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
Status of the Claims
1. Claims 1-17 are the original claims filed 9/26/2022. In the Preliminary Amendment of 11/5/2024, Claims 1-17 are canceled and new claims 18-44 are added. In the Response of 12/5/2025, Claims 18, 21-22, 24-27, 29, 33, and 40-44 are amended, and Claims 19-20, 23, 30-32, and 34-36 are canceled.
Claims 18, 21-22, 24-29, 33, and 37-44 are all the claims.
Applicants amendments to the specification raises new grounds for objection.
The Office Action is final.
Priority
2. USAN 17/914,432, filed 09/26/2022, is a National Stage entry of PCT/JP2021/013795, International Filing Date: 03/31/2021, claims foreign priority to JP 2020-062601, filed 03/31/2020.
Information Disclosure Statement
3. As of 2/13/2026, a total of eighteen (18) IDS are filed: 10/5/2022; 10/25/2022; 12/7/2022; 1/5/2023; 5/26/2023; 7/27/2023; 8/23/2023; 9/5/2023; 10/10/2023; 12/6/2023; 1/24/2024; 3/28/2024; 5/13/2024; 7/23/2024; 8/5/2024; 8/27/2024; 1/8/2025; and 12/5/2025. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
4. The objections to the disclosure because of informalities is withdrawn. Both clean substitute copy and marked-up copies of the specification are included with the Response.
a) The specification is amended to rectify the improper use of the term, i.e. BiaCore, Octet, Tris, BiTE, Superdex, HisTrap, Expi293, Chemidoc, Sepharose, FAST-FLOW, IN-FUSION, Tween, GRAPHPAD PRISM, ALPHAScreen, NCBI, UniProt, Megalign, which is a trade name or a mark used in commerce.
b) The specification is amended to delete the embedded hyperlink and/or other form of browser-executable code at [0172].
c) The specification is amended to insert a sequence identifier for those peptide sequences that are > 4 amino acids in length at [0073].
The substitute Sequence Listing is compliant under 37 CFR 1.821-1.825 and ST.25 file format.
Claim Objections
5. The objections to Claims 18-44 because of informalities is moot for the canceled claims and withdrawn for the pending claims.
a) Claims 18-44 are amended to replace the conditional phrase “capable of” with an affirmative phrase “that binds.”
b) Claims 18-44 are amended to recite “cysteine” for consistency throughout the claim set.
c) Claim 24 is amended to recite “at a concentration of the TCEP
d) Claims 29-36 tare amened to insert the term “or” between elements (a14) and (a15) for each of the respective generic claims.
e) Claims 29-36 are amended to recite “the same as or different from the antibody variable region of the first antigen- binding moiety” for consistency in claim drafting amongst the claims.
f) Claims 29-36 are amended to recite “same as or different” for consistency in claim drafting amongst the claims.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
6. The rejection of Claims 20-22 and 24-25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot for the canceled claims (Claims 20) and withdrawn for the pending claims.
a) Claim 20 is canceled and claim 21 is amended to delete the limitation "the CH1 region" and to depend from Claim 18.
b) Claim 21 is amended to replace "the population" with “a population.”
c) Claims 22 and 24-25 are amended to delete the limitation “about.”
Claim Rejections - 35 USC § 101
7. The rejection of Claims 18-44 under 35 U.S.C. 101 because the disclosed invention is inoperative and therefore lacks utility is moot for the canceled claims and withdrawn for the pending claims. The amendment of the claims to identify cysteine as the residue at EU numbering position 191 in claim 18 overcomes the rejection.
Double Patenting
8. The provisional rejection of Claims 18-44 on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 18/978,252 (reference application- yet to publish) is moot in view of the abandonment of the reference application effective and as corroborated on 8/5/2025.
9. The provisional rejection of Claims 18-44 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 10-11, 13-19, 21 of copending Application No. 17/264,388 (reference application 20220195045; now USPN 12435137) is withdrawn. None of the reference claims is drawn to a multispecific molecule where both the 1st and 2nd antigen binding domains has a 191Cys residue (EU numbering) and where the property of the cysteine residues is to confer that both antigens do not bind the respective antigens at the same time.
