SEQ ID NO: 5, and an anti-CD3 scFv comprising the amino acid sequence of instant SEQ ID NO: 8. The skilled artisan would have been motivated to generate a full-length IgG1/kappa anti-CLDN18.2 antibody according to the sequences described by Shitara and Uniprot, having the additional mutations of L234A and L235A as set forth by Wang, because Y. Yang teaches that the bispecific antibodies of the invention can comprise a full-length anti-CLDN18.2 antibody (conjugated to an anti-CD3 scFv), wherein the full-length antibody is an IgG1 antibody. Further, the Fc mutations of Wang reduce effector functions, which are useful in bispecific antibodies where the primary desired therapeutic action is based on the binding to the two antigens. There would have been a reasonable expectation of success because it is routine and conventional in the art to generate full-length antibody constructs comprising a heavy chain having a VH and an IgG1 CH1, CH2, and CH3, with or without the mutations of L234A/L235A, and a light chain comprising a VL and a κ constant chain, and there are a finite number of antibody backbone structures from which to assemble full-length antibodies.
The skilled artisan would have been motivated to generate such an anti-CD3 construct, having the specific VH and VL set forth by Kurtzman, would be expected to have good binding affinity for CD3 and to proliferate CD4+ and CD8+ T cells. Furthermore, it is routine and conventional in the art to generate and optimize scFv antibodies (either in a VH-linker-VL or VL-linker-VH configuration). One of ordinary skill in the art would recognize that there are a finite number of configurations in which the VH and VL domains of an scFv can be arranged.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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(1)
Claims 1, 4, 6-8, 13-15, 17, 19, 22-23, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,415,8532 in view of H. Yang (US 2023/0192903 A1; supra).
Relevant to claims 1 and 4, the reference patent claims a bispecific antibody comprising an anti-CLDN18.2 antibody or antigen-binding fragment thereof, comprising a combination of VH and VL CDRs having the amino acid sequences of SEQ ID NOs: 71, 72, 73, 112, 93, and 107, respectively, which share 100% sequence identity to instant SEQ ID NO: 11, 12, 13, 14, 15, and 16, respectively (‘853 claims 1, 6-7). Patent claim 2 further recites that the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a VH comprising SEQ ID NO: 120 (which shares 100% sequence identity to instant SEQ ID NO: 23) and a VL comprising SEQ ID NO: 124 (which comprises 100% sequence identity to instant SEQ ID NO: 24). Relevant to claim 6, because the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a VH and a VL, the construct comprises at least an Fv.
Relevant to claim 7, ‘853 claim 4 recites that the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising a native or a variant Fc as well as a light chain constant region.
Relevant to claims 13-15 and 17, ‘853 claims 10-13 recite a method of preparing the claimed antibody using a nucleic acid encoding the antibody, or a recombinant vector encoding said nucleic acid, or a host cell comprising said nucleic acid.
Relevant to claim 19, ‘853 claim 14 recites a pharmaceutical composition comprising the claimed antibody. Relevant to claim 23, ‘853 claim 15 recites a similar method of inducing cell death that comprises contacting the pharmaceutical composition of ‘853 claim 14 with CLDN18.2-expressing cells. Relevant to claim 25, ‘853 claims 16-18 recite a method of treating a disease associated with expression of CLDN18.2 in a subject comprising administering the pharmaceutical composition of ‘853 claim 14.
However, the reference patent does not expressly teach a bispecific antibody that specifically binds to both CLDN18.2 and CD3, wherein the anti-CLDN18.2 binding domain is a full-length antibody and the anti-CD3 binding domain is an scFv.
The teachings of H. Yang, with respect to anti-CD3 scFv binding domains and the amino acid sequences thereof, are recited in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the bispecific antibody claimed in the reference patent by incorporating an antigen-binding domain that is specific for CD3, e.g., the anti-CD3 scFv binding domain described by H. Yang. The skilled artisan would have been motivated to do so because H. Yang teaches that bispecific antibodies against CLDN18.2 and CD3 allow the simultaneous targeting of a tumor cell specific antigen (CLDN18.2) and an immune cell surface antigen (CD3), promoting a killing effect of the CD3-expressing immune cells on CLDN18.2-expressing tumor cells. There would have been a reasonable expectation of success because known work in one field of endeavor may prompt variation of it for use in the same field, and one of ordinary skill in the art would have recognized that the anti-CD3 antigen-binding domain in the bispecific antibody disclosed by H. Yang is able to be bodily incorporated into a bispecific antibody construct further comprising an anti-CLDN18.2 antigen-binding domain.
Response to Arguments
Applicant's arguments filed March 18, 2026 have been fully considered but they are not persuasive.
Applicant submits that while H. Yang does disclose a bispecific anti-CLDN18.2/CD3 antibody, it does not provide for the bispecific of the instantly claimed invention, having the combinations of anti-CLDN18.2 and anti-CD3 CDRs set forth in claim 1. Applicant further states that while Y. Yang “discloses a monoclonal antibody with a specific antigen-binding domain against CLDN18.2”, the reference “does not explicitly teach its use for developing a bispecific antibody”. Remarks at page 107. Applicant submits that the instantly claimed bispecific antibody exhibits unexpected technical effects, including high affinity and selectivity for CLDN18.2 and potent anti-tumor activity.
