CTNF 18/016,308 CTNF 78153 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claims 1-56 are pending. 08-25-02 Applicant’s election of species A in the reply filed on November 10, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). However, the election of species is non-responsive to the restriction requirement mailed September 9, 2025. During a telephone conversation with Benjamin A. Berkowitz on December 5, 2025 a provisional election was made without traverse to prosecute the invention of a method for producing an antibody-drug conjugate that read on anti-TROP2 antibody as the species of antibody, (B) wherein the heavy chain variable region consisting of an amino acid sequence consisting of residues 20 to 140 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2 and (C) wherein the antibody comprises six CDRs of SEQ ID NO: 5-10. Affirmation of this election must be made by applicant in replying to this Office action. Claims 25-29 and 51-55 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Claims 1-24, 30-50 and 56, drawn to a method for producing an antibody-drug conjugate that read on (A) anti-TROP2 antibody as the species of antibody, (B) wherein the heavy chain variable region consisting of an amino acid sequence consisting of residues 20 to 140 of SEQ ID NO: 1 and a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2 and (C) wherein the antibody comprises six CDRs of SEQ ID NO: 5-10, are being acted upon in this Office Action. Priority 02-26 AIA Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file. Information Disclosure Statement The information disclosure statements (IDS) submitted on February 3, 2025, January 13, 2023 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action. Drawings The drawings filed on January 13, 2023 are acceptable. Specification 06-31 AIA The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification. Claim Objection Claims 21-23 and 47-49 are objected to because of the following informality: “consisting of an amino acid sequence” should have been “consisting of the amino acid sequence” throughout the claims. Claim Rejections - 35 USC § 112 07-30-02 AIA 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 2-6, 12, 31-35 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 applicant regards as the invention. The “or more” in claims 2-6, 12, 31-35 is indefinite because the metes and bounds of what would constitute “more” cannot be determined. The term "more" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim rejections under - 35 U.S.C. 112 07-30-01 AIA The following is a quotation of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), first paragraph: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 AIA Claim s 1-24, 30-50 and 56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163). Claim 1 encompasses a method for producing any antibody-drug conjugate comprising (i) a step of reacting any antibody with a reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting any drug-linker intermediates with the antibody having thiol groups obtained in the step (i), wherein the step (i) is carried out until the composition ratio of the antibody having four heavy- light interchain thiols and the composition ratio of the antibody having four heavy-heavy interchain thiols reach a steady value. Claim 2 encompasses the production method according to claim 1, wherein the step (i) is carried out for 4 hours or more. Claim 3 encompasses the production method according to claim 1, wherein the step (i) is carried out for 12 hours or more. Claim 4 encompasses the production method according to claim 1, wherein the step (i) is carried out for 16 hours or more. Claim 5 encompasses the production method according to claim 1, wherein the step (i) is carried out for 20 hours or more. Claim 6 encompasses the production method according to claim 1, wherein the step (i) is carried out for 31 hours or more. Claim 7 encompasses the production method according to claim 1, wherein the step (i) is carried out at 0 to 20˚C. Claim 8 encompasses the production method according to claim 1 wherein the step (i) is carried out at 5 to 20˚C. Claim 9 encompasses the production method according to claim 1, wherein the step (i) is carried out at 5 to 10˚C. Claim 10 encompasses the production method according to claim 1 wherein the step (i) is carried out at about 10˚C. Claim 11 encompasses the production method according to claim 1 wherein the average number of units of the drug-linker conjugated per antibody molecule in the produced antibody-drug conjugate composition is in the range of from 3.5 to 4.5. Claim 12 encompasses the production method according to claim 1 wherein the content of the antibody-drug conjugates in which four drug-linkers are conjugated, in the produced antibody-drug conjugate composition is 50% or more. Claim 13 encompasses the production method according to claim 1, wherein the composition ratio of the antibody-drug conjugates in which four drug- linkers are conjugated to heavy-light interchain thiols is 1.5 to 2.5 times the composition ratio of the antibody-drug conjugates in which four drug-linkers are conjugated to heavy-heavy interchain thiols. Claim 14 encompasses the production method according to claim 1, wherein the reducing agent is used at 1.9 to 2.5 equivalents per molecule of antibody. Claim 15 encompasses the production method according to claim 1, wherein the reducing agent is tris(2-carboxyethyl)phosphine or a salt thereof. Claim 16 encompasses the production method according to claim 1, wherein the drug-linker intermediate has an N-substituted maleimidyl group. Claim 17 encompasses the production method according to claim 1, wherein the drug-linker intermediate is a compound represented by the following formula.