10. The provisional rejection of Claims 18, 21-22, 24-29, 33, and 37-44 on the ground of nonstatutory double patenting as being unpatentable over claims 26-29, 32-49 of copending Application No. 17/272,972 (reference application 20210388087) is moot for the canceled claims and withdrawn for the pending claims. None of the reference claims is drawn to a multispecific molecule where both the 1st and 2nd antigen binding domains has a 191Cys residue (EU numbering) and where the property of the cysteine residues is to confer that both antigens do not bind the respective antigens at the same time.
Rejections Withdrawn-in-Part/ Maintained-in-Part
Claim Rejections - 35 USC § 112(a)
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
11. The rejection of Claims 18, 21-22, 24-29, 33, and 37-44 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:
Moot for canceled claims: 19-20, 23, 30-32, and 34-36.
Withdrawn-in-Part The identification of the reducing agent as “TCEP” and cysteine as the residue at EU numbering position 191 in claim 18; deletion of the term “about”; deletion of the negative proviso “not in a hinge”. The argument that “contacting” corresponds to exposing in solution is corroborated by [0131] in the as-filed specification and in [0795] of US 20230121511.
Maintained-in-Part
A Claims 18, 21-22, 24-29, 33, and 37-40
i) The preamble of Claim 18 stating “a method for modifying disulfide bonds in an initial preparation” is interpreted as an initial preparation of a multispecific antigen binding molecule being “modified” following process steps to effectuate a change in disulfide bonds of the molecule. No such active step for a modification, for example, a substitution, insertion, deletion or any combination thereof for any residue is so much as claimed. There are no active modification steps made to the protein structure as claimed and that correspond to what is implied by the preamble. The initial population contains some amount or percentage of a pre-existing multispecific antigen binding molecule comprising 191Cys in both the 1st and 2nd antigen binding moieties but not in the 3rd antigen binding moiety.
If the meaning of a modified disulfide bond is defined in Figure 2b, then the cysteines are capped in one state and uncapped in another state via reduction using TCEP. Further, the meaning of “modification” at [0035] is for “one amino acid mutation” or at [0471] is for “modification by non-naturally occurring amino acids” or is for having a percent amino acid sequence identity for other proteins at [0916].
The specification teaches and supports modifications occurring to/ for amino acids of the invention at
[1175] In the present invention, amino acid residues subjected to modification are not limited to the above-mentioned amino acid residues of the antibody variable regions or the antibody constant regions. Those skilled in the art can identify the amino acid residues that form an interface in mutant polypeptides or heteromultimers by homology modeling and such using commercially available software; and amino acid residues of these positions can then be subjected to modification so as to regulate the association.
But what is claimed is disparate from what is seemingly the intended method invention, namely, a method for enriching or increasing (see Claim 21) from an initial population, a specific isoform subpopulation for a multispecific binding molecule. The claimed method allegedly uses TCEP to separate those isoform structures having paired 191Cys in the 1st and 2nd antigen binding moieties from the initial preparation comprising from two or more structural isoforms of the multispecific binding molecules that differ by a least one disulfide bond (see Claim 21). The product of the claimed process is the enrichment of the isoforms with inherent paired 191Cys residues in the first and second antigen-binding moieties, and not by the creation or production of the specific isoform. The instant claims recite a modification process for a disulfide bond whilst the method steps involve the treatment of various pre-existing isoforms comprising disulfide bonds with TCEP to select for a particular isoform having paired 191 Cys residues. Accordingly, it is not clear how the disulfide bonds are modified to obtain the product outcome of the process when the reducing step is transitional and the product is a non-redox state.
The method steps are incongruous with the intended outcome.
ii) Can the POSA obtain the enriched population of isoforms comprising the 191Cys paired multispecific binding molecules using only TCEP in the claimed method?
No, the POSA could not reasonably predict that the preferred species is selected exclusively by a reduction (TCEP de-cap step) followed by a re-oxidation (buffer exchange step).
