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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 1, 2026 has been entered.
Claims 1, 3-13, 15 and 16 are pending.
Claims 1, 3-13, 15 and 16, drawn to a set of heterodimeric precursor polypeptides that read on (A) E357 and V397Y as the combination of hole and knob mutation in the CH3 domain of the first and second precursor polypeptides, (B) the CH3 domain comprising a knob mutation of the first heterodimeric precursor polypeptide comprises a cysteine mutation and the CH3 domain comprising the hole mutation of the second heterodimeric precursor polypeptide comprising a cysteine mutation in claim 5 subpart (i), are 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.
Claim objection
Claim 6 is objected to because of the following informality: duplicate “binding” at line 2 should be deleted.
Objection and Rejection Withdrawn
The rejection of claims 1, 2 and 6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the claim amendment.
The written description and enablement rejections of claims 1-13, 15-16 and 18 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph are withdrawn in view of the claims amendment.
The objection to claims 2-8, 10 and 18 is withdrawn in light of the claim amendment.
The rejection of claims 7-8 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph is withdrawn in view of claim amendment.
The rejection of claims 1-3, 5-7, 10-13, 15-16 and 18 under 35 U.S.C. 103 as being unpatentable over WO2016087416 publication (published; PTO 892) in view of Brinkmann et al (of record, US20170369595, published December 28, 2017; PTO 892) is withdrawn in view of the amendment to claim 1. The combination of WO2016087416 publication and Brinkmann fails to teach or suggest two heterodimeric precursor polypeptides each comprising a first heavy chain polypeptide, a second heavy chain polypeptide and a light chain.
The rejection of claim 4 under 35 U.S.C. 103 as being unpatentable over WO2016087416 publication (published; PTO 892) in view of Brinkmann et al (of record, US20170369595, published December 28, 2017; PTO 892) as applied to claims 1-3, 5-7, 10-13, 15-16 and 18 mentioned above and further in view of Liu (US20140112926, published April 24, 2014; PTO 892) is withdrawn in view of the claim amendment. The combination of Liu does not cure the deficiency of WO2016087416 publication and Brinkmann.
The rejection of claims 8-9 under 35 U.S.C. 103 as being unpatentable over WO2016087416 publication (published; PTO 892) in view of Brinkmann et al (of record, US20170369595, published December 28, 2017; PTO 892) as applied to claims 1-3, 5-7, 10-13, 15-16 and 18 mentioned above and further in view of Ng et al (of record, US20180193477, published July 12, 2018; PTO 892) is withdrawn in view of the amendment to claim 1. The combination of WO2016087416 publication and Brinkmann fails to teach or suggest two heterodimeric precursor polypeptides each comprising a first heavy chain polypeptide, a second heavy chain polypeptide and a light chain. The addition of Ng does not cure the deficiency of WO2016087416 publication and Brinkmann.
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.
Claims 1, 3, 4, 6, 10, 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Regarding claim 1, the recitation of “wherein the third and fourth antibody variable domains together form a first antigen binding site specifically binding to a second target antigen” at line 22 is confusing and inconsistent with “wherein the first and second antibody variable domains together form a first antigen binding site specifically binding to a first target antigen” at line 10. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention. Amending the claim to recite “wherein the third and fourth antibody variable domains together form a second antigen binding site specifically binding to a second target antigen” at line 22 would obviate this rejection.
Regarding claim 1, part B) i) to ii), the recitation of “…the first and third heterodimeric precursor polypeptide comprising the knob mutation or the CH3 domain of the second and fourth heterodimeric precursor polypeptide comprising the hole mutation, or ii) the CH3 domain of the first and third heterodimeric precursor polypeptide comprising the hole mutation or the CH3 domain of the second and fourth heterodimeric precursor polypeptide…” is indefinite because claim 1 comprises just a first heterodimeric precursor polypeptide and a second precursor polypeptide but ends up with third and fourth heterodimeric precursor polypeptides. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention. Amending the claim to recite “…the first and third precursor polypeptide comprising the knob mutation or the CH3 domain of the second and fourth precursor polypeptide comprising the hole mutation, or ii) the CH3 domain of the first and third precursor polypeptide comprising the hole mutation or the CH3 domain of the second and fourth precursor polypeptide…” would obviate this rejection.
