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 .
Status of the Claims
Claims 1 – 4, 6 – 10, 13 – 14, 16, 18 – 19, 21, 24, 26, 28 – 29, and 33 are currently pending are the subject of this Office Action. This is the first Office Action on the merits of the claims.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 – 4, 6 – 10, 13 – 14, 16, 18 – 19, 21, 24, 26, 28 – 29, and 33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by SCHIBLI (WO 2020/188061 A1, published 09/24/2020, an IDS reference submitted 06/24/2024).
Independent claim 1 of the present application is directed to a method for producing an antibody-linker conjugate by means of a transglutaminase, the method comprising a step of conjugating a linker comprising the structure (shown in N -> C direction) (Sp1)-K-(Sp2)-B-(Sp3) or (Sp1)-B-(Sp2)-K-(Sp3) to a Gln residue comprised in an antibody, wherein " (Sp1) is a chemical spacer or is absent;" (Sp2) is a chemical spacer or is absent; " (Sp3) is a chemical spacer or is absent; " K is lysine or a lysine derivative or a lysine mimetic; " B is a linking moiety or a payload; wherein the linker is conjugated to the Gln residue comprised in the antibody via a primary amine comprised in the side chain of the lysine residue, the lysine derivative or the lysine mimetic; and wherein the antibody is contacted with less than 80 molar equivalents of the linker.
SCHIBLI is directed to a method for generating an antibody-linker conjugate by means of a microbial transglutaminase (MTG), which method comprises the step of conjugating a linker comprising the peptide structure (shown in N -> C direction) Gly-(Aax)m-B-(Aax)n via the N-terminal primary amine of the N-terminal glycine (Gly) residue to a glutamine (Gln) residue comprised in the heavy or light chain of an antibody, wherein
• m is an integer between ≥0 and ≤12
• n is an integer between ≥ 0 and ≤12
• m + n ≥ 0,
• Aax is an amino acid or an amino acid derivative, and
• B is a linking moiety. See SCHIBLI at claim 1. SCHIBLI teaches that the linker comprises at least one lysine (see SCHIBLI at claim 29), and SCHIBLI teaches that the antibody is mixed with at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 molar equivalents excess of peptide linker versus the antibody (SCHIBLI at p. 32, fourth paragraph).
According to the present specification, “the chemical spacers (Sp1), (Sp2) and (Sp3) each independently comprise between 0 and 12 amino acid residues” (specification at p. 19, lines 15 – 16). Because the Sp1 in the claimed (Sp1)-K-(Sp2)-B-(Sp3) structure of present claim 1 may be Gly and Aax in SCHIBLI’s Gly-(Aax)m-B-(Aax)n structure may be lysine (K), SCHIBLI’s Gly-(Aax)m-B-(Aax)n encompasses the presently claimed (Sp1)-K-(Sp2)-B-(Sp3).
Thus, SCHIBLI anticipates present claims 1, 4, 13, and 28 – 29.
Regarding claims 2 and 24, SCHIBLI teaches that the Gln residue in the Fc domain of the antibody is Gln residue Q295 (EU numbering) of the CH2 domain of an IgG antibody. See SCHIBLI at claim 20.
Regarding claim 3, SCHIBLI teaches that the glycosylated antibody is an IgG antibody that is glycosylated at residue N297 (EU numbering) of the CH2 domain. See SCHIBLI at claim 18.
Regarding claims 6 – 7, SCHIBLI teaches that two antibodies of IgG-subclass (antibody 1: anti Her2 IgG1, antibody 2: anti CD38 IgG1) were modified as follows: 1 mg/mL of non-deglycosylated antibody (~6.67mM) was mixed with 80 molar equivalents of peptide linker (i.e. ~533μM), 6 U/mL MTG and buffer (see SCHIBLI at Example 1, p. 68). Thus, SCHIBLI teaches that transglutaminase is added to the conjugation reaction at a concentration of 6 U/mg antibody, which is within the presently claimed range.
Regarding claim 8, SCHIBLI teaches that method is preferably carried out at a pH ranging from 6 to 8.5. See SCHIBLI at p. 32, fifth paragraph.