Example 3.1 teaches chromatography specific methods using antibodies that bind selectively to cysteinyl forms of the antibody (i.e., DUAL/LINC vs unLINC).
[1190] As described in Example 2, an antibody preparation with engineered cysteine (e.g. trivalent 1+2 antibodies shown in FIG. 1, Table 2) comprises heterogenous population of antibody isoforms with engineered disulfide bond (“paired cysteine” or “LINC” form) and without the engineered disulfide bond (“unpaired cysteines” or “unLINC” form). To separate or remove these antibodies without the engineered disulfide bond (“unpaired cysteines” or “unLINC” form) from the antibody preparation, conformation-specific antibody that can specifically bind and/or capture the antibodies of “unpaired cysteines” form but does not bind the antibodies of “paired cysteines” form, can be generated as a tool antibody for use in affinity chromatography purification, analytical and/or quantification applications.
Example 3.4 teaches anti-CH1 antibodies that discriminate antibodies having unpaired cysteines from the antibody preparation
Example 3.4 Use of Conformation-Specific Anti-CH1 Antibodies for Removing Dual/LINC 1+2 Antibodies Having “Unpaired Cysteines” Form from the Antibody Preparation
[1206] The conformation-specific anti-CH1 antibodies described in Example 3.3 can be used as a ligand or binder to selectively capture or remove Dual/LINC 1+2 antibodies which are in “unpaired cysteines” form from an antibody preparation e.g. harvested from cell culture supernatant. For example, conformation-specific anti-CH1 antibodies can be immobilized to a column for removing Dual/LINC 1+2 antibodies which are in “unpaired cysteines” form from the antibody preparations using affinity purification.
[1207] Conformation-specific anti-CH1 antibody, FAB0133Hh/FAB0133L0001; and Dual/LINC 1+2 antibody, DLL3-DualAE05/DualAE05-FF056 were transiently transfected and expressed using Expi293 Expression system (Thermo Fisher Scientific). The format of the DLL3-DualAE05/DualAE05-FF056 has a molecular format shown in FIG. 8a and comprises five polypeptide chains represented by amino acid sequences of SEQ ID NO: 142 (Chain 1), SEQ ID NO: 147 (Chain 2), SEQ ID NO: 148 (Chain 3) and SEQ ID NO: 157 (Chain 4 & 5). Cell culture supernatants were harvested, and antibodies were purified from the supernatants using MabSelect SuRe affinity chromatography (GE Healthcare) followed by gel filtration chromatography using Superdex200 (GE Healthcare).
[1208] For affinity purification, NHS Sepharose resins conjugated with the purified FAB0133Hh/FAB0133L0001 were packed into XK 16/20 column (GE Healthcare). After protein A chromatography treatment, antibody preparation of DLL3-DualAE05/DualAE05-FF056, was applied to the XK 16/20 column to allow specific capturing/binding of DLL3-DualAE05/DualAE05-FF056 which is in “unpaired cysteines” form onto the column, wherein DLL3-DualAE05/DualAE05-FF056 antibodies which are in “paired cysteines” form will not be captured or bound by the column and appear predominantly in the flow through fractions. Subsequently, the affinity captured DLL3-DualAE05/DualAE05-FF056 which is in “unpaired cysteines” form was eluted by treatment with 50 mM HCl. FIG. 10 shows chromatography profile (FIG. 10a) and non-reducing SDS-PAGE analysis (FIG. 10b) of the eluted antibodies in affinity purification of DLL3-DualAE05/DualAE05-FF056 using conformation-specific anti-CH1 antibody FAB0133Hh/FAB0133L0001 column. Specifically, the flow-through fractions comprise high purity of DualAE05/DualAE05-FF056 which is in “paired cysteines” or “LINC” form (flowthrough: white bar) as indicated by one predominant protein band which migrates faster in the non-reducing SDS-PAGE analysis (Lanes 1 to 13); wash fractions comprise mixture of DualAE05/DualAE05-FF056 which is in “unpaired cysteines” form and DualAE05/DualAE05-FF056 which is in “paired cysteines” form (wash: gray bar, Lanes 14 to 19); and eluted fractions comprise predominantly DualAE05/DualAE05-FF056 which is in “unpaired cysteines” form (acid elution: black bar) as indicated by one predominant protein band which migrates slower in the non-reducing SDS-PAGE analysis (Lanes 20 to 23).
