DETAILED ACTION
1. 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 amendment filed on March 16, 2026 is acknowledged.
Note that applicant’s original election was Group I and the species of K409W in one CH3 and F405R in the other CH3 an no other substitutions in the constant regions (see Response filed on September 14, 2023).
The Examiner upon further consideration extended search and examination to cover following species:
One CH3 other CH3
K409W F405R
K409W F405A
After two RCE filings, applicant now amended the claims and added additional previously withdrawn substitutions to the independent claim 1 after a third RCE filing, resulting additional Request for Restriction/Election (mailed on September 15, 2022).
In response applicant elects:
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Given that applicant has already received several Office Actions regarding the originally elected invention and in view of applicant’s own election set forth above, the only claims recite 1st CH3 having K409W and S364K and 2nd CH3 having F405R/A and K370S would be under consideration.
Claims 2, 3, 5-17, 19, 20, 29-42, 45-48, and 50 have been canceled.
Claims 1, 4, 18, 21-28, 43, 44, and 49 are pending.
Claims 21-28, 43, 44, and 49 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected invention/species.
Claims 1, 4, and 18 are currently under consideration as they read on the elected invention described above.
3. 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.
4. 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.
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.
5. Claims 1, 4, and 18 stand rejected under 35 U.S.C. 103 as being unpatentable over Neijseen et al. (WO 2012/143524) in view of Bernett et al. (US 2015/0307629, published on October 29, 2015 and filed on March 20, 2015) for the reasons of record.
Neijseen et al. teach an IgG bispecific antibody that binds HER2 and CD3 antigens comprising two full length Fc regions, each having CH3 domains and wherein the CH3 domains consists of K409 substituted with any other naturally occurring amino acid residues and show that K409R and K409W both show high Fab-arm exchange indicating bispecific antibody formation (e.g. see Example 33 in page 148). Neijseen et al. further selected K409R to combine with F405X (substituted F405 to any other naturally occurring amino acid residues)(e.g. see Table 17 in page 150). Neijseen specifically teach a mutation at position 405 in one CH3 and a mutation at position 409 in the other CH3 (e.g. see page 6). Neijseen further teaches IgG1-K409X wherein position K409 was changed to all other eighteen amino acid residues and shows that K409W has high Fab-arm exchange indicating high bispecific antibody formation and K409F shows intermediate Fab-arm exchange (e.g. see Example 33 in pages 148-149). Neijseen further chose K409R substitution (also high Fab-arm exchange) to combine with F405X in Example 35 in pages 149-150.
Given that Neijseen et al. teach that K409W and K409R both can induce high Fab-arm exchange –feature desired in bispecific antibody formation, and since F405K and K409R pair was known to induce high bispecific antibody formation by Neijseen et al., an ordinary skill in the art would have been motivated to simply substitute K409R in the F405X/K409R pair with K409W to produce bispecific antibody. Given that K409W was shown to have the same high Fab-arm exchange as K409R (disclosed by Neijseen in Example 33 in pages 148-149), it would have been obvious for one of ordinary skill in the art at the time the invention was filed to replace K409R with K409W and combine it with IgG1-F405X the same way as shown in Example 35 of Neijseen and achieve the result of K409W-F405R for enhanced bispecific antibody formation. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since Neijseen et al. teach both K409R and K409W can promote high bispecific antibody formation. As such, simple substitution of K409R with K409W to pair with F405X would be expected to produce F405R and K409W pair and would inherently have function of bispecific antibody formation.
Neijseen et al. further teach in one embodiment, the first Fc has an amino acid substitution in at position 409 and the second Fc-region has an amino acid substitution at a position selected from the group consisting of: 366, 368, 370, 399, and 405 (e.g. see 72).
The reference teachings differ from the instant invention by not describing K409W and F405R and additionally S364K and K370S.
Bernett et al. teach skew variants that can be used in “plug and play” format in that the effects of the variants transfer into different antibodies with different antigen binding region easily and are very stable (e.g. see [0078]) and FIG. 34. Specifically, Bernett et al. teach skew variants having 368D/370S substitutions paired with S364K/E357Q (e.g. see left col. in page 19) and the skew variants can skew the formation of heterodimers over homodimers (e.g. see [0113]). Bernett et al. also teach K409R is part of the structure of steric variants that skew the formation towards heterodimerization (e.g. see [0112] and [0192]).
It would thus be obvious to one of ordinary skill in the art at the time the instant invention was filed to combine the reference teachings to produce a bispecific antibody targeting two different antigens having a first modified CH3 domain and a second modified CH3 domain comprising modified amino acid pairs, wherein modified amino acid pairs comprises K409W/F405R and S364K/K370S. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, this is because Neijseen et al. teach both K409R and K409W can promote high bispecific antibody formation which motivates a simple substitution of K409R with K409W to pair with F405X would be expected to produce F405R and K409W pair and would inherently have function of bispecific antibody formation. Bernett et al. teach that skew pairs 368D/370S substitutions and S364K/E357Q when combined with bispecific promoting substitutions can skew the formation of heterodimers over homodimers. As such, the combination of the teachings of the references would have yielded the predictable results of the formation of a bispecific antibody that binds two different antigens.
Applicant’s arguments in conjunction with the Bae declaration under 37 CFR 1.132 filed on March 16, 2026 have been fully considered but have not been found persuasive.
The Bae declaration provided Table 1 generated by quantifying the band intensities in Figures 9a-9c in the instant specification and asserts that XS (A-chain S364K/K409F paired with B-chain K370S/F405R) and ZW (A-chain S364K/K409W paired with B-chain K370S/F405R) showed 100% heterodimer formation as compared to UD (A-chain S364K/K409W, B-chain L368D/F405R) with only 91% heterodimer and 9% homodimer (see summary below).
