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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 29 June 2026 has been entered.
Claim Status
Claims 1-76, 80, 82, and 90-92 are cancelled. Claims 77-79, 81, 83-89, and 93-102 as filed on 29 June 2026 are pending and under examination.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 77-79, 81, 84, and 87-89 are rejected under 35 U.S.C. 103 as being unpatentable over Kuramochi (CA 2853230 A1) (Of Record) and Hosken et. al. (Anal. Chem. 88:5662-5669 (2016))(Of Record).
Regarding claims 77, 79, and 84, Kuramochi teaches the use of isoelectric point for purification of antibodies by ion exchange chromatography (page 36 in lines 11-16). Kuramochi teaches multiple amino acid substitutions in its invention including Q175K (Tables 2-4 and Example 3). Kuramochi teaches host cells expressing nucleic acids that encode the modified antibodies (page 39 in lines 4-5 and Reference Example 1 page 69). Kuramochi teaches the bispecific antibodies of the invention comprise first and second heavy chains (page 20 in lines 19-22). Kuramochi teaches the heteromeric multimer bispecific (page 42 in lines 15-18 and page 12 in lines 34). The specification does not provide a limiting definition for antibody fragment so the isolation of the multispecific antibody from any amino acid sequence of any length would fulfill the requirement of separating the multispecific antibody from an antibody fragment.
Regarding claim 78, Kuramochi teaches collecting antibody from a cell culture of the host cells (page 39 in line 6).
Regarding claims 87-89, Kuramochi teaches the preparation of human type IgG bispecific antibodies (page 1 in lines 14-16 and Example 8).
Kuramochi teaches the invention uses amino acid substitutions associated will participate in the interface of antibodies (page 13 in lines 33-35) and teaches Q175K is at a location that participates in the interface (Tables 2-3 and page 51 in lines 4-8 and Example 1). Kuramochi teaches the preparation of the antibody is more efficient by combining modifications (page 55 in lines 10-14).
Kuramochi provides isoelectric point for purification of antibodies by ion exchange chromatography as part of possible methods for isolating antibodies and teaches towards combining its amino acid substitutions with additional modifications.
Kuramochi does not teach the modification of the claim in isoelectric point purification of antibodies by ion exchange chromatography.
This deficiency is filled by Hosken.
Hosken teaches capillary isoelectric focusing (cIEF) is widely used in the biopharmaceutic industry to measure charge distribution of therapeutic proteins. Hosken further teaches fractionating charge variants for characterization by using free-flow electrophoresis (FFE) (abstract). FFE is a form of isoelectric focusing (page 5663 in col 2 in first full paragraph). Hosken teaches the isolation of different antibodies of interest (rhumAb1, rhumAb2, rhumAb3)) from FFE Fractions (page 5664, col 1 in third paragraph, Figure 2). Hosken teaches that “protein isoforms can be separated continuously with excellent recovery of the fractionated material.” (page 5668 col 2 last paragraph).
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to combine the method of producing a multispecific antibody using the amino acid substation of Q175K of Kuramochi that is taught can be used in isoelectric point focusing in the method of Hosken. Kuramochi teaches the amino acid substitution for use in isolating multispecific antibodies but the limited success of single modifications would teach towards use of isoelectric focusing taught by Hosken. There would have been a reasonable expectation of success as Kuramochi and Hosken both teach use of isoelectric focusing in the method of preparing multispecific antibodies and Hosken teaches the superiority of its method.
Applicant Arguments
Applicant argues the rejection fails to provide the required motivation to consult or select Kuramochi. Applicant argues the requirement of production and separation of a desired immunoglobulin protein from mixtures of immunoglobulin proteins and points to the instant specification with the inventors discovered introducing charged residues at non-surface exposed amino acid positions. Applicant argues Kuramochi is to the different objective of improving efficiency of heterodimer formation. Applicant argues Kuramochi is directed to a different field than the present invention. Applicant further agues that a POSA would not teach or suggest the selection of the specific substitutions required by the claims and relied upon in the rejection. Applicant argues there is no teaching to use the selected residues of K147 and Q175 to function independently as Kuramochi teaches a combination of residues.
Applicant argues Kuramochi does not teach K147 and Q175 would result in isoelectic focusing-based separation recited in the claims without additional substitutions.
Applicant argues Hosken does not cure the deficiencies of Kuramochi outlined in the applicant arguments.
Response to Arguments
Applicant's arguments filed 29 June 2026 have been fully considered but they are not persuasive.
Regarding the requirement of introducing charged residues at non-surface exposed amino acid positions and its resulting effect on the production of immunoglobulins. Kuramochi explicitly teaches the substitutions required by the claims by teaching Q175K (Tables 2-4 and Example 3). Claim 77 includes a method for producing a multispecific antibody that comprises the listed substitutions which applicant has identified as introducing charged residues at non-surface exposed amino acid positions.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., substitution of Q175 and K147 without additional substitutions) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Claim 77 is to a method of producing a multispecific antibody that comprises a host cell with a nucleic acid that encodes the multispecific antibody, the culturing of the host cell so that a nucleic acid is expressed, and purifying the multispecific protein by isoelectric focusing. Claim 77 requires the presence of one of the listed amino acid substitutions in the multispecific antibodies encoded by the nucleic acid, by reciting in subpart (a) lines 4-5 “wherein at least one of said regions comprises a CH1 region amino acid variation selected from “ the claim includes CH1 regions that comprise one of the listed variations in combination with additional substitutions. Kuramochi does not need to teach the substitution of only Q175K to teach the requirement of claim 77 subpart (a), the presence of a nucleic acid encoding a multispecific antibody where the antibody will contain the Q175K substitution teaches all of the requirements of that subpart. Kuramochi then teaches its presence in a host cell being cultured to produce antibodies that can be separated by isoelectric point for purification.