The POSA could reasonably conclude that Applicants are not in possession of the full breadth and scope of the instant claimed method at the time of filing.
B Claims 18, 21-22, 24-29, 33, and 37-44
Applicants allege the concept of a “dual antigen binding domain” that each binds to different antigens but not at the same time, is supported in the specification.
All of the generic claims 18, 41 and 42 require of the 1st and 2nd antigen binding moieties of the multispecific binding molecules that they “not bind both antigens at the same time”. The claims identify no other structural properties of the 1st and 2nd antigen binding moieties other than being a Fab molecule (Claim 18) and sharing 191Cys residues (EU numbering; Claims 18, 40 and 41). Neither composition claims 41-42 identify a Fab structure as is required of the process used to make the same product of those compositions.
The specification identifies critical structures that need to met for a predictable assembly of the molecule and reduced undesirable crosslinking much less that confer a cis mode:
[0450] FIG. 2a is an illustration to depict that LINC-Ig technology in 1+2 format can reduce toxicity. LINC-Ig (comprises “LINC”, i.e. the engineered disulfide bond at e.g. CH1 region) can restrict antigen binding of the antibody shown in FIG. 1(a) primarily to cis mode i.e. binding to antigens present on the same immune cell. In contrast, (1+2) trivalent format without the engineered disulfide bond shown in FIG. 1(b) could result in trans antigen-binding mode i.e. binding of the antibody of FIG. 1(b) to antigens present on two different immune cells. This may cause cross-linking of two immune cells independent of tumor antigen binding which could increase toxicity.
[0035] … binding to the first antigen and/or a second antigen comprise at least one amino acid mutation(s) respectively, which create a disulfide linkage between the first and second antigen-binding moieties to hold them close to each other, and, for example, promote cis-antigen binding to the same single effector cell as a result of steric hindrance or shorter distance between the two Dual-Fabs, thereby improving the safety profile of the trispecific antibody (trispecific Ab) by preventing undesirable crosslinking of two CD3/CD137-expressing immune cells mediated by the two Dual-Fabs in an DLL3-independent manner.
[1183] CD137 receptor clustering is critical for efficient agonistic activity. To improve cytotoxicity, binding number to CD137 molecules is increased through designing a new trivalent antibody format named as DUAL/LINC, 1+2 (FIG. 1(a), Table 2). Specifically, the new antibody format is a trivalent tri-specific antibody with “1+2” format which comprises two monovalent Dual-Fabs each capable of binding to one CD3 or CD137 but not simultaneously (FvB and FvC of FIG. 1, prepared in Reference Example 3) and one monovalent tumor-antigen binding arm (FvA of FIG. 1), wherein one disulfide bond (“LINC”) is introduced/engineered between the two Dual-Fabs by introducing a cysteine substitution e.g. at the 191 position (S191C with Kabat numbering) of the CH1 domain of each of the two Dual-Fabs (FIG. 1a). Without wishing to be bound by a theory, we envisioned that such engineered disulfide bond (“LINC”) would restrict the antigen (CD3 or CD137) binding orientation of the two Dual-Fabs to cis antigen-binding (i.e. binding to two antigens on the same cell) as a result of steric hindrance or shorter distance between the two Dual-Fabs, thereby improving the safety profile of the trispecific Ab by preventing undesirable crosslinking of two CD3/CD137-expressing immune cells mediated by the two Dual-Fabs in an tumor antigen-independent manner (FIG. 2a). Fc region was Fc gamma R silent and deglycosylated. The target antigen of each Fv region and naming rule of each binding domain in the trispecific antibodies are shown in Table 2 a) and the SEQ ID NOs are shown in Table 2 b) and c).
MPEP 2163 II(A)(3)(a)
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that inventor was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that “if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function”.). “Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.” Id.