Regarding claims 9 – 10, SCHIBLI teaches the peptide structure Gly-(Aax)m-B-(Aax)n, wherein m is an integer between ≥ 0 and ≤12, n is an integer between ≥ 0 and ≤12, and Aax is an amino acid or an amino acid derivative (see SCHIBLI at claim 1). Thus, SCHIBLI teaches spacers with 0 – 12 amino acids each. Furthermore, SCHIBLI teaches that the net charge of the linker is neutral or positive (see SCHIBLI at claim 26) and that the linker does not comprise negatively charged amino acid residues (see SCHIBLI at claim 27).
Regarding claim 14, SCHIBLI teaches that at least one of the one or more linking moieties B comprises a bioorthogonal marker group, or a non-bio-orthogonal entity for crosslinking. See SCHIBLI at claim 4.
Regarding claim 16, SCHIBLI teaches a method for generating an antibody-payload conjugate, the method comprising the steps of a) generating an antibody-linker conjugate and b) linking a payload to the one or more linking moieties B of the antibody-linker conjugate. See SCHIBLI at claim 6.
Regarding claim 18, SCHIBLI teaches that B is a payload. See SCHIBLI at claim 33.
Regarding claim 19, SCHIBLI teaches that one or more payloads is selected from a group consisting of: a toxin, a cytokine, a growth factor, a radionuclide, a hormone, an anti-viral agent, an anti-bacterial agent, a fluorescent dye, an immunoregulatory/ immunostimulatory agent, a half-life increasing moiety, a solubility increasing moiety, a polymer-toxin conjugate, a nucleic acid, a biotin or streptavidin moiety, a vitamin, a target binding moiety, and an anti-inflammatory agent. See SCHIBLI at claim 11.
Regarding claim 21, SCHIBLI teaches that linker may further comprise other motifs or self-immolative groups that allow efficient release of the payload inside a target cell if required. See SCHIBLI at p. 19, last sentence of first paragraph.
Regarding claim 26, SCHIBLI teaches a bond formed between the γ-carboxamide of the glutamyl residue of the acyl glutamine-containing amino acid donor sequence and a primary (1°) amine of the amino donor-comprising substrate. See SCHIBLI at p. 2, third paragraph.
Regarding claim 33, SCHIBLI teaches the treatment of a patient suffering from, being at risk of developing, and/or being diagnosed for a neoplastic disease, neurological disease, an autoimmune disease, an inflammatory disease or an infectious disease. See SCHIBLI at claim 79.
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 – 4, 6 – 10, 13 – 14, 16, 18 – 19, 21, 24, 26, 28 – 29, and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 26 of U.S. Patent No. 12,076,412 in view of SCHIBLI.
Patented claim 1 recites antibody-drug conjugate comprising:
a) an IgG antibody; and
b) a linker comprising a drug moiety B, wherein the drug moiety B is a toxin covalently linked to a peptide selected from the group consisting of: RKAA (SEQ ID NO:1), RKA (SEQ ID NO:2), ARK (SEQ ID NO:3), or RK-Val-Cit (SEQ ID NO:54);
wherein the linker is conjugated to the IgG antibody via an isopeptide bond formed between the γ-carboxamide group of glutamine residue Q295 (EU numbering) of the CH2 domain of the antibody and the primary amine comprised in the side chain of the lysine residue comprised in the peptide.
Patented claim 2 recites that the toxin is linked to the N- or C-terminus of the peptide via a self-immolative moiety.
Patented claim 3 recites that the IgG antibody is glycosylated at residue N297 (EU numbering) of the CH2 domain.
Patented claim 4 recites that the IgG antibody is an IgG1 antibody.
The main difference between the present claims and the patented claims is that the present claims recite a method for producing an antibody-linker conjugate by means of a transglutaminase, wherein the antibody is contacted with less than 80 molar equivalents of the linker. However, SCHIBLE teaches this difference. The teachings of SCHIBLE, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 102 above.
Because the patented claims recite the antibody-drug conjugate of present claim 1 and SCHIBLE teaches a method for producing the antibody-drug conjugate by means of a transglutaminase, wherein the antibody is contacted with less than 80 molar equivalents of the linker, it would have been obvious to one having ordinary skill in the art to produce the patented claims’ antibody-drug conjugate with the method of SCHIBLI to arrive to the method of the present claims. There would have been a reasonable expectation of success because SCHIBLI provides an antibody conjugation technology that allows the manufacture of highly homogenous conjugation products, both as regards stoichiometry as well as site-specificity of the conjugation.(see SCHIBLI at p. 3, second to last paragraph).
