Office Action 1: Non-Final Rejection (2024-07-31)
Rejection types: 102 - Lack of Novelty, 103 - Obviousness, 112 - Written Description/Enablement, Double Patenting

CLAIMS:
CLAIMS

1\. A conjugate comprising an antibody conjugated to a cytotoxic agent, wherein the antibody is capable of binding to MUC1 or TA-MUC1, and wherein the antibody comprises (i) a heavy chain variable region comprising the complementarity-determining
regions (CDRs) CDR-H1 having the amino acid sequence of SEQ ID NO: 1, CDR-H2 having the amino acid sequence of SEQ ID NO: 2 and CDR-H3 having the amino acid sequence of SEQ ID NO: 3, and(ii) a light chain variable region comprising the complementarity-determining regions (CDRs) CDR-L1 having the amino acid sequence of SEQ ID NO: 4, CDR-L2 having
the amino acid sequence of SEQ ID NO: 5 and CDR-L3 having the amino acid sequence of SEQ ID NO: 6.

2\. The conjugate according to claim 1, wherein the amino acid at position 8 of SEQ ID NO: 2 is selected from the group consisting of glutamine, histidine, tryptophan,
tyrosine, lysine and arginine, or wherein the CDR-H2 has the amino acid sequence of SEQ
ID NO: 7.

3\. The conjugate according to claim 1, wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 9.

4\. The conjugate according to claim 1, wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 10.

5\. The conjugate according to claim 1, wherein the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 12.

6\. The conjugate according to claim 1, wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 10 and the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 12.

7\. The conjugate according to claim 1, wherein the antibody comprises an Fc region and is an IgG1-, IgG2-, or IgG4-type antibody.

8\. The conjugate according to claim 7, wherein the antibody comprises a glycosylation pattern having one or more of the following characteristics:
(i) a detectable amount of glycans carrying a bisecting GlcNAc residue;

(ii) a relative amount of glycans carrying at least one galactose residue of at least 25% of the total amount of glycans attached to the Fc glycosylation sites of the antibody in a composition.
9\. The conjugate according to claim 1, wherein the heavy chain of the antibody has the amino acid sequence of SEQ ID NO: 15, and the light chain of the antibody has the
amino acid sequence of SEQ ID NO: 16.

10\. The conjugate according to claim 1, wherein the heavy chain of the antibody has the amino acid sequence of SEQ ID NO: 22 or a variant thereof in which one amino acid has been removed from the C-terminus, and the light chain of the antibody has the amino acid sequence of SEQ ID NO: 16.

11\. The conjugate according to claim 1, wherein the antibody has the activity of being internalized into MUC1- or TA-MUC1-expressing cells through binding to MUC-1 or TA-MUC1.

12\. The conjugate according to claim 1, wherein the cytotoxic agent is an anti- tumor agent.

13\. The conjugate according to claim 1, wherein the cytotoxic agent is a chemotherapeutic agent.

14\. The conjugate according to claim 13, wherein the chemotherapeutic agent is selected from the group consisting of a microtubule inhibitor, a topoisomerase I inhibitor, a DNA damaging agent, a DNA alkylating agent and a DNA minor groove binder.

15\. The conjugate according to claim 14, wherein the chemotherapeutic agent is a topoisomerase I inhibitor.

16\. The conjugate according to claim 15, wherein the topoisomerase I inhibitor is an antitumor compound represented by the following formula:Me SVG {EMBED HERE} 1.3671.73F

17\. The conjugate according to claim 1, wherein the antibody is conjugated to the cytotoxic agent via a linker having any structure selected from the group consisting of the following formulas (a) to (f):
(a) -(Succinimid-3-yl-N)-CH2CH2-C(=0)-GGFG-NH-CH2CH2CH2-C(=0)-,
(b) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2CH2CH2-
C(=O)-,(c) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2-O-CH2- C(=0)-,
(d) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2CH2-O-CH2- C(=0)-,
(e) -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)- GGFG-NH-CH2CH2CH2-C(=0)-, and
(f) -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O- CH2CH2O-CH2CH2-C(=0)-GGFG-NH-CH2CH2CH2-C(=0)-,
wherein the antibody is connected to the terminus of -(Succinimid-3-yl-N), the cytotoxic
0 agent is connected to the carbonyl group in the rightmost of formulas (a) to (f) with the nitrogen atom of the amino group at position 1 as a connecting position, GGFG represents an amino acid sequence consisting of glycine-glycine-phenylalanine-glycine linked through peptide bonds, and-(Succinimid-3-yl-N)- has a structure represented by the following formula:SVG {EMBED HERE} 0.8070.513-
which is connected to the antibody at position 3 thereof and is connected to a methylene group in the linker structure containing this structure on the nitrogen atom at position 1.

18\. The conjugate according to claim 1, wherein the linker is represented by any
0 formula selected from the group consisting of the following formulas (a) to (c):

(a) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2- C(=0)-,
(b) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2CH2-O-CH2- C(=0)-, and
(c) -(Succinimid-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH20-CH2CH20-CH2CH2-C(=O)-
GGFG-NH-CH2CH2CH2-C(=0)-.

19\. The conjugate according to claim 1, wherein the linker is:-(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2-O-CH2-C(=0)-.

20\. The conjugate according to claim 1, wherein the antibody is conjugated to a drug linker represented by the following formula (wherein asterisk\* represents the point of
connection to the antibody) by a thioether bond:
SVG {EMBED HERE} 2.3175.55
21\. The conjugate according to claim 1, which is represented by the following formula;SVG {EMBED HERE} 2.7236.107

y wherein AB represents the antibody, y represents an average number of units of the drug- linker structure conjugated to the antibody per itself, and the antibody is conjugated to a drug linker represented by the above formula by a thioether bond.

22\. The conjugate according to claim 20, wherein the antibody comprises any one
of the following combinations a) to b) of a heavy chain variable region and a light chain variable region, or heavy chain and light chain:(a) the heavy chain variable region has the amino acid sequence of SEQ ID NO:
10 and the light chain variable region has the amino acid sequence of SEQ ID NO: 12, and(b) the heavy chain has the amino acid sequence of SEQ ID NO: 22 and the light
chain has the amino acid sequence of SEQ ID NO: 16.

