DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant is advised that the Final Rejection mailed December 2, 2025 is vacated. The Examiner inadvertently overlooked the after final amendment filed 11/03/2025. Therefore, the following Non-final rejection is set forth which is the same as the Office Action mailed on 12/02/2025.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on October 27, 2025 has been entered.
The Applicant’s amendment filed October 27, 2025 is acknowledged.
Claims 1-17 are pending.
Claims 11-13 and 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-10 and 14 are currently under consideration.
Claims 1 and 2 are independent.
In view of Applicant’s amendment filed on October 27, 2025, the rejections under 35 USC § 102 and 103 as set forth in the Office Action mailed on August 29, 2025 are maintained as set forth below.
Interview Summary
In an Applicant-initiated interview with the attorneys of record, Andrew Baraniak and Weihong Hsing, on January 22, 2026, the rejection under 35 USC § 102 in the Office Action mailed on December 2, 2025 was discussed. No agreement was reached.
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.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 5, 6, and 14 stand rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yan et al. 2017 (WO2017205014A1, a reference of record).
Independent claim 1 is drawn to an isolated bispecific antibody or antigen-binding fragment thereof, wherein one arm of the bispecific antibody or antigen-binding fragment thereof comprises the native interchain disulfide bond between the CH1 and CL regions and the other arm of the bispecific antibody or antigen-binding fragment thereof comprises a non-native interchain disulfide bond between the CH1 and CL regions, wherein the non-native interchain disulfide is made by the one of the groups of amino acid substitution selected from:
(1) K133C and C220X in CH1, and F209C and C214X in CL;
(2) K133C and C220X in CH1, and K207C and C214X in CL;
(3) K133C and C220X in CH1, and I117C and C214X in CL;
(4) R133C and C131X in CH1, and K207C and C214X in CL;
(5) R133C and C131X in CH1, and I117C and C214X in CL;
(6) R133C and C131X in CH1, and L117C and C214X in CL;
(7) K133C and C220X in CH1, and L117C and C214X in CL;
(8) R133C and C131X in CH1, and F209C and C214X in CL;
(9) R133C and C131X in CH1, and V209C and C214X in CL; or
(10) K133C and C220X in CH1, and V209C and C214X in CL;
wherein X is selected from S, A or G.
Yan et al. teach a bispecific antibody, Antibody 3, which binds both Antigens A and B and comprises an heavy chain (HC) and light chain (LC) from each of Antibody 1 (H1 and L1) and Antibody 2 (H2 and L2) (e.g. see page 26, lines 27-28; page 27, lines 7-8; and Figures 2-4). In figure 3B (copied below), H1 and H2 both comprise a VH, a CH1, a CH2, and a CH3 region, and L1 and L2 both comprise a VL and a CL region (e.g. see page 26, line 30 – page 27, line 8). Yan et al. further teach that the HCs are derived from human lgG1 , lgG2, lgG3, or lgG4 (e.g. see page 2, lines 8-9) and that the LCs can be human lambda or kappa chains (e.g. see page 53, lines 18-20).
It is noted that Antibody 3 in figure 3B clearly has the native interchain disulfide bond between the CH1 and CL regions on the A-binding arm while the B-binding arm mutant interchain disulfide bonds. Yan et al. teach that the naturally occurring disulfide bridge between the HC and LC is indicated by a heavy line between the CH1 domain and the carboxy terminus of the LC (or CL) which is pointed out in the copy of Figure 3B below (e.g. see Page 26, lines 34-36).
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Annotated “Antibody 3” from Figure 3B of Yan et al. 2017 (WO2017205014A1).
Regarding these mutant disulfide bonds, Yan et al. further teach that in the DNA encoding the HC, mutations encoding a C220S alteration were made; and mutations encoding a C214S alteration were made in the DNA encoding the LC (e.g. see paragraph spanning pages 73 and 74). Together, these alterations completely eliminate the naturally occurring interchain disulfide bridge between the cysteine residues normally present at these positions. Further, the DNA encoding the HC with the C220S mutation was also mutated to encode a K133C mutation and the DNA encoding the LC with the C214S mutation was also mutated to encode an I117C or F209C mutation (e.g. see paragraph spanning pages 73 and 74).
Yan et al. explicitly teach that the cysteine substitutions K133C (CH1) - I117C (CLK) and K133C (CH1) - F209C (CLK) can mediate disulfide bond formation in a human IgG1 antibody which lack cysteine residues normally present at C220 (HC) and C214 (LC) (which form the naturally-occurring interchain disulfide bridge) (e.g. see page 76, lines 10-20).
