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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 18, 2025 has been entered.
Claims 1, 4-12 and 15 are pending and being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Objection and Rejection Withdrawn
The written description and enablement rejections of claims 1-12 and 15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph are withdrawn in view of the claim amendment and the Examiner’s amendment set forth below.
The objection to claims 2-6 is withdrawn in view of the claim amendment.
The rejection of claims 1 and 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in light of the claim amendment.
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)(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, 4-12 and 15 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by U.S. patent no. 12,180,279 (claimed earliest priority to EP17199086, filed Oct 30, 2017; PTO 892).
(Currently amended) A set of heterodimeric precursor polypeptides comprising:
a first heterodimeric precursor polypeptide comprising:
a first heavy chain polypeptide comprising from N- to C-terminal direction a first VH domain, a CHI domain, a second antibody variable domain selected from a VH domain and a VL domain, and a CH3 domain,
a second heavy chain polypeptide comprising from N- to C-terminal direction a CH2 domain and a CH3 domain, wherein the first heavy chain polypeptide and the second heavy chain polypeptide are associated with each other via the CH3 domains and form a heterodimer, wherein one of the CH3 domains comprises a knob mutation and the other CH3 domain comprises a hole mutation; and
a light chain polypeptide comprising from N-to C-terminal direction a first VL domain and a CL domain, wherein the first VH domain and the first VL domain are associated with each other and form an antigen binding site specifically binding to a target antigen; and
a second heterodimeric precursor polypeptide comprising
a third heavy chain polypeptide comprising from N- to C-terminal direction a second VH domain, a CH1 domain, a third antibody variable domain selected from a VH domain and a VL domain, and a CH3 domain,
a fourth heavy chain polypeptide comprising from N- to C-terminal direction a CH2 domain and a CH3 domain, wherein the third heavy chain polypeptide and the fourth heavy chain polypeptide associate with each other via the CH3 domains and form a heterodimer, wherein one of the CH3 domains comprises a knob mutation and the other CH3 domain comprises a hole mutation; and
a light chain polypeptide comprising from N- to C-terminal direction
a second VL domain and a CL domain, wherein the second VH domain and the second VL domain associate with each other and form an antigen binding site specifically binding to a target antigen;
wherein the variable domains of the first heavy chain polypeptide and the third heavy chain polypeptide form an antigen binding site specifically binding to a target antigen; wherein
A) either
i) the first heavy chain polypeptide comprises the CH3 domain with the knob mutation and the third heavy chain polypeptide comprises the CH3 domain with the hole mutation, or
ii) the first heavy chain polypeptide comprises the CH3 domain with the hole mutation and the third heavy chain polypeptide comprises the CH3 domain with the knob mutation; and wherein
B) either
i) the CH3 domain of the first heterodimeric precursor polypeptide comprising the knob mutation and the CH3 domain of the second heterodimeric precursor polypeptide comprising the hole mutation, or
ii) the CH3 domain of the first heterodimeric precursor polypeptide comprising the hole mutation and the CH3 domain of the second heterodimeric precursor polypeptide comprising the knob mutation comprises one or more destabilizing mutations,
wherein when the CH3 domain comprising the knob mutation comprises a destabilizing mutation, the CH3 domain comprising the hole mutation of said heterodimeric precursor polypeptide does not comprise a destabilizing mutation, or
when the CH3 domain comprising the hole mutation of a heterodimeric precursor polypeptide comprises a destabilizing mutation, the CH3 domain comprising the knob mutation of said heterodimeric precursor polypeptide does not comprise a destabilizing mutation; and wherein the destabilizing mutations are substitutions selected from the group indicated in the following table, wherein the numbering is according to the Kabat numbering system:
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Regarding claim 1, the ‘279 patent discloses a set of two heterodimeric precursor polypeptides (starting heterodimers) comprising
a first heterodimeric precursor (starting) polypeptide comprising a VH domain, a CH1 domain, a second antibody variable domain, e.g., VH domain, a CH2 domain and a CH3 domain comprising a hole substitution.
