DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 08/07/2023, is acknowledged.
3. Claims 1, 2, 4-6 and 8-20 are pending.
4. Applicant’s IDS, filed 09/20/2023, 10/06/2023, 10/10/2025, is acknowledged.
5. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
6. Claims 1, 2, 4-6 and 8-20 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
(i) The recitation “represented by” in claims 1, 8-9, 16 implies any member of a genus that is “represented by” the respective SEQ ID NO: X. Such language fails to establish the metes and bounds of amino acid sequence encompassed by the instant claim language; therefore, the claim is indefinite.
7. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
8. Claims 1, 2, 4-6 and 8-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 16 and dependent claims thereof encompass a broad genus of CLDN18.2 antibodies comprising less than the required 6 CDRs.
Claims 8 encompass a broad genus of anti-CD3 antibodies comprising less than the required 6 CDRs.
Claim 5 encompasses a genus of anti-CLDN18.2 antibodies variants and a genus of anti-CD3 antibodies variants.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of binding CLDN18.2 and binding CD3 in the treatment of cancer. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The specification at [0069] and FIG. 2A-2C show the confirmation of binding affinity of CLDN18.2 monoclonal antibody m-13 to hCLDN18.2 protein (FIG. 2A), CLDN18.2 overexpressing HEK293 cells (FIG. 2B) and SNU601 cells (FIG. 2C).
[0125] VH and VL sequences of m-13 are shown in Table 1, the heavy chain constant region of m-13 is the constant region of mouse IgG2a heavy chain, and the light chain of m-13 is a mouse kappa light chain. The sequences thereof are listed in Table 4.
[0155] As m-13 and m-6 clones displayed high binding affinity, high specificity, and potent cytotoxicity, m-13 was finally chosen as a lead candidate for humanization and m-6 also was humanized as a back-up clone. The VH and VL sequences of humanized m-6 (i.e., h-6) are shown as SEQ ID Nos. 29-30 listed in Table 2-1, respectively. For m-13, the top 3 humanized variable light chains and 5 variable heavy chains were obtained, which reached high human-ness scores (VL1-90.1%, VL2-89.1%, VL3-88.1%, VH1-86.7%, VH2-82.7%, VH3-81.6%, VH4-80.6%, and VH5-79.6%) (VH and VL sequences are listed in Table 2). To characterize the CLDN18.2-13 antibodies (i.e. CLDN18.2-h-13 antibodies) resulting from those humanized heavy chains (i.e. VH1-VH5) and light chains (i.e. VL1-VL3), each humanized light chain was co-transfected with each humanized CLDN18.2-13 heavy chain in CD3 bispecific format. As a result, 15 humanized CLDN18.2-13/CD3 bispecific antibodies were generated. To determine their apparent binding activity, high CLDN18.2 expressing HEK293 and SNU620 cell lines as targets were incubated in varying concentrations of humanized CLDN18.2/CD3 bispecific antibodies, and with anti-human IgG-PE as a secondary antibody. The cells were then washed twice with FACS buffer. FACS analysis was carried out on a FACS Flow Cytometer. Through flow cytometry assays, we characterized the binding affinity of humanized CLDN18.2-13/CD3 subclones to CLDN18.2 on hCLDN18.2 over-expressing HEK293 cells (high expression of CLDN18.2) and CLDN18.2 natural expressing SNU-620 cells (medium expression of CLDN18.2). We found that all 15 humanized CLDN18.2-13/CD3 candidates had comparable binding affinities as parental m-13 (FIG. 10) as judged by median fluorescence intensity (MFI) on both CLDN18.2 highly expressing HEK cells as well as CLDN18.2 medium expressing SNU620 cells
FIG. 13 of the specification shows the humanized CLDN18.2-13/CD3 subclones induced potent T cell redirected cytotoxicity against their targets. As expected, the killing potency mediated by humanized CLDN18.2-13/CD3 subclones and parental m-13/CD3-p was 100-fold higher than that of AMG-910 (FIG. 13). Taken together, these functional assays indicated that the murine CLDN18.2 clone 13 has been successfully humanized [0162].
[0164] Since h-13/CD3-p carried SP34 as a CD3 arm, which has high binding affinity to CD3, potential cytokine release syndrome (CRS) may be induced in the clinic. To generate safe and effective CLDN18.2/CD3 bispecific antibody and to reduce the potential CRS related toxicity, we used our optimized CD3 platform, which includes several CD3 binders with various binding affinities.
Most importantly, h-13/CD3-v2 subclones mediated significantly lower cytokine release as compared to h-13/CD3-p, which was clearly driven by the higher CD3 binding affinity of h-13/CD3-p. Taken together, h-13VH1-VL1/CD3-v2 was selected as the lead candidate antibody based on its higher killing potency and similar cytokine release as compared to the other two h-13/CD3-v2 subclones [0174].
However, the claims encompass a genus of antibodies comprising less than the required 6 CDRs for hCLDN18.2 and CD3 antibodies.
The specification provides six anti-CLDN18.2 antibody, 841, 808, m-6, m-12, m-13, which were not random combinations of VH and VL i.e., they had specific VH domain (SEQ ID NO: 1, 3, 5, 7, 9) paired with specific VL domain (SEQ ID NO: 2, 4, 6, 8, 10, respectively). Clone m-13 comprises VH-CDR1-3 of SEQ ID NO: 11-13 and VL-CDR1-3 of SEQ ID NO: 14-16 and humanized m-13, h-13 comprising VH of SEQ ID NO: 17-21 and VL of SEQ ID NOs: 22-24. There is no teaching of anti-CLDN18.2 antibodies that comprise only three CDRs, either VH-CDR1-3 or VL-CDR1-3 and binds to CLDN18.2 and treat cancers. Brown et al (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g. 6CDR's) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds the CLDN18.2 to satisfy the WD requirement for the claims.
