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 on January 14, 2026 are acknowledged. Claims 16, 21, 23, 25, 33, and 37 have been amended. Claims 17 and 20 have been canceled. Claim 41 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 16, 21-23, 25, 29, 33-35, 37-38, 40-41, 46, 51-56, 58, 62-63, 65, 67, 70, and 73-74 are pending.
Claims 16, 21-23, 25, 29, 33-35, 37-38, 40, 46, 51-56, 58, 62-63, 65, 67, 70, and 73-74 are under examination herein.
Two attempts by the Examiner to reach Attorney James Zhu by telephone on April 20, 2026 and on April 22, 2026 were unsuccessful. Voicemail messages left with Attorney Zhu on these dates were not returned as of April 30, 2026.
WITHDRAWN OBJECTIONS AND REJECTIONS
Specification
All prior grounds of objection to the specification are withdrawn in view of Applicant's amendments thereto.
Claims
All prior grounds of objection and/or rejection of claims 17 and 20 are rendered moot by the cancelation of the claims.
The objection to claim 25 is withdrawn in view of Applicant's amendments to the claim.
The rejection of claims 23 and 37 under 35 U.S.C. § 112(b) is withdrawn in view of Applicant's claim amendments.
The rejection of claims 25 and 37 under 35 U.S.C. § 112(d) is withdrawn in view of Applicant's claim amendments.
The rejection of claims 16, 21-23, 29, 33-35, 37-38, 40, 46, 51-56, 58, 62-63, 65, 67, 70, and 73-74 under 35 U.S.C. § 112(a) for failing to comply with the written description requirement is withdrawn in view of Applicant's amendments to claim 16.
MAINTAINED AND NEW CLAIM OBJECTIONS AND REJECTIONS
Claim Objections (New)
Claims 21, 46, and 62 are objected to for the following informalities:
Regarding claim 21, the subscript formatting for the variable residues does not appear throughout the claim as amended (i.e., “X17” now appears as “X17”, etc.). It is suggested that this formatting be reinstated to retain consistency with that of the independent claim.
Claim 46 recites “a DNA-alkylators” in lines 4-5 and “a tubulin-binders” in line 5. It is suggested that these be amended to “a DNA-alkylator” and “a tubulin-binder” (singular) for consistency with the remainder of the claim.
Claim 62 recites that “the cancer is gastric cancer, lung cancer, … and adenocarcinoma.” With the recitation of “and” in line 8, the claim recites that the cancer is simultaneously all of the cancers listed in the claim. For clarity, it is suggested that the claim be amended to recite “the cancer is selected from gastric cancer, …, and adenocarcinoma” or “the cancer is gastric cancer, … or adenocarcinoma”.
Appropriate correction is required.
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 33 and 46 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.
As amended, claim 33 recites that the constant region of the instantly claimed antibody or antigen-binding fragment thereof comprises “one or more amino acid residue substitutions relative to SEQ ID NO: 49, selected from the group consisting of L118V, F126L, R175P, Y183L, P279L, or any combination thereof.” This limitation lacks antecedent basis to the specification as filed, which recites L235V, F243L, R292P, Y300L, and P279L (e.g., ¶ 0034 or 0258). (By comparison, claim 34 – which depends from claim 33 – recites the amino acid sequence of SEQ ID NO: 51, which does have antecedent basis to the specification as filed.)
In the interest of promoting compact prosecution, it is suggested that claim 33 be canceled and that claim 34 be amended to depend from claim 29.
This is a new rejection necessitated by claim amendment.
Claim 46 recites the limitation “(e.g. vcMMAE)” in line 5. The claim is indefinite in part because the use of “e.g.” (which is analogous to “for example”) renders it unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The use of parentheses to denote an exemplary limitation – as opposed to, e.g., an abbreviation of a term immediately prior – further renders the claim indefinite because it is unclear if the phrase in parentheses is intended to be limiting or merely exemplary of a tubulin binder that is within the scope of the claim.
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.
It is suggested that the parenthetical/exemplary language be omitted from the claim.