Regarding claim 1 at the second to last wherein clause, the recitation of “said knob mutation of a heterodimeric precursor polypeptide…said heterodimeric precursor polypeptide” is indefinite because it is unclear whether the knob mutation applies to either the first precursor polypeptide, the second precursor polypeptide, or both.
Claim 3 recites the limitation "mutation indicated in C" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites the limitation “the CH3 domain with the knob mutation …comprises a mutation E357K, the CH3 domain with the hole mutation in B) V397Y; K329D; or double mutation K370E K439E” in claim 1. There is insufficient antecedent basis for this limitation in the claim. This is because claim 1 recites the hole mutation comprises a E357K and the knob mutation comprises V397Y; K329D; or double mutation K370E K439E. Amending the claim to recite “the CH3 domain with the hole mutation …comprises a mutation E357K, the CH3 domain with the knob mutation in B) V397Y; K329D; or double mutation K370E K439E” would obviate this rejection.
Claim 6 recites the limitation "the second antigen binding binding site" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 10 recites the limitation “the two polypeptide chains comprising the CH3 domains of the first and second heterodimeric polypeptide” in claim 1. There is insufficient antecedent basis for this limitation in the claim. Amending claim 10 to recite “The set of heterodimeric precursor polypeptide of claim 1, wherein the first heavy chain polypeptide and the second heavy chain polypeptide of the first heterodimeric precursor, and the third heavy chain polypeptide and the fourth heavy chain polypeptide of the second heterodimeric precursor comprise no interchain disulfide bond” would obviate this rejection.
Claim 13 recites the limitation “the two polypeptide chains comprising the CH3 domains of the first and second heterodimeric polypeptide” in claims 13 and 1. There is insufficient antecedent basis for this limitation in the claim.
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, 3-4, 5-13, 15 and 16 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO2019086362 to Brinkmann et. al. published 09 May 2019 and effectively filed 30 October 2017 (hereinafter “the ‘362 publication”; PTO 1449).
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Regarding claims 1, 3, 4, 7, 15, 16, the ‘362 publication discloses a set of heterodimeric precursor polypeptides comprising
a first heterodimeric precursor polypeptide 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 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 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 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 (specificity 4) when associated, see entire document, p. 73, line 1-2, p. 110 in particular. The ‘362 publication teaches that wherein the CH3 domain of the first polypeptide comprises a hole mutations and the CH3 domain of the second polypeptide comprises the knob-mutation, see p. 4, line 12-16. The heterodimers in the CH3 domain may comprise the mutations E357K, V397Y, K392D, K370E in p. 4 lines 19-31, Table on p. 221).
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, see p. 109, lines 22 to p. 110, line 6.
Regarding claim 5, the ‘362 publication 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.
Regarding claim 6, the ‘362 publication teaches that first antigen binding site and the second antigen binding sites are Fab fragment (VH-CH1 paired with VL-CL), see Figure 18 above.
Regarding claim 8, the ‘362 publication teaches:
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Regarding claim 9, the ‘362 publication teaches that VH domain and the VL domain indicated in A0 form an antigen binding site specifically binding to CD3, see Figure 28, below:
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Regarding claim 10, the ‘362 publication 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.
Regarding claim 11, the ‘362 publication teaches that the set of heterodimeric polypeptides in Figure 18 above wherein 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 18 above.
Regarding claim 12, the ‘362 publication teaches that the triFab A+B comprises 3 antigen binding sites having a first specificity, a second specificity and a third specificity from by VH and VL domains, see Figure 18 above.
Regarding claim 13, the ‘362 publication 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.
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.
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, 3-4, 5-13, 15 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/443,662 (Reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims overlap in scope.
