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 .
Support for the amendments is within the instant application specification.
Applicant’s amendment to the claims filed on 3/19/2026 in response to the Non-Final Rejection mailed on 12/19/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
Claims 1-8, 10 are pending.
Claims 9, 11 are cancelled.
Applicant’s remarks filed on 3/19/2026 in response to the Non-Final Rejection mailed on 12/19/2025 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Withdrawn Rejections
The rejection of claims 1-11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), is withdrawn in view of Application amendment of claim 1 to recite ‘matrix’; delete the recitation ‘about’ in claims 1, 2; delete the recitation ‘such as’ in claim 7.
The rejection of claims 9, 11 under 35 U.S.C. 102(a)(1) as being anticipated by Giese et al (EP 3472177B1, Date Filed: 06-16-2017, cited in PTO-892 date 12/19/2025) {Giese} as evidenced by Wang et al (2019, Journal of Chromatography A, cited in PTO-892 date 12/19/2025) {herein Wang), Jansson et al (1997, FEMS Immunology and Medical Microbiology, cited in PTO-892 date 12/19/2025) {herein Jansson}, Fumoux et al (1993, Blood, cited in PTO-892 date 12/19/2025) {herein Fumoux} is withdrawn in view of cancellation of claims 9, 11.
Maintained Claim Rejections - 35 USC § 102
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.
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.
The rejection of claims 1-8, 10 under 35 U.S.C. 102(a)(1) s being anticipated by Giese et al (EP 3472177B1, Date Filed: 06-16-2017, cited in PTO-892 date 12/19/2025) {Giese} as evidenced by Wang et al (2019, Journal of Chromatography A, cited in PTO-892 date 12/19/2025) {herein Wang), Jansson et al (1997, FEMS Immunology and Medical Microbiology, cited in PTO-892 date 12/19/2025) {herein Jansson}, Fumoux et al (1993, Blood, cited in PTO-892 date 12/19/2025) {herein Fumoux}. See MPEP 2131.01 regarding multiple reference 102 rejections is maintained. The rejection has been modified in view of Applicant’s cancellation of claims 9, 11 and amendment of claim 1 to recite ‘and wherein said bispecific antibody or bispecific antibody fragment is any antibody or antibody fragment comprising two different VH-chains, of which one VH-chain is VH3.’
As amended, claims 1-8, 10 are drawn to a method of separating bispecific antibodies or bispecific antibody fragments, said method comprising the steps of: a) providing a feed comprising bispecific antibodies or bispecific antibody fragments; b) contacting the feed with a separation matrix having affinity ligands coupled to a support; c) optionally washing the separation matrix with a washing liquid; d) applying an elution buffer to the separation matrix, to elute the antibodies or antibody fragments bound to the affinity ligand; wherein in step d) a pH gradient is applied over the elution buffer, said pH gradient being from 6 to 2, and wherein said bispecific antibody or bispecific antibody fragment is any antibody or antibody fragment comprising two different VH-chains, of which one VH-chain is VH3.
With respect to claims 1-8, 10, Giese teaches a method for purifying (separating) bispecific antibodies and fragments thereof (para 0097) via mixed column chromatography comprising Protein A affinity chromatography (para 0108) and hydroxyapatite chromatography such as CHT Ceramic Hydroxyapatite Type I/II support (para 0096). The knob-into-hole (KiH) may be introduced into the VH/VL interfaces of antibodies thereby driving the pairing of two different heavy chains together during the manufacture of multi-specific antibodies (para 0047). Multi-specific antibodies having KiH in their Fc regions can further comprise different heavy chain variable domains that pair with different light chain variable domains (para 0047). Additionally, diabody technology can be utilized for making bispecific antibody fragments (para 0223). Said technology is wherein the VH and VL domains of one fragment
are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. It is known by those of average skill in the art that Protein A affinity chromatography is comprised of protein A resin (para 0316). As such, absent evidence otherwise, it is the Examiner’s position that the resin to which protein A is attached is the support. Furthermore, the evidentiary reference of Wang is cited to demonstrate that CHT Ceramic Hydroxyapatite Type I/II support contains elongated nanocrystals with sizes about 20 x 100 nm for Type I and about 50 x 200 nm for Type II (abstract). As such, absent evidence otherwise, it is the Examiner’s position that said support fits within the cited range of 10 – 1000 nm, as recited in claim 7 of the instant application. The mixed mode chromatography had a pH gradient of less than about any of 10, 9, 8, 7, 5 or 5. Evidentiary reference of Jansson is cited to demonstrated that Protein A inherently contains domains E, D, A, B and C. As such, absent evidence otherwise, it is the Examiner’s position that the Protein A taught by Giese is the same as the Protein A recited in the instant application. As such the Protein A recited in the instant application inherently consists of domains E, D, A, B and C. Additionally, it is the Examiner’s position that the Protein A taught by Giese is native as Giese does not teach said Protein A is mutated. As such, it would inherently contain a native C domain as recited in the instant application claim 5. Giese further teaches the agarose within the mixed mode chromatography is highly crosslinked (claim 4). Protein A columns were prepared by applying three column volumes of elution buffer followed by three column volumes of regeneration buffer (para 0316). The columns were then equilibrated, loaded, washed three times (equilibration buffer wash, potassium phosphate wash, equilibration buffer wash), eluted, and regenerated for sufficient cycles to process the load material (para 0316). In some embodiments, the cell lysate is clarified by centrifugation prior to chromatography (para 0087). The bivalent antibodies and fragments may be derived from IgG3 (para 0040) and/or IgG4 (para 0214). Evidentiary reference of Fumoux is cited to demonstrated that the most common VH within IgG4 is VH3, with VH4, VH5 and VH6 also being expressed from B-cells from which IgG4 is secreted (abstract). As such, absent evidence otherwise, it is the Examiner’s position that the IgG4 antibody and fragments thereof taught by Giese would inherently contain VH3 and VH4, VH5 and VH6. Giese further teaches that in certain embodiments the fragments of antibodies consists of diabodies (para 0173).