23\. The conjugate according to claim 1, wherein the antibody comprises one or more modifications selected from the group consisting of defucosylation, reduced fucose, N- linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing,
deamidation, isomerization of aspartic acid, oxidation of methionine, the substitutions of two
leucine (L) residues to alanine (A) at position 234 and 235 of the heavy chain (LALA),
amidation of a proline residue, and a deletion or lack of one or two amino acids at the carboxyl terminus.

24\. A pharmaceutical composition comprising the conjugate of claim 22.

25\. A pharmaceutical composition comprising a conjugate comprising an antibody conjugated to a cytotoxic agent, wherein the antibody is capable of binding to MUC1, and
wherein the antibody comprises (i) a heavy chain variable region comprising the complementarity-determining regions (CDRs) CDR-H1 having the amino acid sequence of SEQ ID NO: 1, CDR-H2 having
the amino acid sequence of SEQ ID NO: 2 and CDR-H3 having the amino acid sequence of SEQ ID NO: 3, and(ii) a light chain variable region comprising the complementarity-determining regions (CDRs) CDR-L1 having the amino acid sequence of SEQ ID NO: 4, CDR-L2 having the amino acid sequence of SEQ ID NO: 5 and CDR-L3 having the amino acid sequence of
SEQ ID NO: 6.

26\. The conjugate according to claim 22, wherein the antibody comprises a deletion or lack of one or two amino acid(s) in the carboxyl terminus of the heavy chain.

27\. The conjugate according to claim 22, wherein the antibody comprises two heavy chains, both of which lack one carboxyl-terminal amino acid residue.

28\. The conjugate according to claim 1, wherein the average number of the cytotoxic agents conjugated per antibody is in a range of from 1 to 10.

29\. The conjugate according to claim 1, wherein the average number of the cytotoxic agents conjugated per antibody is in a range of from 2 to 8.

30\. The conjugate according to claim 1, wherein the average number of the
cytotoxic agents conjugated per antibody is in a range of from 3 to 8.

31\. The conjugate according to claim 1, wherein the average number of the cytotoxic agents conjugated per antibody is in a range of from 7 to 8.

32\. The conjugate according to claim 1, wherein the average number of the cytotoxic agents conjugated per antibody is in a range of from 7.5 to 8.

33\. The conjugate according to claim 1, wherein the number of conjugated cytotoxic agents per antibody molecule is 8. 5 10 15 20 25 30 2 3