1. A set of heterodimeric precursor polypeptides comprising:
a) a first heterodimeric precursor polypeptide comprising at least two polypeptide chains comprising a CH3 domain,
wherein the two polypeptide chains comprising the CH3 domain 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,
wherein the first heterodimeric precursor polypeptide comprises a first antigen binding moiety,
wherein at least a part of the first antigen binding moiety is arranged on one of the two polypeptide chains comprising the CH3 domain, and
b) a second heterodimeric precursor polypeptide comprising at least two polypeptide chains comprising a CH3 domain,
wherein the two polypeptide chains comprising the CH3 domain 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,
wherein the second heterodimeric precursor polypeptide comprises a second antigen binding moiety, wherein at least a part of the second antigen binding moiety is arranged on one of the two polypeptide chains comprising the CH3 domain;
wherein
A) either
i) within the first heterodimeric precursor polypeptide the polypeptide chain comprising the CH3 domain comprising the knob mutation comprises at least a part of the first antigen binding moiety and within the second heterodimeric precursor polypeptide the polypeptide chain comprising the CH3 domain with the hole mutation comprises at least a part of the second antigen binding moiety, or
ii) within the first heterodimeric precursor polypeptide the polypeptide chain comprising the CH3 domain comprising the hole mutation comprises at least a part of the first antigen binding moiety and within the second heterodimeric precursor polypeptide the polypeptide chain comprising the CH3 domain with the knob mutation comprises at least a part of the second antigen binding moiety; 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 comprise the following amino acid substitutions, wherein the numbering is according to the Kabat numbering system:
- the CH3 domain with the hole mutation comprises at least one amino acid substitution selected from the group of:
o replacement of S354 with a hydrophobic amino acid;
o replacement of D356 with a positively charged amino acid;
o replacement of E357 with a positively charged amino acid or with a hydrophobic amino acid;
o replacement of D356 with a positively charged amino acid, and replacement of E357 with a positively charged amino acid or with a hydrophobic amino acid;
o replacement of S364 with a hydrophobic amino acid;
o replacement of A368 with a hydrophobic amino acid;
o replacement of E392 with a negatively charged amino acid;
o replacement of T394 with a hydrophobic amino acid;
o replacement of D399 with a hydrophobic amino acid and replacement of S400 with a positively charged amino acid; o replacement of D399 with a hydrophobic amino acid and replacement of F405 with a positively charged amino acid;
o replacement of V407 with a hydrophobic amino acid; and
o replacement of K409 with a negatively charged amino acid; and
o replacement of K439 with a negatively charged amino acid;
- the CH3 domain with the knob mutation comprises at least one amino acid substitution selected from the group of:
o replacement of Q347 with a positively charged amino acid, and replacement of K360 with a negatively charged amino acid;
o replacement of Y349 with a negatively charged amino acid;
o replacement of L351 with a hydrophobic amino acid, and replacement of E357 with a hydrophobic amino acid;
o replacement of S364 with a hydrophobic amino acid;
o replacement of W366 with a hydrophobic amino acid, and replacement of K409 with a negatively charged amino acid;
o replacement of L368 with a hydrophobic amino acid;
o replacement of K370 with a negatively charged amino acid;
o replacement of K370 with a negatively charged amino acid, and replacement of K439 with a negatively charged amino acid;
o replacement of K392 with a negatively charged amino acid;
o replacement of T394 with a hydrophobic amino acid; o replacement of V397 with a hydrophobic amino acid;
o replacement of D399 with a positively charged amino acid, and replacement of K409 with a negatively charged amino acid;
o replacement of S400 with a positively charged amino acid; o F405W; o Y407W; and
o replacement of K439 with a negatively charged amino acid, which corresponds to instant claim 1.
2. The set of heterodimeric polypeptides according to claim 1 or 2,
wherein the CH3 domains indicated in b) comprise the following amino acid substitutions:
- the CH3 domain with the hole mutation comprises at least one amino acid substitution selected from the group of S354V, D356K, E357K, E357F, S364L, A368F, K392E, T3941, V407Y, K409E, K439E and a double mutation D399A S400K; and
- the CH3 domain with the knob mutation comprises at least one amino acid substitution selected from the group of Y349E, S364V, L368F, K370E, K392D, T3941, V397Y, S400K, F405W, Y407W,K349E, and double mutations Q347K K360E, L351F E357F, W366I K409E, and D399K K409E, which corresponds to instant claim 1.