This is a new rejection.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
(1)
Claims 16, 21-23, 25, 29, 35, 37, 51, 56, 65, 67, 70, and 73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-13, 18, 21, 24-26, 31, 36, 39, 43, and 47 of co-pending Application No. 18/546,980 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention. This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Regarding claim 16, co-pending claims 1 and 12 recite an antibody conjugate comprising an anti-CLDN18.2 antibody or antigen-binding fragment thereof comprising identical CDRs as set forth in the instant claim, conjugated to a radionuclide. Co-pending claim 13 recites that the anti-CLDN18.2 antibody comprises heavy chain variable region (VH) CDRs comprising the sequences of SEQ ID NO: 1, 19, and 21, respectively, and light chain variable region (VL) CDRs comprising the sequences of SEQ ID NO: 14, 16, and 18, respectively, which share 100% sequence identity to the instantly claimed CDRs comprising the same SEQ ID NOs.
Regarding claims 21-23 and 25, co-pending claim 18 recites that the VH comprises a sequence of SEQ ID NO: 25 and the VL comprises a sequence of SEQ ID NO: 26 (which share 100% sequence identity to instant SEQ ID NO: 25 and 26, respectively, and comprise the instantly claimed heavy chain and light chain FRs).
Regarding claim 29, co-pending claim 21 recites that the anti-CLDN18.2 antibody or antigen-binding fragment thereof further comprises an immunoglobulin constant region.
Regarding claim 35, co-pending claim 24 recites that the anti-CLDN18.2 antibody is humanized.
Regarding claim 37, co-pending claim 25 recites that the anti-CLDN18.2 antibody or antigen-binding fragment thereof is a diabody, a Fab, etc. as recited in the instant claim.
Regarding claim 51, co-pending claim 26 recites a pharmaceutical composition comprising the anti-CLDN18.2 antibody conjugate.
Regarding claims 56 and 65, co-pending claim 39 recites a method of treating a CLDN18.2-related disease or condition in a subject in need thereof that comprises administering an effective amount of the anti-CLDN18.2 antibody conjugate.
Regarding claims 67 and 73, co-pending claim 43 recites a kit comprising an anti-CLDN18.2 antibody conjugate comprising a therapeutic radionuclide and a diagnostic radionuclide.
Regarding claim 70, co-pending claims 31 and 36 recite methods comprising the steps of (1) contacting a sample from the subject with the antibody conjugate (“administering”), (2) determining Claudin 18.2 expression, and (3) comparing expression levels or distribution of Claudin 18.2 before and after treatment and correlating these levels to therapeutic efficacy or responsiveness.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(2)
Claims 16, 29, 33, 37-38, 40, 52-56, 58, 62-63, and 74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-13, 18, 21, 24, 26, 31, 36, 39, 43, and 47 of co-pending Application No. 18/546,980 as applied to claims 16, 21-23, 25, 29, 35, 51, 56, 65, 67, 70, and 73 above in (1), further in view of Liu (US 2021/0230272 A1; cited in PTO-892 mailed September 2025). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
The teachings of the reference application are recited in the non-statutory double patenting rejection above.
However, the reference application does not teach that the anti-CLDN18.2 antibody comprised in the antibody conjugate comprises an immunoglobulin constant region comprising one or more constant region substitutions, or that the antibody is a bispecific antibody, comprising a second antigen-binding domain specific for PD-L1. The reference application also does not claim a method of preparing the antibody of the antibody conjugate or a chimeric antigen receptor (CAR) comprising an antigen-binding fragment of said antibody.
Liu teaches an anti-CLDN18.2 antibody, bispecific antibodies and conjugates thereof, and methods of preparation and use thereof (e.g., Abstract). Relevant to claims 29 and 33, Liu discloses IgG1 antibodies of the disclosure in which the Fc region comprises heavy chain Fc mutations of F243L (corresponding to position 126 in SEQ ID NO: 49) to mediate ADCC and CDC activity (e.g., Example 19 and Table 19, pages 21-23; ¶ 0177). Based on the teachings of Liu, 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 antibody conjugate of the co-pending reference application by incorporating a F243L substitution in the constant region, because Liu teaches that such a mutation enhances ADCC/CDC activity of the resulting antibody. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that such a modification to the constant region would be suitable to achieve the same desired purpose (reducing ADCC/CDC) in both antibodies.