OFFICE ACTION:
DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims benefit to EP18173253.8, filed May 18, 2018.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on July 10, 2023, July 27, 2023, August 3, 2023, September 6, 2023, September 29, 2023, November 9, 2023, November 17, 2023, March 7, 2024, and April 29, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Claims 1-33 are under consideration in this office action.
Claim Objections
Claim 11 is objected to because of the following informalities: the claim uses the abbreviation “MUC-1” whereas “MUC1” is used in the other claims. Consistent use of terminology is required in the claims.  Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA  35 U.S.C. 112, the applicant), regards as the invention.
Claims 20 use parentheses to enclose “wherein asterisk* represents the point of connection to the antibody”. The use of parentheses that encompasses a limitation in the claim is found indefinite because it is unclear whether the limitation within the parentheses is part of the claimed invention or are just set forth as a possible example. Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 5, 7, 9, 11-12, and 25 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by US 20120128676, published May 24, 2015 (“Goletz”; see IDS from 7/10/23, citation A122).
Goletz teaches an anti-MUC1 antibody comprised of a heavy chain variable region comprising HCDR1-3 of SEQ ID NOs: 1, 3, and 5 and LCDR1-3 of SEQ ID NOs: 17, 19, and 21 [0065], which reads on the anti-MUC1 antibody of HCDR1-3 of SEQ ID NOs: 1-3 and LCDR1-3 of SEQ ID NOs: 4-6 of claim 1. The anti-MUC1 antibody of Goletz is comprised of heavy chain variable region (HCVR) of SEQ ID NO: 16 and light chain variable region (LCVR) of SEQ ID NO: 28 [0053], which reads on the HCVR of SEQ ID NO: 9 of claim 3 and LCVR of SEQ ID NO: 12 of claim 5. It is noted that HCDR2 of SEQ ID NO: 2, HCVR of SEQ ID NO: 9, and heavy chain of SEQ ID NO: 15 at position 8 of HCDR2 include a wildcard amino acid, which is an amino acid that can be any amino acid. As such, the sequences of Goletz of HCDR2 of SEQ ID NO: 3 and HCVR of SEQ ID NO: 16 with the amino acid asparagine at position 8 of HCDR2 read on the antibody sequences of claims 1, 3, and 5.
The antibody of heavy chain of SEQ ID NO: 15 and light chain of SEQ ID NO: 16 of instant claim 9 are comprised of HCVR of SEQ ID NO: 16 and light chain of SEQ ID NO: 32 of Goletz. Notably, the heavy chain of Goletz of SEQ ID NO: 31  is not identical to the claimed heavy chain amino acid sequence; however, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs, which provide the majority of the contact residues for the binding of the antibody to its target epitope (as evidenced by Almagro & Fransson, see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1, instant PTO-892). Since the heavy chain of instant claim 9 is comprised of the same three CDRs and the same HCVR as Goletz, the claimed antibody is not patentably distinct from the antibody of Goletz.
The anti-MUC1 antibody of Goletz may be coupled to an agent capable of killing cancer cells, forming a conjugate [0073], which reads on the antibody cytotoxic agent conjugate of claim 1 and the anti-tumor agent of claim 12. The antibody is of the IgG1 isotype subclass IgG1 [0057], which reads on claim 7. Goletz teaches a composition comprising the anti-MUC1 antibody [0078], which reads on instant claim 25.
Regarding claim 11, while the references are silent regarding the internalization of the antibody into MUC1- or TA-MUC1-expressing cells through binding to MUC1 or TA-MUC1, it is clear that the same antibody directed the MUC1 or TA-MUC18 would have the same characteristics as the instantly claimed conjugate since there is no evidence to the contrary. Note that rejections for anticipation are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III).  In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not the same or an obvious variant; see MPEP § 2112(V).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary.  Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5, 7, 9, 11-21, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over US 20120128676 (“Goletz”) in view of Ogitani et al, published July 2016 (see IDS from 7/10/2023).
Goletz teaches the antibody conjugate of claim 1; Goletz does not teach a specific linker for the antibody conjugate nor does it teach a cytotoxic agent that is a chemotherapeutic agent or a topoisomeriase I inhibitor, as required by claims 13-21.
Ogitani et al teaches that antibody-drug conjugates are a promising class of drugs for efficient and specific drug delivery to antigen-expressed cancer cells (pg 1039, column 1). Specifically, Ogitani et al teaches a novel HER2-targeting antibody-drug conjugate prepared using a linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DS-8901a) (see abstract). This exatecan derivative meets the limitations regarding the cytotoxic agent of claims 13-16. The linker of Ogitani et al, as illustrated below, is identical to the linker of claims 17-19.
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The linker and payload of the antibody conjugate of Ogitani et al are identical to those of instant claims 20-21 (see Figure 1, shown below).
For comparison, see structure from instant claim 21, shown below.
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Based on the combined teachings of the disclosures of Goletz and Ogitani, it would have been obvious to one of ordinary skill in the art to prepare a conjugate that is comprised of the anti-MUC1 antibody of Goletz and the cytotoxic agent of Ogitani et al, because this conjugation strategy was already known in the art to specifically target cells that are overexpressing a known oncogene that regulates various aspects of cancer. The artisan would have been motivated to try and use the antibody of Goletz in this way and have a reasonable expectation of success because the novel topoisomerase I inhibitor, exatecan derivative of Ogitani demonstrates potent antitumor activity and favorable stability and safety profiles when linked to an antibody targeted a surface protein upregulated on cancer cells (pg 1039-1040). It would have been obvious to replace the anti-HER2 antibody of Ogitani et al with another antibody known to target a surface protein expressed on cancer cells (e.g., MUC1), because one of ordinary skill in the art would have been able to carry out such a substitution, and the results would have been reasonably predictable.
Claims 1, 3, 5, 7-9, 11-21, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over US 20120128676 (“Goletz) in view of Jefferis, published Mary 28, 2017 (see instant PTO-892).
Goletz teaches the antibody conjugate of claim 1. Goletz also teaches that the antibody is glycosylated; the glycosylation pattern may enhance the antibody’s affinity to Fc receptors and/or antibody-dependent cell-mediated cytotoxicity [0060]. Goletz does not teach an antibody conjugate with a detectable amount of glycans carrying a bisecting GlcNAc residue.
Jefferis teaches methods for engineering antibodies of various glycosylation patterns (pg 229, column 1), including  the differential addition of galactose and bisecting GlcNAc (pg 230). See Figure 2 (pg 230) for detection of oligosaccharide structure using HPLC.
Given that Goletz teaches the antibody conjugate and further given that Jefferis teaches methods for modifying the glycosylation pattern of antibodies, it would have been obvious to one of ordinary skill in the art to modify the glycosylation of the antibody Goletz. The motivation comes from Jefferis, which teaches modification of oligosaccharides of recombinant monoclonal antibodies to provide maximum therapeutic efficacy for a given disease (see abstract). The ordinary artisan would be would have been able to carry out such a modification, and the results would have been reasonably predictable.
Claims 1, 3, 5, 7, 9, 11-21, 25, and 28-33 are rejected under 35 U.S.C. 103 as being unpatentable over US 20120128676 (“Goletz) in view of Hamblett et al, published October 15, 2004 (see instant PTO-892).
Goletz teaches the antibody conjugate of claim 1. Goletz does not teach the average number of cytotoxic agents conjugated per antibody.
Hamblett teaches an antibody-drug conjugate consisting of eight cytotoxic drug (i.e. MMAE) moieties per monoclonal antibody (see abstract). Hamblett further teaches how therapeutic efficacy can be altered depending on the number of drugs per antibody (e.g., two, four, or eight drug molecules per antibody) (see abstract), as in the average number of cytotoxic agents conjugated per antibody of instant claims 28-33.
