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
Claims 1-76, 80, 82, and 90-92 are cancelled. Claims 77-79, 81, 83-89, and 93-102 as filed on 24 February 2026 are pending and under examination.
Rejections Withdrawn
Rejection of claims 77-79, 81, and 83-93 under 35 U.S.C. 103 is withdrawn with applicant amendment of claims necessitating new rejections.
Applicant’s arguments with respect to claim(s) 77-79, 81, and 83-93 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
New Rejection Necessitated By Applicant Amendment of Claims
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) (PTO-892) 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).
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 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.
Claims 77, 81, and 83 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 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.
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.
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
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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/F.E./Examiner, Art Unit 1643
/Meera Natarajan/Primary Examiner, Art Unit 1643