None of the claims rejected by Kuramochi require Q175K alone as all allow for the presence of additional amino acid variation.
There are no deficiencies for Hosken to cure regarding the amino acid substitutions of claim 77. Hosken is relied upon to teach the method of isoelectric focusing.
Claims 77, 81, and 83 are rejected under 35 U.S.C. 103 as being unpatentable over Kuramochi (CA 2853230 A1) (Of Record) and Hosken et. al. (Anal. Chem. 88:5662-5669 (2016))(Of Record) as applied to claims 77-79, 81, 84, and 87-89 above, and further in view of De Kruif (NZ 728228 B2) (Of Record)
The teachings of Kuramochi and Hosken from the previous art rejection are incorporated here in full.
Kuramochi teaches the use of substitutions in the CH1 and CL are more efficient than methods of knob and hole singly into CH3 (abstract). Kuramochi teaches the invention includes substitutions in the CH3 region including at T366 and L368 (page 36 in lines 1-4).
Kuromachi in view of Hosken does not teach the substitutions in the CH3 domain of T366K:L351K and L351D:L368E.
This deficiency is filled by De Kruif.
De Kruif teaches methods and means of production of therapeutic antibodies (Field). De Kruif teaches the dimerization of antibodies by engineering the CH3 domains to favor heterodimerization over homodimerization using ‘knob-into-hole’ approaches. De Kruif teaches this promotes heteromultimer formation and hinders homomultimer formation (Page 10 last paragraph).
De Kruif further teaches preferred embodiments of the first CH3 comprises amino acid substitutions T366K and L351K and the second CH3 domain comprises the amino acid substitutions L351D and L368E to produce a heterodimeric Ig-like molecule (page 39 in lines 1-6). This is embodied in Example 17 and Table 14 as bispecific antibody with the T366K:L351K and L351D:L368E was a preferred embodiment as it produced a 92% of bispecific heterodimers which De Kruif teaches is easier to purify (Page 79 in lines 6-14).
It would have been obvious at the time the application was filed to combine the isolated by isoelectric focusing multispecfic antibodies comprising Q175K of Kuramochi in view of Hosken with the CH3 substitutions of De Kruif producing an antibody of the substitutions of Q175K with T366K:L351K and L351D:L368E. One of ordinary skill in the art would have been motivated by the teachings of Kuramochi that the substitutions taught could be combined with additional substitutions including those to the CH3 domain. Further, one of skill in the art would have been motivated to combine with the preferred embodiment of De Kruif. There would have been a reasonable expectation of success as Kuramochi teaches the combination of its altered antibodies with additional changes to the CH3 domain.
Applicant Arguments
Applicant argues De Kruif does not cure the deficiencies of Kuramochi outlined in the applicant arguments.
Response to Arguments
Applicant's arguments filed 29 June 2026 have been fully considered but they are not persuasive.
There are no deficiencies for De Kruif to cure regarding the amino acid substitutions of claim 77. See response to arguments for first rejection under 35 U.S.C. 103.
Claims 77 and 85 are rejected under 35 U.S.C. 103 as being unpatentable over Kuramochi (CA 2853230 A1) (PTO-892) and Hosken et. al. (Anal. Chem. 88:5662-5669 (2016))(Of Record) as applied to claims 77-79, 81, 84, and 87-89 above, and further in view of Calarese (WO 2017218698 A1) (PTO-892).
The teachings of Kuramochi and Hosken from the previous art rejection are incorporated here in full.
Kuramochi teaches the use of substitutions in the CH1 and CL are more efficient than methods of knob and hole singly into CH3 (abstract). Kuramochi teaches the invention includes substitutions in the CH3 region including at T366 and L368 (page 36 in lines 1-4).
Kuromachi in view of Hosken does not teach the CH2 substitutions of V303K or V303R.
This deficiency is filled by Calarese.
Calarese teaches antibodies with engineered CH2 domains with one or more site-specific mutations which improved characteristic including thermal stability, antibody yields, antibodies titers, and cell killing relative to the parent antibody (abstract). Calarese teaches the substitution of V303R increased antibody yields without compromising thermostability of the antibody (Table 5 and [00224]).
It would have been obvious at the time the application was filed to combine the isolated by isoelectric focusing multispecfic antibodies comprising Q175K of Kuramochi in view of Hosken with the CH2 substitution of V303R of Calarese that has increased antibody yields without compromising thermostability of the antibody. One of skill in the art would have been motivated by the teachings of Kuramochi to combine the substitutions of their invention with further substitutions and the teachings of Calarese to produce higher antibody yields. There would have been a reasonable expectation of success as Kuramochi teaches combining with other known in the art amino acid substitutions in the CH1, CH2, and CH3 domains.
Applicant Arguments
Applicant argues Calabrese does not cure the deficiencies of Kuramochi outlined in the applicant arguments.
Response to Arguments
Applicant's arguments filed 29 June 2026 have been fully considered but they are not persuasive.
There are no deficiencies for De Calabrese to cure regarding the amino acid substitutions of claim 77. See response to arguments for first rejection under 35 U.S.C. 103.
Allowable Subject Matter
Claims 93-102 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 93-102 are to a method for producing multispecific antibodies comprising a first heavy chain and a second heavy chain whose isoelectric points are different wherein a host cell encodes a CH1 region with amino acid variations wherein the variations are A172P/S190A/N201K, A172P/S190A/N201D, D148K/Q175K, K147E/Q175E, Y149A/V154/A172P/S190A, N159D/K213Q, N159D/N201D, N159D/N201D/K213Q, N159K/N201K, N201D/K213Q, T120K/N159K, T120K/N159K/N201K, T120K/N201K, or T197D/K213Q.
Conclusion
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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