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 .
Claims 1-2, 4-6, 18-19, 21-23, 35-36, 38-40, 49-50, and 52-54, of record 12/16/2025, are pending and subject to prosecution. Claims 1-2, 4-6, 18-19, 21, 23, 40, and 54 are amended.
Status of Prior Rejections/Response to Arguments
RE: Objection to the drawings:
The submission of replacement drawings is effective to obviate the objection. The objection is withdrawn.
RE: Objection to claims 1-2, 4-5, and 54:
The amendment to claims 1-2, 4-5, and 54 is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claims 5-6, 18-19, 21, 23, 40, and 54 under 35 U.S.C. 112(b):
The amendment to claims 5-6, 18-19, 21, 23, 40, and 54 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claims 1-2, 4-5, 18-19, 21-22, 35-36, 38, 49-50, and 52 under 35 U.S.C. 103 over Bacac et al. (US 20190177413 A1) in view of Babb et al. (WO 2017184831 A1) and Kawabe et al. (Cytotechnology, 2012):
The applicant asserts that the prior art combination does not teach the particular arrangements of expression cassettes recited in the instant claims (Applicant Remarks, page 37-38). The applicant asserts that the cases cited in MPEP 2144.04(VI)(C) (cited in the rejection) do not involve technology analogous to the claimed invention and argues that the rejection is “essentially” an “obvious to try” argument, which allegedly only applies where a finite number of identified, predictable solutions exist (Applicant Remarks, page 38).
The applicant’s arguments have been fully considered but are not found persuasive. It appears that the applicant is attempting to argue that the MPEP only applies in situations that involve the same technology and/or problems as the invention at hand. However, the rearrangement of parts within a whole remains prima facie obvious, whether the parts are aspects of a mechanical device or antibody chain expression cassettes in a nucleic acid. As further evidence that rearranging the order of expression cassettes would be obvious, Kawabe et al. teach that optimal orientation for multiple expression units should be considered to achieve higher expression of antibody genes (See page 276, col. 1, full ¶1), which implies not only that one of ordinary skill can reorder antibody chain expression cassettes but that one should do so in order to optimize expression levels. Additionally, as a trivalent bispecific antibody comprises a limited number of chains that can be expressed from a limited number of cassettes, even if the copy number of an integrated expression cassette is increased (per Kawabe et al., see Abstract and fig. 1 and 3), the number of combinations is finite and each yields predictable results, absent contrary evidence.
The rejection is maintained.
RE: Rejection of claims 1-2, 4-6, 18-19, 21-23, 35-36, 38-40, 49-50, and 52-53 under 35 U.S.C. 103 over Bacac et al. (US 20190177413 A1) in view of Babb et al. (WO 2017184831 A1) and Kawabe et al. (Cytotechnology, 2012), further in view of Sauer (Nucleic Acids Research, 1996):
RE: Rejection of claims 1-2, 4-6, 18-19, 21-23, 35-36, 38-40, 49-50, and 52-54 under 35 U.S.C. 103 over Bacac et al. (US 20190177413 A1) in view of Babb et al. (WO 2017184831 A1) and Kawabe et al. (Cytotechnology, 2012), further in view of Sauer (Nucleic Acids Research, 1996), further in view of Ponsaerts et al. (Gene Therapy, 2004):
The applicant asserts that Sauer discloses only native yeast lox sites and does not teach heterospecific mammalian lox sites (Applicant remarks, page 39).
This argument is not found persuasive. Sauer teaches the minimum requirements for a functional lox site as well as the generation of synthetic lox sites (See page 4609, col. 2, full 2 and page 4610, col. 1, 1). One of ordinary skill in the art (i.e., one capable of the design and construction of polynucleotides comprising recombination sites) would be able to apply the teachings of Sauer to mammalian cells or even incorporate the native yeast lox sites, since lox sites are recognized by Cre across species.
However, in light of the amendment to claims 6, 23, 40, and 54, the rejections are withdrawn.
RE: Provisional rejection of claims 18-19 and 21-23 on the ground of nonstatutory double patenting over claims 1-2, 4-7, and 9-10 of co-pending Application No. 17/553516:
RE: Provisional rejection of claims 35-36 and 38-40 on the ground of nonstatutory double patenting over claims 1-2 and 4-6 of co-pending Application No. 17/553523:
The terminal disclaimers filed on 12/16/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on Application Nos. 17/553516 and 17/553523 have been reviewed and are accepted. The terminal disclaimers have been recorded. The rejections are withdrawn.