As Goletz teaches the antibody conjugate of claim 1 and Hamblett teaches an antibody-drug conjugate with an average number of 2-8 cytotoxic agents conjugated per antibody, the ordinary artisan would have been able to immediately envision the antibody of claim 1 conjugated with 2-10 cytotoxic agents. One would have been motivated to do so because of the art recognized need to develop more effective therapies for the treatment of cancer. As taught by Hamblett, drug loading is an important design parameter of antibody-drug conjugates; determining the optimum load needs to take into consideration the parameters of efficacy and toxicity (pg 7064, Column 1, ln 7-23). One of ordinary skill in the art would have been able to carry out such a modification and have a reasonable expectation of success of generating a antibody conjugate with 1-10 or 7.5-8 cytotoxic agent per antibody.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 5, 9, 11-21, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 13-14 of U.S. Patent No. 9,217,038 in view of Ogitani et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the drug conjugate of the instant claims is comprised of the same anti-MUC1 antibody of ‘038.
Patent ‘038 teaches an anti-MUC1 antibody comprised of a heavy chain variable region comprising HCDR1-3 of SEQ ID NOs: 1, 3, and 5 and LCDR1-3 of SEQ ID NOs: 17, 19, and 21 [0065], which reads on the anti-MUC1 antibody of HCDR1-3 of SEQ ID NOs: 1-3 and LCDR1-3 of SEQ ID NOs: 4-6 of claim 1. The anti-MUC1 antibody of ‘038 is comprised of heavy chain variable region (HCVR) of SEQ ID NO: 16 and light chain variable region (LCVR) of SEQ ID NO: 28 [0053], which reads on the HCVR of SEQ ID NO: 9 of claim 3 and LCVR of SEQ ID NO: 12 of claim 5. It is noted that HCDR2 of SEQ ID NO: 2, HCVR of SEQ ID NO: 9, and heavy chain of SEQ ID NO: 15 at position 8 of HCDR2 include a wildcard amino acid, which is an amino acid that can be any amino acid. As such, the sequences of ‘038 of HCDR2 of SEQ ID NO: 3 and HCVR of SEQ ID NO: 16 with an amino acid of asparagine at the position 8 of HCDR2 reads on the antibody sequences of claims 1, 3, and 5.
The antibody of heavy chain of SEQ ID NO: 15 and light chain of SEQ ID NO: 16 of instant claim 9 are comprised of HCVR of SEQ ID NO: 16 and light chain of SEQ ID NO: 32 of ‘038. Notably, the heavy chain of ‘038 of SEQ ID NO: 31  is not identical to the claimed heavy chain amino acid sequence; however, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs, which provide the majority of the contact residues for the binding of the antibody to its target epitope (as evidenced by Almagro & Fransson, see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Since the heavy chain of instant claim 9 is comprised of the same three CDRs and the same HCVR as ‘038, the claimed antibody is not patentably distinct from the antibody of ‘038.
The anti-MUC1 antibody of ‘038 may be coupled to an agent capable of killing cancer cells, forming a conjugate, which reads on the antibody cytotoxic agent conjugate of claim 1 and the anti-tumor agent of claim 12. ‘038 teaches a composition comprising the anti-MUC1 antibody, which reads on instant claim 25.
Regarding claim 11, while the claims of ‘038 are silent regarding the internalization of the antibody into MUC1- or TA-MUC1-expressing cells through binding to MUC1 or TA-MUC1, it is clear that the same antibody directed the MUC1 or TA-MUC18 would have the same characteristics as the instantly claimed conjugate since there is no evidence to the contrary. Note that rejections for anticipation are appropriate when the prior art discloses a method (or product) that appears to be identical except that the art is silent as to an inherent property; see MPEP § 2112(III).  In such situations, the burden is on applicant to provide evidence that the prior art product (or method) is not the same or an obvious variant; see MPEP § 2112(V).
Patent ‘038 claims do not teach a specific linker for the antibody conjugate nor does it teach a cytotoxic agent that is a chemotherapeutic agent or a topoisomeriase I inhibitor, as required by claims 13-21.
Ogitani et al teaches that antibody-drug conjugates are a promising class of drugs for efficient and specific drug delivery to antigen-expressed cancer cells (pg 1039, column 1). Specifically, Ogitani et al teaches a novel HER2-targeting antibody-drug conjugate prepared using a linker-payload system with a potent topoisomerase I inhibitor, exatecan derivative (DS-8901a) (see abstract). This exatecan derivative meets the limitations regarding the cytotoxic agent of claims 13-16. The linker of Ogitani et al, as illustrated below, is identical to the linker of claims 17-19
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The linker and payload of the antibody conjugate of Ogitani et al are identical to those of instant claims 20-21 (see Figure 1, shown below).
For comparison, see structure from instant claim 21, shown below.
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Greyscale
Based on the combined teachings of the disclosures of ‘038 and Ogitani, it would have been obvious to one of ordinary skill in the art to prepare a conjugate that is comprised of the anti-MUC1 antibody of ‘038 and the cytotoxic agent of Ogitani et al, because this conjugation strategy was already known in the art to specifically target cells that are overexpressing a known oncogene that regulates various aspects of cancer. The artisan would have been motivated to try and use the antibody of ‘038 in this way and have a reasonable expectation of success because the novel topoisomerase I inhibitor, exatecan derivative of Ogitani demonstrates potent antitumor activity and favorable stability and safety profiles when linked to an antibody targeted a surface protein upregulated on cancer cells (pg 1039-1040). It would have been obvious to replace the anti-HER2 antibody of Ogitani et al with another antibody known to target a surface protein expressed on cancer cells (e.g., MUC1), because one of ordinary skill in the art would have been able to carry out such a substitution, and the results would have been reasonably predictable.
For these reasons, the invention of the instant claims fully overlaps with that of ‘303, and therefore, the indicated claims are not patentably distinct from each other.
Claims 1-6 and 8-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,872,289. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to overlapping subject matter: the anti-MUC1 antibody conjugate of the instant claims is directed to the same anti-MUC1 antibody and the same formula for the conjugate taught by the claims of patent ‘289.
Claim 1 of patent ‘289 teaches an anti-MUC1 antibody of HCVR SEQ ID NO: 10 and LCVR SEQ ID NO: 12, which are comprised of the same HCDR1-3 and LCDR1-3 of instant claims 1-2 and 22. Further, ‘289 SEQ ID NO: 10 and SEQ ID NO: 12 are identical to instant SEQ ID NO: 10 and SEQ ID NO: 12 of instant claims 3-6 and 22. It is noted that HCDR2 of SEQ ID NO: 2, HCVR of SEQ ID NO: 9, and heavy chain of SEQ ID NO: 15 at position 8 of HCDR2 include a wildcard amino acid, which is an amino acid that can be any amino acid. As such, the sequence of ‘289 of HCVR of SEQ ID NO: 10 with an amino acid of glutamine at the position 8 of HCDR2 reads on the antibody sequences of claims 1, 3, and 5.
Patent ‘289 claims 1 and 13 teaches antibody modification, including glycosylation, N-terminal processing, C-terminal processing, and deletion or lack of one or two amino acids at the carboxyl terminus, as in instant claims 8, 23, and 26-27.
The antibody of heavy chain/light chain pair SEQ ID NO: 15/SEQ ID NO: 16 of instant claim 9 and heavy chain/light chain pair of SEQ ID NO: 22/SEQ ID NO: 16 of instant claims 10 and 22 are comprised of HCVR of SEQ ID NO: 22 and light chain of SEQ ID NO: 16 of ‘289.
The antibody conjugate and linker of ‘289 claim 1 is identical to the linker and cytotoxic agent of instant claims 12-22. Further, ‘289 claim 22 teaches the pharmaceutical composition of instant claim 24.
Patent ‘289 claims 15-21 teach average number of the cytotoxic agent conjugated per antibody of instant claims 28-33.
Thus, the invention of the instant claims fully overlaps with that of ‘289, and therefore, the indicated claims are not patentably distinct from each other.
Conclusion
No claim is allowed.

