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 .
Application Status
Claims 97-104 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
Previous objection to the specification and drawings for sequence non-compliance and containing an embedded hyperlink are withdrawn in view of specification amendment.
Claim Rejections - 35 USC § 102
New Rejection Necessitated by Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims are 97-104 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Enami (US 2015/0291703 A1, IDS entered September 23, 2021).
Regarding claims 97-98, Enami teaches a composition comprising at least two antibodies comprising Fab regions, the Fab regions being different between the at least two antibodies, wherein at least one Fab region comprises a cysteine residue which forms a non-natural disulfide bond between a light chain and a heavy chain, thereby forming a non-natural disulfide bond, wherein due to the presence of said non-natural disulfide bond, the position of a disulfide bond between a light chain and a heavy chain of a Fab region is different from the position of a disulfide bond between a light chain and a heavy chain of at least one other Fab region (claim 6), wherein the antibody is a chimeric antibody, a humanized antibody or a human antibody (claim 12), wherein the non-natural disulfide bond is formed by a cysteine residue introduced at least one set of light chain-heavy chain positions selected from a) light chain position 116-heavy chain position 134, b) light chain position 116-heavy chain position 141, c) light chain position 118-heavy chain position 128, d) light chain position 121-heavy chain position 126, e) light chain position 121-heavy chain position 127, f) light chain position 124-heavy chain position 126, g) light chain position 162-heavy chain position 170, h) light chain position 162-heavy chain position 171 and i) light chain position 162-heavy chain position 173 (claim 13). Although the goal of Enami is the bispecific product, Enami produces mixtures comprising a homodimer of the first antibody (comprised of 2 HC and 2 LC), a homodimer of the second antibody (comprised of different chains from the first, 2 HC and 2 LC), and a bispecific heterodimer (paragraph 0316, Figure 1C). Enami further teaches wherein the antibody is an IgG1, IgG2, IgG3, IgG4 or IgM antibody (paragraph 0214). Enami teaches testing of the full length individual antibodies with heavy chain-light chain non-natural disulfide bonds as well as heavy chain mutants that demonstrated high binding selectivity (paragraphs 0309 and 0312), then reformatting to prepare the bispecific antibody (paragraph 0314). Therefore with different residue variations used for each full length antibody tested when combined should produce only two major antibody species.
Utilizing the residue variations as taught by Enami with two different IgG isoforms for each antibody produced, it naturally follows that this would result in only two major antibody species produced.
Regarding claim 100, Enami teaches one embodiment of the present invention is a method for making an antibody comprising at least two different Fab regions; or a composition comprising at least two antibodies comprising Fab regions, the Fab regions being different between the at least two antibodies; the method comprising: i) a step of culturing a host cell comprising a nucleic acid encoding said antibody or antibodies under conditions to express said antibody, and ii) a step of recovering said antibody or antibodies from the host cell culture, wherein said nucleic acid encodes at least one region comprising a cysteine residue which forms a non-natural disulfide bond between a light chain and a heavy chain of said Fab region, wherein due to the presence of said non-natural disulfide bond, the position of a disulfide bond between a light chain and a heavy chain in a Fab region is different from the position of a disulfide bond between a light chain and a heavy chain in at least one other Fab region (paragraphs 0173-0175).
Regarding claims 99 and 101-103, Enami teaches obtaining antibody expression vectors (paragraphs 0280-0282) and transfection of various expression vectors into 293-F cells (paragraph 085). Transfection into mammalian 293-F cells necessitates that the vectors used for cloning were mammalian expression vectors.
Regarding claim 104, Enami teaches that by transfecting the nucleic acid of any of the above embodiments into a host cell that does not produce antibodies (for example, E. coli, simian COS cell, Chinese hamster ovary (CHO) cell or myeloma cell) and culturing in an appropriate nutrient medium, the antibody encoded by the nucleic acid may also be produced (paragraph 0244).
Response to Arguments
Applicant's arguments filed April 22, 2025 have been fully considered but they are not persuasive.
Applicant submits: Thus, Applicant's claimed mixture, as amended, does not include bispecific antibodies. In contrast, nowhere does Enami disclose nucleic acids encoding, methods of making, or host cells containing, a mixture of antibodies comprising not more than two different major antibody species, where the mixture does not contain a bispecific antibody. It is respectfully submitted that Enami merely discloses the production of bispecific antibodies in the presence at least 3 antibody species, as opposed to the not more than two different major antibody species, required by Applicant's claimed invention. Thus, Enami cannot anticipate Applicant' s claimed invention. Accordingly, reconsideration and withdrawal of this rejection is respectfully requested.
In response: The broadest reasonable interpretation of claim 97 as written is a mixture of nucleic acids encoding antibodies comprising not more than two different major antibody species but can include other minor antibody species. As defined in the instant specification a “major antibody species” is more than 10% of the composition. The applicant’s examples require use of two different IgG isoforms for each antibody in the mixture with residue alterations to ensure cognate binding thus producing only two major species of antibody. The claims as written do not. If the claims were used as currently written to produce two antibodies of the same isoform it follows that a bispecific antibody would also be produced.
As Enami teaches the same residue modifications for the different possible isoforms (see paragraphs 0195-0200) it naturally follows that if two different isoforms were used with the residue alterations as taught by Enami that only two major antibody species would be produced or if the same isoform was used with different non-natural disulfide residue substitutions. Enami teaches testing of the full length individual antibodies with heavy chain-light chain non-natural disulfide bonds as well as heavy chain mutants that demonstrated high binding selectivity (paragraphs 0309 and 0312), then reformatting to prepare the bispecific antibody (paragraph 0314).
Further Enami’s claims as written are not limited to a bispecific but by BRI could also be drawn to a composition comprising two separate antibodies with different Fab regions and different cysteine modifications.
Further claims 100-102 are drawn to a method of making a mixture of antibodies with no residue alterations or specific isoforms recited, which would produce more than two major antibody species. Enami specifically teaches a method of producing a mixture comprising at least two antibodies which reads on two major antibody species.
Conclusion
No claims 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643