Relevant to claims 37-38 and 40, Liu teaches bispecific antibodies (which reads on a “multispecific antibody”) comprising an anti-CLDN18.2 binding domain and a second binding domain against an immune checkpoint antigen, e.g., PD-L1, which Liu says achieves “the combined effect of tumor immunity and targeted antibody in one molecule, resulting in an effect equal to combined 2 molecules or better synergistic effect and bringing more convenient options for drug development for the combination of tumor immunotherapy and targeted therapy” (e.g., ¶ 0045-0052, 0149; Example 25, pages 43-44). Based on the teachings of Liu, it would have been further obvious to modify the anti-CLDN18.2 antibody of the co-pending reference application by adding a second antigen-binding domain specific for PD-L1, because Liu teaches that such a bispecific construct would achieve a more synergistic combined effect of tumor immunity and targeted therapy and provide more convenient options for drug development. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody of the co-pending reference application is likewise suitable for the purpose of generating a bispecific anti-CLDN18.2/anti-PD-L1 antibody.
Relevant to claims 52-55, Liu teaches isolated nucleic acids encoding an anti-CLDN18.2 antibody of the invention, expression vectors comprising said nucleic acid, and genetically modified host cells transfected with said expression vector, and further, provides methods of preparing an antibody of the invention using the same (e.g., ¶ 0138-0143; Examples 3-5, pages 21-24). Relevant to claims 56, 58, and 62-63, Liu discloses that the anti-human CLDN18.2 antibodies and conjugates thereof may be used to treat tumors, e.g., gastric cancer or lung cancer, in human cancer patients (e.g., ¶ 0145-0150, 0218-0224; Example 14, pages 34-35). Based on the teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of preparing the anti-CLDN18.2 antibody comprised in the antibody conjugate of the co-pending reference application according to the steps set forth by Liu, and to use said antibody to treat cancer in human patients. The skilled artisan would have been motivated to do so because such an antibody would have utility for treating CLDN18.2-mediated cancers in a patient in need thereof. Furthermore, antibody preparation methods are routine and conventional in the biotechnological art. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that identical steps to those carried out by Liu for a structurally and functionally similar class of molecule could be applied to prepare the anti-CLDN18.2 antibody disclosed in the co-pending reference application.
Relevant to claim 74, Liu describes CARs comprising an anti-CLDN18.2 antigen-binding fragment of the invention, a hinge domain, a transmembrane domain, a costimulatory domain, and a signaling domain, and having high binding activity and affinity (e.g., ¶ 0115-0137; Example 37, pages 57-58). Liu teaches that CAR T cell cells specifically recognize cancer cells and have a tumor-treating effect (e.g., ¶ 0005). Based on the teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute a scFv antigen-binding fragment thereof of the anti-CLDN18.2 antibody disclosed in the co-pending reference application into a CAR construct. The skilled artisan would have been motivated to do so because CARs can be expressed in T cells to use as a tumor-targeting therapy for cancer. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody fragment of the co-pending reference is likewise suitable for the purpose of generating a CAR with specificity for CLDN18.2-expressing cancer cells.
This is a provisional nonstatutory double patenting rejection.
(3)
Claims 16, 21-23, 25, 29, 33-35, 37-38, 51, 56, 58, 62, 65, 67, and 73-74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 22-23, 32-34, 39-40, 43-44, 48, 65, 67, and 74 of co-pending Application No. 18/710,628 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention. This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Regarding claims 16, 21-23, 25, 35, 51, 56, and 65, co-pending claims 1, 32-34, 43-44 and 48 recite a method of treating a CLDN18.2-associated disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of an anti-CLDN18.2 antagonist (antibody) and a PD-1/PD-L1 axis inhibitor (antibody), wherein the anti-CLDN18.2 antibody comprises the heavy chain and light chain CDR sequences of SEQ ID NO: 1-6, respectively (which share 100% sequence identity to instant SEQ ID NO: 1, 19, 21, 14, 16, and 18, respectively), a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 12 (which shares 100% sequence identity to instant SEQ ID NO: 25), and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 15 (which shares 100% sequence identity to instant SEQ ID NO: 26). Further relevant to claims 37-38 and 74, co-pending claim 32 recites that the CLDN18.2 antagonist is a bispecific antibody (which reads on “multispecific antibody”) or an immune cell expressing a chimeric antigen receptor (CAR) comprising an anti-CLDN18.2 binding domain. Regarding claims 29 and 33-34, co-pending claims 39-40 further recite that the constant region comprises one or more amino acid substitutions relative to SEQ ID NO: 9 (which shares 100% sequence identity to instant SEQ ID NO: 49) selected from the group consisting of L235V, F243L, R292P, Y300L, P396L, or any combination thereof (corresponding to positions 118, 126, 175, 183, and 279 of instant SEQ ID NO: 49), wherein the constant region comprises the sequence of SEQ ID NO: 11 (which shares 100% sequence identity to instant SEQ ID NO: 51). A method of treatment necessarily confers possession of the antibody pharmaceutical composition administered in said method.
