Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 52, 54, 56, 59, 65, 69-71, 73-74, 86, 88, 92-93, 96 and 99-100 are pending and being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 61/545,863 filed October 11, 2011,
61/546,503 filed Oct 12, 2011, 61/560,704 filed November 16, 2011 and 61/676,837 filed July 27, 2012, is acknowledged.
Objection and Rejection Withdrawn
The objection to claims 52, 96 and 100 is withdrawn in light of the claim amendment.
The rejection of claim 92 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the claim amendment.
Rejection Maintained
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
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Claims 52, 54, 56, 59, 65, 69-71, 73-74, 86, 88, 92-93, 96, 99 and 100 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 39-55 of U.S. Patent No. 9,862,778. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in wording.
Issued claim 39 recites a method of producing a multispecific antibody comprising the steps of
a. providing a first half-antibody at pH 5-9 in the presence of arginine or histidine, wherein the first half-antibody comprises a heteromultimerization domain;
b. providing a second half-antibody at pH 5-9 in the presence of arginine or histidine, wherein the second half-antibody comprises a heteromultimerization domain;
c. mixing the first and second half-antibodies to form an assembly mixture in a reducing condition comprising 50-400× molar excess of glutathione (GSH) with respect to the total amount of the half-antibodies; and
d. incubating the assembly mixture to form a multispecific antibody comprising the first and second half-antibodies, wherein the first half-antibody interacts with the second half-antibody at the heteromultimerization domain, which corresponds to instant claim 52, 86, 88.
Issued claim 40 recites the method of claim 39, wherein the arginine or histidine is present at a concentration of between 20 mM and 400 mM, which corresponds to instant claim 59.
Issued claim 41 recites the method of claim 39, wherein the first half-antibody and the second half-antibody are purified before mixing, which corresponds to instant claim 65.
Issued claim 42 recites the method of claim 39, wherein the first and second half-antibodies are produced by a bacterial cell, a yeast cell, a baculovirus, or a mammalian cell, which corresponds to instant claim 69.
Issued claim 43 recites the method of claim 42, wherein the first and second half-antibodies are produced by a mammalian cell, which corresponds to instant claim 70.
Issued claim 44 recites the method of claim 43, wherein the mammalian cell is a CHO cell, which corresponds to instant claim 71.
Issued claim 45 recites the method of claim 39, wherein the first or second half-antibody is of the IgG1, IgG2 or IgG4 isotype, which corresponds to instant claim 73.
Issued claim 46 recites the method of claim 39, wherein the first or second half-antibody comprises an Fc component, which corresponds to instant claim 74.
Issued claim 47 recites the method of claim 39, wherein one or more of steps a-d are heated at a temperature of between 25°C. and 42° C, which corresponds to instant claim 52. The reference temperature of between 25° C. and 42° C includes the claimed temperature at about 37°C.
Issued claim 48 recites the method of claim 39, wherein the GSH is added in 100-300× molar excess to the assembly mixture, which within the claimed range of 50-600 of instant claim 88.
Issued claim 49 recites the method claim 39, wherein the heteromultimerization domain of the first half antibody or the second half antibody comprises one or more of a knob, a hole, a leucine zipper, a coiled coil, or a polar amino acid residue capable of forming an electrostatic interaction, which corresponds to instant claim 92.
Issued claim 50 recites the method of claim 49, wherein the heteromultimerization domain of the first half-antibody comprises a knob and the heteromultimerization domain of the second half-antibody comprises a hole, which corresponds to instant claim 93.
Issued claim 51 recites the method of claim 39, further comprising adding a stabilizer in one or more of steps a-d, which corresponds to instant claim 52.
Issued claim 52 recites the method of claim 51, wherein the stabilizer is added to step c or step d, which corresponds to instant claim 95.
Issued claim 53 recites the method of claim 52, wherein the stabilizer is arginine or polyvinylpyrrolidone (PVP) , which corresponds to instant claim 96.
Issued claim 54 recites the method of claim 39, further comprising the step of recovering the multispecific antibody, which corresponds to instant claim 99.
