Office Action 2: Notice of Allowance (2024-12-27)

CLAIMS:
Listing of Claims:

Amendment to the ClaimsThis listing of claims will replace all prior versions and listings of claims in the application:

1\. (Original) 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\. (Currently Amended) 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, arginine, aspartic acid, and glutamic acid or wherein the CDR- H2 has the amino acid sequence of SEQ ID NO: 7.

3\. (Original) 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\. (Original) 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\. (Original) 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\. (Original) 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\. (Original) The conjugate according to claim 1, wherein the antibody comprises an Fc region and is an IgGI-, IgG2-, or IgG4-type antibody.

8\. (Original) 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\. (Original) 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\. (Original) 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\. (Currently Amended) The conjugate according to claim 1, wherein the antibody has the activity of being internalized into MUC 1- or TA-MUC 1-expressing cells through binding to MUC1 or TA-MUC1.

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

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

14\. (Original) 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\. (Original) The conjugate according to claim 14, wherein the chemotherapeutic agent is a topoisomerase I inhibitor.
16\. (Original) The conjugate according to claim 15, wherein the topoisomerase I inhibitor is an antitumor compound represented by the following formula:SVG {EMBED HERE} 1.3631.817
M

17\. (Original) 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(=0)-,(c) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2--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(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2- C(=0)-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)-,
SVG {EMBED HERE} 0.8070.517

wherein the antibody is connected to the terminus of -(Succinimid-3-yl-N), the cytotoxic 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:- 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\. (Original) The conjugate according to claim 1, 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-SVG {EMBED HERE} 0.1530.52(b) -(Succinimid-3-yl-N)-CH2CH2CH2CH2CH2-C(=0)-GGFG-NH-CH2CH2-0-CH2- C(=0)-, and
(c) -(Succinimid-3-yl-N)-CH2CH2-C(=)-NH-CH2CH2-CH2CH2-CH2CH2- C(=0)-GGFG-NH-CH2CH2CH2-C(=0)-.

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

20\. (Currently Amended) The conjugate according to claim 1, wherein the antibody is conjugated to a drug linker represented by the following formula by a thioether bond:
SVG {EMBED HERE} 2.3635.617

wherein asterisk\* represents the point of connection to the antibody.
21\. (Original) The conjugate according to claim 1, which is represented by the following formula;SVG {EMBED HERE} 2.7231.91 O SVG {EMBED HERE} 2.7232.96 AB HN O 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\. (Original) 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\. (Original) 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, 0-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\. (Original) A pharmaceutical composition comprising the conjugate of claim 22.
25\. (Original) 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\. (Original) 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\. (Original) The conjugate according to claim 22, wherein the antibody comprises two heavy chains, both of which lack one carboxyl-terminal amino acid residue.

28\. (Original) 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\. (Original) 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\. (Original) 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\. (Original) 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\. (Original) 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\. (Original) The conjugate according to claim 1, wherein the number of conjugated cytotoxic agents per antibody molecule is 8.

34\. (Currently Amended) The conjugate according to claim 1, wherein the conjugate is not a conjugate represented bythe following formula:

AB SVG {EMBED HERE} 2.7235.913y wherein (i) AB represents an antibody, the antibody comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 10 and a 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, or (ii) AB represents an antibody, the antibody comprising a heavy chain having 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 a 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.

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.