Regarding claims 58 and 62, co-pending claims 65 and 67 recite that the CLDN18.2-associated disease is a cancer selected from the group consisting of gastric cancer, lung cancer, and others similarly recited in the instant claims.
Regarding claims 67 and 73, co-pending claim 74 recites a kit comprising a CLDN18.2 antagonist and a PD-1/PD-L1 axis inhibitor.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(4)
Claims 16, 37-38, 40, 46, 52-56, 58, and 62-63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 22-23, 32-34, 39-40, 43-44, 48, 65, 67, and 74 of co-pending Application No. 18/710,628 (reference application) as applied to claims 16, 21-23, 25, 29, 33-35, 37-38, 51, 56, 58, 62, 65, 67, and 73-74 above in (3), further in view of Liu (US 2021/0230272 A1; supra). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
The teachings of the reference application are recited in the non-statutory double patenting rejection above. Relevant to claim 46, co-pending claim 2 recites further administering a chemotherapeutic agent in the method of treatment.
However, the reference application does not teach a bispecific antibody comprising an anti-CLDN18.2 antigen-binding domain of the invention and a second antigen-binding domain against PD-L1, or that the anti-CLDN18.2 antibody is linked to a chemotherapeutic moiety. The reference application also does not teach a method of preparing said anti-CLDN18.2 antibody.
The teachings of Liu, with respect to a bispecific anti-CLDN18.2/anti-PD-L1 antibody (relevant to claims 37-38 and 40), are recited in the non-statutory double patenting rejection above. Based on the teachings of Liu, it would have been further obvious to modify the anti-CLDN18.2 antibody of the co-pending reference application by adding a second antigen-binding domain specific for PD-L1, because Liu teaches that such a bispecific construct would achieve a more synergistic combined effect of tumor immunity and targeted therapy and provide more convenient options for drug development (as compared to co-administering an anti-CLDN18.2 antagonist and an anti-PD-L1 antagonist). There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody of the co-pending reference application is likewise suitable for the purpose of generating a bispecific anti-CLDN18.2/anti-PD-L1 antibody.
Relevant to claim 46, Liu further provides antibody-drug conjugates (ADCs) of the invention, wherein the anti-CLDN18.2 antibody of the invention is conjugated to a cytotoxic small molecule drug (e.g., a chemotherapeutic agent) (e.g., ¶ 0083-0114). Liu discloses, “The ADC molecule obtained by conjugation of the antibody with cytotoxin retains the characteristics of the excellent specific binding activity against human and murine CLDN18.2, endocytosis and highly effective killing tumor cells, meanwhile, the ADC molecule carries cytotoxic toxin and can target and kill tumor cells more specifically, target and specifically inhibit tumor cell proliferation, and produce an unexpected and excellent efficacy in the treatment of tumors. These characteristics make the ADC drug of the present disclosure … provide more specific, effective and better treatment options, means and methods for tumor patients, especially for CLDN18.2 positive cancer patients” (¶ 0150). Based on the teachings of Liu, it would have been further obvious to modify the anti-CLDN18.2 antibody of the co-pending reference application by conjugating the antibody to a chemotherapeutic agent to generate an ADC. The skilled artisan would have been motivated to do so because Liu teaches that ADCs combine the specificity of the anti-CLDN18.2 for CLDN18.2-expressing tumor cells with the ability of the cytotoxic payload (e.g., chemotherapeutic agent) to kill tumor cells and inhibit tumor cell proliferation. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody of the co-pending reference application is likewise suitable for the purpose of generating an ADC.