[Formula 1] . PNG media_image1.png 322 668 media_image1.png Greyscale Claim 18 encompasses the production method according to claim 17, wherein the drug- linker in the produced antibody-drug conjugate composition is represented by the following formula:[Formula 2] wherein A represents the connecting position to the antibody, and the drug-linker is conjugated to the antibody via a thioether bond. Claim 19 encompasses the production method according to claim 1, wherein the antibody is any anti-TROP2 antibody or any anti-B7-H3 antibody. Claim 20 encompasses the production method according to claim 19, wherein the antibody is any anti-TROP2 antibody. Claim 21 encompasses the production method according to claim 20, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 5, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 6 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 7, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 8, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 9 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 10. Claim 22 encompasses the production method according to claim 20, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 1 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2. Claim 23 encompasses the production method according to claim 20, wherein the anti- TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2. Claim 24 encompasses the production method according to claim 23, wherein the anti- TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. Claim 30 encompasses any antibody-drug conjugate composition produced by the production method according to claim 1. Claim 31 encompasses a method for producing an antibody-drug conjugate composition, comprising: (i) a step of reacting any antibody with a reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting any drug-linker intermediates with the antibody having thiol groups obtained in the step (i), wherein the step (i) is carried out at 0 to 20°C for 4 hours or more, the content of the antibody-drug conjugates in which four drug-linkers are conjugated, in the produced antibody-drug conjugate composition is 50% or more, and the composition ratio of the antibody-drug conjugates in which four drug-linkers are conjugated to heavy-light interchain thiols is 1.5 to 2.5 times the composition ratio of the antibody-drug conjugates in which four drug-linkers are conjugated to heavy-heavy interchain thiols. Claim 32 encompasses the production method according to claim 31, wherein the step (i) is carried out for 12 hours or more. Claim 33 encompasses the production method according to claim 31, wherein the step (i) is carried out for 16 hours or more. Claim 34 encompasses the production method according to claim 31, wherein the step (i) is carried out for 20 hours or more. Claim 35 encompasses the production method according to claim 31, wherein the step (i) is carried out for 31 hours or more. Claim 36 encompasses the production method according to claim 31, wherein the step (i) is carried out at 5 to 20°C. Claim 37 encompasses the production method according to claim 31, wherein the step (i) is carried out at 5 to 10°C. Claim 38 encompasses the production method according to claim 31, wherein the step (i) is carried out at about 10°C. Claim 39 encompasses the production method according to claim 31, wherein the average number of units of the drug-linker conjugated per antibody molecule in the produced antibody-drug conjugate composition is in the range of from 3.5 to 4.5. Claim 40 encompasses the production method according to claim 31, wherein the reducing agent is used at 1.9 to 2.5 equivalents per molecule of antibody. Claim 41 encompasses the production method according to claim 31, wherein the reducing agent is tris(2-carboxyethyl)phosphine or a salt thereof. Claim 42 encompasses the production method according to claim 31, wherein the drug-linker intermediate has an N-substituted maleimidyl group. Claim 43 encompasses the production method according to claim 31, wherein the drug-linker intermediate is a compound represented by the following formula:[Formula 3] . PNG media_image1.png 322 668 media_image1.png Greyscale Claim 44 encompasses the production method according to claim 43, wherein the drug- linker in the produced antibody-drug conjugate composition is represented by the following formula:[Formula 4]wherein A represents the