DETAILED ACTION
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 .
Claim Status
Applicant’s amendments received 11NOV2025 are acknowledged.
Claims 2, 4-5, 10, and 19 have been canceled.
Claims 1, 3, 6, 8-9, and 23 have been amended.
Claim 25 is new.
Claims 1, 3, 6-9, 11-18, and 20-25 are pending in the instant application (i.e., Claim(s) 1 is/are independent).
Claim 24 remains withdrawn.
Claims 1, 3, 6-9, 11-18, 20-23, and 25 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2020/031914, filed 07MAY2020, which claims the benefit of US Provisional Patent Application No. 62/845594, filed 09MAY2019. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Drawings
Applicant’s arguments, see p 7-9, Amendments to the drawings section, filed 11NOV2025, with respect to objections to the drawings for minor informalities have been fully considered and said objections to the drawings have been withdrawn in view of new drawings filed as part of said response.
Claim Rejections - 35 USC § 112
Indefiniteness
Applicant’s arguments, see p 9, Claim rejections - 35 USC §112(b) section, filed 11NOV2025, with respect to the rejection(s) of claim(s) 23 under 35 USC §112(b) have been fully considered and said rejections of claim 23 have been withdrawn in view of the claim amendments filed as part of said response.
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.
Enablement
Claims 1, 3, 6-9, 11-18, and 20-23 stand rejected and claim 25 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant argues that a method of improving preferential pairing of a HC and LC antibody with the amended independent claim to include the double mutation in LCDR3 is enabled (i.e., does not require undue experimentation to use the method) and furthermore although Applicant considers binding affinity as being outside the scope of a method of improving preferential pairing that the use of affinity maturation to improve binding affinity is also enabled (p 10-12, of the response filed 11NOV2025).
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
As set forth in the rejection of record, the implementation of the broadest claim in view of the breadth of variables (i.e., additional affinity maturation screening to improve binding specificity and affinity following LCDR3 and/or HCDR3 mutations), the lack of predictability in the prior art, which teaches that a single amino acid change in the CDRs could abrogate binding, and the amount of direction provided in the specification, would require undue experimentation for one of ordinary skill in the art to use the method.
In response to Applicant’s argument that the method of improving preferential pairing of essentially any HC and LC antibody by utilizing the double mutation in LCDR3, it is noted that the rejections are maintained because the breadth of a method of improving preferential pairing (i.e., increasing the yield) of any HC and LC antibody, by modifying two positions within LCDR3 as recited in independent claim 1 is not fully enabled. Applicant, argues that “the subject application has provided ample working examples to improve preferential pairing of HC and LC in various bispecific antibodies,” which in this instance is a specialized subset of HC and LC antibodies. Furthermore, the specification defines the term “antibody” in the broadest sense and refers to any Ig molecule comprising two HCs and two LCs, and any fragment, mutant, variant or derivation thereof so long as they exhibit the desired biological activity and exemplary antibodies include monoclonal, multispecific, and antibody fragments as described herein (¶0034). The specification goes on to teach that as a frame of reference, Ig will refer to the structure of an IgG, however one skilled in the art would understand/recognize that an antibody of any Ig class may be utilized and for clarity an IgG molecule contains a pair of HCs and LCs and each LC has a VL and CL domain and each HC has a VH, CH1, CH2, and CH3 (¶0035). It is therefore noted that certain fragments of antibodies do not fit the definition of comprising two HCs and two LCs (e.g., one-armed, scFv, or Fv as in claim 11 of the instant application). The lack of enablement for a method of improving preferential pairing of essentially any HC/LC antibody is further highlighted by Joshi, et al., which teach that LCDR3/HCDR3 modifications can impart pairing preference (i.e., improved BsIgG1 yield) for some, but not all antibody pairs (Joshi, et al., MABS, 2019, 11, 1254-1265, see p 1260, col 2, CDR L3 and H3 can increase bispecific yield for BsIgG1 section) and as taught by Rudikoff, et al., that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982).
In response to Applicant’s argument that binding affinity is outside the scope of a method of improving preferential pairing of a HC and LC antibody, it is noted that the specification teaches that mutant and/or variant antibodies exhibit the desired biological activity (e.g., epitope binding activity) (¶0034). Therefore, in addition to a method of improving preferential pairing of bispecific antibodies (i.e., antibody yield) of any HC/LC antibody, the antibody or antibody fragments thereof, must maintain their desired epitope binding activity, which in order to be fully enabled must include affinity maturation wherein the positions of 94/96 and 95 are not randomized; however independent claim 1 does not include such a limitation.
Claims 3, 6-9, 11-18, 20-23 and 25 are also rejected since they depend from claim 1, but do not remedy these deficiencies.
Written Description
Claims 1, 3, 6-9, 11-18, and 20-23 stand rejected and claim 25 is 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 argues that the specification provides sufficient disclosure and working examples to demonstrate that the Applicant was in possession of the full breadth of the claimed genus of a method that covers all antibodies for improving HC/LC pairing (i.e., increasing bispecific antibody yield) comprising mutations at positions 94 and 96 of LCDR3 at the time the instant application was filed (p 12-13 of the response filed 11NOV2025).
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
As set forth in the rejection of record, the claims encompass antibodies with CDR mutations and/or substitutions relative to any antibody sequence (Kabat), but neither the claims nor the specification define that any antibody species will maintain the claimed specificity. Claims 2-3, 6-9, 11-18, and 20-23 are also rejected since they depend from claim 1, but do not remedy this deficiency. Furthermore, the prior art supports that not all yields of antibody pairs can be improved by a double mutation in LCDR3 and that a single amino acid change in the CDRs can affect binding affinity/specificity (Joshi, et al., MABS, 2019, 11, 1254-1265, see p 1260, col 2, CDR L3 and H3 can increase bispecific yield for BsIgG1 section and Rudikoff, et al., PNAS, 1982, 79, 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982).
Therefore, because the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed multispecific antigen-binding molecules, antibodies, and non-antibody proteins and therefore Applicant was not in possession of the instant claimed invention.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641