a second heavy chain polypeptide comprising from N- to C-terminal direction a variable domain, e.g., VL, a CH2 domain and a CH3 domain wherein the first and second heavy chains are associated with each other via the CH3 domains to form a heterodimer and
a light chain polypeptide comprising from N- to C-terminal direction a first VL domain and a CL domain wherein the first VH domain and the first VL domain are associated together to form a first antigen binding site specifically binds to a first antigen (specificity 1, far left structure in Figure 44,
A second heterodimeric precursor polypeptide comprising
a third heavy chain polypeptide comprising from N- to C-terminal direction a second VH domain, a CH1 domain, a third antibody variable domain, e.g., VL domain, a CH2 and a CH3 domain comprising a knob mutation,
a fourth heavy chain comprising from N- to C- terminal direction an antibody variable domain, e.g., VH domain, a CH2 and a CH3 domain with a hole mutation wherein the third heavy chain and the fourth heavy chain associate with each other via the CH3 domain to form a heterodimer, and
a second light chain comprising from N- to C- terminal direction a second VL and a CL domain wherein the second VH and the VL domain are associated with each other and form a second antigen binding site specifically binding to a second target antigen (specificity 2), see middle in Figure 44 below:
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The first heterodimeric precursor polypeptide comprises one polypeptide chain comprising VL and the CH3 domain and the second heterodimeric precursor polypeptide comprises a VH domain and a CH3 domain wherein the VL and the VH binds an antigen (different specificity) when associated, see entire document, Summary of invention, caption of Figure 18, in particular. It should be noted that the reference Figure 44 is same as instant Figure 3.
The ‘279 patent teaches that typically, the CH3 domain of the first polypeptide comprises knob mutation and the CH3 domain of the second polypeptide comprises a hole mutation or the first polypeptide comprises the hole mutation and the CH3 domain of the second polypeptide comprises a knob-mutation, e.g., Knob/hole CH3 pairing (T366W; T366S/L368A/Y407V), see col. 3, lines 38-43, col. 75, 76, 81-84.
The ‘279 patent teaches that in addition to the knob and hole mutations, the CH3 further comprises one or more perturbing (destabilized or repulsive charge) mutation, e.g., D356K, or E357K or K370E or K439E, see col. 9, line 42-47, col. 10, line 13-23, col. 65, lines 44-58, col. 132, lines 39-43, col. 134, Table, in particular. If one of the CH3 having a hole mutation is E357K, then the knob comprises Y349E, col. 145, Table in particular. The first CH3 domain heterodimers in the CH3 domain may comprise a perturbing (destabilized) mutations D356K, K370E, E357K, S364L, Y349E, numbering according to Kabat EU index to create the destabilized interface that drives exchange, see col. 47, lines 30-42, p. 4 lines 19-31, Table on p. 221).
The ‘279 patent teaches that the CH3 domain of the heterodimeric precursor polypeptide comprises a cysteine mutation, e.g., S354C and the complementary CH3 domain of the second multimer comprises a cysteine mutation, e.g., Y349C, numbering according to Kabat EU index, see p. 122, in particular.
The ‘279 patent teaches that the first and second heterodimeric polypeptide contain no interchain disulfide bond (aka no hinge region) form between the first and second heavy chain comprising CH3 domains, see entire document, Fig, 44, in particular.
The CH3 domains comprises a first destabilizing mutation at position 357, e.g., E357K and a second destabilizing mutation at position 370, e.g., K370E.
Regarding claim 4, the ‘279 patent teaches that the first antigen binding moiety, e.g., VH-CH1 and the second antigen binding moiety, e.g., VL-CL form a Fab fragment in the first heterodimer or the second heterodimer, see Figure 44 above, in particular.
Regarding 5, the ‘279 patent teaches that the first heterodimeric precursor polypeptide further comprises within the heavy chain polypeptide comprising a CH3 domain a further antibody variable domain (first antibody variable domain) and a further polypeptide chain that is a light chain polypeptide comprising a second antibody variable domain, see Figure 44 above.
Regarding claim 7, the ‘279 patent teaches that the antigen binding moiety of the first heterodimeric precursor polypeptide binds to LeY and the antigen binding moiety of the second heterodimeric precursor polypeptide binds to LeY, the same antigen, see Figure 44.
Regarding claim 8, the ‘279 patent teaches that first antigen binding site binds to LeY and the second antigen binding site binds to CD3, see caption of Figure 42, in particular.
Regarding claims 9-10, the ‘279 patent teaches that contacting the first heterodimeric precursor polypeptide and the second heterodimeric precursor polypeptide forma third heterodimeric precursor polypeptide in the absence of a reducing agent, see entire document, Figure 44.