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


CITED REFERENCE SUMMARIES: Ref US20120128676A1: Claims:
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 V 6 E 7 S 8 G 9 G 10 G 11 L 12 V 13 Q 14 P 15 G 16 G 17 S 18 L or M 19 R 20 L 21 S 22 C 23 A or V 24 A 25 S 26 G 27 F 28 P 29 F 30 S for FRH2 (SEQ ID NO: 9) 36 W 37 V 38 R 39 Q 40 A or S 41 P 42 G or E 43 K 44 G 45 L 46 E 47 W 48 V 49 G or A for FRH3 (SEQ ID NO: 11) 66 R 67 F 68 T 69 I 70 S 71 R 72 D 73 D 74 S 75 K 76 N or S 77 S 78 L or V 79 Y 80 L 81 Q 82 M 82a N 82b S 82c L 83 K 84 T 85 E 86 D 87 T 88 A 89 V 90 Y 91 Y 92 C 93 T or A 94 R for FRH4 (SEQ ID NO: 13) 103 W 104 G 105 Q 106 G 107 T 108 L 109 V or L 110 T 111 V 112 S 113 S (h) it comprises a framework region 1 comprising the amino acid sequence of SEQ ID NO: 7; (i) it comprises a heavy chain variable region of an antibody comprising the amino acid sequence of SEQ ID NO: 15; (j) it comprises a light chain variable region of an antibody comprising the amino acid sequence of SEQ ID NO: 27; (k) 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 is a functional fragment or derivative thereof; (l) it shows cross-specificity with the antibody Pankomab comprising heavy and light chain variable region sequences comprising the amino acid sequences of SEQ ID NO: 29 and SEQ ID NO: 30, respectively; (m) it shows cross-specificity with the antibody comprising the amino acid sequences of SEQ ID NO: 16 as heavy chain variable region and SEQ ID NO: 28 as light chain variable region. 4. A nucleic acid encoding the antibody or fragment or derivative thereof according to claim 1. 5. An expression cassette or vector comprising the nucleic acid according to claim 4 and a promoter operatively connected with said nucleic acid. 6. A host cell comprising the nucleic acid according to claim 4. 7. A composition comprising the antibody or fragment or derivative thereof according to claim 1. 8. The composition according to claim 7 further comprising one or more components selected from the group consisting of solvents, diluents, and excipients. 9. The antibody or fragment or derivative thereof according to claim 1 for use in medicine. 10. The antibody or fragment or derivative thereof according to claim 1 for use in the treatment, prognosis, diagnosis and/or monitoring of cancer, wherein the cancer preferably is selected from the group consisting of cancer of the colon, stomach, liver, pancreas, kidney, blood, lung, and ovary. 11. A method for improving the antigen binding and/or recognition of an antibody or a fragment or derivative thereof which is capable of binding to a mucin protein and which comprises at least a portion of a heavy chain variable region, the method comprising the step of providing a proline residue at position 28 of the heavy chain variable region, according to the Kabat numbering. 12. The method according to claim 11, having at least one or more of the following characteristics: (a) the amino acid residue in position 28 is obtained by introducing a mutation into the nucleic acid coding for the antibody or fragment or derivative thereof, wherein the mutation is introduced in the codon coding for said amino acid residue; (b) improving the antigen binding and/or antigen recognition includes enhancing the affinity of the antibody or fragment or derivative thereof to its antigen and/or increasing the specificity of the antibody or fragment or derivative thereof towards its antigen. 13. The method according to claim 11, wherein the antibody or fragment or derivative thereof has one or more of the following characteristics: (a) the specific binding to its epitope is dependent on the conformation and/or the glycosylation pattern of the epitope; (b) it is capable of specifically binding a peptide comprising the amino acid sequence PDTR, which preferably 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 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 antibody framework regions selected from the following (i) FRH1, FRH2, FRH3 and FRH4 for the variable heavy chain VH have the following amino acid sequences, the amino acid position corresponding to the numeration according to Kabat: Pos. Amino for