APPLICANT REBUTTAL: REMARKS
Applicant respectfully requests favorable consideration of the present application in view of the reasons that follow.
Status of Claims
Claims 2, 11, and 20 are currently amended. Support for amended claim 2 is found in Figure 1D which shows antibodies with N54D and N54E. These changes are at position 54 of the heavy chain, which corresponds to position 8 of CDR-H2. Claim 34 is new. Claim 34 excludes certain embodiments and is permitted in view of MPEP 2173.05(i): If alternative elements are positively recited in the specification, they may be explicitly excluded in the claims. See In re Johnson, 558 F.2d 1008, 1019, 194 USPQ 187, 196 (CCPA 1977). No claims are canceled.
New claim 34 is being amended in this Supplemental Amendment and Response to correct a minor error in new claim 34: "represented the" should read "represented by the" in the Preamble.
Accordingly, claims 1-34 remain pending in this application.
Claim Ob
j
ections and Claim Re
j
ections Under 35 USC 112
Claim 11 is objected to for an inconsistent use of a claim term. Claim 20 is rejected for use of a parenthesis. Both claims are amended to overcome these issues rendering the rejection moot.
Claim Re
j
ection Under 35 USC 102 and 103
Claims 1, 3, 5, 7, 9, 11-12, and 25 are rejected under 35 USC 102 as anticipated by Goletz (US20120128676).
Claims 1, 3, 5, 7, 9, 11-21, and 25 are rejected under 35 USC 103 as obvious over Goletz (US20120128676) in view of Ogitani. Claims 1, 3, 5, 7-9, 11-21, and 25 are rejected as obvious over Goletz in view of Jefferis. Claims 1, 3, 5, 7, 9, 11-21, 25, and 28-33 are rejected as obvious over Goletz in view of Hamblett.
Applicant addresses all of the prior art rejections together due to a misinterpretation of the scope of the claims by the Office. On pages 4 and 11 of the Office Action, the Office notes "HCDR2 of SEQ ID NO: 2, HCVR of SEQ. ID NO: 9, and heavy chain of SEQ ID NO: 15 at position 8 of HCDR2 include a wildcard amino acid, which is an amino acid that can be any amino acid". Consequently, the Office believes the sequences of Goletz (US20120128676) and US 9,217,038 ('038)1, HCDR2 of SEQ ID NO: 3 and HCVR of SEQ ID NO: 16 with the amino acid residue asparagine at position 8 of HCDR2, read on the antibody sequences of the current claims 1, 3, and 5.
Based on these remarks, it is clear that the Office has not considered that the definition in the sequence listing of the present application for the Xaa amino acid in SEQ ID NOs: 2, 9, 15 and 20 "is any amino acid
except Asn"
[emphasis added], and, as such, does
not
include the wildtype amino acid asparagine.
The Office's conclusions are therefore based on the misinterpretation that the pending claims cover a con
jug
ate of the unmodified PankoMab antibody as well as the modified PankoMab antibody.
The pending claims are limited to a conjugate of the
modified
antibody only. Applicants note that the above prior art rejections do not reject claim 2, which covers the specific substitutions of the modified PankoMab antibody, nor the pending claims (claims 4, 6, 10, etc.) which are directed to the substitution being glutamine. Consequently, it appears settled that the Office concedes the principle that a conjugate of the modified antibody is novel and nonobvious. Therefore, the pending claims which relate to a conjugate of the modified antibody are novel and nonobvious over Goletz, Ogitani, Jefferis, and Hamblett.
Applicant requests reconsideration and withdrawal of the prior art rejections.
1 See double patenting rejection below.
Double Patenting
Claims 1, 3, 5, 9, 11-21, and 25 are rejected on the ground of nonstatutory double
patenting for over claims 1, 4, and 13-14 of US 9,217,038 ('038) in view of Ogitani. The '038 patent relates to the same patent family as Goletz. Applicant respectfully traverses this rejection. As noted above regarding the obviousness rejection over Goletz, this rejection is based on an improper interpretation of the scope of the claims. The claims cover a different scope than Goletz/'038. Consequently, the claims of the current application are not obvious over the cited patents. Applicants request withdrawal of the rejection.
Claims 1-6 and 8-33 are rejected on the grounds of nonstatutory double patenting over
claims 1-22 of US 11,872,289. US 11,872,289 is the parent to the present application. Applicant traverses.
As is well known to the Office, the current application is a properly filed divisional application to US 11,872,289, and should receive the safe harbour protection of 35 USC 121. The Office issued a restriction requirement in the parent application necessitating the filing of the current application. In order to facilitate prosecution in the parent application, the current divisional was filed and the claims directed to the nonelected group were cancelled in the parent application. As divisionals are protected from an assertion of double patenting, the current rejection should be withdrawn.
Applicant acknowledges that after the current application was filed and after the
nonelected claims were cancelled from the parent application, the Office decided to withdraw the restriction requirement in the parent application. The Office Action which noted the withdrawal of the restriction requirement did not identify any prior art rejections to the pending claims. See Office Action in US 17/878,611 dated August 10, 2023. The only rejection which was asserted was a double patenting rejection, but that rejection was overcome without the need to amend the claims. Consequently, the Office affectively withdrew the restriction requirement on allowable claims and the case proceeded to allowance.
MPEP 821.02, which relates to handling of an application after election without traverse, instructs, "that even if an election was made without traverse, claims directed to nonelected species and nonelected inventions that are eligible for rejoinder should be rejoined," but in this situation, the claims directed to nonelected inventions had already been cancelled prior to the withdrawal of the restriction. MPEP 821.04 explains, "[r]ejoined claims must be fully examined for patentability in accordance with 37 CFR 1.104" and "to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103, and 112." No such finding was ever made by the Office and the rejoined claims could not be "fully examined for patentability" because they had already been cancelled and were being concurrently pursued in a properly filed divisional application. Thus, the withdrawal of the restriction was improper because there were no claims pending for rejoinder.
Further improprieties of the withdrawal include a failure to follow the instruction of MPEP 821.04(a), which relates to rejoinder of product inventions. This section provides for a situation in which withdrawn claims have been cancelled, and it instructs, "[f]orm paragraph 8.46 (or form paragraph 8.47 or 8.47.01 if appropriate) must be used to notify applicant when nonelected claim(s) which depended from or required all the limitations of an allowable claim were cancelled by applicant and may be reinstated by submitting the claim(s) in an amendment." Yet, Form paragraph 8.46 (or form paragraph 8.47 or 8.47.01) was not used in the Office Action dated August 10, 2023, which withdrew the restriction. Form paragraph 8.46 should include, among other notices, language noting "[t]he canceled, nonelected claim(s) may be reinstated by applicant if submitted in a timely filed amendment in reply to this action," and "[u]pon entry of the amendment, such amended claim(s) will be examined for patentability under 37 CFR 1.104." None of this required language, which MPEP 821.04(a) says must be in the withdrawal, was present in the Office Action dated August 10, 2023.
For at least the foregoing reasons, the restriction in the parent application, which issued as the '289 patent, was not properly withdrawn, and therefore the present application should still
be treated as a properly filed divisional that is entitled to the protections of the Section 121 safe harbor against nonstatutory double patenting.
Additionally, the principles of equity clearly favor Applicants receiving allowance on the current claims as pursuing the current claims in the parent application would have been clearly prejudicial. The parent application, which issued as the '289 patent, was filed as a Track One application for prioritized examination. Adding back in the claims that were previously cancelled as a result of a restriction requirement after receiving the Office Action dated August 10, 2023 would have not only required Applicant to pay excess fees, but it also would have required Applicant to forfeit the prioritized status it had already paid for and invariably lengthened the duration of prosecution as a result of the examination of the addition of the previously cancelled claims. Applicant should not be penalised for an error made by the USPTO when the Applicant has properly filed and prosecuted the present divisional application in a diligent fashion.
Further, claim 34 is submitted which specifically avoids overlap with the claims of the parent application. In addition to acknowledging the patentability of claims 1-33, Applicant request acknowledgement that the subject matter of claim 34 is outside the scope of the claims of US 11,872,289 and is not subject to a double patenting rejection.
CONCLUSION