Neither the specification, nor the prior art provides any examples to support the premise of anti-CLDN18.2 or CD3 comprising VHCDRs or VLCDRs would result in antigen binding to CLDN18.2 or CD3. The prior art does not support a definition of an antibody structure comprising less than 6CDRs and result in functional anti- CLDN18.2 or CD3 antibody. The specification fails to show that all VH-CDR1-3 and VL-CDR1-3 of the anti- CLDN18.2 or CD3 antibodies are equivalent and can provide antigen binding to CLDN18.2 or CD3. The specification fails to establish that by replacing at least one VH-CDR1-3 of m-13 antibody with VL-CDR1-3 from m-13, maintains CLDN18.2 binding. Such teachings were not made part of the specification at the time the invention was made.
With respect to the recitation an antibody which does not comprise all 6 CDRs of the antibody that is produced by m-13/h-13 and CD3-p, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ((https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Claim 5 and dependent claims thereof encompass a genus of anti-CLDN18.2 antibody m-13/m-13 variants and a broad genus of anti-CD3 antibody variants.
Regarding the antibody variants one skilled in the art have recognized challenge and trade-offs once it is applied in antibody. Rabia et al (Biochem Eng J. 2018 September 15; 137: 365-374) states that optimize antibody properties (affinity, specificity, stability, solubility and effector functions) with amino acid substitutions is challenge and is always trade-offs and states that an outstanding challenge in the field is that optimizing properties such as antibody affinity can lead to defects in other properties such as antibody stability, specificity and solubility. The resulting trade-offs between improvements in some antibody properties and reductions in others highlight that they are often interdependent and cannot be easily separated (introduction). Rabia et al further state given that the maximal chemical diversity of antibody CDRs is unimaginably large (>1078 antibody variants based on 20 different amino acids at ~60 sites in the CDRs), it is extremely challenging to define the sequence determinants of antibody specificity (para 2).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
9. Claims 14-15 and 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating CLDN18.2-positive cancer in a subject comprising administering to the subject an anti-CLDN18.2 X anti CD3 bispecific antibody, wherein the anti-CLDN18.2 antibody comprising the CDRs of SEQ ID NO: 11-16 and the anti-CD3 antibody comprising the CDRs of SEQ ID NOs: 31-36; SEQ ID NOs: 37-39 and 34-36; or SEQ ID NOs: 37, 40, 39, 34-36, does not reasonably provide enablement for a method of treating cancer including CLDN18.2-positive cancer, , hematological cancer or solid cancer, gastric cancer and pancreatic cancer with anti-CLDN18.2 antibody comprising the CDRs of SEQ ID NOs: 11-16. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claims encompass treating cancer with anti-CLDN18.2 antibody, m-13 or humanized version thereof, h-13. However, the specification fails to show any cancer efficacy of anti-CLDN18.2. The specification fails to show the use of the m-13 antibody as a single treatment. The specification shows a T cell-engaging bispecific antibody that targets Claudin 18.2 (CLDN18.2), anti-CLDN18.2 X anti-CD3 bispecific exert activity on CLDN18.2-positive cancer due to the dual specificity.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The specification at [0158] (section 2.3) shows that TCR/CD3 signaling strength mediated by CLDN18.2-13/CD3 bispecific antibodies (i.e. h-13/CD3 bsAbs) with CD3-p (i.e. CD3 Parental) arm.
The specification at [0161] (section 2.4) shows that anti-tumor effect of CLDN18.2-13/CD3 bispecific antibodies (i.e. h-13/CD3 bsAbs) with CD3-p (i.e. CD3 Parental) arm.
The specification at [0163] (section 2.5) shows that binding affinity of CLDN18.2-13/CD3 bispecific antibodies (i.e. h-13/CD3 bsAbs) with mutant CD3 am (CD3-V1 or CD3-V2) to CLDN18.2 and CD3.
The specification at [0171] (section 2.7) discloses that cytolytic potency mediated by CLDN18.2-13/CD3 bispecific antibodies (i.e. h-13/CD3 bsAbs) with mutant CD3 arm (CD3-V1 or CD3-V2).
The specification fails to show an anti-CLDN18.2 antibody has beneficial/ability to treat or provide efficacy in CLDN18.2-positive cancer. Given that the specification shows that an anti-CLDN 18.2-13/CD3-p bispecific antibody that can redirect CD3+ effector T cells to CLDN18.2-positive cancer sites which would result in T cells activation and subsequent killing of CLDN18.2 cancer-positive cells. Accordingly, besides the anti-CLDN 18.2-13/CD3-p bispecific comprising the claimed sequences, the specification is not enabled for using anti-CLDN18.2-h-13 antibody alone in the treatment of CLDN18.2-positive cancer.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
10. No claim is allowed.
11. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
(i) Xu et al. Dark horse target Claudin18.2 opens new battlefield for pancreatic cancer. Front. Oncol., 05 March 2024, pages 1-11.
Xu et al introduces the clinical research progress of Claudin18.2 positive pancreatic cancer, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, CAR-T cell therapy, and hope to provide feasible ideas for the clinical treatment of Claudin18.2 positive pancreatic cancer.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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January 26, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644