FRH1 (SEQ ID NO: 33) 1 E 2 V 3 Q or K 4 L 5 V 6 E 7 S 8 G 9 G 10 G 11 L 12 V 13 Q 14 P 15 G 16 G 17 S 18 L or M 19 R 20 L 21 S 22 C 23 A or V 24 A 25 S 26 G 27 F 28 T 29 F 30 S for FRH2 (SEQ ID NO: 9) 36 W 37 V 38 R 39 Q 40 A or S 41 P 42 G or E 43 K 44 G 45 L 46 E 47 W 48 V 49 G or A for FRH3 (SEQ ID NO: 11) 66 R 67 F 68 T 69 I 70 S 71 R 72 D 73 D 74 S 75 K 76 N or S 77 S 78 L or V 79 Y 80 L 81 Q 82 M 82a N 82b S 82c L 83 K 84 T 85 E 86 D 87 T 88 A 89 V 90 Y 91 Y 92 C 93 T or A 94 R for FRH4 (SEQ ID NO: 13) 103 W 104 G 105 Q 106 G 107 T 108 L 109 V or L 110 T 111 V 112 S 113 S (ii) and optionally FRL1, FRL2, FRL3 and FRL4 for the light chain variable region VL have the following amino acid sequences, the amino acid position corresponding to the numeration according to Kabat: Pos. Amino for FRL1 (SEQ ID NO: 23) 1 D 2 I 3 V 4 M 5 T 6 Q 7 S 8 P 9 L 10 S 11 L or N 12 P 13 V 14 T 15 P 16 G 17 E or D 18 P 19 A 20 S 21 I 22 S 23 C for FRL2 (SEQ ID NO: 24) 35 W 36 Y 37 L 38 Q 39 K 40 P 41 G 42 Q 43 S 44 P 45 Q 46 L 47 L 48 I 49 Y for FRL3 (SEQ ID NO: 25) 57 G 58 V 59 P 60 D 61 R 62 F 63 S 64 G 65 S 66 G 67 S 68 G 69 T 70 D 71 F 72 T 73 L 74 K or R 75 I 76 S 77 R 78 V 79 E 80 A 81 E 82 D 83 V 84 G 85 V 86 Y 87 Y 88 C for FRL4 (SEQ ID NO: 26) 98 F 99 G 100 Q or G 101 G 102 T 103 K 104 V 105 E 106 I 107 K 108 R (h) it comprises a framework region 1 comprising the amino acid sequence of SEQ ID NO: 33 or 34; (i) it comprises a heavy chain variable region of an antibody comprising the amino acid sequence of SEQ ID NO: 38 or 29; (j) it comprises a light chain variable region of an antibody comprising the amino acid sequence of SEQ ID NO: 27 or 30; (k) it comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 27 or is a functional fragment or derivative thereof; (l) it shows cross-specificity with the antibody Pankomab comprising the amino acid sequence of SEQ ID NO: 29 (heavy chain variable region) and SEQ ID NO: 30 (light chain variable region); (m) it shows cross-specificity with the antibody comprising the amino acid sequences of SEQ ID NO: 16 as heavy chain variable region and SEQ ID NO: 28 as light chain variable region. 14. A method for preparing a nucleic acid according to claim 4, comprising the steps of (a) providing a nucleic acid comprising the nucleic acid sequence coding for an antibody or a fragment or derivative thereof which is capable of binding to MUC1 and which comprises a heavy chain variable region, wherein the heavy chain variable region does not comprise a proline residue at amino acid position 28 according to the Kabat numbering; (b) introducing a mutation into the codon coding for amino acid number 28, according to the Kabat numbering, of the heavy chain variable region so that said codon codes for a proline residue. 15. The antibody or fragment or derivative thereof according to claim 1, having a glycosylation pattern which has one or more of the following characteristics: (a) it is a human glycosylation pattern; (b) it enhances the activity of the antibody, in particular its binding affinity to its specific epitope, its binding affinity to one or more of its downstream receptors such as Fc receptors, its complement dependent cytotoxicity (CDC), and/or its antibody-dependent cell-mediated cytotoxicity (ADCC); (c) it is a glycosylation pattern as obtained when expressing the antibody or fragment or derivative thereof in a cell line selected from the group consisting of K562, KG1, MUTZ-3, NM-F9 [DSM ACC2606], NM-D4 [DSM ACC2605], NM-H9D8 [DSM ACC 2806], NM-H9D8-E6 [DSM ACC 2807], NM H9D8-E6Q12 [DSM ACC 2856], and GT-2X [DSM ACC 2858]. 16. The antibody or fragment or derivative thereof according to claim 3, which includes a framework region 1 comprising the amino acid sequence of SEQ ID NO: 8. 17. The antibody or fragment or derivative thereof according to claim 3, which includes a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 16. 18. The antibody or fragment or derivative thereof according to claim 3, which includes a light chain variable region comprising the amino acid sequence of SEQ ID NO: 28. 