connecting position to the antibody, and the drug-linker is conjugated to the antibody via a thioether bond. Claim 45 encompasses the production method according to claim 31, wherein the antibody is any anti-TROP2 antibody (elected species) or any anti-B7-H3 antibody. Claim 46 encompasses the production method according to claim 45, wherein the antibody is any anti-TROP2 antibody. Claim 47 encompasses the production method according to claim 46, wherein the anti- TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 5, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 6 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 7, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 8, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 9 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 10. Claim 48 encompasses the production method according to claim 46, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 1 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2. Claim 49 encompasses the production method according to claim 46, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2. Claim 50 encompasses the production method according to claim 49, wherein the anti- TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. Claim 56 encompasses any antibody-drug conjugate composition produced by the production method according to claim 31. Thus, the scope of the claims includes a genus of drug-linker intermediates and antibodies encompassed by the claimed methods. Regarding drug-linker intermediates, the specification discloses just one drug-linker intermediate having the following structure: PNG media_image1.png 322 668 media_image1.png Greyscale However, the specification does not describe the structures of all drug-linker intermediates. One species is not representative of all drug-linker intermediates. The specification does not describe the common structure share by members of the genus of drug-linker intermediates sufficient to show possession of the claimed genus at the time of filing. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004). Regarding antibody, the specification discloses just two antibodies. They are anti-Trop2 antibody and anti-B7-H3 antibody. The anti-Trop2 antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region consists of amino acid residues 20 to 140 of SEQ ID NO: 1 and wherein the light chain variable region consisting of amino acid residues 21 to 129 of SEQ ID NO: 2. The anti-B7-H3 antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region consists of amino acid residues 20 to 141 of SEQ ID NO: 3 and wherein the light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 4. However, the description of a limited species of antibodies is not representative of the entire genus because the genus is highly variable, i.e., different heavy and light chains comprising six different CDRs. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The specification does not disclose any relevant, identifying characteristics, such as structure, i.e., amino acid sequences of the heavy and light chain variable region or the six CDRs and/or other physical and/or chemical properties, sufficient to show possession of the claimed genus. The specification does not describe a representative number of species falling with the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed antibody-drug conjugate encompassed by the claimed methods. An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” ( Amgen page 1361). At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion). Similarly, Edwards et al., J Mol Biol. 2003 Nov 14;334(1): 103-118, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract). Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics. For example, Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular. Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie). Regarding antibody in claims 1 and 31, when given the broadest reasonable interpretation, “an antibody” is an antibody of any isotype. It is well known that antibodies can be of the IgG, IgM, IgA, IgD and IgE isotypes and that the IgG isotype can be further divided into IgG1, IgG2, IgG3 and IgG4. Wiggins et al (Journal of Pharmaceutical Sciences, Vol. 104, pp. 1362-1372, 2015; PTO 892) teach that IgG1 contain four inter-chain disulfides comprising two-hinge and two light chain-heavy chain cysteine bond, in contrast to IgG2 which are reported to have differing configurations of six interchain disulfides (page 1362, second column, lines 3-7). Wiggins et al teach that the 3-dimensional conformation of the different IgG2 disulfide isomer configurations can effect solvent accessibility of the interchain disulfides thus driving the conjugation to favor specific locations (page 1363, second column, lines 13-16). Wiggins et al also teach that the type of light chain is also likely to influence the ability of the light chain to conjugate the free cysteine available after reduction (page 1363, second column, lines 16-18). Wiggins et al teach that conjugation sites modulate the in vivo stability, thereby affecting