Applicants demonstrated limited examples of Cys191 DUAL-FABs that bind to different antigens but not at the same time as discussed in the previous Office Action. Applicants have not demonstrated that a 191Cys in the dual Fab antigen binding moieties is what confers those two functions for the genus of all antibodies. Notably no sequences are claimed for a full Cys191 DUAL-Fab that possess the properties of steric hindrance or shorter distance between the Dual-Fabs in order to achieve a cis-antigen binding Dual-Fab that is the preferred isoform of the invention, i.e., that bind to different antigens but not at the same time.
Summary
The method steps of claim 18 are bereft of details. The method steps (claim 18) and the compositions (claims 41-42) are indefinite and lacking in support as set forth above for the phrase “does not bind both antigens at the same time” absent a defined structure/function correlation for specific features of the antibodies that “do not bind both antigens at the same time”. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
The POSA could reasonably conclude that Applicants were not in possession of the claimed method invention based on each of the separate and combined analyses above, that substantiate the absence of a structure/function correlation for the claimed inventions.
The rejection is maintained.
Rejections Maintained
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.
12. The rejection of Claims 18, 21-22, 24-29, 33, and 37-44 on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 11274151 is moot for the canceled claims and maintained for the pending claims. The reference patent is not afforded safe harbor under 35 USC 121 because it does not share continuity or a restriction/speciation with the claims of the instant application.
Ref claims read on and anticipate the product produced by the claimed process (claim 18) and the compositions of claims 41-42 by reciting
Ref 6. The multispecific antigen-binding molecule of claim 4, wherein each of the first and second antigen-binding moieties is a Fab that has a cysteine residue at EU numbering position 191, and wherein a disulfide bond links these two cysteine residues.
Ref 7. The multispecific antigen-binding molecule of claim 5, wherein each of the first and second antigen-binding moieties is a Fab that has a cysteine residue at EU numbering position 191, and wherein a disulfide bond links these two cysteine residues.
Ref +8. The multispecific antigen-binding molecule of claim 6, wherein each of the first, second and third antigen binding moieties is in the form of a Fab comprising a VH, a VL, a CH1 domain and a light chain constant (CL) domain, and wherein the C-terminus of the CH1 domain of the third antigen-binding moiety is fused, directly or via a peptide linker, to the N-terminus of the VH of either the first antigen binding moiety or the second antigen binding moiety.
9. The multispecific antigen-binding molecule of claim 7, wherein each of the first, second and third antigen binding moieties is in the form of a Fab comprising a CH1 domain and a light chain constant (CL) domain, and wherein the C-terminus of the CH1 domain of the third antigen-binding moiety is fused, directly or via a peptide linker, to the N-terminus of the VH of either the first antigen binding moiety or the second antigen binding moiety.
Instant claims 18and 21 and 41-42 are drawn to the multispecific molecule comprising an isoform having a disulfide bond between cysteine residues at EU numbering position 191 in each of the 1st and 2nd binding moieties of the molecule.
13. The rejection of Claims 18, 21-22, 24-29, 33, and 37-44 on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 11718672 is moot for the canceled claims and maintained for the pending claims. The reference patent is not afforded safe harbor under 35 USC 121 because it does not share continuity or a restriction/speciation with the claims of the instant application.
Ref claims read on and anticipate the product produced by the claimed process (claim 18) and the compositions of claims 41-42 by reciting
Ref 5. The pharmaceutical composition of claim 3, wherein each of the first and second antigen-binding moieties is a Fab that has a cysteine residue at EU numbering position 191, and wherein a disulfide bond links these two cysteine residues.
Ref 6. The pharmaceutical composition of claim 4, wherein each of the first and second antigen-binding moieties is a Fab that has a cysteine residue at EU numbering position 191, and wherein a disulfide bond links these two cysteine residues.
Ref 7. The pharmaceutical composition of claim 5, wherein each of the first, second and third antigen binding moieties is in the form of a Fab comprising a VH, a VL, a CH1 domain and a light chain constant (CL) domain, and wherein the C-terminus of the CH1 domain of the third antigen-binding moiety is fused, directly or via a peptide linker, to the N-terminus of the VH of either the first antigen binding moiety or the second antigen binding moiety.