It is noted that the HCs and LCs of the two bispecific antibody binding arms are derived from different antibodies (antibody 1 and antibody 2) which bind different antigens. Thus, their VH and VL regions will have different amino acid sequences which dictate their different antigen specificity.
Yan et al. further teach that the mixture of antibodies can be further purified, and the mixture can be formulated as is appropriate for its pharmaceutical use (e.g. see page 51, lines 25-26).
Therefore, claims 1, 5, 6, and 14 are anticipated by Yan et al.
The Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant argues that claims 1, 5, 6, and 14 are not anticipated by Yan et al. The Applicant argues that the elements disclosed in Yan are not disclosed in a way that is "arranged as in the claim." The Applicant further argues that the disclosure of Yan fails to provide a person skilled in the art the capability to envisage the claimed arrangement as encompassed by claim 1. The Applicant asserts that there is no disclosure in Yan to explicitly arrive at the claimed bispecific antibody of claim 1.
The Applicant further argues that Yan fails to describe these substitution pairs in the context of a bispecific antibody. The Applicant asserts that, instead, Yan discloses the presence of cysteine substitutions at positions 133 and 209 and 133 and 117 and explicitly concludes that the K133C-F209C and K133C-I117C pairings are unsuitable for forming new interchain disulfide bonds when used in combination with additional charged pairs, and as such, the pairings are unsuitable for forming a bispecific antibody (see, e.g., Table 20, Variants 12A-12D, 13A-13B, 14A-14B, 16A-16D). Thus, there is no disclosure in Yan of the actual formation of a bispecific antibody with the specific substitutions as outlined in items (1)-(10) of claim 1 in the HI and Li in the first arm of the bispecific antibody, wherein the second arm of the bispecific antibody comprising H2 and L2 does not comprise the amino acid substitutions of the first arm of the bispecific antibody.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s arguments that the elements disclosed in Yan are not disclosed in a way that is arranged as in the claim and that a person skilled in the art would not be capable of explicitly arriving at the claimed bispecific antibody of claim 1; note that Yan et al. teach, in a single embodiment, the HC mutations C220S and K133C and the LC mutations C214S and I117C or F209C all in combination in one antibody construct LC (e.g. see paragraph spanning pages 73 and 74). Together, these alterations completely eliminate the native interchain disulfide bridge between C220 and C214 and insert an non-native interchain disulfide bridge between residues 133 and 117 or 209 (e.g. see paragraph spanning pages 73 and 74; Figure 3B, and page 76, lines 10-20).
Further, contrary to the Applicant’s argument that Yan fails to describe these substitution pairs in the context of a bispecific antibody and one arm comprises the amino acid substitutions and the other does not; note that Yan et al. teach a bispecific antibody, Antibody 3, that comprises the mutant interchain disulfide bond on one arm and the native interchain disulfide bond on the other (e.g. see figure 3B, copied above, and page 26, lines 34-36).
Finally, regarding the Applicant’s arguments that Yan et al. does not disclose the actual formation of a bispecific antibody with the specific substitutions as outlined in items (1)-(10) of claim 1; is noted that a reference is no less anticipatory if, after disclosing the invention, the reference then disparages it. The question whether a reference "teaches away" from the invention is inapplicable to an anticipation analysis. See MPEP 2131.05.
Nonetheless, in response to the Applicant’s arguments that the K133C-F209C and K133C-I117C pairings are unsuitable for forming a bispecific antibody, pointing to the variants in Table 20 of Yan et al., because Yan et al. explicitly concludes that the parings are unsuitable for forming new interchain disulfide bonds when used in combination with additional charged pairs; it is noted that these features upon which applicant relies (i.e., mutations in both arms of the bispecific antibody (i.e. those in table 20) and “in combination with additional charged pairs”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See MPEP 2145 VI. This is applicable to the Applicant’s arguments that Yan et al. teaches that the K133C-F209C and K133C-I117C pairings are unsuitable for forming new interchain disulfide bonds when used in combination with additional charged pairs. These charged pairs are not recited in the claims.