pharmacokinetics, clearance and ultimately, the therapeutic index (page 1362, second column, lines 19-22). Wiggins et al teach in the case of an IgG1 conjugate, about 54% of the light chain is conjugated, whereas only 8% of the light chain is conjugated in IgG2 (page 1366, second column, lines 13-15 under “Reduced RP-UPLC”). Wiggins et al teach LC-MS analysis shows almost equal products representing IgG1 conjugated and unconjugated light chain, wherein IgG2 showed mostly unconjugated light chain (page 1367, second column, lines 2-6). However, the specification provides data pertaining only to IgG1 isotype. Thus, there is no objective evidence that the desired average number of bound drugs will be 3.5-4.5 and the content of the antibody drug conjugates in which four drug linker are bound to heavy-light inter-chain thiols in the population will be 50% or more for non-IgG1 antibody isotypes. Regarding an amino acid sequence represented by any SEQ ID NO: set forth in claims 21, 22, 47, 48, 49, the phrase “an amino acid sequence” encompasses a full-length sequence as well as any fragment thereof. The specification does not describe any fragment of the six CDRs or heavy chain variable region and light chain variable region still maintains conformation and antigen-binding. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. It is unlikely that an antibody as defined by the claims, which may contain less than the full complement of CDRs from the heavy and light chain variable regions have the required binding function. The state of the art at the time the invention was made recognized that even single amino acid differences can result in drastically altered function of antibodies. For example, Lund et al. (The Journal of Immunology 1996, 157:4963-4969, reference on IDS) show that even a single amino acid replacement within the CH2 domain of IgG can alter the glycosylation profile of an antibody therefore influence its effector functions of Fc receptor binding and complement activation (see entire document, particularly Discussion on pages 4966-4968). Regarding antibody-drug conjugate (claims 30 and 56), the use of the claimed antibody-drug conjugate is another issue to be considered. Given the lack of guidance as to the binding specificity of the antibody conjugated to which drug-linker intermediate, it is unpredictable such antibody-drug conjugate is effective for treating any and all cancer. Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular. Vas-Cath Inc. v. Mahurkar , 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.). Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel , 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddles v. Baird , 30 USPQ2d 1481, 1483. In Fiddles v. Baird , claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences. For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010). Therefore, only (1) a method of a method for producing an antibody-drug conjugate composition comprising: (i) a step of reacting an IgG1 antibody with a reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting drug-linker intermediate with the antibody having thiol groups obtained in the step (i), wherein the antibody is an anti-TROP2 antibody, wherein the drug-linker intermediate is PNG media_image1.png 322 668 media_image1.png Greyscale wherein step (i) is carried out until the ratio of the antibody having four heavy-light interchain thiols and the ratio of the antibody having four heavy-heavy interchain thiols reach a steady constant value over time, (2) The production method according to claim 1, wherein the step (i) is carried out for 4 hours to 31 hours, (3) The production method according claim 1, wherein the step (i) is carried out at 0 to 20˚C, (4) The production method according claim 1, wherein average number of drug-linker conjugated per antibody is in the range from 3.5 to 4.5, (5) The production method according claim 1, wherein reducing agent is tris(2-carboxyethyl)phosphine, (6) The production method according claim 1, wherein the reducing agent is used at 1.9 to 2.5 equivalents per molecule of antibody, (7) The production method according claim 1, wherein the anti-TROP2 antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 5, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 6 and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 7, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 8, CDRL2 consisting of the amino acid sequence represented by SEQ ID NO: 9 and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 10, (8) The production method according claim 1, wherein the anti-TROP2 antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region consisting of amino acid residues 20 to 140 of SEQ ID NO: 1 and the light chain variable region consisting of the amino acid residue 21 to 129 of SEQ ID NO: 2, (9) The production method above, wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115). Claims 1-24, 30-50 and 56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for (1) a method of a method for producing an antibody-drug conjugate composition comprising: (i) a step of reacting an IgG1 antibody with a reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting drug-linker intermediate with the antibody having thiol groups obtained in the step (i), wherein the antibody is an anti-TROP2 antibody, wherein the drug-linker intermediate is PNG media_image1.png 322 668 media_image1.png Greyscale wherein step (i) is carried out until the ratio of the antibody having four heavy-light interchain thiols and the ratio of the antibody having four heavy-heavy interchain thiols reach a steady constant value over time, (2) The production method according to claim 1, wherein the step (i) is carried out for 4 hours to 31 hours, (3) The production method according claim 1, wherein the step (i) is carried out at 0 to 20˚C, (4) The production method according claim 1, wherein average number of drug-linker conjugated per antibody is in the range from 3.5 to 4.5, (5) The production method according claim 1, wherein reducing agent is tris)2-carboxyethyl)phosphine, (6) The production method according claim 1, wherein the reducing agent is used at 1.9 to 2.5 equivalents per molecule of antibody, (7) The production method according claim 1, wherein the anti-TROP2 antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 5, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 6 and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 7, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 8, CDRL2 consisting of the amino acid sequence represented by SEQ ID NO: 9 and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 10, (8) The production method according claim 1, wherein the anti-TROP2 antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region consisting of amino acid residues 20 to 140 of SEQ ID NO: 1 and the light chain variable region consisting of the amino acid residue 21 to 129 of SEQ ID NO: 2, (9) The production method above, wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain, does not reasonably provide enablement for any antibody-drug conjugates as set forth in claims 1-24, 30-50 and 56 for treating any cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. Enablement is not commensurate in scope with claims as how to make and use the antibody-drug conjugates for treating any and all cancer. Claim 1 encompasses a method for producing any antibody-drug conjugate comprising (i) a step of reacting any antibody with a reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting any drug-linker intermediates with the antibody having thiol groups obtained in the step (i), wherein the step (i) is carried out until the composition ratio of the antibody having four heavy- light interchain thiols and the composition ratio of the antibody having four heavy-heavy interchain thiols reach a steady value. Claim 2 encompasses the production method according to claim 1, wherein the step (i) is carried out for 4 hours or more. Claim 3 encompasses the production method according to claim 1, wherein the step (i) is carried out for 12 hours or more. Claim 4 encompasses the production method according to claim 1, wherein the step (i) is carried out for 16 hours or more. Claim 5 encompasses the production method according to claim 1, wherein the step (i) is carried out for 20 hours or more. Claim 6 encompasses the production method according to claim 1, wherein the step (i) is carried out for 31 hours or more. Claim 7 encompasses the production method according to claim 1, wherein the step (i) is carried out at 0 to 20˚C. Claim 8 encompasses the production method according to claim 1 wherein the step (i) is carried out at 5 to 20˚C. Claim 9 encompasses the production method according to claim 1, wherein the step (i) is carried out at 5 to 10˚C. Claim 10 encompasses the production method according to claim 1 wherein the step (i) is carried out at about 10˚C. Claim 11 encompasses the production method according to claim 1 wherein the average number of units of the drug-linker conjugated per antibody molecule in the produced antibody-drug conjugate composition is in the range of from 3.5 to 4.5. Claim 12 encompasses the production method according to claim 1 wherein the content of the antibody-drug conjugates in which four drug-linkers are conjugated, in the produced antibody-drug conjugate composition is 50% or more. Claim 13 encompasses the production method according to claim 1, wherein the composition ratio of the antibody-drug conjugates in which four drug- linkers are conjugated to heavy-light interchain thiols is 1.5 to 2.5 times the composition ratio of the antibody-drug conjugates in which four drug-linkers are conjugated to heavy-heavy interchain thiols. Claim 14 encompasses the production method according to claim 1, wherein the reducing agent is used at 1.9 to 2.5 equivalents per molecule of antibody. Claim 15 encompasses the production method according to claim 1, wherein the reducing agent is tris(2-carboxyethyl)phosphine or a salt thereof. Claim 16 encompasses the production method according to claim 1, wherein the drug-linker intermediate has an N-substituted maleimidyl group. Claim 17 encompasses the production method according to claim 1, wherein the drug-linker intermediate is a compound represented by the following formula.