NEXT OFFICE ACTION: DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on July 23, 2024 and October 28, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Claim Status
Claims 1-34 are under consideration in this office action.
Withdrawn Claims Objections/Rejections
The objection of claim 11 is withdrawn in view of applicant’s amendment.
The rejection of claim 20 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of applicant’s amendment to remove the parentheses in the claim.
Applicant’s arguments, see pg 12-14, filed November 4, 2024, with respect to the rejection of claims 1, 3, 5, 9, 11-21, and 25 on the ground of nonstatutory double patenting as being unpatentable over the claims of patent 9,217,038 and patent 11,872,289 have been fully considered and are persuasive. The rejection has been withdrawn.
REASONS FOR ALLOWANCE
The following is an examiner’s statement of reasons for allowance:
The prior art fails to teach or suggest a conjugate comprising an anti-MUC2/TA-MUC1 antibody of CDR-H1-3 of SEQ ID NOs: 1-3 and CDR-L1-3 of SEQ ID NOs: 4-6, where X in SEQ ID NO: 2 is any amino acid except Asn.
The closest prior art is US 2012/0128676A1, published May 24, 2012 (see IDS from 8/1/22, A121), which teaches an antibody or antigen binding fragment thereof that binds to MUC1 [0045] and a conjugate thereof [0073]. However, it has been determined that the prior art does not teach the anti- MUC1 antibody that is comprised of the distinct CDRs of instant claim 1. The claimed invention is therefore free of the prior art.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 1-34 are allowed.