Furthermore, regarding the Applicant’s argument that Yan et al. explicitly teach that the K133C-F209C and K133C-I117C pairings are unsuitable for forming a bispecific antibody based on variants 12A-12D, 13A-13B, 14A-14B, 16A-16D in Table 20; it is noted that these variants do not comprise the native disulfide bridge between C220 and C214 and instead comprise another non-native disulfide bridge, such as the F170C-S162C paring in variant 12A, in the arm of the bispecific antibody that does not comprise the K133C-F209C or K133C-I117C pairings. Thus, the Applicant’s arguments related to these variants of Yan et al.’s disclosure not forming bispecific antibodies are not commensurate in scope with the claims. The instant claims are drawn to a genus of bispecific antibodies that encompass those that comprise the native disulfide bridge between C220 and C214 on the arm of the bispecific antibody that does not comprise the K133C-F209C or K133C-I117C pairings.
As such, the applicant’s arguments have not been found persuasive.
Thus, the rejection under 35 U.S.C. 102(a)(1) to claims 1, 5, 6, and 14 is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 2 stands rejected under 35 U.S.C. 103 as being unpatentable Yan et al. 2017 (WO2017205014A1, a reference of record) in view of Raum et al. 2017 (US20170037130A1, a reference of record) for the reasons of record.
The Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant arguments are substantially the same as those made for the 102 rejection above and so is the Examiner’s response.
As such, the applicant’s arguments have not been found persuasive.
Thus, the rejection under 35 U.S.C. 103 to claim 2 is maintained.
Claim 3 stands rejected under 35 U.S.C. 103 as being unpatentable Yan et al. 2017 (WO2017205014A1, a reference of record) in view of Piccione et al. 2015 (mAbs 7:5, 946-956, a reference of record) for the reasons of record.
The Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant arguments are substantially the same as those made for the 102 rejection above and so is the Examiner’s response.
As such, the applicant’s arguments have not been found persuasive.
Thus, the rejection under 35 U.S.C. 103 to claim 3 is maintained.
Claim 7 stands rejected under 35 U.S.C. 103 as being unpatentable Yan et al. 2017 (WO2017205014A1, a reference of record) in view of Carter et al. 2018 (US20180177873A1, a reference of record) for the reasons of record.
The Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant argues that Yan explicitly teaches away from the instantly claimed bispecific antibodies, as Yan merely discloses the presence of cysteine substitutions at positions 133 and 209 and 133 and 117, and explicitly concludes that the K133C-F209C and K133C-I117C pairings are unsuitable for forming new interchain disulfide bonds when used in combination with additional charged pairs, and as such, the pairings are unsuitable for forming a bispecific antibody.
This is not found persuasive for the following reasons:
In response to the Applicant’s arguments that the K133C-F209C and K133C-I117C pairings are unsuitable for forming a bispecific antibody because Yan et al. explicitly concludes that the K133C-F209C and K133C-I117C pairings are unsuitable for forming new interchain disulfide bonds when used in combination with additional charged pairs; it is noted that variants disclosed by Yan et al. that comprise charged pairs, such as Table 20, and do not form bispecific antibodies are not commensurate in scope with the claims. These variants do not comprise the native disulfide bridge between C220 and C214 and instead comprise another non-native disulfide bridge, such as the F170C-S162C paring in variant 12A, in the arm of the bispecific antibody that does not comprise the K133C-F209C or K133C-I117C pairings. Furthermore, Yan et al. does not teach the charged pairs recited in instant claim 7 and therefore does not teach that they are not suitable for forming bispecific antibodies. Thus, Yan et al. does not discourage the K133C-F209C or K133C-I117C pairings in combination with any charged pairs in general, but instead discourages a very specific set of charged pairs which do not encompass those that are recited in instant claim 7.
As such, the applicant’s arguments have not been found persuasive.
Thus, the rejection under 35 U.S.C. 103 to claim 7 is maintained.
Claims 8 and 10 stand rejected under 35 U.S.C. 103 as being unpatentable Yan et al. 2017 (WO2017205014A1, a reference of record) in view of Piccione et al. 2015 (mAbs 7:5, 946-956, a reference of record) and Nagai et al. 2015 (Monoclonal Antibodies Immunodiagn. Immunother. 34, 3; 181-190, a reference of record) for the reasons of record.
The Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant arguments are substantially the same as those made for the 102 rejection above and so is the Examiner’s response.
As such, the applicant’s arguments have not been found persuasive.
Thus, the rejection under 35 U.S.C. 103 to claims 8 and 10 are maintained.
Conclusion
Claims 1-3, 5-8, 10, and 14 are rejected.
Claims 4 and 9 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 5:00 a.m. - 3:00 p.m. (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on (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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/GRACE H LUNDE/Examiner, Art Unit 1641 /CHUN W DAHLE/Primary Examiner, Art Unit 1641