[Formula 1] . PNG media_image1.png 322 668 media_image1.png Greyscale Claim 18 encompasses the production method according to claim 17, wherein the drug- linker in the produced antibody-drug conjugate composition is represented by the following formula:[Formula 2] wherein A represents the connecting position to the antibody, and the drug-linker is conjugated to the antibody via a thioether bond. Claim 19 encompasses the production method according to claim 1, wherein the antibody is any anti-TROP2 antibody (elected species) or any anti-B7-H3 antibody. Claim 20 encompasses the production method according to claim 19, wherein the antibody is any anti-TROP2 antibody. Claim 21 encompasses the production method according to claim 20, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 5, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 6 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 7, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 8, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 9 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 10. Claim 22 encompasses the production method according to claim 20, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 1 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2. Claim 23 encompasses the production method according to claim 20, wherein the anti- TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2. Claim 24 encompasses the production method according to claim 23, wherein the anti- TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. Claim 30 encompasses any antibody-drug conjugate composition produced by the production method according to claim 1. Claim 31 encompasses a method for producing an antibody-drug conjugate composition, comprising: (i) a step of reacting any antibody with a reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting any drug-linker intermediates with the antibody having thiol groups obtained in the step (i), wherein the step (i) is carried out at 0 to 20°C for 4 hours or more, the content of the antibody-drug conjugates in which four drug-linkers are conjugated, in the produced antibody-drug conjugate composition is 50% or more, and the composition ratio of the antibody-drug conjugates in which four drug-linkers are conjugated to heavy-light interchain thiols is 1.5 to 2.5 times the composition ratio of the antibody-drug conjugates in which four drug-linkers are conjugated to heavy-heavy interchain thiols. Claim 32 encompasses the production method according to claim 31, wherein the step (i) is carried out for 12 hours or more. Claim 33 encompasses the production method according to claim 31, wherein the step (i) is carried out for 16 hours or more. Claim 34 encompasses the production method according to claim 31, wherein the step (i) is carried out for 20 hours or more. Claim 35 encompasses the production method according to claim 31, wherein the step (i) is carried out for 31 hours or more. Claim 36 encompasses the production method according to claim 31, wherein the step (i) is carried out at 5 to 20°C. Claim 37 encompasses the production method according to claim 31, wherein the step (i) is carried out at 5 to 10°C. Claim 38 encompasses the production method according to claim 31, wherein the step (i) is carried out at about 10°C. Claim 39 encompasses the production method according to claim 31, wherein the average number of units of the drug-linker conjugated per antibody molecule in the produced antibody-drug conjugate composition is in the range of from 3.5 to 4.5. Claim 40 encompasses the production method according to claim 31, wherein the reducing agent is used at 1.9 to 2.5 equivalents per molecule of antibody. Claim 41 encompasses the production method according to claim 31, wherein the reducing agent is tris(2-carboxyethyl)phosphine or a salt thereof. Claim 42 encompasses the production method according to claim 31, wherein the drug-linker intermediate has an N-substituted maleimidyl group. Claim 43 encompasses the production method according to claim 31, wherein the drug-linker intermediate is a compound represented by the following formula:[Formula 3] . PNG media_image1.png 322 668 media_image1.png Greyscale Claim 44 encompasses the production method according to claim 43, wherein the drug- linker in the produced antibody-drug conjugate composition is represented by the following formula: [Formula 4]wherein A represents the connecting position to the antibody, and the drug-linker is conjugated to the antibody via a thioether bond. Claim 45 encompasses the production method according to claim 31, wherein the antibody is any anti-TROP2 antibody or any anti-B7-H3 antibody. Claim 46 encompasses the production method according to claim 45, wherein the antibody is any anti-TROP2 antibody. Claim 47 encompasses the production method according to claim 46, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 5, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 6 and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 7, and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 8, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 9 and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 10. Claim 48 encompasses the production method according to claim 46, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 1 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2. Claim 49 encompasses the production method according to claim 46, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2. Claim 50 encompasses the production method according to claim 49, wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain. Claim 56 encompasses any antibody-drug conjugate composition produced by the production method according to claim 31. Thus, the scope of the claims includes a genus of drug-linker intermediates and antibodies encompassed by the claimed methods. Regarding drug-linker intermediates, the specification discloses just one drug-linker intermediate having the following structure: PNG media_image1.png 322 668 media_image1.png Greyscale However, the specification does not teach the structures of all drug-linker intermediates to enable one of skill in the art to make and use without undue experimentation. Regarding antibody, the specification discloses just two antibodies. They are anti-Trop2 antibody and anti-B7-H3 antibody. The anti-Trop2 antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region consists of amino acid residues 20 to 140 of SEQ ID NO: 1 and wherein the light chain variable region consisting of amino acid residues 21 to 129 of SEQ ID NO: 2. The anti-B7-H3 antibody comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region consists of amino acid residues 20 to 141 of SEQ ID NO: 3 and wherein the light chain variable region consisting of amino acid residues 21 to 128 of SEQ ID NO: 4. However, the specification does not teach i. Complete structure, e.g., heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs and functional features share by members of the genus of antibodies that correlated with binding to which antigen conjugated to which drug-linker intermediates encompass by the claimed antibody-drug conjugate (claims 30 and 56) for treating all cancers. At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion). Similarly, Edwards et al., J Mol Biol. 2003 Nov 14;334(1): 103-118, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract). Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics. Poosarla et al (Biotechn. Bioeng., 2017, 114(6): 1331-1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.) Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen , and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen . Regarding antibody in claims 1 and 31, when given the broadest reasonable interpretation, “an antibody” is an antibody of any isotype. It is well known that antibodies can be of the IgG, IgM, IgA, IgD and IgE isotypes and that the IgG isotype can be further divided into IgG1, IgG2, IgG3 and IgG4. Wiggins et al (Journal of Pharmaceutical Sciences, 2015, Vol. 104, pp. 1362-1372) teach that IgG1 contain four inter-chain disulfides comprising two-hinge and two light chain-heavy chain cysteine bond, in contrast to IgG2 which are reported to have differing configurations of six interchain disulfides (page 1362, second column, lines 3-7). Wiggins et al teach that the 3-dimensional conformation of the different IgG2 disulfide isomer configurations can effect solvent accessibility of the interchain disulfides thus driving the conjugation to favor specific locations (page 1363, second column, lines 13-16). Wiggins et al also teach that the type of light chain is also likely to influence the ability of the light chain to conjugate the free cysteine available after reduction (page 1363, second column, lines 16-18). Wiggins et al teach that conjugation sites modulate the in vivo stability, thereby affecting pharmacokinetics, clearance and ultimately, the therapeutic index (page 1362, second column, lines 19-22). Wiggins et al teach in the case of an IgG1 conjugate, about 54% of the light chain is conjugated, whereas only 8% of the light chain is conjugated in IgG2 (page 1366, second column, lines 13-15 under “Reduced RP-UPLC”). Wiggins et al teach LC-MS analysis shows almost equal products representing IgG1 conjugated and unconjugated light chain, wherein IgG2 showed mostly unconjugated light chain (page 1367, second column, lines 2-6). The specification provides data pertaining only to IgG1 isotype. Thus, there is no objective evidence that the desired average number of bound drugs will be 3.5-4.5 and the content of the antibody drug conjugates in which four drug linker are bound to heavy-light inter-chain thiols in the population will be 50% or more for non-IgG1 antibody isotypes. One of skill in the art would be subject to undue experimentation without reasonable expectation of success in order to make the broadly claimed antibody-drug conjugate composition. Regarding an amino acid sequence represented