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. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 10, 2026 has been entered.
Claims 2-20, 29-42, 45-48, and 50 have been canceled.
Claims 1, 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Claims 21-28, 43, 44, and 49 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected invention/species.
Claim 1 is currently under consideration as they read on the elected invention described above.
3. In view of applicant’s amendment, following rejection is set forth.
4. 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.
5. 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.
6. Claim 1 stands 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 and K409F has intermediate Fab-arm exchange relative to K409 (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. Note that K409F also shows intermediate Far-arm exchange which is better than K409 (no substitution).
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 K409F/W/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, K409W, and K409F can promote high bispecific antibody formation which motivates a simple substitution of K409R with K409W or K409F to pair with F405X would be expected to produce F405R and K409W/F 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.
Applicant argues that the claims have been amended to recite “comprise modified amino acid pairs…. wherein the modification consists of” K409W/F and F405R and S364K and K370S which limits the substitutions to only the recited ones and nothing else. As such, applicant asserts that Bernett’s teachings encompassing 368D/370S substitutions paired with S364K/E357Q would be outside the scope of the instant amended claims.
This is not found persuasive for following reasons:
In contrast to applicant’s reliance on the claim amendment, note that when the phrase "consists of" appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. Mannesmann Demag Corp. v. Engineered Metal Products Co., 793 F.2d 1279, 230 USPQ 45 (Fed. Cir. 1986). >See also In re Crish, 393 F.3d 1253, 73 USPQ2d 1364 (Fed. Cir. 2004).
Here, the use of “consists of” in the body of the claims with respect to the modifications did not limit the open-ended “comprise” language in the claims. The transitional phrase “consists of” does not limit the claims to only the recited specific modifications in specific positions in the first CH3 and the second CH3 and the transitional language “comprise modified amino acid pairs forming respective amino acid-amino acid bonds between the first CH3 and the second CH3” allowed the claims to cover the other modifications such as the two additional substitutions 368D/370S substitutions and S364K/E357Q disclosed in Bernett.
Applicant argues that a person of ordinary skill in the art would not have selected F405R/K409R pairing because Example 33 of Neijseen et al. teach K409X in combination with IgG1-ITL construct and reports different Fab-arm exchange outcomes depending on the residues in 409. Applicant acknowledges that Neijseen teach K409W promotes high Fab-arm exchange (promoting heterodimer formation) but asserts that K409F only shows intermediate and is therefore not equivalent to K409W. Applicant further asserts that Example 34 of Neijseen et al. F405R combined with K409R only yielded low Fab-arm exchange. 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 but not the S364K/K370S pair as recited.
Once again, 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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Applicant asserts that Neijseen’s Fab-arm-exchange ranking did not predict performance in the heterodimerization system recited in the instant claims and Bernett’s higher-yield L368-based package do not render obvious the amended closed claim that excludes L368D.
As such, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
In contrast to applicant’s 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]).
Contrary to applicant’s assertion, the instantly amended claims do not exclude L368D and R357Q, rather the recitation of “comprising … consisting of” would encompass other modifications including L368D and R357Q, see detail explanation above.
In contrast to applicant’s assertion that there is no reason to combine K409F showing only intermediate Fab-arm-exchange with the modifications in Bernett, note that even the intermediate improvement is still better than wildtype unmutated CH3. As such, the teachings of Neijseen are not limited to the K409W but also including K409X wherein X represent amino acid residues showing improvement over the naturally occurring amino acid residue K.
Further, contrary to applicant’s assertion that the Neijseen and Bernett teach 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 CH3 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 and K409F (similar to K409R) has high to intermediate Fab-arm exchange compared to K409 unmutated, indicating high bispecific antibody formation (higher Fab-arm exchange than unmutated K409) (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 and K409F were shown to have the same or similar high Fab-arm exchange as K409R relative to K409 (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 or K409F 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 teaches 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/F-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.
7. No claim is allowed.
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
