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 .
Applicant’s amendment filed on 3/26/2026 is acknowledged.
Claims 1, 3-8, 10-11, 13-16, 19, 21-27 are pending. Claims 2, 9, 12, 17-18, and 20 are cancelled.
Information Disclosure Statement
The references on the information disclosure statement (IDS) filed on 7/31/2023 have been considered.
Priority
This application is a 371 of PCT/CN2022/073207 effectively filed on 1/21/2022 and claims foreign priority to Chinese Application 20210117724.4 effectively filed on 1/28/2021.
Election/Restrictions
Applicant's election with traverse of Group I’s CLDN18.2 antibody in the reply filed on 3/26/2026 is acknowledged. The traversal is on the ground(s) that the claimed subject matter makes a contribution over the prior art disclosed in WO2020/139956 (Zhu). Applicant argues that Zhu does not disclose the presently claimed antibody comprising all six of the claimed CDRs together in one heavy- and light- chain construct (page 6-7). Applicant has amended claims 1, 3-8, 10-11, 13-16, 19, and 21-27 to encompass the claimed antibody comprising all six of the claimed CDRs. Applicant’s arguments and amendments to claims 1, 3-8, 10-11, 13-16, 19, and 21-27 are sufficient to overcome the lack of unity restriction requirement set forth in the Office action mailed on 1/26/2026.
As such, claims 1, 3-8, 10-11, 13-16, 19, and 21-27 are under consideration for their full scope.
Claim Objections
Claims 1 are objected to because of the following informalities:
Claim 1 recites, “the LCDR1 sequence comprises the amino acid sequence of SEQ ID NO: 4)”. The parenthesis after the “4” should be deleted.
Claim 22 recites, “human CLDN18.2 or a monkey CLDN18.2”. The “or” should be replaced with an “and” since the listing with “or” is not proper Markush group language.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Written Description
Claims rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant is in possession of: an antibody or an antigen binding portion thereof that specifically binds to CLDN18.2 comprising the amino acid sequence of the heavy chain variable region of SEQ ID NO:7, 9, or 11 and a light chain variable region of SEQ ID NO:8, 10, or 12.
Applicant is not in possession of: an antibody or an antigen binding portion thereof that specifically binds to CLDN18.2 comprising the amino acid sequence of the heavy chain variable region as shown in SEQ ID NO:7, 9, or 11 and a light chain variable region as shown in SEQ ID NO:8, 10, or 12.
One of ordinary skill in the art does not have possession of antibodies which comprise sequences which are “shown” in SEQ ID NOs:7-12. The recitation of “as shown in” opens up the claims to sequences which include subfragments of SEQ ID NOs:7-12 which are not full length SEQ ID NOs:7-12. The specification has not demonstrated full possession of the recited structure of the antibody which can be used for the recited function of binding to CLDN18.2.
Consequently, conception cannot be achieved until a representative description of the structural and functional properties of the claimed invention has occurred, regardless of the complexity or simplicity of the method.
The specification must set forth the structural features that allow one of ordinary skill in the art to identify and produce the recited antibodies. In the instant case, definition by function does not suffice to define the genus because it is only an indication of what the antibodies do, rather than what they are.
As such claims 3 and 15-16 do not meet the requirements of 35 U.S.C. 112(a) for written description as they are currently written.
Enablement
Claims 3, 11, 13, 15-16, 21, 23-24, and 26-27 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
While being enabled for: an antibody or an antigen binding portion thereof that specifically binds to CLDN18.2 comprising the amino acid sequence of the heavy chain variable region of SEQ ID NO:7, 9, or 11 and a light chain variable region of SEQ ID NO:8, 10, or 12; methods of treating gastric tumors; a pharmaceutical composition for the treatment of gastric cancer.
The specification does not reasonably provide enablement for: an antibody or an antigen binding portion thereof that specifically binds to CLDN18.2 comprising the amino acid sequence of the heavy chain variable region as shown in SEQ ID NO:7, 9, or 12 and a light chain variable region as shown in SEQ ID NO:8, 10, or 12; methods of treating a CLDN18.2-related disease wherein the CLDN18.2-related disease is a tumor; AND a pharmaceutical composition for the treatment of tumors.
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 specification disclosure does not enable one skilled in the art to practice the invention without undue amount of experimentation.
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 bread of claims 3 and 15-16 with the recitation of limitation “as shown in” encompass antibodies that specifically bind CLDN18.2 with alternative amino acid sequences or peptide subfragments of the heavy chain variable region sequence which are “shown in” the SEQ ID NOs:7, 9, or 11 which not full length SEQ ID NO:7, 9, or 11 and alternative amino acid sequences or peptide subfragments of the light chain variable region sequence which are “shown in” the SEQ ID NOs:8, 10, or 12 which not full length SEQ ID NO:8, 10, or 12. Subfragments encompass any peptide of any length that are “shown in” SEQ ID NOs:7, 9, or 11 and SEQ ID NOs:8, 10 or 12.
The specification (Example 2; Tables 1-2) discloses the preparation of anti-CLDN18.2 hybridomas that secreted five different monoclonal antibodies where only hybridoma cell 7D10 secreted an antibody that bound to CLDN18.2 cells and hardly bound to CLDN18.1 cells. The 7D10 hybridoma has five different subclones where 7D10-1 secreted an antibody with the heavy chain variable region as shown in SEQ ID NO:7 and the light chain variable region as shown in SEQ ID NO:8 and further prepared an anti-CLDN18.2 chimeric antibody with the heavy chain variable region as shown in SEQ ID NO:9 and the light chain variable region as shown in SEQ ID NO:10 (Examples 3-4). The specification (Example 5) additionally discloses the preparation of an anti-CLDN18.2 humanized antibody with the heavy chain variable region as shown in SEQ ID NO:11 and a light chain variable region as shown in SEQ ID NO:12.