Ref 8. The pharmaceutical composition of claim 6, wherein each of the first, second and third antigen binding moieties is in the form of a Fab comprising a CH1 domain and a light chain constant (CL) domain, and wherein the C-terminus of the CH1 domain of the third antigen-binding moiety is fused, directly or via a peptide linker, to the N-terminus of the VH of either the first antigen binding moiety or the second antigen binding moiety.
Instant claims 18 and 21 and 41-42 are drawn to the multispecific molecule comprising an isoform having a disulfide bond between cysteine residues at EU numbering position 191 in each of the 1st and 2nd binding moieties of the molecule.
14. The provisional rejection of Claims 18, 21-22, 24-29, 33, and 37-44 on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of copending Application No. 19/277,602 (reference application- yet to publish) is moot for the canceled claims and maintained for the pending claims. The reference application is not afforded safe harbor under 35 USC 121 because it does not share continuity or a restriction/ speciation with the claims of the instant application.
Ref claims read on and anticipate the product produced by the claimed process (claim 18) and the compositions of claims 41-42 by reciting
Ref 4. The multispecific antigen-binding molecule of any one of claims 1 to 3, wherein each of the first antigen-binding moiety and the second antigen-binding moiety is a Fab molecule and comprises at least one disulfide bond formed between the CH1 region of the first antigen-binding moiety and the CH1 region of the second antigen-binding moiety.
Ref 5. The multispecific antigen-binding molecule of claim 4, wherein each of the first antigen- binding moiety and the second antigen-binding moiety is a Fab molecule and comprises one disulfide bond formed between the amino acid residues at position 191 according to EU numbering in the respective CH1 region of the first antigen-binding moiety and the second antigen-binding moiety.
Ref 6. The multispecific antigen-binding molecule of any one of claims 1 to 5, wherein each of the first, second and third antigen binding moiety is a Fab molecule, wherein the third antigen binding moiety is fused at the C-terminus of the Fab heavy chain (CH1) to the N- terminus of the Fab heavy chain of either one of the first antigen binding moiety or the second antigen binding moiety, optionally via a peptide linker.
Instant claims 18 and 21 and 41-42 are drawn to the multispecific molecule comprising an isoform having a disulfide bond between cysteine residues at EU numbering position 191 in each of the 1st and 2nd binding moieties of the molecule.
15. The provisional rejection of Claims 18, 21-22, 24-29, 33, and 37-44 on the ground of nonstatutory double patenting as being unpatentable over claims 19-20 of copending Application No. 18/696,717 (reference application 20240400721) is maintained. The reference application is not afforded safe harbor under 35 USC 121 because it does not share continuity or a restriction/ speciation with the claims of the instant application.
Ref claims read on and anticipate the product produced by the claimed process (claim 18) and the compositions of claims 41-42 by reciting
Ref 19. (New) The method of claim 17, wherein each of the first and second antigen-binding moieties is a Fab comprising a CHI domain with a cysteine residue at EU numbering position 191, wherein a disulfide bond links the two cysteine residues.
Ref 20. (New) The method of claim 18, wherein each of the first and second antigen-binding moieties is a Fab comprising a CHI domain with a cysteine residue at EU numbering position 191, wherein a disulfide bond links the two cysteine residues.
Ref 21. (New) The method of claim 17, wherein each of the first, second and third antigen binding moieties is a Fab comprising a heavy chain comprising a VH and a CH1 domain and a light chain comprising a VL and a light chain constant (CL) domain, and the C-terminus of the Fab heavy chain of the third antigen binding moiety is fused, directly or via a peptide linker, to the N-terminus of the Fab heavy chain of either the first antigen binding moiety or the second antigen binding moiety.
Instant claims 18 and 21 and 41-42 are drawn to the multispecific molecule comprising an isoform having a disulfide bond between cysteine residues at EU numbering position 191 in each of the 1st and 2nd binding moieties of the molecule.