3. The set of heterodimeric polypeptides according to one of
The set of heterodimeric polypeptides according to one of wherein the CH3 domains indicated in b) comprise the following amino acid substitutions:
- the CH3 domain with the hole mutation comprises at least one amino acid substitution selected from the group of D356K, E357K, E357F, S364L, V407Y, K409E, and a double mutation D399A S400K; and
- the CH3 domain with the knob mutation comprises at least one amino acid substitution selected from the group of Y349E, K370E, K392D, T394I, V397Y, F405W, Y407W, K349E, and double mutations Q347K K360E, W366I K409E, and D399K K409E.
4. The set of heterodimeric polypeptides according to one of the preceding claims, wherein in case the CH3 domain with the knob mutation indicated in b) comprises a mutation E357K, the CH3 domain with the hole mutation indicated in b) does not comprise a mutation K370E; and wherein in case the CH3 domain with the knob mutation indicated in b) comprises a mutation D356K,the CH3 domain with the hole mutation indicated in b) does not comprise a mutation K439E, which corresponds to instant claim 1.
5. The set of heterodimeric polypeptides according to one of the preceding claims,
wherein either
the CH3 domain comprising the knob mutation of the first heterodimeric precursor polypeptide comprises a cysteine mutation and the CH3 domain comprising the hole mutation of the second heterodimeric precursor polypeptide comprises a cysteine mutation, or
ii) the CH3 domain comprising the hole mutation of the first heterodimeric precursor polypeptide comprises a cysteine mutation and the CH3 domain comprising the knob mutation of the second heterodimeric precursor polypeptide comprises a cysteine mutation, which corresponds to instant claim 5.
6. The set of heterodimeric polypeptides according to claim 5, wherein
within the first heterodimeric precursor polypeptide the CH3 domain comprising the knob mutation comprises a substitution S354C and the CH3 domain comprising the hole mutation comprises Y at position 349; and
wherein within the second heterodimeric precursor polypeptide the CH3 domain comprising the hole mutation comprises a substitution Y349C and the CH3 domain comprising the knob mutation comprises S at position 354, which corresponds to instant claim 5.
7. The set of heterodimeric polypeptides according to one of the preceding claims, wherein the first antigen binding moiety and/or the second antigen binding moiety is an antibody fragment.
8. The set of heterodimeric polypeptides according to one of the preceding claims,
wherein a) the first heterodimeric precursor polypeptide comprises:
- a first heavy chain polypeptide comprising a CH3 domain and a first antibody variable domain,
- a second heavy chain polypeptide comprising 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 a second antibody variable domain, wherein the first and second antibody variable domain together form a first antigen binding site specifically binding to a target antigen; and
wherein b) the second heterodimeric precursor polypeptide comprises:
- a third heavy chain polypeptide comprising a CH3 domain and a third antibody variable domain,
- a fourth heavy chain polypeptide comprising a CH3 domain,
wherein the third heavy chain polypeptide and the fourth 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 a fourth antibody variable domain,
wherein the third and fourth antibody variable domain together form a second antigen binding site specifically binding to a target antigen; and
wherein c) either
the first heavy chain polypeptide comprises a CH3 domain comprising a knob mutation and the third heavy chain polypeptide comprises a CH3 domain comprising a hole mutation; or
ii) the first heavy chain polypeptide comprises a CH3 domain comprising a hole mutation and the third heavy chain polypeptide comprises a CH3 domain comprising a knob mutation.
9. The set of heterodimeric polypeptides according to one of the preceding claims, wherein the first heterodimeric precursor polypeptide and the second heterodimeric precursor polypeptide comprise at least two polypeptide chains comprising from N- to C-terminal direction a hinge region, a CH2 domain and the CH3 domain, which corresponds to instant claim 8.
