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 Interpretation
Claim 1 recites a cysteine engineered antibody construct comprising one or more cysteine insertion mutations wherein a cysteine is inserted between positions denoted by Kabat numbering for VH, VL, CH1, or VL domains or EU numbering for the CH2 domain. Insertion is interpreted in line with the Specification to mean that the cysteine residue is incorporated into the polypeptide chain between the two number positions – not that one of the residue at one of the number positions is substituted with a cysteine nor that the residue at one of the number positions is thiolated; see paragraphs 0005 and 0038. This language is repeated in claims 23 and 32. Claim 5 recites symmetrical mutations and is interpreted as comprising the same position insertion on both the heavy chains or on both light chains; see paragraph 0076.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 7-11, 14-16, 18-28, 31-34, and 38-42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 23, and 32 recite an antibody construct which Specification paragraph 0044 defines as encompassing full-length antibodies, functional fragments of full-length antibodies, and Fc fusion proteins. Claims 1, 23, and 32 also recite that the antibody construct is based on an immunoglobulin G (IgG). Specification paragraph 0049 states that the limitation “based on” is “used herein to describe an amino acid sequence, mean[s] that the subject amino acid sequence is substantially identical to the stated.” Paragraph 0050 defined “substantially identical” as “the amino acid sequence shares at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with its reference amino acid sequence. […] In general, for peptides, the length of comparison sequences will be at least 10 amino acids, but one skilled in the art will understand that the actual length will depend on the overall length of the sequences being compared. In certain embodiments, the length of comparison sequences may be the full-length of the protein or peptide sequence.” Similarly, claim 18 recites the phrase “based on an IgG1”.
The claims have been amended to recite that the Fc region comprises two CH2 and two CH3 domains, and the Fab, of which only one is required, comprises one of each: CL, VL, CH1, and VH domains. In contrast with an IgG, the instantly claimed construct lacks a second Fab, comprising CL, VL, CH1, and VH domains, and two hinges.
Given that each light chain, comprising a VL and CL domain, is approximately 215 amino acids long and each heavy chain, comprising VH, CH1, CH2, and CH3 domains, is approximately 475 amino acids long, then an IgG comprising two heavy and two light chains would be approximately 1,380 amino acids long. If construct comprises only those required domains (i.e. lacking the second Fab and two hinges), then it lacks one light chain (approximately 215 amino acids), two hinges (approximately 15 amino acids each) and the VH and CH1 domains (approximately 223 amino acids). A construct comprises only those required domains would total approximately 912 amino acids, or about 66% of the amino acids of an IgG antibody. All amino acid approximations come from the IMGT Scientific chart for numbering of the constant domains of the heavy and light chains of an IgG1 antibody.
Thus, it is unclear how a construct only required to comprise approximately 66% of an IgG could be “based on” or “substantially identical to” an IgG antibody.
For the purpose of compact prosecution, the claims have been interpreted as comprising the CH1, CH2, and CH3 domains based on an IgG. The Office suggests replacing “wherein the antibody construct is based on an immunoglobulin G (IgG).” with “wherein the CH1, CH2, and CH3 domains are based on an immunoglobulin G (IgG).” in claims 1, 23, and 32 and replacing claim 18 with “wherein the CH1, CH2, and CH3 domains are based on an IgG1.”
Examiner left a voicemail for Applicant’s Attorney of record, Brett Lovejoy, on September 15, 2026 asking to discuss a proposed Examiner’s Amendment, but did not receive a call back.
Claims 2-5, 7-11, 13-22, 24-28, 31, 33, 34, and 38-42 are rejected for depending from claims 1, 23, or 32 and failing to remedy the indefiniteness. Claim 43 is not included in this rejection because it requires the construct to be comprised of both Fabs and, thus, only lacks requirement of two hinges (total of 30 amino acids – well within the 85% identity) relative to the components of an IgG.
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 7-11, 14, 16, 18, 20-24, 26-28, 38-40, and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, 9, 11, 12, 16, 17, 23, 29, 30, 32, 62, 63, and 67-69 of copending Application No. 19/091,242 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1-5, 7-11, 14, 18, 20-24, 26, and 42, copending claims 1, 6, 8, 9, 12, 16, 17, 29, 30, and 32 teach an antibody-drug conjugate with formula of instant claims 23 and 24 and the cysteine substitution mutations of instant claims 1, 8, 9, 11, and 23 wherein the antibody sequence is of an IgG. Regarding the number of mutations, copending claim 17 recites five different insertion mutations and claim 1 recites up to 8 linkers, therefore, some insertion mutations from those five recited in copending claim 17 must be duplicated in the other heavy or light chain making the mutation a symmetrical mutation. Copending claims 6, 8, and 9 recite a heterodimeric Fc comprising knob-in-hole mutations. Regarding thermal stability, Table 2.2 evidences that that cysteine insertion mutations recited do not alter the Tm by more than 8 degrees Celsius from the parent antibody. Regarding instant claim 16, copending claims 30 and 32 teach an antibody-drug conjugate where the antibody comprises an antigen binding site binds c-Met, a tumor associated antigen.