In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In contrast to Applicant's assertions, Y. Yang does in fact expressly teach embodiments of a multispecific antibody having an anti-CLDN18.2 antigen-binding domain of the invention (e.g., ¶ patented claim 6). Furthermore, one of ordinary skill in the art would have been motivated to use the anti-CD3 antigen-binding domain of H. Yang (and Kurtzman) in the multispecific antibody provided for by the reference patent because the antigen-binding domain has specificity for CD3 and potentiates the proliferation of CD4+ and CD8+ T cells in the tumor microenvironment.
With respect to Applicant's arguments regarding unexpected technical effect, it is submitted that the cited references teach that antibodies comprising each individual antigen-binding domain similarly show that they show strong anti-tumor activity and affinity for their respective antigens, which would have motivated one of ordinary skill in the art to try using them in a bispecific antibody construct.
For these reasons, the rejection is maintained.
(2)
Claims 1, 5, and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,415,853 in view of H. Yang (US 2023/0192903 A1; supra) as applied to claims 1, 4, 6-8, 13-15, 17, 19, 22-23, and 25 above, further in view of Kurtzman (US 2023/0374130 A1; supra).
The teachings of the reference patent and H. Yang are recited in the 35 U.S.C. § 103 and non-statutory double patenting rejections above.
However, the reference patent does not expressly claim an anti-CD3 antigen-binding domain comprising a VH having 100% sequence identity to instant SEQ ID NO: 6 and a VL comprising 100% sequence identity to instant SEQ ID NO: 7. However, this deficiency is remedied by Kurtzman (supra).
In view of the further teachings of Kurtzman, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the bispecific anti-CLDN18.2/CD3 claimed in the reference patent by substituting into the anti-CD3 antigen-binding domain the antigen-binding domain taught by Kurtzman. The skilled artisan would have been motivated to do so because said anti-CD3 antigen-binding domain would be expected to share similar binding affinity to that of the reference patent (by virtue of having the same CDRs) and because Kurtzman teaches that the 160C9 clone potentiates the proliferation of CD4+ and CD8+ T cells in the tumor microenvironment. There would have been a reasonable expectation of success because the skilled artisan would recognize that the two anti-CD3 antigen-binding domains are functional equivalents that are useful for achieving the same desired purpose.
(3)
Claims 1 and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,415,853 in view of H. Yang (US 2023/0192903 A1; supra) and Kurtzman (US 2023/0374130 A1; supra) as applied to claims 1, 5, and 9 above, further in view of Shitara (U.S. Patent No. 8,883,981; supra), Uniprot (Uniprot Accession No. P01834 “IGKC_HUMAN”; supra), and Wang (Protein Cell (2018) 9(1): 63-73; supra).
The teachings of the reference patent and H. Yang are recited in the non-statutory double patenting and 35 U.S.C. § 103 rejections above.
However, the reference patent does not expressly claim that the anti-CLDN18.2 antigen-binding domain comprises a heavy chain amino acid sequence as set forth in instant SEQ ID NO: 1, a light chain amino acid sequence as set forth in instant SEQ ID NO: 5, and an anti-CD3 binding domain (scFv) comprising the amino acid sequence of instant SEQ ID NO: 8. However, these deficiencies are remedied by Kurtzman, Shitara, Wang, and Uniprot based on the teachings set forth above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a bispecific anti-CLDN18.2/CD3 antibody comprising an anti-CLDN18.2 heavy chain having the amino acid sequence of instant SEQ ID NO: 1, an anti-CLDN18.2 light chain having the amino acid sequence of instant SEQ ID NO: 5, and an anti-CD3 scFv comprising the amino acid sequence of instant SEQ ID NO: 8. The skilled artisan would have been motivated to generate a full-length IgG1/kappa anti-CLDN18.2 antibody according to the sequences described by Shitara and Uniprot, having the additional mutations of L234A and L235A as set forth by Wang, because the reference patent teaches that the bispecific antibodies of the invention can comprise a full-length anti-CLDN18.2 antibody (conjugated to an anti-CD3 scFv). Further, the Fc mutations of Wang reduce effector functions, which are useful in bispecific antibodies where the primary desired therapeutic action is based on the binding to the two antigens. There would have been a reasonable expectation of success because it is routine and conventional in the art to generate full-length antibody constructs comprising a heavy chain having a VH and an IgG1 CH1, CH2, and CH3, with or without the mutations of L234A/L235A, and a light chain comprising a VL and a κ constant chain, and there are a finite number of antibody backbone structures from which to assemble full-length antibodies.
The skilled artisan would have been motivated to generate such an anti-CD3 construct, having the specific VH and VL set forth by Kurtzman, would be expected to have good binding affinity for CD3 and to proliferate CD4+ and CD8+ T cells. Furthermore, it is routine and conventional in the art to generate and optimize scFv antibodies (either in a VH-linker-VL or VL-linker-VH configuration). One of ordinary skill in the art would recognize that there are a finite number of configurations in which the VH and VL domains of an scFv can be arranged.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 Claim 9 was previously indicated as containing allowable subject matter in the Office action mailed December 18, 2025. This position has been reconsidered in the present Office action.
2 U.S. Patent No. 12,415,853 is the issued patent corresponding to US 2022/0411492 A1 (“Y. Yang”), which is cited in the 35 U.S.C. § 103 rejection above. The reference patent appears to have a common inventor (Yingying Yang) with the instant application.
Prosecution Insights