Claims 1 – 4, 6 – 10, 13 – 14, 16, 18 – 19, 21, 24, 26, 28 – 29, and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 36 – 37, 41, 48, 53, 64, 78 – 91 of copending Application No. 18/177,430 in view of SCHIBLI.
Copending claim 1 recites a method for generating an antibody-linker conjugate by means of a microbial transglutaminase (MTG), the method comprising a step of conjugating a linker comprising the structure (shown in N—>C direction) Aax-(Sp1)-B1-(Sp2) via a primary amine in the N-terminal residue Aax to a glutamine (Gln) residue comprised in the antibody, wherein Aax is an amino acid having the structure NH2—Y—COOH, wherein Y comprises a substituted or unsubstituted alkyl or heteroalkyl chain;
(Sp1) is a chemical spacer or is absent; (Sp2) is a chemical spacer or is absent; and B1 is a linking moiety or a payload.
The main difference between the present claims and the copending claims is that the present claims recite that the antibody is conjugated via a primary amine comprised in the side chain of the lysine residue, the lysine derivative or the lysine mimetic on the linker and that the antibody is contacted with less than 80 molar equivalents of the linker. However, SCHIBLI teaches this difference. The teachings of SCHIBLI, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 102 above.
Because the copending claims recite the antibody-drug conjugate similar to that of present claim 1 and SCHIBLI teaches a method for producing the antibody-drug conjugate wherein the antibody is conjugated via a primary amine comprised in the side chain of the lysine residue, the lysine derivative or the lysine mimetic on the linker and wherein the antibody is contacted with less than 80 molar equivalents of the linker, it would have been obvious to one having ordinary skill in the art to produce the copending claims’ antibody-drug conjugate with the method of SCHIBLI to arrive to the method of the present claims. There would have been a reasonable expectation of success because SCHIBLI provides an antibody conjugation technology that allows the manufacture of highly homogenous conjugation products, both as regards stoichiometry as well as site-specificity of the conjugation.(see SCHIBLI at p. 3, second to last paragraph).
This is a provisional nonstatutory double patenting rejection.
Claims 1 – 4, 6 – 10, 13 – 14, 16, 18 – 19, 21, 24, 26, 28 – 29, and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 117 – 136 of copending Application No. 18/630,821 in view of SCHIBLI.
Copending claim 117 recites conjugate comprising: a) an IgG antibody or IgG antibody fragment comprising at least the CH2 domain of an antibody; and b) a linker comprising the structure:
(Sp1)-RK-(Sp2)-B-(Sp3) or (Sp1)-B-(Sp2)-RK-(Sp3); wherein
(Sp1) is a chemical spacer or is absent;
(Sp2) is a chemical spacer or is absent;
(Sp3) is a chemical spacer or is absent;
R is arginine or an arginine derivative or an arginine mimetic;
K is lysine or a lysine derivative or a lysine mimetic;
B is a linking moiety or a payload;
wherein the linker is conjugated to the CH2 domain of the IgG antibody or antibody fragment via an isopeptide bond formed between a γ-carboxamide group of a glutamine residue Q295 (EU numbering) of the CH2 domain of the IgG antibody or antibody fragment and a primary amine comprised in the side chain of the lysine residue, the lysine derivative or the lysine mimetic comprised in the RK motif comprised in the linker.
The main difference between the present claims and the copending claims is that the present claims recite that the antibody is contacted with less than 80 molar equivalents of the linker. However, SCHIBLI teaches this difference. The teachings of SCHIBLI, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 102 above.
Because the patented claims recite the antibody-drug conjugate of present claim 1 and SCHIBLI teaches a method for producing the antibody-drug conjugate, it would have been obvious to one having ordinary skill in the art to produce the patented claims’ antibody-drug conjugate with the method of SCHIBLI to arrive to the method of the present claims. There would have been a reasonable expectation of success because SCHIBLI provides an antibody conjugation technology that allows the manufacture of highly homogenous conjugation products, both as regards stoichiometry as well as site-specificity of the conjugation (see SCHIBLI at p. 3, second to last paragraph).
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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