For the reasons stated herein, the teachings of Giese anticipate claims 1-8, 10.
RESPONSE TO REMARKS: Applicant's arguments filed 3/19/2026 have been fully considered but they are not persuasive. Beginning on p. 4 of Applicants’ remarks, Applicants in summary contends that although Giese teaches the general concept of bispecific antibodies, it does not disclose, teach or suggest the purification of bispecific antibodies having two different VH-chains, one of which is VH-3.
These arguments are found to be not persuasive. Examiner contends that Giese teaches the knob-into-hole (KiH) may be introduced into the VH/VL interfaces of antibodies thereby driving the pairing of two different heavy chains together during the manufacture of multi-specific antibodies (para 0047). Multi-specific antibodies having KiH in their Fc regions can further comprise different heavy chain variable domains that pair with different light chain variable domains (para 0047). Additionally, diabody technology can be utilized for making bispecific antibody fragments (para 0223). Said technology is wherein the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another (Examiner interpreted as different) fragment, thereby forming two antigen-binding sites.
Applicant contends that Giese does not disclose, teach or suggest the use of affinity ligands for the separation of bispecific antibodies. Instead, Giese uses mixed-mode chromatography with cation and anion ligands in combination with hydrophobic moieties and N-benzyl-n-methyl- ethanolamine to separate the bispecific antibodies. See e.g. Giese, paragraph [0006]. The protein A capture chromatography referenced by the Examiner, discussed e.g. in Giese paragraphs [0108] and [0128], is only envisioned as an initial pre-purification step before the actual separation of the bispecific antibodies.
These arguments are found to be not persuasive. Examiner contends that Giese explicitly teaches the claimed invention. Examiner contends that Giese teaches following expression of the claimed antibody arm in the host cell, whole cell broth is collected and homogenized, and the antibody arm is extracted (para 0084). Examiner contends that Giese teaches each arm of the multi-specific antibody is then purified by capture chromatography (such that each arm is purified on a separate chromatography column or membrane) via affinity chromatography (Protein A chromatography) (para 0084). Examiner contends that Giese teaches following capture chromatography, purified antibody arms may be analyzed (para 0084). Additionally, Examiner contends that the claim language ‘comprising’ is open-ended. Thereby, it does not limit the scope of the instant application to one type of affinity chromatography.
Applicant contends that Giese does not provide sufficient guidance to the skilled artisan to arrive at the claimed method of purifying bispecific antibodies with affinity ligands, wherein the antibody or antibody fragments comprise at least one VH-3 chain. Applicant contends that Giese only contemplates the use of mixed-mode chromatography with cation and anion ligands to separate bispecific antibodies.
These arguments are found to be not persuasive. Examiner contends that although Giese may contemplate other forms of chromatography, it does not negate the fact that Giese explicitly teaches the purification of the claimed antibodies by protein A chromatography (para 0084) and its subsequent, immediate, analysis.
Applicant contends that Giese does not contain the crucial insight that bispecific antibodies bearing one VH3 chain can be easily separated by using a protein A pH gradient. Applicant contends that there are a variety of VH chains which are known, and there is no specific teaching or suggestion that the ones expressed in the experiments of Giese comprise VH-3.
These arguments are found to be not persuasive. Examiner contends that Giese teaches the bivalent antibodies and fragments may be derived from IgG3 (para 0040) and/or IgG4 (para 0214). As such, it is the Examiner’s position that VH3 would necessarily be purified by the method taught by Gieses. Supporting the Examiner’s position is the evidentiary reference of Fumoux which demonstrate that the most common VH within IgG4 is VH3 (abstract).
Conclusion
Status of Claims
Claims 1-8, 10 are pending.
Claims 9, 11 are cancelled.
Claims 1-8, 10 are rejected.
No claims are in condition for allowance.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERICA NICOLE JONES-FOSTER whose telephone number is (571)270-0360. The examiner can normally be reached mf 7:30a - 4:30p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERICA NICOLE JONES-FOSTER/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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