11. The set of heterodimeric polypeptides according to one of the preceding claims, wherein the first heterodimeric precursor polypeptide comprises one polypeptide chain comprising a VL domain and the CH3 domain, and wherein the second heterodimeric precursor polypeptide comprises one polypeptide chain comprising a VH domain and the CH3 domain, wherein said VL domain and said VH domain specifically bind to an antigen when associated to a pair of a VH domain and a VL domain.
12. A heterodimeric polypeptide comprising at least two polypeptide chains comprising a CH3 domain, wherein the two polypeptide chains comprising the CH3 domain 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; wherein the heterodimeric polypeptide comprises a first antigen binding moiety, wherein at least a part of the first antigen binding moiety is arranged on one of the two polypeptide chains comprising the CH3 domain; and wherein the heterodimeric polypeptide comprises a second antigen binding moiety, wherein at least a part of the second antigen binding moiety is arranged on the other one of the two polypeptide chains comprising the CH3 domain; and wherein the CH3 domain with the hole mutation comprises at least one amino acid substitution selected from the group of:- replacement of S354 with a hydrophobic amino acid;- replacement of D356 with a positively charged amino acid;- replacement of E357 with a positively charged amino acid or with a hydrophobic amino acid;- replacement of D356 with a positively charged amino acid, and replacement of E357 with a positively charged amino acid or with a hydrophobic amino acid;- replacement of S364 with a hydrophobic amino acid;- replacement of A368 with a hydrophobic amino acid;- replacement of E392 with a negatively charged amino acid;- replacement of T394 with a hydrophobic amino acid;- replacement of D399 with a hydrophobic amino acid and replacement of S400 with a positively charged amino acid;- replacement of D399 with a hydrophobic amino acid and replacement of F405 with a positively charged amino acid;- replacement of V407 with a hydrophobic amino acid; and- replacement of K409 with a negatively charged amino acid; and -7- - replacement of K439 with a negatively charged amino acid; and wherein the CH3 domain with the knob mutation comprises at least one amino acid substitution selected from the group of: - replacement of Q347 with a positively charged amino acid, and replacement of K360 with a negatively charged amino acid; - replacement of Y349 with a negatively charged amino acid; - replacement of L351 with a hydrophobic amino acid, and replacement of E357 with a hydrophobic amino acid; - replacement of S364 with a hydrophobic amino acid; - replacement of W366 with a hydrophobic amino acid, and replacement of K409 with a negatively charged amino acid; - replacement of L368 with a hydrophobic amino acid; - replacement of K370 with a negatively charged amino acid; - replacement of K370 with a negatively charged amino acid, and replacement of K439 with a negatively charged amino acid; - replacement of K392 with a negatively charged amino acid; - replacement of T394 with a hydrophobic amino acid; - replacement of V397 with a hydrophobic amino acid; - replacement of D399 with a positively charged amino acid, and replacement of K409 with a negatively charged amino acid; - replacement of S400 with a positively charged amino acid; - F405W; - Y407W; and - replacement of K439 with a negatively charged amino acid.
15. A heterodimeric polypeptide obtained by a method according to any one of
18. A multispecific heterodimeric polypeptide obtained by a method according to any one of claims 16 or 17.
19. A first heterodimeric precursor polypeptide as defined in any one of claims 1to 12, which corresponds to instant claim 15.
