Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-15, 18, 21-24, 30-41, 44, 47-50 and 56 are pending and being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Objection and Rejection Withdrawn
The objection to claims 21-22 and 47-48 is withdrawn in view of the claim amendment.
The rejection of claims 2-6, 12, 31-35 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in light of the claim amendment.
The enablement rejection of claims 1-24, 30-50 and 56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of the claim amendment.
Applicant’s arguments, see p. 14-15, filed March 23, 2026, with respect to Noguchi et al and Igawa have been fully considered and are persuasive. The rejection of claims 1-16, 19-24, 30-42, 45-50 and 56 under 35 U.S.C. 103 as being unpatentable over Noguchi et al (US20180147292, published May 31, 2018; PTO 892) in view of Igawa (US20110098450, published April 28, 2011; PTO 892) has been withdrawn.
The rejection of claims 17-18, 43-44 under 35 U.S.C. 103 as being unpatentable over Noguchi et al (US20180147292, published May 31, 2018; PTO 892) in view of Igawa (US20110098450, published April 28, 2011; PTO 892) as applied to claims 1-16, 19-24, 30-42, 45-50 and 56 mentioned above and further in view of Nakada et al (Bioorganic & Medicinal Chemistry Letters 26: 1542-1545, 2016; PTO 892) is withdrawn because the addition of Nakada does not cure the deficiency of Noguchi et al and Igawa.
Claim Objection
Claim 23 is objected to because of the following informality: “a heavy chain consisting of the amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO 1 and a light chain consisting of the amino acid sequence consisting of amin acid residues 21 to 234 of SEQ ID NO: 2” should have been “a heavy chain consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of amino acid residues 21 to 234 of SEQ ID NO: 2”.
Claim 49 is objected to because of the following informality: “a heavy chain consisting of the amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO 1 and a light chain consisting of the amino acid sequence consisting of amin acid residues 21 to 234 of SEQ ID NO: 2” should have been “a heavy chain consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of amino acid residues 21 to 234 of SEQ ID NO: 2”.
Claim rejections under - 35 U.S.C. 112
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.
Claims 1-15, 18, 21-24, 30-41, 44, 47-50 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 IgG1 antibody with any reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting a drug-linker intermediate with the antibody obtained in the step (i), wherein 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, and wherein the antibody is an anti-TROP2 antibody, and the drug-linker intermediate is a compound represented by the following formula:[Formula 1]
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Claim 2 encompasses the production method according to claim 1, wherein step (i) is carried out for at least 4 hours.
Claim 3 encompasses the production method according to claim 1, wherein step (i) is carried out for at least 12 hours.
Claim 4 encompasses the production method according to claim 1, wherein step (i) is carried out for at least 16 hours.
Claim 5 encompasses the production method according to claim 1, wherein step (i) is carried out for at least 20 hours.
Claim 6 encompasses the production method according to claim 1, wherein step (i) is carried out for at least 31 hours.
Claim 7 encompasses the production method according to claim 1, wherein step (i) is carried out at 0 to 20˚C.
Claim 8 encompasses the production method according to claim 1 wherein step (i) is carried out at 5 to 20˚C.
Claim 9 encompasses the production method according to claim 1, wherein step (i) is carried out at 5 to 10˚C.
Claim 10 encompasses the production method according to claim 1 wherein step (i) is carried out at about 10˚C.
Claim 11 encompasses the production method according to claim 1 wherein an average number of units of 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 at least 50%.
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 18 encompasses the production method according to claim 1, wherein the drug- linker in the produced antibody-drug conjugate composition is represented by the following formula:[Formula 2]
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wherein A represents the connecting position to the antibody, and the drug-linker is conjugated to the antibody via a thioether bond.
Claim 21 encompasses the production method according to claim 20, wherein the anti-TROP2 antibody comprises 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.
Claim 22 encompasses the production method according to claim 20, wherein the anti-TROP2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of the 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 the 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 comprises a heavy chain consisting of the amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of the 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:
a step of reacting any antibody with a reducing agent to obtain an antibody having thiol groups; then
a step of reacting any drug-linker intermediates with the antibody obtained in the step (i), wherein step (i) is carried out at 0 to 20°C for at least 4 hours,
the content of the antibody-drug conjugates in which four drug-linkers are conjugated, in the produced antibody-drug conjugate composition is at least 50%, 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, and wherein the antibody is any anti-TROP2 antibody, and
the drug-linker intermediate is a compound represented by the following formula:
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.
Claim 32 encompasses the production method according to claim 31, wherein step (i) is carried out for at least 12 hours.
Claim 33 encompasses the production method according to claim 31, wherein step (i) is carried out for at least 16 hours.
Claim 34 encompasses the production method according to claim 31, wherein step (i) is carried out for at least 20 hours.
Claim 35 encompasses the production method according to claim 31, wherein step (i) is carried out for at least 31 hours.
Claim 36 encompasses the production method according to claim 31, wherein step (i) is carried out at 5 to 20°C.