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Regarding claim 12, the ‘279 patent discloses a set of heterodimeric precursor polypeptides
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comprising
a first heterodimeric precursor polypeptide (upper left, specificity 1) comprising VH domain, a CH1 domain, a second VH domain and a CH3 domain comprising a hole substitution, the term “comprising” is open ended. It expands the first polypeptide to include additional domain.
a second heavy chain polypeptide comprising from N- to C-terminal direction a variable domain, e.g., VL and a CH3 domain wherein the first and second heavy chains are associated with each other via the CH3 domains to form a heterodimer and
a light chain polypeptide comprising from N- to C-terminal direction a first VL domain and a CL domain wherein the first VH domain and the first VL domain are associated together to form a first antigen binding site specifically binds to a first antigen (specificity 1, left upper structure in Figure 18),
A second heterodimeric precursor polypeptides (upper right, specificity2) comprising
a third heavy chain polypeptide comprising from N- to C-terminal direction a second VH domain, a CH1 domain, a third antibody variable domain, e.g., VL domain and a CH3 domain comprising a knob mutation,
a fourth heavy chain comprising from N- to C- terminal direction an antibody variable domain, e.g., VH domain and a CH3 domain with a hole mutation wherein the third heavy chain and the fourth heavy chain associate with each other via the CH3 domain to form a heterodimer, and
a second light chain comprising from N- to C- terminal direction a second VL and a CL domain wherein the second VH and the VL domain are associated with each other and form a second antigen binding site specifically binding to a second target antigen (specificity 2), see upper right in Figure 18:
The first heterodimeric precursor polypeptide comprises one polypeptide chain comprising VL and the CH3 domain and the second heterodimeric precursor polypeptide comprises a VH domain and a CH3 domain wherein the VL and the VH binds an antigen (specificity 4) when associated, see entire document, Figure 18, in particular. The ‘279 patent teaches that in addition to the knob and hole mutations, the CH3 further comprises one or more perturbing (destabilized or repulsive charge) mutation, e.g., D356K, or E357K or K370E or K439E, see col. 9, line 42-47, col. 10, line 13-23, col. 65, lines 44-58, col. 132, lines 39-43, col. 134, Table, in particular. If one of the CH3 having a hole mutation is E357K, then the knob comprises Y349E, col. 145, Table in particular. The first CH3 domain heterodimers in the CH3 domain may comprise a perturbing (destabilized) mutations D356K, K370E, E357K, S364L, Y349E, numbering according to Kabat EU index to create the destabilized interface that drives exchange, see col. 47, lines 30-42, col. 134, Table, in particular).
The ‘279 patent teaches that the set of heterodimeric polypeptides comprise no interchain disulfide bonds between the first and second heavy chains of the first and second heterodimeric complexes, see Figure 18, in particular.
The ‘279 patent teaches that the set of heterodimeric polypeptides in Figure 18 above when mixed together form a third heterodimeric polypeptide comprising at least one polypeptide chain comprising a CH3 domain from the first heterodimeric precursor polypeptide and at least one polypeptide chain comprising a CH3 domain from the second heterodimeric polypeptide, see TriFab A+B or specificity 4 in Figure 28 below.
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The ‘279 patent teaches that the triFab A+B comprises 3 antigen binding sites having a first specificity, e.g., LeY, a second specificity, e.g., CD3 and a third specificity, e.g., EGFR from by VH and VL domains, see Figure 28 above.
Claim 8 is included as it is within the purview of one of ordinary skill in the art substitute the second variable domain, e.g., VH and VL in the heavy chains of the first and second heterodimeric precursor for any VH and VL that binds to CD3 to direct CD3 expressing T cells to LeY expressing cells.
The ‘279 patent teaches that the triFab A+B heterodimer comprises no interchain disulfide bond between the two heavy chain comprising the CH3 domain of the first and second heterodimeric polypeptide, see Figure 18 above and generation of bispecific antibodies without reduction, see Example 19.
Regarding claim 15, the ‘279 patent teaches pharmaceutical composition comprising the set of heterodimeric precursor polypeptides and a pharmaceutically acceptable carrier, e.g. phosphate or citrate buffer, see col 91, lines 20-21, col. 93, lines 25-26.
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/Primary Examiner, Art Unit 1641
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