CITED REFERENCE SUMMARIES: Ref EP18173253: Claims:
1. A conjugate comprising an antibody conjugated to a cytotoxic agent, wherein the antibody is capable of binding to MUC1 , which comprises
(i) a heavy chain variable region comprising the complementarity-determining regions (CDRs) CDR-H1 having the amino acid sequence of SEQ ID NO: 1 , CDR-H2 having the amino acid sequence of SEQ ID NO: 2 and CDR-H3 having the amino acid sequence of SEQ ID NO: 3, and
(ii) a light chain variable region comprising the complementarity-determining regions (CDRs) CDR-L1 having the amino acid sequence of SEQ ID NO: 4, CDR-L2 having the amino acid sequence of SEQ ID NO: 5 and CDR-L3 having the amino acid sequence of SEQ ID NO: 6.
2. The conjugate according to claim 1 , wherein the amino acid at position 8 of SEQ ID NO: 2 is selected from the group consisting of glutamine, histidine, tryptophan, tyrosine, lysine and arginine, or wherein the CDR-H2 has the amino acid sequence of SEQ ID NO: 7.
3. The conjugate according to claim 1 , wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence which is at least 90% identical to the amino acid sequence of SEQ ID NO: 9.
4. The conjugate according to any one of claims 1 to 3, wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence which is at least 90% identical to the amino acid sequence of SEQ ID NO: 10.
5. The conjugate according to any one of claims 1 to 4, wherein the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence which is at least 90% identical to the amino acid sequence of SEQ ID NO: 12.
6. The conjugate according to any one of claims 1 to 5, wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 10 and the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 12.
7. The conjugate according to any one of claims 1 to 6, wherein the antibody comprises an Fc region and preferably is an lgG1 , lgG2 or lgG4-type antibody.
8. The conjugate according to any one of claims 1 to 7, wherein the heavy chain of the antibody has the amino acid sequence of SEQ ID NO: 15, in particular SEQ ID NO: 22, and the light chain of the antibody has the amino acid sequence of SEQ ID NO: 16.
9. The conjugate according to claim 1 , wherein the CDR-H2 has the amino acid sequence of SEQ ID NO: 8.
10. The conjugate according to claim 1 or 9, wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 1 1 or an amino acid sequence which is at least 90% identical to the amino acid sequence of SEQ ID NO: 1 1 .
1 1. The conjugate according to any one of claims 1 , 9 and 10, wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence which is at least 90% identical to the amino acid sequence of SEQ ID NO: 12.
12. The conjugate according to any one of claims 1 and 9 to 1 1 , wherein the heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 1 1 and the light chain variable region of the antibody has the amino acid sequence of SEQ ID NO: 12.
13. The conjugate according to any one of claims 1 and 9 to 12, wherein the antibody comprises an Fc region and preferably is an lgG1 , lgG2 or lgG4-type antibody.
14. The conjugate according to any one of claims 1 and 9 to 13, wherein the heavy chain of the antibody has the amino acid sequence of SEQ ID NO: 19 and the light chain of the antibody has the amino acid sequence of SEQ ID NO: 16.
15. The conjugate according to claims 7, 8, 13 and 14, wherein the antibody comprises a glycosylation pattern having one or more of the following characteristics:
(i) a detectable amount of glycans carrying a bisecting GlcNAc residue;
(ii) a relative amount of glycans carrying at least one galactose residue of at least 25% of the total amount of glycans attached to the Fc glycosylation sites of the antibody in a composition.
16. The conjugate according to any one of claims 1 to 15, wherein the antibody is obtainable by production in a mammalian cell.
17. The conjugate according to any one of claims 1 to 16, wherein the antibody is obtainable by production in a human cell line selected from the group consisting of NM-H9D8 (DSM ACC 2806), NM-H9D8-E6 (DSM ACC 2807), NM-H9D8-E6Q12 (DSM ACC 2856) and cell lines derived therefrom.
18. The conjugate according to any one of claims 1 to 16, wherein the antibody is obtainable by production in a CHO cell line and cell lines derived therefrom.
19. The conjugate according to any one of claims 1 to 18, wherein the antibody is obtainable by a production method comprising the steps of (i) providing a host cell comprising a nucleic acid encoding the antibody according to claims 1 to 14, (ii) culturing the host cell under conditions suitable for expression of the antibody, and (iii) obtaining the antibody expressed by the host cell.
20. The conjugate according to any one of claims 1 to 19, wherein the antibody competes with the antibody comprising a heavy chain variable region with the amino acid sequence of SEQ ID NO: 10 and a light chain variable region with the amino acid sequence of SEQ ID NO:12, or the antibody comprising a heavy chain variable region with the amino acid sequence of SEQ ID NO:1 1 and a light chain variable region with the amino acid sequence of SEQ ID NO:12 for the binding to TA-MUC1.
21. The conjugate according to any one of claims 1 to 20, wherein the antibody has the activity of being internalized into MUC1 -expressing cells through binding to MUC-1 .
22. The conjugate according to any one of claims 1 to 21 , wherein the cytotoxic agent is an anti-tumor agent.
23. The conjugate according to according to any one of claims 1 to 22, wherein the cytotoxic agent is a chemotherapeutic agent.
24. The conjugate according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of a microtubule inhibitor, a topoisomerase I inhibitor, a DNA damaging agent, a DNA alkylating agent and a DNA minor groove binder.
25. The conjugate according to claim 24, wherein the chemotherapeutic agent is a topoisomerase I inhibitor.
26. The conjugate according to claim 25, wherein the topoisomerase I inhibitor is an antitumor compound represented by the following formula: [Formula 1 ]
Figure imgf000095_0001
27. The conjugate according to any one of claims 1 to 26, wherein the antibody is conjugated to the cytotoxic agent or antitumor compound via a linker having any structure selected from the group consisting of the following formulas (a) to (f):
(a) -(Succinimid-3-yl-N)-CH2CH2-C(=0)-GGFG-NH-CH2CH2CH2-C(=0)-,
(b) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2CH2CH2- C(=0 )-,
(c) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2-0-CH2- C(=0)-,
(d) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2CH2-0-CH2- C(=0)-,
(e) -(Succinimid-3-yl-N)-CH2CH2-C(=0)-NH-CH2CH20-CH2CH20-CH2CH2-C(=0)- GGFG-NH-CH2CH2CH2-C(=0)-, and
(f) -(Succinimid-3-yl-N)-CH2CH2-C(=0)-NH-CH2CH20-CH2CH20-CH2CH20- CH2CH20-CH2CH2-C(=0)-GGFG-NH-CH2CH2CH2-C(=0)-, wherein the antibody is connected to the terminus of -(Succinimid-3-yl-N), the cytotoxic agent or antitumor compound is connected to the carbonyl group in the rightmost of formulas (a) to (f) with the nitrogen atom of the amino group at position 1 as a connecting position, GGFG represents an amino acid sequence consisting of glycine-glycine-phenylalanine-glycine linked through peptide bonds, and
-(Succinimid-3-yl-N)- has a structure represented by the following formula: [Formula 2]
Figure imgf000096_0001
which is connected to the antibody at position 3 thereof and is connected to a methylene group in the linker structure containing this structure on the nitrogen atom at position 1.
28. The conjugate according to claim 27, wherein the linker is represented by any formula selected from the group consisting of the following formulas (a) to (c):
(a) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2-0-CH2- C(=0)-, (b) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2CH2-0-CH2-
C(=0)-, and
(c) -(Succinimid-3-yl-N)-CH2CH2-C(=0)-NH-CH2CH20-CH2CH20-CH2CH2-C(=0)- GGFG-NH-CH2CH2CH2-C(=0)-.
29. The conjugate according to any one of claims 27 to 28, wherein the linker is represented by the following formula (a):
(a) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2-0-CH2- C(=0)-.
30. The conjugate according to any one of claims 26 to 29, wherein the antibody is conjugated to a drug linker represented by the following formula (wherein asterisk* represents the point of connection to the antibody) by a thioether bond:
[Formula 3]
Figure imgf000097_0001
31 . The conjugate according to any one of claims 26 to 30, which is represented by the following formula; [Formula 4]
Figure imgf000097_0002
wherein AB represents the antibody thereof, y represents an average number of units of the drug-linker structure conjugated to the antibody per itself, and the antibody is conjugated to a drug linker represented by the above formula by a thioether bond.
32. The conjugate according to claim 30 or 31 , wherein the antibody comprises any one of the following combinations a) to d) of a heavy chain variable region and a light chain variable region, or heavy chain and light chain: (a) the heavy chain variable region has the amino acid sequence of SEQ ID NO:
10 and the light chain variable region has the amino acid sequence of SEQ ID NO: 12,
(b) the heavy chain variable region has the amino acid sequence of SEQ ID NO:
1 1 and the light chain variable region has the amino acid sequence of SEQ ID NO: 12,
(c) the heavy chain has the amino acid sequence of SEQ ID NO: 22 and the light chain has the amino acid sequence of SEQ ID NO: 16, and
(d) the heavy chain has the amino acid sequence of SEQ ID NO: 19 and the light chain has the amino acid sequence of SEQ ID NO: 16.