Claim 37 encompasses the production method according to claim 31, wherein step (i) is carried out at 5 to 10°C.
Claim 38 encompasses the production method according to claim 31, wherein step (i) is carried out at about 10°C.
Claim 39 encompasses the production method according to claim 31, wherein an average number of units of 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 44 encompasses the production method according to claim 31, wherein the drug- linker in the produced antibody-drug conjugate composition is represented by the following formula:
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wherein A represents the connecting position to the antibody, and the drug-linker is conjugated to the antibody via a thioether bond.
Claim 47 encompasses the production method according to claim 31, wherein the anti- TROP2 antibody comprises 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.
Claim 48 encompasses the production method according to claim 31, wherein the anti-TROP2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of the 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 the 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 31, wherein the anti-TROP2 antibody comprises a heavy chain consisting of the amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1 and a light chain consisting of the 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 47, 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 method encompasses any and all possible IgG 1 anti-TROP2 antibodies.
Regarding anti-TROP2 antibody, the specification discloses just 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.
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 describe 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 within 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 (of record, Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003, PTO 892), 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 (of record, 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).
Nejadmoghaddam (of record, 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.
“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).
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
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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, 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, (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 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).
Applicant's arguments filed March 23, 2026 have been fully considered but they are not persuasive. The pending claims have been amended to recite subject matter acknowledged as complying with the written description and enablement rejection, see Office Action, pages 15-18.
In response, the amendment to the claims is acknowledged.
The amended claim 1 encompasses a method for producing any antibody-drug conjugate comprising (i) a step of reacting any IgG1 antibody with any reducing agent to obtain an antibody having thiol groups; then (ii) a step of reacting a drug-linker intermediate with the antibody obtained in the step (i), wherein 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, and wherein the antibody is an anti-TROP2 antibody, and the drug-linker intermediate is a compound represented by the following formula:
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Claim 31 encompasses a method for producing an antibody-drug conjugate composition, comprising:
a step of reacting any antibody with a reducing agent to obtain an antibody having thiol groups; then
a step of reacting any drug-linker intermediates with the antibody obtained in the step (i), wherein step (i) is carried out at 0 to 20°C for at least 4 hours,
the content of the antibody-drug conjugates in which four drug-linkers are conjugated, in the produced antibody-drug conjugate composition is at least 50%, 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, and wherein the antibody is any anti-TROP2 antibody, and
the drug-linker intermediate is a compound represented by the following formula:
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.
Regarding anti-TROP2 antibody, the specification discloses just 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.
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 describe 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 within 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 (of record, Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003, PTO 892), 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 (of record, 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).
Nejadmoghaddam (of record, 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.
“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).
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 these reasons, the rejection is 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).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-15, 18, 21-24, 30-41, 44, 47-50 and 56 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-9, 12-18 of U.S. Patent No. 11,173,213. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in scope. The independent claims in the present application limits the method for producing an antigen-drug conjugate to IgG1 anti-TROP2 antibody whereas the independent claims in the ‘213 patent are generic with respect to the antibody. Further, the subject matter claimed in the instant application is fully disclosed in the issued patent, see Examples 1-3, 3-2, Fig. 26, 27.
Issued claim 1 recites a method for producing an antibody-drug conjugate composition, comprising: (i) a step of reacting an antibody with a reducing agent in a buffer to reduce interchain disulfides, wherein the buffer comprises a chelating agent; and (ii) a step of reacting drug linker intermediates with the antibody having thiol groups obtained in the step (i), wherein the reaction temperature in the step (i) is −10° C. to 10° C., and the average number of bound drugs in the produced antibody-drug conjugate composition is 3.5 to 4.5, and the content of the antibody-drug conjugates in which four drug linkers are bound to heavy-light interchain thiols, in the produced antibody-drug conjugate composition is 50% or more.
2. The production method according to claim 1, wherein the average number of bound drugs in the produced antibody-drug conjugate composition is 4.0 to 4.1.
3. The production method according to claim 1, wherein the reaction temperature in the step (i) is −5° C. to 5° C, which is within the claimed range of at 0 to 20°C as per instant claim 7.
4. The production method according to claim 3, wherein the reaction temperature in the step (i) is −3° C. to 3° C, which is within the claimed range of at 0 to 20°C as per instant claim 7.
5. The production method according to claim 4, wherein the reaction temperature in the step (i) is 0° C. to 2° C, which is within the claimed range of at 0 to 20°C as per instant claim 7.
6. The production method according to claim 5, wherein the reaction temperature in the step (i) is 0° C. to 1° C, which is within the claimed range of at 0 to 20°C as per instant claim 7.
7. The production method according to claim 1, wherein the reducing agent is used in an amount of 2 to 3 molar equivalents per molecule of the antibody, which overlaps the claimed range of at 1.9 to 2.5 molar equivalents as per instant claims 14 and 40.