The teachings of Liu with respect to a method of preparing an anti-CLDN18.2 antibody, and a method of using said antibody to treat human patients with a CLDN18.2-expressing cancer (relevant to claims 52-56, 58, and 62-63), are recited in the non-statutory double patenting rejection above. Based on the teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of preparing the anti-CLDN18.2 antibody administered in the method of the co-pending reference application according to the steps set forth by Liu, and to administer such an antibody to a human patient in need thereof. The skilled artisan would have been motivated to do so because such an antibody would have utility for treating CLDN18.2-mediated cancers in the patient in need thereof. Furthermore, antibody preparation methods are routine and conventional in the biotechnological art. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that identical steps to those carried out by Liu for a structurally and functionally similar class of molecule could be applied to prepare the anti-CLDN18.2 antibody disclosed in the co-pending reference application.
This is a provisional nonstatutory double patenting rejection.
(5)
Claims 16, 70, and 73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 22-23, 32-34, 39-40, 43-44, 48, 65, 67, and 74 of co-pending Application No. 18/710,628 (reference application) as applied to claims 16, 21-23, 25, 29, 33-35, 37-38, 51, 56, 58, 62, 65, 67, and 73-74 above in (3), further in view of Sahin (US 2015/0147763 A1; cited in PTO-892 mailed September 2025). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
The teachings of the reference application are recited in the non-statutory double patenting rejection above.
However, the co-pending claims do not recite a method of diagnosing a CLDN18.2-related disease using the anti-CLDN18.2 antibody.
Sahin describes anti-CLDN18.2 antibodies that are useful for diagnosing cancer and/or determining whether cancer cells express CLDN18.2 (e.g., Abstract). Sahin teaches that CLDN18.2 is expressed in many cancers, including pancreatic cancer, esophageal cancer, breast cancer, and others (e.g., ¶ 0003). Relevant to claim 70, Sahin teaches a method of detecting CLDN18.2 or determining the quantity of CLDN18.2 in a sample comprising the steps of (i) contacting a sample with an anti-CLDN18.2 antibody or antigen-binding fragment thereof of the invention and (ii) detecting the formation of a complex or determining the quantity of a complex between the anti-CLDN18.2 antibody or antigen-binding fragment thereof and CLDN18.2. Sahin further provides diagnostic methods that comprise said contacting and detecting steps, where the level of CLDN18.2 or CLDN18.2-expressing cells in a biological sample is compared to a reference level, and deviation from said reference level indicates the presence or stage of cancer disease (e.g., ¶ 0029-0046). Relevant to claim 73, Sahin also provides for a diagnostic kit comprising an antibody or antigen-binding fragment thereof of the invention (e.g., ¶ 0047).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to use the anti-CLDN18.2 antibody disclosed in the reference application in a diagnostic method or kit based on the teachings of Sahin. The skilled artisan would have been motivated to do so because Sahin teaches that CLDN18.2 is expressed in many cancers and the anti-CLDN18.2 antibody, having specificity for CLDN18.2, would have utility for detecting the presence of CLDN18.2 in tumor cells. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Sahin are functional equivalents and that the antibody of the co-pending reference application is likewise suitable for the purpose of detecting the presence of CLDN18.2 in a biological sample.
This is a provisional nonstatutory double patenting rejection.
(6)
Claims 16, 21-23, 25, 35, 51, 56, 58, and 62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16, and 37-38 of co-pending Application No. 18/879,798 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention. This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Regarding claims 16, 21-23, 25, 35, and 51, co-pending claims 1 and 16 recite a pharmaceutical composition comprising an anti-CLDN18.2 antibody, wherein the antibody comprises heavy chain and light chain CDRs as set forth in SEQ ID NO: 1-6, respectively (which share 100% sequence identity to the instantly claimed CDRs comprising SEQ ID NO: 1, 19, 21, 14, 16, and 18, respectively), or a VH and VL comprising the sequences set forth in SEQ ID NO: 7 and 8, respectively (which share 100% sequence identity to instant SEQ ID NO: 25 and 26, respectively).
Regarding claims 56, 58, and 62, co-pending claims 37-38 recite a method of treating CLDN18.2-related cancers (e.g., gastric cancer, lung cancer) that comprises administering the anti-CLDN18.2 antibody pharmaceutical composition to a subject in need thereof.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(7)
Claims 16, 29, 33, 37-38, 40, 46, 52-56, 58, 62-63, and 74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16, and 37-38 of co-pending Application No. 18/879,798 (reference application) as applied to claims 16, 21-23, 25, 35, 51, 56, 58, and 62 above in (6), further in view of further in view of Liu (US 2021/0230272 A1; supra). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
The teachings of the reference application are recited in the non-statutory double patenting rejection above.