It is well established in the art that it is highly unpredictable which changes in amino acid sequence can be made in binding structures such that the derived polypeptide retains the ability to bind. One of ordinary skill in the art could not predict which alternative amino acid sequence, peptide or antibody subfragments within the full-length amino acid sequences of the recited genus of antibodies could be utilized and whether the resulting polypeptide or antibody combinations exhibits binding to CLDN18.2. Predicting polypeptide structure from sequence data of a single amino acid sequence and attempting to utilize the predicted structural determinations to ascertain binding or functional aspects of any protein and what changes can be tolerated with respect thereto is complex and well outside the realm of routine experimentation. In re Fisher indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
As such the claims are not enabled for the genus of antibodies or antibody-binding portion that specifically bind CLDN18.2 comprising a heavy chain variable region as shown in SEQ ID NOs:8, 10, or 12 and light chain variable region as shown in SEQ ID NOs:7, 9, or 11. One of ordinary skill in the art cannot use antibodies with unpredictable functions. One of ordinary skill in the art would be required to practice undue experimentation to practice the invention commensurate in scope with the claims.
In view of the quantity of experimentation necessary, the lack of working examples, the unpredictability in the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to make and use the encompassed antibody comprising a heavy chain variable region “as shown” in SEQ ID NOs:8, 10, or 12 and light chain variable region “as shown” in SEQ ID NOs:7, 9, or 11 recited in the claims for predictable function to specifically bind CLDN18.2.
The breadth of claims 11, 13, 21, and 23-27 encompass all diseases and all tumors (including malignant and benign) with any level of CLDN18.2 expression and/or activity. CLDN18.2-related diseases and tumors all have different causes, affect different physiological processes, and are treated with different agents.
The art of Wu et al (PTO-892; Reference U; “Wu”) teaches in a multi-omic analysis of CLDN18.2 expression in a TCGA pan-cancer cohort that CLDN18.2 was expressed in higher levels in upper gastrointestinal tract cancers (PAAD, STAD, and STAD), but high expression may be associated with poor prognosis and promotes disease progression through angiogenesis mechanisms (Wu; Abstract; page 14, left column, section 5). Interestingly, Wu teaches the CLDN18.2 had high expression levels in CRC, but improves the prognosis of patients with CRC (Wu; page 4, left column, section 2.6). Additionally, Wu teaches CLDN18.2 expression significantly differed between tumor samples and normal samples in patients with STAD, CRC, and ESCA indicating highly specific expression levels of CLDN18.2 across different cancers (Wu; page 6, left column, paragraph 1). Wu teaches that in another study, gastric cancer tumor tissues exhibited lower levels of CLDN18.2 expression compared to normal tissues while the combination of low expression of CLDN18.2 with increased CD4+ or CD8+ T cell infiltration was associated with a better prognosis (Wu; page 2, right column, paragraph 2).
The American Cancer Society (PTO-892; Reference V; “ACS”) teaches tumors are defined by abnormal growth, mass or lesion, but not all tumors are cancer since some can be benign while others are malignant (ACS; pages 1-4). Benign and malignant tumors have distinct characteristics where malignant tumors are characterized by cells that invade surrounding tissue and spread to other parts of the body while benign tumor cells do not have this capability (ACS; pages 1-5). Additionally, ACS teaches that cancer causes the growth of malignant tumors while tumors are the byproduct of cancer illustrating tumors are not defined as a disease (ACS; page 4).
The prior art does not appear to provide any evidence as to treatment of the full scope of the claims of any as such, not any disease or tumor with any expression and/or activity level of CLDN18.2 can be treated effectively with the claimed CLDN18.2 antibody without undue experimentation.
The specification (page 7, paragraph 5) discloses a CLDN18.2 related disease to include conditions associated with CLDN18.2 signaling pathways which can include tumors such as gastric cancer, pancreatic cancer, colon cancer, esophageal cancer, liver cancer, ovarian cancer, lung cancer, and bladder cancer, as well as metastatic cancer. The specification additionally discloses in Example 6 (pages 26-27) , the in vitro activity of the claimed anti-CLDN18.2 antibody in a human gastric cancer cell line NUGC4 where the EC50 of ADCC was calculated to be 0.18mM. However, there are no other examples or discussion of how a disease’s association with the CLDN18.2 signaling pathway is determined, what level of CLDN18.2 expression and/or activity is necessary for a relation to be established with a specific disease or tumor, and if this subsequent relation indicates an appropriate subject can be treated with an anti-CLDN18.2 antibody.
As such the claims are not enabled for treating the genus of CLDN18.2-related diseases and the genus of tumors with the claimed anti-CLDN18.2 antibody. One of ordinary skill in the art cannot treat the genus of CLDN18.2-related diseases and genus of tumors with the claimed anti-CLDN18.2 since it would be unpredictable if the CLDN18.2-related disease or tumor would respond or respond in a clinically significant way to the claimed anti-CLDN18.2 antibody.
In view of the quantity of experimentation necessary, the lack of working examples, the unpredictability in the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trials and errors to make and use the encompassed anti-CLDN18.2 antibody with the genus of CLDN18.2-related diseases and tumors.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view 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.
Allowable Subject Matter
Claims 4-8, 10, 14, 19 and 25 appear to be in condition for allowance.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH ELIZABETH STEIN whose telephone number is (571)272-0093. The examiner can normally be reached M-F 8-5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (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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/LEAH ELIZABETH STEIN/Examiner, Art Unit 1641
/NORA M ROONEY/Primary Examiner, Art Unit 1641
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