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 .
There is no support for the amendment within the instant application specification. See 112a New Matter Rejection.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/14/2024 has been entered.
Applicant’s amendment to the claims filed on 7/14/2024 in response to the Final Rejection mailed on 4/21/2026 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 7/14/2026 in response to the Final Rejection mailed on 4/21/2026 have been fully considered and are not 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.
New Claim Rejections - 35 USC § 112
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.
Claims 1-8, 10 are newly 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.
The following new matter is within amended claims dated 7/14/2026: page 2 claim 1, lines 14-17. The added material which is not supported by the original disclosure is as follows ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography.’ There is no support within the instant applicant specification for said recitation. Applicants have not provided any guidance of where the new matter added to the instant applicant claim 1 ‘wherein separation of the bispecific antibodies is achieved during steps a)-d), without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography.’ The specification is silent to the recitation 'and wherein separation of the bispecific antibodies is achieved during steps a)-d), without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography.'
New Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8, 10 are newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The new rejection is necessitated by Applicant’s amendment of claim 1 to recite ‘and wherein separation of the bispecific antibodies is achieved during steps a)-d), without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography.’
Regarding claim 1 (claims 2-8, 10 dependent thereof) the added claim amendment ‘and wherein separation of the bispecific antibodies is achieved during steps a)-d), without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography’ is not a claim limitation. Furthermore, the recitation ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography’ is not part of steps a-d of the instant application claim 1. As such, it is not clear as to how said amendment adds any weight to the patentability of the instant application claim 1 as Applicant’s recitation ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography’ is not part of steps a-d. Appropriate correction is suggested.
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 amendment of claim 1 to recite ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography.’
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, and wherein separation of the bispecific antibodies is achieved during steps a)-d), without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography.
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 7 to 2.9 (para 0128), which fits within the recited pH gradient limitation of a pH gradient from 6 to 2, as recited in the instant application claim 1, and a pH gradient from 5.5, or from 5.2, or from 5.0, to 2.0, or to 2.5, as recited in the instant application claim 2.-(Claim number??) 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 claim 3 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. 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).
It is noted that Giese teaches each of the capture chromatography, first mixed mode chromatography, and/or second mixed mode chromatography are optionally preceded and/or followed by one or more additional chromatography steps. It is the Examiner’s position that said teaching by Giese is the same as the recitation ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography’ of the instant application claim 1.
RESPONSE TO REMARKS: Applicant's arguments filed 7/14/2026 have been fully considered but they are not persuasive. Beginning on p. 4 of Applicants’ remarks, Applicants in summary contends that
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. Applicant contends that Giese does not teach or suggest the separation of bispecific antibodies on an affinity column without subsequent chromatographic separation. Applicant contends that Giese teaches away from this concept in at least paragraph [0006], where it details its proposed procedure for the purification of bispecific antibodies using mixed-mode chromatography following capture chromatography (i.e. affinity chromatography). Giese notes that "[a]pplicants have discovered that the use of at least two mixed mode ... chromatography steps after an initial capture chromatography step results in greater removal of product-specific impurities and an improved process for purifying multispecific antibodies." Applicant contends that Giese further notes that the mixed-mode chromatography steps comprise anion- and cation-exchange chromatography. In contrast, the instant claims require purification using affinity chromatography which is not followed by mixed-mode chromatography. Applicant maintains 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, and wherein the affinity chromatography is not followed by subsequent mixed-mode chromatography. Applicant contends that Giese only contemplates the use of mixed-mode chromatography with cation and anion ligands to separate bispecific antibodies; it does not disclose the crucial insight that VH3-comprising antibodies can be sufficiently separated on an affinity column alone by using a pH gradient.
The arguments are not persuasive. Examiner appreciates Applicant’s remarks. However,
Examiner contends that Applicant is claiming affinity purification in addition to any other type of purification without subsequent purification due to the ‘comprising’ claim language within the instant application claim 1. After separation, there is no subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography taught by Giese.
Applicant contends that the amended claim limitation is supported by Examples 3 and 4, corresponding with the chromatograms shown in Figures 4 and 5. These Examples demonstrate that protein A chromatography practicing the claimed method separates the desired bispecific antibodies without subsequent chromatographic purification, as required by the instant claims. This provides direct support for the claim amendments. This claim limitation is also supported by paragraphs [0045]-[0057] and [0006]-[0009], which discusses the ways in which the instantly-claimed method improves upon previous methods.
Examiner contends that the specification is silent to the recitation/limitation of ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography’ within the instant application claim 1. Examiner contends that the fact that Applicant states that the method may be performed using any commercially available Protein A ligand with maintained VH3 interaction within the ‘Remarks’ does not provide sufficient evidence for the recitation ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography’ within claim 1 of the instant application due to Applicant’s statement within the ‘Remarks’ that ‘the method may be performed using any commercially available Protein A ligand.’ Said statement does not limit the number of chromatography steps before the recitation ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography.’
Examiner acknowledges Applicant’s ‘comments on page 7 of the ‘Remarks’ identifying where support for the recitation is located within the instant application specification. However, Examiner contends that para 0045-0057, 0006-0009 and examples 3-4 that correspond to figures 4-5 of the specification do not remedy the new matter issue. Examiner contends that Giese teaching of each of the capture chromatography, first mixed mode chromatography, and/or second mixed mode chromatography are optionally preceded and/or followed by one or more additional chromatography steps (para 0014) is the same as the recitation ‘without subsequent ion-exchange chromatography, hydrophobic interaction, chromatography or mixed-mode chromatography’ of the instant application claim 1.
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.
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