However, the reference application does not teach a bispecific antibody comprising an anti-CLDN18.2 antigen-binding domain of the invention and a second antigen-binding domain against PD-L1, or that the anti-CLDN18.2 antibody is linked to a chemotherapeutic moiety. The reference application also does not teach a method of preparing said anti-CLDN18.2 antibody or a chimeric antigen receptor (CAR) comprising an antigen-binding fragment of said antibody. The reference application also does not teach that the pharmaceutical composition is administered in combination with a second therapeutic agent.
The teachings of Liu, with respect to a bispecific anti-CLDN18.2/anti-PD-L1 antibody (relevant to claims 37-38 and 40), are recited in the non-statutory double patenting rejection above. Based on the teachings of Liu, it would have been further obvious to modify the anti-CLDN18.2 antibody of the co-pending reference application by adding a second antigen-binding domain specific for PD-L1, because Liu teaches that such a bispecific construct would achieve a more synergistic combined effect of tumor immunity and targeted therapy and provide more convenient options for drug development (as compared to co-administering an anti-CLDN18.2 antagonist and an anti-PD-L1 antagonist). There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody of the co-pending reference application is likewise suitable for the purpose of generating a bispecific anti-CLDN18.2/anti-PD-L1 antibody.
The teachings of Liu, with respect to ADCs comprising a chemotherapeutic agent (relevant to claim 46), are recited in the non-statutory double patenting rejection above. Based on the teachings of Liu, it would have been further obvious to modify the anti-CLDN18.2 antibody of the co-pending reference application by conjugating the antibody to a chemotherapeutic agent to generate an ADC. The skilled artisan would have been motivated to do so because Liu teaches that ADCs combine the specificity of the anti-CLDN18.2 for CLDN18.2-expressing tumor cells with the ability of the cytotoxic payload (e.g., chemotherapeutic agent) to kill tumor cells and inhibit tumor cell proliferation. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody of the co-pending reference application is likewise suitable for the purpose of generating an ADC.
The teachings of Liu with respect to a method of preparing an anti-CLDN18.2 antibody, and a method of using said antibody to treat human patients with a CLDN18.2-expressing cancer (relevant to claims 52-56, 58, and 62-63), are recited in the non-statutory double patenting rejection above. Based on the teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of preparing the anti-CLDN18.2 antibody administered in the method of the co-pending reference application according to the steps set forth by Liu, and to administer such an antibody to a human patient in need thereof. The skilled artisan would have been motivated to do so because such an antibody would have utility for treating CLDN18.2-mediated cancers in the patient in need thereof. Furthermore, antibody preparation methods are routine and conventional in the biotechnological art. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that identical steps to those carried out by Liu for a structurally and functionally similar class of molecule could be applied to prepare the anti-CLDN18.2 antibody disclosed in the co-pending reference application.
Relevant to claim 65, Liu further teaches that the compositions and methods of the disclosure may be combined with other active agents or therapeutic methods, e.g., an effective amount of an anti-CLDN18.2 antibody of the invention is administered in combination with one or more inhibitors of PD-1, PD-L1, PD-L2, LAG-3, CTLA-4, or other immunomodulatory therapeutic antibodies, in a method of treating cancer (e.g., ¶ 0218-0222). Liu teaches that the immune checkpoint molecules targeted by immunomodulators are molecules expressed on the cell surface of immune cells “which can act as a ‘gate’ to reduce or inhibit immune responses, such as anti-tumor immune response, and thus can be combined with the antibodies of the present disclosure to treat tumors” (¶ 0221). Based on the teachings of Liu, it would have been further obvious to modify the method of treatment taught in the co-pending reference application, which comprises administering an anti-CLDN18.2 antibody, to additionally include administering an immunomodulatory antibody (e.g., anti-PD-L1 antibody or anti-LAG3 antibody). The skilled artisan would have been motivated to do so because the anti-CLDN18.2 antibody would specifically target CLDN18.2-expressing tumor cells, while the immunomodulator would act on immune cells to enhance anti-tumor responses and further increase the efficacy of treatment. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody of the co-pending reference application is suitable for use in a method of treating cancer.