Issued claim 55 recites the method of claim 54, wherein the step of recovering the multispecific antibody comprises purifying the multispecific antibody, which corresponds to instant claim 100.
Applicants’ arguments filed September 12, 2025 have been fully considered but are not found persuasive.
Applicant’s position is that claim 52 has been amended to recite, "incubating the assembly mixture with a stabilizer at about 37°C." Reference claims 39-55 of U.S. Patent No. 9,862,778 do not incubation with a stabilizer at about 37°C. Thus, the pending claims are patentably distinct from claims 39-55 of U.S. Patent No. 9,862,778. Applicant respectfully requests the rejection to claims 52, 54, 56, 59, 65, 69-71, 73- 74, 79, 86, 88, 92-96, 99 and 100 for nonstatutory obviousness-type double patenting over claims 39-55 of U.S. Patent No. 9,862,778 be withdrawn.
In response, the amendment to claim 52 is acknowledged.
Issued claim 22 recites the method of claim 1, wherein one or more of steps a-d are heated at a temperature of between 25° C. and 42° C.
Issued claim 34 recites the method of claim 1, further comprising adding a stabilizer in one or more of steps a-d.
Issued claim 35 recites the method of claim 34, wherein the stabilizer is added to step c or step d.
Issued claim 36 recites the method of claim 35, wherein the stabilizer is arginine or polyvinylpyrrolidone (PVP).
Issued claim 47 recites the method of claim 39, wherein one or more of steps a-d are heated at a temperature of between 25° C. and 42° C. The reference temperature of between 25°C and 42°C includes the claimed temperature at about 37°C.
Issued claim 51 recites the method of claim 39, further comprising adding a stabilizer in one or more of steps a-d.
Issued claim 52 recites the method of claim 51, wherein the stabilizer is added to step c or step d.
Issued claim 53 recites the method of claim 52, wherein the stabilizer is arginine or polyvinylpyrrolidone (PVP).
Issued claim 65 recites the method of claim 56, wherein incubating the assembly mixture is done at a temperature between 15°C and 39°C in the presence of Polyvinylpyrrolidone (PVP). The reference temperature of between 15°C and 42°C includes the claimed temperature at about 37°C.
For these reasons, the rejection is maintained.
Claims 52, 54, 56, 59, 65, 69-71, 73-74, 86, 88, 92-93, 96, 99 and 100 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,725,065. Although the conflicting claims are not identical, they are not patentably distinct from each other because while the ‘065 patent issued from 16/820,660 was not subjected to restriction requirement, which served as the parent for presence case and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 1 recites a method of producing a heteromultimeric protein (aka bispecific or multispecific antibody), said method comprising:
a. obtaining a first half-antibody, wherein the first half-antibody comprises a heterodimerization domain;
b. obtaining a second half-antibody, wherein the second half-antibody comprises a heterodimerization domain;
c. adjusting pH of each half-antibody to between pH 4 and 9;
d. mixing the first and second half-antibodies to obtain an assembly mixture; e. adding a 50-400x molar excess of glutathione (GSH) to the assembly mixture; and
f. incubating the assembly mixture to form a heteromultimeric protein comprising the first half-antibody and the second half-antibody, which corresponds to instant claims 52, 86, 88. The reference 50-400x molar excess of glutathione (GSH) is within the claimed range of 50-600x molar excess of glutathione of instant claim 88.
Issued claim 2 recites the method of claim 1, wherein the first and second half-antibodies each comprise an Fc component, which corresponds to instant claim 74.
Issued claim 3 recites the method of claim 1, wherein in step c the pH of the first and second half-antibodies are adjusted to pH 4-9 in the presence of a solubilizer, which corresponds to instant claim 52 step a and b.
Issued claim 4 recites the method of claim 3, wherein the solubilizer is arginine that is added to a final concentration of between 20 mM to 1M prior to adjusting the pH, which overlaps the claimed range of between 20 mM to 400 mM of instant claim 59.
Issued claim 5 recites the method of claim 1, wherein the heterodimerization domain of the first and/or second half-antibodies comprises one or more of a knob, a hole, a leucine zipper, a coiled coil, or a polar amino acid residue capable of forming an electrostatic interaction, which corresponds to instant claim 92.
