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 .
2. Applicant’s response filed on 11/07/2025 is acknowledged.
3. Applicant’s election without traverse of Group I, claims 1-20 in the reply filed on 11/07/2025 is acknowledged.
4. Claim 21 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/07/2025.
5. Claims 1-20 are under consideration for their full scope.
6. Applicant’s IDS documents filed on 04/04/2023, 04/14/2023 and 11/07/2025 have been considered.
7. The listing of references in the specification at paragraphs [0009[-[0010] is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
8. 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.
9. Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18, 21-22, 24-29, 33 and 37-40 of copending Application No. 17/914,432 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims are directed to a method for modifying disulfide bonds in an initial preparation of a multispecific antigen binding molecule, the method comprising providing an initial preparation comprising multiple structural isoforms of the multispecific antigen binding molecule and contacting the initial preparation with tris (2-carboxyethyl)phosphine (TCEP), thereby producing a modified preparation of the multispecific antigen binding molecule, wherein the multispecific antigen binding molecule comprises:(a) a first antigen-binding moiety and a second antigen-binding moiety, wherein each of the first and second antigen-binding moieties is a Fab molecule that binds to a first antigen and a second antigen different from the first antigen, but does not bind both antigens at the same time, and each of the first and second antigen-binding moieties comprises a cysteine residue at EU numbering position 191; and (b) a third antigen-binding moiety that is a Fab or scFv that binds to a third antigen different from the first and second antigens, wherein the third antigen- binding moiety is fused to either the first antigen binding moiety or the second antigen binding moiety of claim 18; wherein the initial preparation comprises two or more structural isoforms that differ by at least one disulfide bond, including a disulfide bond formed between cysteine residues at EU numbering position 191 of each of the first and second antigen-binding moieties, and wherein the contacting with the TCEP preferentially enriches or increases a population of a structural isoform having a disulfide bond between cysteine residues at EU numbering position 191 of each of the first and second antigen-binding moieties of claim 21; wherein the pH of the TCEP is within the range of 6-8 of claim 22; wherein the TCEP is contacted with the initial preparation at a concentration of the TCEP in the range of 0.01 mM to 100 mM of claim 24; wherein the concentration of the multispecific antigen binding molecule in the initial preparation is in the range of 0.1 mg/ml to 50 mg/ml of claim 25; further comprising removing the TCEP from the modified preparation, thereby promoting formation of cysteine disulfide bonds of claim 26; the TCEP is removed from the modified preparation by dialysis or buffer exchange of claim 27; and wherein the multispecific antigen binding molecule further comprises a Fc region of claim 40.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112
10. 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.
11. Claims 9, 12-13 and 17 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.
The term “about” in claims 9, 12-13 and 17 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Correction is required.
12. 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.
13. Claims 1-20 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 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 has not adequately described a method of producing an antibody preparation wherein antibody structural isoforms which differ by at least one disulfide bond are produced by the method recited in claim 1 wherein the antigen binding domains are capable of being linked with each other via at least one disulfide bond between amino acid residues which are not in the hinge region. Disulfide bonds in a VH and/or VL domain would have unpredictable consequences for the antigen binding.
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 has neither demonstrated a structure function relationship nor provided a representative number of species of antibodies with the recited binding specificity or many recited functions.
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.
One of ordinary skill in the art skilled could not predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. A person of ordinary skill cannot visualize or otherwise predict, what a VH or VL with a particular set of functional properties would look like structurally based on the instant claimed method steps.
Minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, (PTO-892; Reference U) teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (In particular, page 1172, left col and Table 1a). Sulea (PTO-892; Reference V) teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (In particular, Abstract). Hasegawa et al. (PTO-892; Reference W) reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (In particular, whole document). Altshuler et al. (PTO-892; Reference X) teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (In particular, page 1600, col. 1).
As such, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antigen binding molecule, without increasing, eliminating, or in some way altering antigen binding.
Researchers are still unable to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” (In particular, page 226, col. 2 of Vajda et al (PTO 892; Page 2; Reference U)
Researchers are still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” Marks et al (PTO-892; Page 2; Reference V) (In particular, page 9831, col. 2). Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” Akbar et al. (PTO-892; Page 2; Reference W) (In particular, page 2, col. 2). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See Lo et al (PTO 892; Page 2; Reference X) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
As such, there is insufficient written description of the required kind of structure identifying information about the corresponding makeup of the claimed antibodies produced by the method to demonstrate possession.
14. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
15. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
16. Claims 1, 3-5, 9-11, 15, 17 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/232088 (IDS filed on 04/04/2023; Reference FP25).
WO 2018/232088 teaches an antibody comprising an IgG heavy chain constant region and light chain constant region wherein said antibody comprises a cysteine at residue 162 in the CH1 domain (In particular, claim 1). The reference teaches the method of preparation of antibody-peptide bioconjugates as follows; an antibody containing the engineered cysteine residues is reduced by dithiothreitol (DTT) under the condition of pH 7.5 room temperature for 16 hours (example 3). The residue 162 in the CH1 domain is not in a hinge region.
It is reasonable to conclude that the Cys residue 162 in the CH1 domain of a first antigen-binding domain is linked with another Cys residue in a second antigen-binding domain because the substitution to Cys at residue 162 in the CH1 domain stabilizes the Fab-Fab dimers (see Table 5 in D3).
The reference teachings anticipate the claimed invention.
17. Claims 1, 3-5, 9-11, 15, 17 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2016/040856 (IDS filed on 04/04/2023; Reference FP21).
WO 2016/040856 teaches antibodies which are substituted to Cys at every position. Each antibody is separately conjugated to linker drugs and the list is shown in Table 3. The method of preparation of conjugates is also taught as follows: Each antibody was reduced in the presence of dithiothreitol in buffer overnight with agitation at room temperature, the reducing agent and any cysteine or glutathione blocks were purified away by washing, the antibody was allowed to reoxidize, and the linker drug (either MC-vc-PAB-MMAE or PDS-MMAE) was added and incubated([00269]-[00284]).
A158C (Kabat Numbering) of Table 3 in WO 2016/040856 corresponds to A162C (EU numbering). It is reasonable to conclude that the Cys residue 158 in the CH1 domain of a first antigen-binding domain is linked with another Cys residue in a second antigen -binding domain because the substitution to Cys at residue 158 in the CH1 domain stabilizes the Fab-Fab dimers. The positions of mutation to Cys in the instant application include the position of mutation to Cys in WO 2016/040856, so the method for producing an antibody in WO 2016/040856 would also inherently prepare structural isoforms.
The reference teachings anticipate the claimed invention.
18. No claim is allowed.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NORA MAUREEN ROONEY whose telephone number is (571)272-9937. The examiner can normally be reached on M-F from 8:00am 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 10, 2026
/Nora M Rooney/
Primary Examiner, Art Unit 1641