16. The provisional rejection of Claims 18, 21-22, 24-29, 33, and 37-44 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 17/797,540 (reference application 20230348528) are moot for the canceled claims and maintained for the pending claims. The reference application is not afforded safe harbor under 35 USC 121 because it does not share continuity or a restriction/ speciation with the claims of the instant application. For purposes of brevity, see the provisional rejection of the claims with the reference application in the Office Action for USAN 17/797,540 under section 9 pp. 4-5 of 13 (1/30/2026; PTO 892 form).
17. The provisional rejection of Claims 18, 21-22, 24-29, 33, and 37-44 on the ground of nonstatutory double patenting as being unpatentable over claims 16, 18-37 of copending Application No. 17/280,239 (reference application 20220112296; USPN 12509524; claims 1-21) is moot for the canceled claims and maintained for the pending claims. The reference application/patent is not afforded safe harbor under 35 USC 121 because it does not share continuity or a restriction/ speciation with the claims of the instant application.
Ref claims read on and anticipate the product produced by the claimed process (claim 18) and the compositions of claims 41-42 by reciting
Ref 1. An antigen-binding molecule comprising: (i) a first antigen-binding domain comprising a first heavy chain variable (VH) region, a first heavy chain constant (CH1) region, a first light chain variable (VL) region, and a first light chain constant (CL) region; and (ii) a second antigen-binding domain comprising a second VH region, a second CH1 region, a second VL region, and a second CL region; and (iii) a third antigen-binding domain comprising a third VH region and a third VL region, wherein the antigen-binding molecule further comprises one or more of the following; at least one bond between an amino acid residue in the first CH1 region and an amino acid residue in the second CH1 region, at least one bond between an amino acid residue in the first CL region and an amino acid residue in the second CL region, at least one bond between an amino acid residue in the first CH1 region and an amino acid residue in the second CL region, and at least one bond between an amino acid residue in the first CL region and an amino acid residue in the second CH1 region; wherein the first antigen-binding domain is linked to the second antigen-binding domain via an Fc region, a disulfide bond, or a linker, wherein the first antigen-binding domain binds to a first antigen and to a second antigen different from the first antigen, but does not bind to both the first and second antigens at the same time when the first and second antigens are expressed on cell membranes of separate cells, wherein the third antigen-binding domain binds to a third antigen that is different from the first and second antigens; wherein the third antigen-binding domain is linked to one of the following: the first antigen-binding domain, the second antigen-binding domain, or an Fc region; and wherein either (a) or (b) is true; (a) the second antigen-binding domain binds to the first antigen and to the second antigen, but does not bind to both the first and second antigens at the same time when the first and second antigens are expressed on cell membranes of different cells; or (b) the second antigen-binding domain binds to either the first antigen or the second antigen, and not to the other.
Ref 3. The antigen-binding molecule of claim 1, wherein the first antigen-binding domain and the second antigen-binding domain are linked via an Fc region.
Ref 6. The antigen-binding molecule of claim 1, wherein the at least one bond is a disulfide bond, wherein the first antigen-binding domain comprises a heavy chain hinge region, wherein the second antigen-binding domain comprises a heavy chain hinge region, and wherein the first antigen-binding domain and the second antigen-binding domain are linked to each other by one or more native disulfide bonds between their respective hinge regions.
Ref 7. The antigen-binding molecule of claim 1, wherein the amino acid residue at EU numbering position 191 in the first CH1 region forms a bond with the amino acid residue at EU numbering position 191 in the second CH1 region.
Instant claims 18 and 21 and 41-42 are drawn to the multispecific molecule comprising an isoform having a disulfide bond between cysteine residues at EU numbering position 191 in each of the 1st and 2nd binding moieties of the molecule.
New Grounds for Objection
Specification
18. The disclosure is objected to because of the following informalities:
a) The substitute specification filed 12/5/2025 is objected to because the line spacing is too closely crowded together. According to MPEP 608.01 and 37 CFR 1.52(b)(2), the specification, including claims and abstract, must be formatted with lines that are 1-1/2 or double-spaced to ensure readability and allow for examiner annotations.
Appropriate correction is required.
Conclusion
19. No claims are allowed.
20. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643