Issued claim 6 recites the method of claim 1, wherein the heterodimerization domain of the first half-antibody comprises a knob and the heterodimerization domain of the second half-antibody comprises a hole, which corresponds to instant claim 93.
Issued claim 7 recites the method of claim 1, wherein the pH is adjusted after mixing, which is within the purview of one of ordinary skill in the art and is an obvious variation.
Issued claim 8 recites the method of claim 1, further comprising incubating the assembly mixture at a temperature of between 15° C. and 39° C for at least 30 minutes. The temperature between 15° C. and 39° C include the claimed range at least about 37° C of instant claim 52.
Issued claim 9 recites the method of claim 1, wherein the assembly mixture in step f has an oxidation potential of between −200 to −600 mV. The instant specification also teaches oxidation potential of between −200 to −600 mV.
Issued claim 10 recites the method of claim 1, wherein incubating the assembly mixture is done at a temperature between 15° C and 39° C in the presence of Polyvinylpyrrolidone (PVP), which corresponds to instant 52.
Issued claim 11 recites the method of claim 10, wherein the PVP is added up to 40% (w/v, species), whereas instant claim 96 is generic with respect to the concentration.
Issued claim 12 recites the method of 1, wherein the first or second half-antibody is produced by a bacterial cell, a yeast cell, a baculovirus, or a mammalian cell, which corresponds to instant claim 69.
Issued claim 13 recites the method of claim 1, wherein the first or second half-antibody is produced by a CHO cell, which corresponds to instant claim 71.
Issued claim 14 recites the method of claim 1, wherein the GSH is added in 100-300X molar excess (species) whereas instant claim 88 is generic with respect to the reductant. Further, the 100-300X molar excess is within the claimed 50-600X molar excess of instant claim 88. Instant claim 86 recites the reductant is glutathione (GSH).
Issued claim 15 recites the method of claim 1, wherein the GSH is added in 200X molar excess, which corresponds to instant claims 85, 88. The 200X molar excess is within the claimed 50-600X molar excess of instant claim 88.
Issued claim 16 recites the method of claim 6, wherein the knob comprises a T366W substitution and the hole comprises T366S, L368A, and Y407V substitutions (species), whereas instant claims 92 and 93 are generic with respect to the knob and hole substitution.
Issued claim 17 recites the method of claim 1, further comprising adjusting the pH after the heteromultimeric protein is formed in step f.
Issued claim 18 recites the method of claim 17, wherein the pH is lowered after the heteromultimeric protein is formed in step f.
Issued claim 19 recites the method of claim 1, further comprising adjusting the temperature after the heteromultimeric protein is formed in step f.
Issued claim 20 recites the method of claim 19, wherein the temperature is lowered after the heteromultimeric protein is formed in step f.
Adjusting the pH or temperature after the formation of heteromultimeric protein, e.g., multispecific or bispecific antibody is within the purview of one of ordinary skill in the art to improve solubility (reducing aggregation) of the antibody.
Applicants’ arguments filed September 12, 2025 have been fully considered but are not found persuasive.
Applicant’s position is that claim 52 has been amended to recite, "incubating the assembly mixture with a stabilizer at about 37°C." Reference claims 1-20 of U.S. Patent No. 11,725,065 do not recite incubation with a stabilizer at about 37°C. Thus, the pending claims are patentably distinct from claims 1-20 of U.S. Patent No. 11,725,065. Applicant respectfully requests the rejection to claims 52, 54, 56, 59, 65, 69-71, 73- 74, 79, 86, 88, 92-96, 99 and 100 for nonstatutory obviousness-type double patenting over claims 1-20 of 11,725,065 be withdrawn.
In response, the amendment to claim 52 is acknowledged.
Issued claim 10 recites The method of claim 1, wherein incubating the assembly mixture is done at a temperature between 15°C. and 39°C in the presence of Polyvinylpyrrolidone (PVP). The reference temperature of between 15° C. and 42° C includes the claimed temperature at about 37°C.
For these reasons, the rejection is maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641