33. A conjugate, which is represented by the following formula,
[Formula 5]
Figure imgf000098_0001
wherein AB represents the antibody, the antibody comprises the heavy chain variable region having the amino acid sequence of SEQ ID NO: 10 and the light chain variable region having the amino acid sequence of SEQ ID NO: 12, y represents an average number of units of the drug-linker structure conjugated to the antibody per itself, and the antibody is conjugated to a drug linker represented by the above formula by a thioether bond.
34. A conjugate, which is represented by the following formula, [Formula 6]
Figure imgf000099_0001
wherein AB represents the antibody, the antibody comprises the heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 1 and the light chain variable region having the amino acid sequence of SEQ ID NO: 12, y represents an average number of units of the drug-linker structure conjugated to the antibody per itself, the antibody is conjugated to a drug linker represented by the above formula by a thioether bond.
35. A conjugate, which is represented by the following formula,
[Formula 7]
Figure imgf000099_0002
wherein AB represents the antibody, the antibody comprises the heavy chain having the amino acid sequence of SEQ ID NO: 22 and the light chain having the amino acid sequence of SEQ ID NO: 16, y represents an average number of units of the drug-linker structure conjugated to the antibody per itself, and the antibody is conjugated to a drug linker represented by the above formula by a thioether bond.
36. A conjugate, which is represented by the following formula,
[Formula 8]
Figure imgf000100_0001
wherein AB represents the antibody, the antibody comprises the heavy chain having the amino acid sequence of SEQ ID NO: 19 and the light chain having the amino acid sequence of SEQ ID NO: 16, y represents an average number of units of the drug-linker structure conjugated to the antibody per itself, and the antibody is conjugated to a drug linker represented by the above formula by a thioether bond.
37. The conjugate according to any one of claims 1 to 36, wherein the antibody comprises one or more modifications selected from the group consisting of defucosylation, reduced fucose, N-linked glycosylation, O-linked glycosylation, N- terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, the substitutions of two leucine (L) residues to alanine (A) at position 234 and 235 of the heavy chain (LALA), amidation of a proline residue, and a deletion or lack of one or two amino acids at the carboxyl terminus.
38. The conjugate according to claim 37, wherein the antibody comprises a deletion or lack of one or two amino acid(s) in the carboxyl terminus of the heavy chain.
39. The conjugate according to claim 38, wherein the antibody comprises two heavy chains, both of which lack one carboxyl-terminal amino acid residue.
40. The conjugate according to any one of claims 1 to 39, wherein the average number y of the cytotoxic agents, in particular drug-linker structures, conjugated per antibody is in a range of from 1 to 10.
41 . The conjugate according to any one of claims 1 to 40, wherein the average number y of the cytotoxic agents, in particular of units of the selected one drug- linker structure, conjugated per antibody is in a range of from 2 to 8.
42. The conjugate according to any one of claims 1 to 41 , wherein the average number y of the cytotoxic agents, in particular of units of the selected one drug- linker structure, conjugated per antibody is in a range of from 3 to 8.
43. The conjugate according to any one of claims 1 to 42, wherein the average number y of the cytotoxic agents, in particular of units of the selected one drug- linker structure, conjugated per antibody is in a range of from 7 to 8.
44. The conjugate according to any one of claims 1 to 43, wherein the average number y of the cytotoxic agents, in particular of units of the selected one drug- linker structure, conjugated per antibody is in a range of from 7.5 to 8.
45. The conjugate according to any one of claims 1 to 44, wherein the number of conjugated cytotoxic agents per antibody molecule is 8.
46. A composition comprising the conjugate according to any one of claims 1 to 45.
47. The conjugate according to any one of claim 1 to 45 for use in medicine.
48. The conjugate according to claim 47, or the composition according to claim 46 for use in the treatment of cancer, an infection, an autoimmune disease or an immunodeficiency disorder.
49. The conjugate or the composition according to claim 47 or 48, wherein the cancer is characterized by expressing TA-MUC1 .
50. The conjugate or the composition according to claim 49, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, stomach cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid cancer, leukemias, seminomas, melanomas, carcinomas, teratomas, lymphomas, sarcomas, mesotheliomas, neuroblastomas, gliomas, rectal cancer, adrenal cancer, skin cancer, cancer of the brain, cervical cancer, intestinal cancer, intestine cancer, head and neck cancer, gastrointestinal cancer, lymph node cancer, esophagus cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, cancer of the uterus and the metastases thereof.
51. The conjugate or the composition according to any one of claims 46 to 50, wherein the composition is used in combination with a further agent.
52. A method for treating cancer in a subject in need thereof comprising, administering to the subject with cancer a therapeutically effective amount of the conjugation according to any one of claims 1 to 45 or the composition according to claim 46.
53. The method according to claim 52, wherein the cancer is characterized by expressing TA-MUC1 .
54. The method for treating cancer according to claim 52 or 53, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, stomach cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid cancer, leukemia, seminomas, melanomas, carcinomas, teratomas, lymphomas, sarcomas, mesotheliomas, neuroblastomas, gliomas, rectal cancer, adrenal cancer, skin cancer, cancer of the brain, cervical cancer, intestinal cancer, intestine cancer, head and neck cancer, gastrointestinal cancer, lymph node cancer, esophagus cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, bladder cancer, cancer of the uterus and the metastases thereof.
55. The method for treating cancer according to claim 54, further comprising administering a further therapeutic agent.
Ref US20120128676: Claims:
1. An antibody or a fragment or derivative thereof which is capable of binding to a mucin protein, wherein the antibody comprises at least a portion of a heavy chain variable region comprising a proline residue at amino acid position 28 according to the Kabat numbering.
2. The antibody or fragment or derivative thereof according to claim 1, having the following characteristics:
(a) it specifically binds the glycosylated MUC1 tumor epitope, and (b) it comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 16 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28; or it is a functional fragment or derivative of the antibody having the characteristics (a) and (b), said functional fragment or derivative showing cross-specificity with an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 16 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28.
3. The antibody or fragment or derivative thereof according to claim 1, having one or more of the following characteristics:
(a) the specific binding to its epitope is dependent on the conformation or the glycosylation pattern of the epitope; (b) it is capable of specifically binding a peptide comprising the amino acid sequence PDTR, which is glycosylated at the threonine residue with N-acetyl galactosamine (Tn) or galactose β1-3 N-acetyl galactosamine (TF); (c) it is capable of specifically binding to MUC1, in particular to at least a portion of the glycosylated extracellular tandem repeats of tumor-derived MUC1; (d) it specifically binds the glycosylated MUC1 tumor epitope such that the strength of the bond is increased at least by a factor 20 in comparison with the bond to the non-glycosylated peptide of identical length and identical peptide sequence; (e) it is engineered, preferably humanized; (f) it comprises at least one heavy chain complementarity determining region selected from the group consisting of
(i) CDR1 having the amino acid sequence of SEQ ID NO: 1,
(ii) CDR2 having the amino acid sequence of SEQ ID NO: 3, and
(iii) CDR3 having the amino acid sequence of SEQ ID NO: 5;
 (g) it comprises the antibody framework regions selected from the following:
(i) FRH1, FRH2, FRH3 and FRH4 for the variable heavy chain VH having the following amino acid sequences, the amino acid position corresponding to the numeration according to Kabat:
Pos.
                  Amino
                 
                   
                   
                 
                   
                 
               
               
                  for FRH1 (SEQ ID NO: 7)
                 
               
               
               
               
                   
                   1
                  E
                 
                   
                   2
                  V
                 
                   
                   3
                  Q or K
                 
                   
                   4
                  L
                 
                   
                   5
             
[Truncated to input limit]