The teachings of Liu with respect to anti-CLDN18.2 CARs (relevant to claim 74) are recited in the non-statutory double patenting rejection above. Based on the teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute a scFv antigen-binding fragment thereof of the anti-CLDN18.2 antibody disclosed in the co-pending reference application into a CAR construct. The skilled artisan would have been motivated to do so because CARs can be expressed in T cells to use as a tumor-targeting therapy for cancer. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody fragment of the co-pending reference is likewise suitable for the purpose of generating a CAR with specificity for CLDN18.2-expressing cancer cells.
This is a provisional nonstatutory double patenting rejection.
(8)
Claims 16, 70, and 73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16, and 37-38 of co-pending Application No. 18/879,798 (reference application) as applied to claims 16, 21-23, 25, 35, 37, 51, 56, 58, and 62 above in (6), further in view of further in view of Sahin (US 2015/0147763 A1; supra). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
The teachings of the reference application are recited in the non-statutory double patenting rejection above.
However, the co-pending claims do not recite a method of diagnosing a CLDN18.2-related disease using the anti-CLDN18.2 antibody.
The teachings of Sahin are recited in the non-statutory double patenting 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 use the anti-CLDN18.2 antibody disclosed in the reference application in a diagnostic method or kit based on the teachings of Sahin. The skilled artisan would have been motivated to do so because Sahin teaches that CLDN18.2 is expressed in many cancers and the anti-CLDN18.2 antibody, having specificity for CLDN18.2, would have utility for detecting the presence of CLDN18.2 in tumor cells. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Sahin are functional equivalents and that the antibody of the co-pending reference application is likewise suitable for the purpose of detecting the presence of CLDN18.2 in a biological sample.
This is a provisional nonstatutory double patenting rejection.
(9)
Claims 16, 21-23, 25, 29, 33-35, 37-38, 46, 51, 56, 58, 62-63, 65, 70, and 73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-70 of co-pending Application No. 19/489,267 (reference application). This is a new rejection necessitated by the filing of the co-pending reference application after the mailing of the previous Office action.
Regarding claims 16, 21-23, 25, 35, 37-38, 40, 51, 56, 58, and 65, co-pending claims 25, 31, 35-36, 46-47 recite a method of treating a CLDN18.2-expressing cancer by administering a humanized anti-CLDN18.2 antibody comprising a VH having the amino acid sequence of SEQ ID NO: 12 (which shares 100% sequence identity to instant SEQ ID NO: 25) and a VL having the amino acid sequence of SEQ ID NO: 15 (which shares 100% sequence identity to instant SEQ ID NO: 26), in combination with chemotherapy and a PD-1/PD-L1 axis inhibitor. Regarding claim 62, co-pending claims 58-60 recite that the cancer is selected from gastric cancer and others. Regarding claim 63, co-pending claim 50 recites that the subject is human.
Regarding claim 29, co-pending claims 38-39 recites that the anti-CLDN18.2 antibody comprises an Ig constant region. Regarding claims 33-34, co-pending claims 38-43 recite that the constant region comprises the same amino acid substitutions relative to SEQ ID NO: 9 (which shares 100% sequence identity to instant SEQ ID NO: 49) and/or the amino acid sequence of SEQ ID NO: 11 (which shares 100% sequence identity to instant SEQ ID NO: 51).
Regarding claim 46, co-pending claims 48-49 recite that the anti-CLDN18.2 antibody is conjugated to a chemotherapeutic agent.
Regarding claim 70, co-pending claims 31-32 and 35-36 recite a method that comprises detecting and determining the presence of CLDN18.2 in a patient-derived cancer sample.
Regarding claim 73, co-pending claim 70 recites a kit comprising a CLDN18.2 antagonist, useful for detecting CLDN18.2-expressing cancer.
This is a provisional nonstatutory double patenting rejection.
(10)
Claims 16, 52-55, and 74 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-70 of co-pending Application No. 19/489,267 (reference application) as applied to claims 16, 21-23, 25, 29, 33-35, 37-38, 46, 51, 56, 58, 62-63, 65, 70, and 73 above, further in view of further in view of Liu (US 2021/0230272 A1; supra). This is a new rejection necessitated by the filing of the co-pending reference application after the mailing of the previous Office action.