19. The antibody or fragment or derivative thereof according to claim 3, wherein the FRL1, FRL2, FRL3 and FRL4 for the light chain variable region VL have the following amino acid sequences, the amino acid position corresponding to the numeration according to Kabat: Pos. Amino for FRL1 (SEQ ID NO: 23) 1 D 2 I 3 V 4 M 5 T 6 Q 7 S 8 P 9 L 10 S 11 L or N 12 P 13 V 14 T 15 P 16 G 17 E or D 18 P 19 A 20 S 21 I 22 S 23 C for FRL2 (SEQ ID NO: 24) 35 W 36 Y 37 L 38 Q 39 K 40 P 41 G 42 Q 43 S 44 P 45 Q 46 L 47 L 48 I 49 Y for FRL3 (SEQ ID NO: 25) 57 G 58 V 59 P 60 D 61 R 62 F 63 S 64 G 65 S 66 G 67 S 68 G 69 T 70 D 71 F 72 T 73 L 74 K or R 75 I 76 S 77 R 78 V 79 E 80 A 81 E 82 D 83 V 84 G 85 V 86 Y 87 Y 88 C for FRL4 (SEQ ID NO: 26) 98 F 99 G 100 Q or G 101 G 102 T 103 K 104 V 105 E 106 I 107 K 108 R
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.
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.
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 V 6 E 7 S 8 G 9 G 10 G 11 L 12 V 13 Q 14 P 15 G 16 G 17 S 18 L or M 19 R 20 L 21 S 22 C 23 A or V 24 A 25 S 26 G 27 F 28 P 29 F 30 S for FRH2 (SEQ ID NO: 9) 36 W 37 V 38 R 39 Q 40 A or S 41 P 42 G or E 43 K 44 G 45 L 46 E 47 W 48 V 49 G or A for FRH3 (SEQ ID NO: 11) 66 R 67 F 68 T 69 I 70 S 71 R 72 D 73 D 74 S 75 K 76 N or S 77 S 78 L or V 79 Y 80 L 81 Q 82 M 82a N 82b S 82c L 83 K 84 T 85 E 86 D 87 T 88 A 89 V 90 Y 91 Y 92 C 93 T or A 94 R for FRH4 (SEQ ID NO: 13) 103 W 104 G 105 Q 106 G 107 T 108 L 109 V or L 110 T 111 V 112 S 113 S (h) it comprises a framework region 1 comprising the amino acid sequence of SEQ ID NO: 7; (i) it comprises a heavy chain variable region of an antibody comprising the amino acid sequence of SEQ ID NO: 15; (j) it comprises a light chain variable region of an antibody comprising the amino acid sequence of SEQ ID NO: 27; (k) 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 is a functional fragment or derivative thereof; (l) it shows cross-specificity with the antibody Pankomab comprising heavy and light chain variable region sequences comprising the amino acid sequences of SEQ ID NO: 29 and SEQ ID NO: 30, respectively; (m) it shows cross-specificity with the antibody comprising the amino acid sequences of SEQ ID NO: 16 as heavy chain variable region and SEQ ID NO: 28 as light chain variable region.
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 V 6 E 7 S 8 G 9 G 10 G 11 L 12 V 13 Q 14 P 15 G 16 G 17 S 18 L or M 19 R 20 L 21 S 22 C 23 A or V 24 A 25 S 26 G 27 F 28 P 29 F 30 S for FRH2 (SEQ ID NO: 9) 36 W 37 V 38 R 39 Q 40 A or S 41 P 42 G or E 43 K 44 G 45 L 46 E 47 W 48 V 49 G or A for FRH3 (SEQ ID NO: 11) 66 R 67 F 68 T 69 I 70 S 71 R 72 D 73 D 74 S 75 K 76 N or S 77 S 78 L or V 79 Y 80 L 81 Q 82 M 82a N 82b S 82c L 83 K 84 T 85 E 86 D 87 T 88 A 89 V 90 Y 91 Y 92 C 93 T or A 94 R for FRH4 (SEQ ID NO: 13) 103 W 104 G 105 Q 106 G 107 T 108 L 109 V or L 110 T 111 V 112 S 113 S (h) it comprises a framework region 1 comprising the amino acid sequence of SEQ ID NO: 7; (i) it comprises a heavy chain variable region of an antibody comprising the amino acid sequence of SEQ ID NO: 15; (j) it comprises a light chain variable region of an antibody comprising the amino acid sequence of SEQ ID NO: 27; (k) 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 is a functional fragment or derivative thereof; (l) it shows cross-specificity with the antibody Pankomab comprising heavy and light chain variable region sequences comprising the amino acid sequences of SEQ ID NO: 29 and SEQ ID NO: 30, respectively; (m) it shows cross-specificity with the antibody comprising the amino acid sequences of SEQ ID NO: 16 as heavy chain variable region and SEQ ID NO: 28 as light chain variable region.
A nucleic acid encoding the antibody or fragment or derivative thereof according to claim 1.
An expression cassette or vector comprising the nucleic acid according to claim 4 and a promoter operatively connected with said nucleic acid.
A host cell comprising the nucleic acid according to claim 4.
A composition comprising the antibody or fragment or derivative thereof according to claim 1.
The composition according to claim 7 further comprising one or more components selected from the group consisting of 
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