20. A second heterodimeric precursor polypeptide as defined in any one of claims 1 to 12 which corresponds to instant claim 16.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-4, 5-13, 15 and 16 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-3, 5, 9-14, 17 and 18 of U.S. Patent No. 12,180,279. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in scope; the claims in the present application subject to this rejection (claims 1 and 11 are drawn to a set of heterodimeric precursor polypeptides comprising:
a first heterodimeric precursor polypeptide comprising:
a first heavy chain polypeptide comprising a CH3 domain and a first antibody variable domain,
a second heavy chain polypeptide comprising a CH3 domain,
wherein the first heavy chain polypeptide and the second heavy chain polypeptide associate with each other via the CH3 domains to form a heterodimer,
wherein one of the CH3 domains comprises a knob mutation and the other CH3 domain comprises a hole mutation, and
a first light chain polypeptide comprising a second antibody variable domain,
wherein the first and second antibody variable domains together form a first antigen binding site specifically binding to a first target antigen; and
a second heterodimeric precursor polypeptide comprising:
a third heavy chain polypeptide comprising a CH3 domain and a third antibody variable domain,
a fourth heavy chain polypeptide comprising a CH3 domain,
wherein the third heavy chain polypeptide and the fourth heavy chain polypeptide associate with each other via the CH3 domains to form a heterodimer,
wherein one of the CH3 domains comprises a knob mutation and the other CH3 domain comprises a hole mutation, and
a second light chain polypeptide comprising a fourth antibody variable domain,
wherein the third and fourth antibody variable domains together form a first antigen binding site specifically binding to a second target antigen; and
wherein either
i) the first heavy chain polypeptide comprises a CH3 domain comprising a knob mutation and the third heavy chain polypeptide comprises a CH3 domain comprising a hole mutation, or
ii) the first heavy chain polypeptide comprises a CH3 domain comprising a hole mutation and the third heavy chain polypeptide comprises a CH3 domain comprising a knob mutation;
wherein A) either
the first heterodimeric precursor polypeptide comprises one polypeptide chain comprising a VH domain and the CH3 domain, and
wherein the second heterodimeric precursor polypeptide comprises one polypeptide chain comprising a VL domain and the CH3 domain, wherein said VL domain and said VH domain specifically bind to an antigen when associated to a pair of a VH domain and a VL domain; or
the first heterodimeric precursor polypeptide comprises one polypeptide chain comprising a VH domain and a CH3 domain, and
wherein the second heterodimeric precursor polypeptide comprises one polypeptide chain comprising a VL domain and a CH3 domain, wherein said VL domain and said VH domain specifically bind to any antigen when associated to a pair of a VH domain and a VL domain; and
wherein B) either
the CH3 domain of the first and third heterodimeric precursor polypeptide comprising the knob mutation or the CH3 domain of the second and fourth heterodimeric precursor polypeptide comprising the hole mutation, or
ii) the CH3 domain of the first and third heterodimeric precursor polypeptide comprising the hole mutation the CH3 domain of the second and fourth heterodimeric precursor polypeptide comprising the knob mutation comprise the following amino acid substitutions, wherein the numbering is according to the Kabat numbering system;
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And wherein if the CH3 domain comprising said knob mutation of a heterodimeric precursor polypeptide comprises an amino acid substitution selected from the group indicated in the above table, the CH3 domain comprising the hole mutation of said heterodimeric precursor polypeptide does not comprise the amino acid substitutions selected from the group indicated in the above table; and wherein the knob mutation comprises in the first heterodimeric polypeptide is identical to the knob mutation comprised in the second heterodimeric precursor polypeptide (species) whereas the claims of the ‘279 patent are generic with respect to the CH2 domain.
Issued claim 1 recites:
A multimeric polypeptide comprising
a first polypeptide comprising i) in N- to C-terminal direction
a) a first antibody variable domain selected from a pair of an antibody light and heavy chain variable domain specifically binding to a first target, and
b) a first human immunoglobulin G CH3 domain, and
ii) a pair of an antibody light and heavy chain variable domain specifically binding to a second target either N-terminal to the first antibody variable domain or C-terminal to the first CH3 domain, and
a second polypeptide comprising in N- to C-terminal direction
a) a second antibody variable domain selected from a pair of an antibody light and heavy chain variable domain specifically binding to a third target, and
b) a second human immunoglobulin G CH3 domain, wherein the second polypeptide lacks a pair of an antibody light and heavy chain variable domain specifically binding to a target, wherein the second antibody variable domain is an antibody light chain variable domain if the first antibody variable domain is an antibody heavy chain variable domain; or
the second antibody variable domain is an antibody heavy chain variable domain if the first antibody variable domain is an antibody light chain variable domain, and
wherein the second CH3 domain comprises a perturbing mutation selected from the group of mutations consisting of D356K, E357K, K370E and K439E,
wherein the first CH3 domain comprises
a) the amino acid residue K at position 439 if the perturbing mutation is D356K, or
b) the amino acid residue K at position 370 if the perturbing mutation is E357K, or
c) the amino acid residue E at position 357 if the perturbing mutation is K370E, or
d) the amino acid residue D at position 356 if the perturbing mutation is K439E, wherein all numbering is according to Kabat EU index.