A-chain B-chain heterodimer homodimer
XS S364K/K409F K370S/F405R 100% 0%
ZW S364K/K409W K370S/F405R 100% 0%
UD S364K/K409W L368D/F405R 91% 9%
The Bae declaration further states:
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Thus, applicant asserts that replacing L368D with K370S in B-chain increases heterodimers from 91% to 100% which constitutes superior results as compared to all tested mutations including L368D-based heterodimers and other substitutions in position 409 such as K409A/D/E/G/Q/S.
Applicant continually argues that a person of ordinary skill in the art would not have selected F405R/K409R pairing because Figure 27B of Neijseen et al. teaches that the bispecific formation is worse and therefore, teaches away from the instant invention. Applicant further argues that the claims recite add additional pair comprising S364K and K307S substitutions which is not disclosed in Neijseen et al. Applicant further asserts that the Examiner’s rationale requires impermissible hindsight by combining K409W in Example 33 and F405R from Example 34 in Neijseen et al. which is not suggested by the prior art. Applicant asserts that Bernett teaches anti-CD38canti-CD3 plug-and-play format and does not teach S364K and K370S pair as standalone solution and Figure 6A of Bernett listed numerous multi-residues preferred steric variants rather than narrowly claimed two-pair combination in the instant application. Applicant also asserts that Bernett teach E357 of monomers S364K/E357Q cannot form a functional pair with L368D and E357Q/K370S pair not, the S364K/K370S pair as recited.
As such, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
In contrast to applicant and the assertion made by Bae declaration regarding surprising results, note that the instantly recited substitution pair in the CH3 region S364K and K370S were well known and explicitly disclosed by Bernett. For example, Bernett teaches ten working examples of CH3 heterodimers in Figure 10 showing variant 12758 having L368D/K370S in chain 1 and S364K in chain 2 exhibits 94.4% heterodimers, the highest percentage of heterodimers among all ten variants (e.g. see Figure 10).
Further, Bernett teaches that the presence of L368D/K370S-S364K/E357D variant (CENP 12760 in Figure 19) introduced an extreme bias toward the desired heterodimer formation of 95.5% compared to the absence of this variant of 52.7% (e.g. see [0361]).
Bernett states that the L368D/K370S-S364K/E357Q variant with high heterodimer yield and high thermal stability is especially preferred (e.g. see [0363]).
While applicant has deleted unelected species of substitution at position 368, the instant claims are drawn to the first CH3 and the second CH3, each comprises the recited modified amino acid pairs comprising S364K and K370S. The transitional term “comprising” is inclusive or open-ended and does not exclude additional unrecited elements (e.g. L368D). Therefore, Bernett’s heterodimer pair L368D/K370S and S364K reads on the instantly recited K370S and S364K pair in view of the recitation of “comprising” which allowed unspecified elements.
Further, contrary to applicant’s assertion that the Neijseen and Bernett teaches different antigen targeting of the bispecific antibody, note that both Neijseen (e.g. page 150) and Bernett (e.g. in Example 5) teaches modifications made in the Fc region of human IgG1.
Furthermore, contrary to applicant’s arguments that the Examiner’s conclusion of obviousness is based on improper hindsight reasoning, note that there is no requirement that an express, written motivation to combine must appear in prior art references before a finding of obviousness. See MPEP 2143.01.
Here, once again, Neijseen specifically teach a mutation at position 405 in one CH3 and a mutation at position 409 in the other CH3 (e.g. see page 6). Neijseen further teaches IgG1-K409X wherein position K409 was changed to all other eighteen amino acid residues and shows that K409W (similar to K409R) has high Fab-arm exchange, indicating high bispecific antibody formation and K409F shows intermediate Fab-arm exchange (e.g. see Example 33 in pages 148-149). Neijseen further choses K409R substitution in combination with F405X in Example 35 in pages 149-150. Given that K409W was shown to have the same high Fab-arm exchange as K409R (disclosed by Neijseen in Example 33 in pages 148-149), it would have been obvious for one of ordinary skill in the art at the time the invention was filed to replace K409R with K409W and combine it with IgG1-F405X (replacing F405 with all eighteen amino acid residues) the same way as shown in Example 35 of Neijseen and achieve the result of K409W-F405R for enhanced bispecific antibody formation.
Bernett teach that the L368D/K370S-S364K/E357Q variant with high heterodimer yield and high thermal stability is especially preferred.
Therefore, adding the skew pairs to the K409R/W and F405R pair would enhance the heterodimer formation over homodimer formation. Given that Neijseen et al. teach that K409W and K409R both can induce high Fab-arm exchange –feature desired in bispecific antibody formation, and since F405K and K409R pair was known to induce high bispecific antibody formation by Neijseen et al., an ordinary skill in the art would have been motivated to simply substitute K409R in the F405X/K409R pair with K409W to produce bispecific antibody.
Further, given that Bernett teaches L368D/K370S in chain 1 and S364K in chain 2 exhibits 94.4% heterodimers and L368D/K370S-S364K/E357D variant (CENP 12760 in Figure 19) introduced an extreme bias toward the desired heterodimer formation of 95.5%, an ordinary skill in the art would have been motivated to combine the teachings of the references to produce a heterodimeric protein comprising a human IgG1 Fc region comprising two CH3 regions comprising two pairs of substitutions K409W-F405R and comprising the amino acid substitutions L368D/K370S-S364K or L368D/K370S-S364K/E357D that would enhance heterodimer formation more than without the combination. Such combination would be expected to yield greater heterodimer formation than each pair alone (e.g. more than 95.5%).
As such, applicant’s arguments have not been found persuasive.
6. No claim is allowed.
7. 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.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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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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/CHUN W DAHLE/Primary Examiner, Art Unit 1641