New/Maintained Rejections
Claim Rejections - 35 USC § 103
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-5, 18-19, 21-22, 35-36, 38, 49-50, and 52 remain rejected under 35 U.S.C. 103 as being unpatentable over Bacac et al. (US 20190177413 A1), of record, in view of Babb et al. (WO 2017184831 A1), of record in IDS dated 3/10/2021, and Kawabe et al. (Cytotechnology, 2012), of record in IDS dated 3/10/2021.
Regarding claim 1-2, 4-5, 18-19, 21-22, 35-36, 38, 49-50, and 52: Bacac et al. teach bispecific antigen binding molecules, such as antibodies, that can comprise three antigen binding moieties (which reads on “trivalent, bispecific antibody”) and methods of making and using the molecules (See ¶0021, 0086, and 0240-0241). One antigen binding moiety can be a crossover Fab molecule wherein the heavy and light chain constant regions are exchanged (which reads on “domain exchanged Fab fragment VH-VL or CH1-CL”) (See ¶0018 and fig. 1). The crossover Fab molecule can be linked to a heavy chain (which reads on “an extended heavy chain”) (See ¶0321). The Fc domain of the antibody (which reads on “CH3 domain”) can have a knob-in-hole modification, comprising a T366W mutation in one heavy chain and T366S, L368A, and Y407V mutations in the other heavy chain (See ¶0034 and 0174-0180). The knob can be formed on the same heavy chain bearing the crossover Fab molecule (which reads on “the first heavy chain”) (See ¶0321). Bacac et al. teach a method of producing the bispecific antibody comprising culturing (which reads on “cultivating”) a host cell (which also reads on “a composition”) comprising a polynucleotide (which reads on “deoxyribonucleic acid” and “exogenous nucleotide sequence”) encoding the antibody and recovering the expressed antibody from the host cell or culture medium (See ¶0238). The host cell can be a mammalian cultured cell, such as a CHO cell (See ¶0109). The antibody can be encoded by two or more co-expressed polynucleotides (which reads on “a first deoxyribonucleic acid and a second deoxyribonucleic acid”) (See ¶0229).
Bacac et al. do not expressly teach the order of the expression cassettes or multiple expression cassettes encoding the antibody chains.
Babb et al. teach integration and expression of genes encoding a bispecific antibody (See Abstract). The relative positions of the nucleic acids encoding the heavy and light chains can vary (See ¶0012, 0024, and 0082-0089). Babb et al. also teach that multiple different recombination sites can be provided for genomic integration, along with multiple different selectable markers (See ¶0034-0036 and 0069-0070).
Kawabe et al. teach Cre recombinase-mediated cassette exchange for the site-specific integration (which reads on “stably integrated into the genome”) of antibody genes in CHO cells (See Abstract and fig. 4). The expression cassettes are flanked by loxP sites (which read on “recombination recognition sequence”) and can have fluorescent or drug resistance markers for screening (See Abstract; page 276, col. 2, full ¶1; and fig. 1-4). The recombination reaction can be repeated in order to increase copy number of an integrated expression cassette (See Abstract and fig. 1 and 3). A Cre expression vector is transfected into host cells along with a transgene donor vector (which reads on “the recombinase(s) and the deoxyribonucleic acids are introduced… simultaneously”) (See page 270, col. 1, ¶1). Kawabe et al. teach that optimal orientation for multiple expression units should be considered to achieve higher expression of the transgene (See page 276, col. 1, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Bacac et al. to incorporate recombinase-mediated cassette exchange, as taught by Babb et al. and Kawabe et al. One be would be motivated to make this modification because Kawabe et al. teach that the system can be used for increasing the production of recombinant antibodies through integration at a stable genomic site and through insertion of multiple copies of an expression cassette (See Abstract and fig. 1 and 3). There would be a reasonable expectation of success in making this modification because Babb et al. teach that the use of multiple recombination recognition sites can be used to integrate nucleic acids encoding multiunit antibodies (See ¶0031, 0033, 0035, and 0045-0048).