Regarding instant claims 27 and 28, copending claims 62 and 63 recite a pharmaceutical composition comprising the antibody-drug conjugate and pharmaceutically acceptable carrier or diluent and the method of treating cancer.
Regarding instant claims 38-40, copending claims 67-69 teach a polynucleotide encoding the antibody construct, a vector comprising the polynucleotide, and a host cell comprising the vector.
Claims 1, 6, 8, 9, 11, 12, 16, 17, 23, 29, 30, 32, 62, 63, and 67-69 of copending Application No. 19/091,242 read on instant claims 1-5, 7-11, 13, 14, 16-18, 20-24, 26-28, 38-40, and 42 in an anticipatory manner.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 31-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, 9, 11, 12, 16, 17, 23, 29, 30, 32, 62, 63, and 67-69 of copending Application No. 19/091,242 in view of Katragadda et al. (US 2019/0099499 A1; Published: April 4, 2019).
The teachings of Application No. 19/091,242 as related to claim(s) 1-5, 7-11, 13, 14, 16-18, 20-24, 26-28, 38-40, and 42, from which these claims depend are given previously in this Office action and are fully incorporated here.
The copending claims do not teach the method of preparing the antibody-drug conjugate.
Regarding instant claims 31-34, Example 3 of Katragadda et al. demonstrates preparing an antibody conjugate with by reducing cysteine residues (see TCEP in paragraph 0183) and incubating the antibody with a linker-payload moiety wherein the linker is thiol reactive (mal for maleimide in paragraph 0186).
Given that the copending claims teach linker-payload moieties with a maleimide linker (see ADC 001, ADC 003, and ADC 004 in copending claims 29 and 30), it would have been obvious and one would have had a reasonable expectation of success and predictability to combine the antibody and linker-payload moieties recited in the copending claims by the method taught in Katragadda et al. to prepare the antibody-drug conjugate.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 15, 41, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, 9, 11, 12, 16, 17, 23, 29, 30, 32, 62, 63, and 67-69 of copending Application No. 19/091,242 in view of Dimasi et al. (WO 2009/092011 A1; Published: July 23, 2009).
The teachings of Application No. 19/091,242 as related to claim(s) 1-5, 7-11, 13, 14, 16-18, 20-24, 26-28, 38-40, and 42, from which these claims depend are given previously in this Office action and are fully incorporated here.
The copending claims do not teach a bispecific cysteine engineered antibody construct.
Regarding instant claim 15, Dimasi et al. recites a cysteine engineered bispecific antibody construct; see claim 29. Regarding instant claims 41 and 43, Dimasi et al. exemplifies a cysteine engineered antibody described as an IgG and comprising two Fab antigen bind domains, which as a result is bivalent; see Figure 1A.
Because the copending claims and Dimasi et al. recite cysteine engineered antibodies conjugated to a drug or therapeutic agent and administered in a method of treating cancer, it would have been obvious and one would have had a reasonable expectation of success modifying the copending antibody construct to bind c-Met and another tumor-associated antigen. One would have been motivated to target two tumor associated antigens in a bispecific antibody-drug conjugate in order to improve specificity and avoid resistance by antigen escape.
Additionally, because Dimasi et al. exemplifies an IgG antibody comprising the cysteine modifications, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to make an IgG antibody, which comprises two Fabs and is bivalent, having the cysteine modifications.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s amendments filed June 23, 2026 are acknowledged. Any rejection not repeated above is resolved by amendment.
Applicant’s arguments, see the top paragraph on page 14, filed June 23, 2026, with respect to the rejection(s) of claim(s) 1-5, 7-11, 14-16, 18-28, 31-34, and 38-40 under U.S.C. 112(a) and (b) have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the “based on an immunoglobulin G (IgG)” limitation interpreted in light of the claim amendments.
Regarding the provisional nonstatutory double patenting rejections, the provisional nonstatutory double patenting rejections over the copending claims of 19/091,242 will be withdrawn when it is the last remaining rejection of record. The instant application has an earlier patent term filing date of March 25, 2022, the filing date of the PCT, compared to September 28, 2023 for Application No. 19/091,242; see MPEP 804 I.B.1.a. and 1490 VI.D.2.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Vollmar et al. (Bioconjugate Chemistry. 28: 2538-2548; Published: September 8, 2017) teaches that a cysteine-substituted antibody-drug conjugate at position 149 of the CL domain demonstrated favorable in vivo stability and persistent tumor growth inhibition compared to cysteine substitutions at other sites including position 118 of the CH1 domain and 205 of the CL domain. Benjamin et al. (Molecular Pharmaceutics. 16: 2795-2807; Published: May 8, 2019) teaches the thiolation and conjugation of Q295 of the CH2 domain.
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 KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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