2. A multimeric polypeptide comprising a first polypeptide comprising
i) in N- to C-terminal direction
a) a first human immunoglobulin G CH3 domain, and
b) a first antibody variable domain selected from a pair of an antibody light and heavy chain variable domain specifically binding to a first target,
ii) a pair of an antibody light and heavy chain variable domain specifically binding to a second target either N-terminal to the first CH3 domain or C-terminal to the first variable domain,
a second polypeptide comprising in N- to C-terminal direction
a) a second human immunoglobulin G CH3 domain and
b) a second antibody variable domain selected from a pair of an antibody light and heavy chain variable domain specifically binding to a third target,
wherein the second antibody variable domain is an antibody light chain variable domain if the first antibody variable domain is an antibody heavy chain variable domain; or
the second antibody variable domain is an antibody heavy chain variable domain if the first antibody variable domain is an antibody light chain variable domain, and
wherein the second CH3 domain comprises a perturbing mutation selected from the group of mutations consisting of D356K, E357K, K370E and K439E, whereby the first CH3 domain comprises a) the amino acid residue K at position 439 if the perturbing mutations is D356K, or b) the amino acid residue K at position 370 if the perturbing mutations is E357K, or c) the amino acid residue E at position 357 if the perturbing mutations is K370E, or d) the amino acid residue D at position 356 if the perturbing mutations is K439E, wherein all numbering is according to Kabat EU index.
5. The multimeric polypeptide according to claim 1, wherein the first polypeptide and the second polypeptide are a non-covalent dimer.
9. The multimeric polypeptide according to claim 1, wherein the first, second and third target are different.
10. The multimeric polypeptide according to claim 1, wherein the first target and/or the third target is human CD3.
11. The multimeric polypeptide according to claim 1, wherein the pair of an antibody light and heavy chain variable domain specifically binding to the second target is an Fv, scFv, Fab, scFab, dsscFab, CrossFab, or bispecific Fab.
12. The multimeric polypeptide according to claim 1, wherein each of the first and the second polypeptide further comprises an immunoglobulin G CH2 domain directly N-terminal to the CH3 domain, which corresponds to instant claim 1.
13. The multimeric polypeptide according to claim 1, wherein the human immunoglobulin G is human IgG1 or human IgG2 or human IgG3 or human IgG4.
14. A composition comprising a first multimeric polypeptide and a second multimeric polypeptide according to claim 1, wherein the second CH3 domain of the first multimeric polypeptide comprises the mutation D356K and the second CH3 domain of the second multimeric polypeptide comprises the mutation K439E, or the second CH3 domain of the first multimeric polypeptide comprises the mutation E357K and the second CH3 domain of the second multimeric polypeptide comprises the mutation K370E, and the first antibody variable domain of the first multimeric polypeptide and the first variable domain of the second multimeric polypeptide are a pair of an antibody light chain variable domain and an antibody heavy chain variable domain that specifically bind to the first target, and the second antibody variable domain of the first multimeric polypeptide and the second variable domain of the second multimeric polypeptide are a pair of an antibody light chain variable domain and an antibody heavy chain variable domain that specifically bind to the third target, wherein all numbering is according to Kabat EU index.
17. The composition according to claim 14, wherein the first and/or the third target is human CD3 (species).
18. The composition according to claim 14, wherein the composition is a pharmaceutical composition and optionally further comprises a pharmaceutically acceptable excipient.
The ‘279 patent further teaches
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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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