The teachings of the reference application are recited in the non-statutory double patenting rejection above.
However, the reference application does not claim (1) a method of preparing the anti-CLDN18.2 antibody, (2) a chimeric antigen receptor (CAR) comprising an antigen-binding fragment of said antibody, or (3) a kit comprising the anti-CLDN18.2 in combination with a second therapeutic agent.
Liu teaches an anti-CLDN18.2 antibody, bispecific antibodies and conjugates thereof, and methods of preparation and use thereof (e.g., Abstract). Relevant to claims 52-55, Liu teaches isolated nucleic acids encoding an anti-CLDN18.2 antibody of the invention, expression vectors comprising said nucleic acid, and genetically modified host cells transfected with said expression vector, and further, provides methods of preparing an antibody of the invention using the same (e.g., ¶ 0138-0143; Examples 3-5, pages 21-24). Based on the teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of preparing the anti-CLDN18.2 antibody recited in the the co-pending reference application according to the steps set forth by Liu, and to use said antibody to treat cancer in human patients. The skilled artisan would have been motivated to do so because such an antibody would have utility for treating CLDN18.2-mediated cancers in a patient in need thereof. Furthermore, antibody preparation methods are routine and conventional in the biotechnological art. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that identical steps to those carried out by Liu for a structurally and functionally similar class of molecule could be applied to prepare the anti-CLDN18.2 antibody disclosed in the co-pending reference application.
Relevant to claim 74, Liu describes CARs comprising an anti-CLDN18.2 antigen-binding fragment of the invention, a hinge domain, a transmembrane domain, a costimulatory domain, and a signaling domain, and having high binding activity and affinity (e.g., ¶ 0115-0137; Example 37, pages 57-58). Liu teaches that CAR T cell cells specifically recognize cancer cells and have a tumor-treating effect (e.g., ¶ 0005). Based on the teachings of Liu, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute a scFv antigen-binding fragment thereof of the anti-CLDN18.2 antibody disclosed in the co-pending reference application into a CAR construct. The skilled artisan would have been motivated to do so because CARs can be expressed in T cells to use as a tumor-targeting therapy for cancer. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Liu are functional equivalents and that the antibody fragment of the co-pending reference is likewise suitable for the purpose of generating a CAR with specificity for CLDN18.2-expressing cancer cells.
This is a provisional nonstatutory double patenting rejection.
(11)
Claims 16 and 67 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-70 of co-pending Application No. 19/489,267 (reference application) as applied to claims 16, 21-23, 25, 29, 33-35, 37-38, 46, 51, 56, 58, 62-63, 65, 70, and 73 above, further in view of Sahin (US 2015/0147763 A1; supra). This is a new rejection necessitated by the filing of the co-pending reference application after the mailing of the previous Office action.
The teachings of the reference application are recited in the non-statutory double patenting rejection above.
However, the co-pending claims do not recite a kit comprising the anti-CLDN18.2 antibody (antagonist) and a second therapeutic agent.
The teachings of Sahin are recited in the non-statutory double patenting rejection above. Sahin further recites kits comprising a combination of antibodies and/or antigen-binding fragments (e.g., ¶ 0047).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess a kit comprising a combination of the anti-CLDN18.2 antibody recited in the co-pending claims in combination with a second therapeutic agent (e.g., the PD-1/PD-L1 axis inhibitor co-administered in the method of treatment recited in the co-pending claims) based on the teachings of Sahin. The skilled artisan would have been motivated to do so because Sahin teaches that the kits have utility for diagnosis, detection, and monitoring, which would be desirable when seeking to carry out a method of treatment in which detection of both CLDN18.2 and PD-L1 in the subject’s cancer sample is necessary such as in the co-pending claims. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the anti-CLDN18.2 antibodies of the co-pending reference application and Sahin are functional equivalents, and because it is considered routine and conventional in the art to generate kits containing multiple reagents for use in diagnostics.
This is a provisional nonstatutory double patenting rejection.
Conclusion
In the interest of promoting compact prosecution, it is noted that claim 41 (withdrawn) contains exemplary language – “(e.g. vcMMAE)” – in line 5. It is suggested by the Examiner that this limitation be removed.
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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