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 .
DETAILED ACTION
Claims 20-40, 42, and 43 are pending.
Claim 41 is canceled.
Claims 20, 21, 25, 28-30, 36, 37, 42, and 43 are currently amended.
Claims 20-40, 42, and 43 are under examination on the merits.
Objections Withdrawn
The objection to the drawings is withdrawn in view of the submission of new drawings, dated 07/20/2026.
Rejections Withdrawn
35 U.S.C. 112(b)
The rejection of claim 36 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of the amendments to the claim, dated 07/20/2026.
Rejections Withdrawn
35 U.S.C. 112(a)
The rejection of claims 37-40, 42, and 43 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to satisfy the enablement requirement, is withdrawn in view of the amendments to claim 37. Claim 41 is canceled.
Rejections Maintained
35 U.S.C. 112(a)
The rejection of claims 20-40, 42, and 43 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 is maintained. Claim 41 is withdrawn.
Response to Arguments
In Applicant Arguments, dated 07/20/2026, Applicant asserts the following:
The present application teaches that a bispecific binding molecule that binds both human CD3 and human CLDN18.2 can induce cytotoxicity against CLDN18.2-expressing cells. See, e.g., Example 7. Thus, the present application demonstrates that CLDN18.2-expressing cells can be effectively targeted by bringing them together with CD3-expressing immune cells through the respective binding domains of the bispecific binding molecule. Unlike a claim reciting a function such as neutralizing or blocking a receptor interaction, the recited binding domains do not require any particular function beyond binding for which a separate structure-function correlation must be shown. It is the combination of the two binding domains as a bispecific molecule that allows CLDN18.2-expressing cells to be brought together with CD3-expressing cytotoxic T cells, resulting in the claimed cytotoxicity. That the cytotoxic activity of the bispecific molecules is dependent on the binding to human CLDN18.2 is evidenced by the data in the application showing that the tested bispecific molecules did not induce significant cytotoxicity in cells that express the CLDN18.2 paralogue CLDN18.1, even at concentrations well above the recited EC₅₀ cutoff of 300 pm. See, e.g., Example 7.3 and Table 4. Thus, the structural feature common to the recited bispecific antibody constructs is the combination, in a single molecule, of a domain that binds human CLDN18.2 and a domain that binds human CD3. In light of the above, Applicants submit that one of ordinary skill in the art, in view of the present disclosure, would reasonably conclude that the inventors were in possession of the recited bispecific binding molecules comprising a binding domain that binds to human CLDN18.2 and a binding domain that binds to human CD3. Moreover, the application provides data for a representative set of constructs with two distinct anti-CLDN18.2 binding domains (CL-1 and CL-2) in more than one bispecific format (CL-1 x I2C-6His, CL-1 X I2C-scFc, and CL-2 x I2C-scFc). In every case, the representative constructs display an EC₅₀ within the recited range across multiple independent assays, CLDN18.2-positive cell lines, and effector cells. For example, CL-1 X I2C-6His and CL-1 X I2C-scFc both displayed cytotoxicity EC₅₀ values well within the recited ≤ 300 pM threshold against CHO cells stably transfected with human CLDN18.2, using unstimulated human PBMC as effector cells. See Example 7.3 and Table 4. Further, against five CLDN18.2-positive cancer cell lines (GSU, IM95, NUGC4, SNU-601, and SNU-620) as well as CHO cells stably transfected with human CLDN18.2, with human T cells as effector cells, CL-1 X I2C-scFc and CL-2 X I2C-scFc displayed EC₅₀ values from single- to low-triple-digit pM, all well within the recited ≤ 300 pM threshold. See Example 7.4 and Table 5. The CL-1 X I2C-6His and CL-1 X I2C-scFc constructs also displayed potent activity (EC₅₀ of single- to double-digit pM) with macaque T cells (see Example 7.5 and Table 6). The consistent demonstration that structurally distinct, reduced-to-practice CLDN18.2 X CD3 constructs all display the recited potency under varied assay conditions conveys possession of the claimed methods.
These arguments have been fully considered but are not deemed persuasive. As indicated at p. 9 of the Non-Final Rejection, dated 02/20/2026, the claims encompass a large genus of molecules that includes any anti-CLDN18.2 x anti-CD3 bispecific antibody that has an EC50 of ≤ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells, and as indicated in the Non-Final Rejection, three species comprised within the claimed genus have been reduced to practice; however the issue with respect to written description in this case is that, in view of the high level of unpredictability in the antibody arts, screening methodologies are required to determine which anti-CLDN18.2 x CD3 bispecific antibodies are comprised within the claimed genus. For example as indicated in the Non-Final Rejection, it is well- known in the art that different antibodies specific for the same antigen will display markedly different EC₅₀ values. For example at Table 7 (p. 31), Li et al. (US PG PUB 2006/0127393, publication date: 06/15/2006) teach that different clones of antibodies specific for the same antigen (DKK-1) will display markedly different EC50 values as measured in a cell-based viability assay using the same cell type (ST2 cells). In viability assays using mouse DKK-1, anti- DKK-1 antibody clone 5H6-1 displayed an EC50 value of 2068 nM compared to an EC₅₀ value of 272 nM for anti-DKK-1 antibody clone 10A7-1. In viability assays using human DKK-1, anti- DKK-1 antibody clone 7D6-1 displayed an EC₅₀ value of 1465 nM compared to an EC₅₀ value of 63 nM for anti-DKK-1 antibody clone 10A7-3.
Furthermore Hornsby et al. (Molecular & Cellular Proteomics 14.10, 2833-2847, 2015) developed methodologies for screening anti-transcription factor (TF) antibody fragments (Fabs) for high affinity (EC50 < 20 nM), high stability, good expression in E. coli, and an ability to bind antigen in complex cell lysates, see Abstract. A screen of approx. 200 Fabs demonstrated a wide range of antibody affinities (EC50s), ranging from <0.5 nM to >50 nM, see Figure 2C, below.
PNG
media_image1.png
162
245
media_image1.png
Greyscale
Based upon these teachings, it is submitted that one skilled in the art would be unable to readily envision which anti-CLDN18.2 x CD3 bispecific antibodies display an EC50 of 300 pM. Additionally although Applicant has disclosed three species within the genus claimed, given the substantial antibody structure variation within the claimed genus, as well as the high level of unpredictability in the art, the disclosure of three species comprised within the claimed genus is not sufficiently representative of the entire genus. Furthermore Applicant has not disclosed relevant, identifying characteristics of anti-CLDN18.2 X anti-CD3 bispecific antibodies that display an EC₅₀ of ≤ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells, because the instant specification does not provide structural antibody features that correlate with a functional ability to display an EC₅₀ of ≤ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells.
As indicated in the Non-Final Rejection, although screening techniques can be used to isolate CLDN18.2 X anti-CD3 bispecific antibodies that display an EC₅₀ of ≤ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description' requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
In conclusion one skilled in the art would not reasonably conclude that the inventors were in possession of the recited genus of anti-CLDN18.2 X anti-CD3 bispecific antibodies that display an EC₅₀ of ≤ 300 pM, as measured in a cell-based viability assay comprising combining CLDN18.2-positive human cells and human T cells. Therefore the rejection of the claim under 35 U.S.C. 112(a) have been maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NELSON B MOSELEY II whose telephone number is (571)272-6221. The examiner can normally be reached on M-F 9:00 am - 6:00 pm EST
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
Prosecution Insights