8. The production method according to claim 1, wherein the reducing agent is tris(2-carboxyethyl)phosphine or a salt thereof, which corresponds to instant claim 15.
9. The production method according to claim 8, wherein the salt of tris(2-carboxyethyl)phosphine is tris(2-carboxyethyl)phosphine hydrochloride, which corresponds to instant claim 15.
12. The production method according to claim 1, wherein the antibody is an anti-TROP2 antibody (genus), an anti-CD98 antibody, an anti-B7-H3 antibody, or an anti-HER2 antibody.
13. The production method according to claim 1, wherein the drug linker intermediate has an N-substituted maleimidyl group.
14. The production method according to claim 13, wherein the drug linker intermediate is ##STR00032## wherein -GGFG- (SEQ ID NO: 35) represents a tetrapeptide residue consisting of glycine-glycine-phenylalanine-glycine, which corresponds to instant claim 1 and 18.
15. The production method according to claim 12, wherein the antibody is an anti-TROP2 antibody, which corresponds to instant claim 1 and 31.
16. The production method according to claim 15, wherein the anti-TROP2 antibody retains CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 5 (TAGMQ), CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 6 (WINTHSGVPKYAEDFKG), CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 7 (SGFGSSYWYFDV), CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 8 (KASQDVSTAVA), CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 9 (SASYRYT), and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 10 (QQHYITPLT), which corresponds to instant claims 21 and 47.
18/016,308
11,173,213
SEQ ID NO: 5
TAGMQ
TAGMQ
SEQ ID NO: 6
WINTHSGVPKYAEDFKG
WINTHSGVPKYAEDFKG
SEQ ID NO: 7
SGFGSSYWYFDV
SGFGSSYWYFDV
SEQ ID NO: 8
KASQDVSTAVA
KASQDVSTAVA
SEQ ID NO: 9
SASYRYT
SASYRYT
SEQ ID NO: 10
QQHYITPLT
QQHYITPLT
SEQ ID NO: 1
SEQ ID NO: 12
SEQ ID NO: 2
SEQ ID NO: 4
Issued patent teaches SEQ ID NO:2 comprises the claimed SEQ ID NO: 5, 6 and 7, see sequence alignment below.
Query Match 82.0%; Score 112.3; Length 106;
Best Local Similarity 35.6%;
Matches 26; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 RASSRLIYMH---------------ATSNLAS---------------------------- 17
|||||||||| |||||||
Db 24 RASSRLIYMHWYQQKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAA 83
Qy 18 ----QQWNSNPPT 26
|||||||||
Db 84 TYYCQQWNSNPPT 96.
Issued patent teaches SEQ ID NO:26 comprises the claimed SEQ ID NO: 8, 9 and 10.
17. The production method according to claim 15, wherein the anti-TROP2 antibody consists of a heavy chain consisting of an amino acid sequence consisting of amino acid residues at positions 20 to 470 of SEQ ID NO: 2, and a light chain consisting of an amino acid sequence consisting of amino acid residues at positions 21 to 234 of SEQ ID NO: 4, which corresponds to instant claims 22, 23, 48, 49.
The reference SEQ ID NO: 12 is identical to the claimed SEQ ID NO: 1, see sequence alignment below.
Query Match 100.0%; Score 2513; Length 470;
Best Local Similarity 100.0%;
Matches 470; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MKHLWFFLLLVAAPRWVLSQVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVRQAP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MKHLWFFLLLVAAPRWVLSQVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVRQAP 60
Qy 61 GQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYYCARSGF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYYCARSGF 120
Qy 121 GSSYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSSYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS 180
Qy 181 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP 240
Qy 241 KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW 300
Qy 301 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS 360
Qy 361 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 420
Qy 421 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 470
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 470
The reference SEQ ID NO: 4 is identical to the claimed SEQ ID NO: 2, see sequence alignment below.
Query Match 100.0%; Score 1207; Length 234;
Best Local Similarity 100.0%;
Matches 234; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MVLQTQVFISLLLWISGAYGDIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MVLQTQVFISLLLWISGAYGDIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKP 60
Qy 61 GKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGQ 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGQ 120
Qy 121 GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ 180
Qy 181 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 234
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 234
18. The production method according to claim 15, wherein the anti-TROP2 antibody consists of a heavy chain consisting of an amino acid sequence consisting of amino acid residues at positions 20 to 469 of SEQ ID NO: 2, and a light chain consisting of an amino acid sequence consisting of amino acid residues at positions 21 to 234 of SEQ ID NO: 4, which corresponds to instant claims 22, 23, 48 and 49.
26. The production method according to claim 14, wherein the drug linker intermediate is
PNG
media_image5.png
205
515
media_image5.png
Greyscale
wherein -GGFG- (SEQ ID NO: 35) represents a tetrapeptide residue consisting of glycine-glycine-phenylalanine-glycine, which has the chemical structure as shown
PNG
media_image6.png
132
262
media_image6.png
Greyscale
and corresponds to instant claim 44.
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
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