While Bacac et al., Babb et al., and Kawabe et al. do not expressly teach the order of the antibody expression cassettes, the rearrangement of parts is considered to be an obvious modification. See MPEP 2144.04(VI)(C). Arriving at the claimed ordering of heavy and light chain cassettes would be obvious to one having ordinary skill in the art. Further, Kawabe et al. teach that increasing copy number can increase transgene production and that optimal orientation for multiple expression units should be considered to achieve higher expression of the transgene (See page 276, col. 1, full ¶1 and fig. 1 and 3), which suggests that the expression components of a given antibody will need to be arranged in different positions and in different numbers in order to optimize production. The combined teachings of Bacac et al., Babb et al., and Kawabe et al. therefore render obvious the limitations of the instant claims.
Claims 1-2, 4-6, 18-19, 21-23, 35-36, 38-40, 49-50, and 52-53 are rejected under 35 U.S.C. 103 as being unpatentable over Bacac et al. (US 20190177413 A1), of record, in view of Babb et al. (WO 2017184831 A1), of record, and Kawabe et al. (Cytotechnology, 2012), of record, further in view of Sauer (Nucleic Acids Research, 1996), of record, and Smith et al. (Nature Genetics, 1995).
The teachings of Bacac et al., Babb et al., and Kawabe et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 6, 23, 39-40, and 53: Following the discussion of claims 1-2, 4-5, 18-19, 21-22, 35-36, 38, 49-50, and 52, Bacac et al., modified by Babb et al. and Kawabe et al., render obvious the production of trivalent bispecific antibodies using site-specific Cre-mediated recombination but do not teach the use of multiple different recombination recognition sequences or a split selection marker.
Sauer teaches variant heterospecific lox sites (which read on “different recombination sequences”) that enable Cre-mediated recombination independently at multiple loci without unwanted inter-locus recombination events (See Abstract and page 4608, col. 2, full ¶2).
Smith et al. teach genetic selection by means of reconstruction of a selectable marker via site-specific recombination (See Abstract). Cre-mediated recombination was used to reconstruct a hypoxanthine phosphoribosyltransferase gene from two polynucleotide sequences, each comprising a non-overlapping 5’ or 3’ segment of the gene with a loxP site (See page 377, col. 2, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Bacac et al., modified by Babb et al. and Kawabe et al., to comprise the use of variant lox sites, as taught by Sauer, for inserting antibody expression cassettes in a given position at a particular site. One would be motivated to make this modification because Sauer teaches that the use of multiple pairs of different lox sites would enable recombination by a single recombinase without generating complicating inversions, translocations, or large-scale deletions (See page 4608, col. 2, full ¶1-2). There would be a reasonable expectation of success in making this modification because variant lox sites could be readily cloned into expression vectors for expression in mammalian cells.
It also would have been obvious to modify the method of Bacac et al., modified by Babb et al. and Kawabe et al., to comprise the use of a split selectable marker, such as is taught by Smith et al., wherein the 5’ portion of the expression cassette is located on one polynucleotide and the 3’ portion on another polynucleotide. One would be motivated to make this modification because Smith et al. teach that it enables rapid confirmation that the desired genomic rearrangements have been achieved (See page 382, col. 2, ¶1), and such a modification could be readily performed.
Claims 1-2, 4-6, 18-19, 21-23, 35-36, 38-40, 49-50, and 52-54 are rejected under 35 U.S.C. 103 as being unpatentable over Bacac et al. (US 20190177413 A1), of record, in view of Babb et al. (WO 2017184831 A1), of record, and Kawabe et al. (Cytotechnology, 2012), of record, further in view of Sauer (Nucleic Acids Research, 1996), of record, and Smith et al. (Nature Genetics, 1995), further in view of Ponsaerts et al. (Gene Therapy, 2004), of record.
The teachings of Bacac et al., Babb et al., Kawabe et al., Sauer, and Smith et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 54: Following the discussion of claims 1-2, 4-6, 18-19, 21-23, 35-36, 38-40, 49-50, and 52-53, Bacac et al., modified by Babb et al., Kawabe et al., Sauer, and Smith et al., render obvious the production of trivalent bispecific antibodies using site-specific Cre-mediated recombination but do not teach delivery of mRNA for Cre expression.
Ponsaerts et al. teach efficient gene editing using electroporated Cre recombinase mRNA (See Abstract and fig. 3).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Bacac et al., modified by Babb et al., Kawabe et al., Sauer, and Smith et al., to substitute Cre mRNA, such as is taught by Ponsaerts et al., for Cre plasmid DNA. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the result of the substitution yields more than predicted results.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic, can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633