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 .
Restriction/Election
Applicant’s election without traverse of Group I, claims 1, 2, 6, 9, 16, 18, 20, 22, 27-28, 30, 32, 34-36, 40, 43, 49, and 53-59, drawn to a polypeptide complex, nucleic acids encoding the polypeptide complex, host cells comprising the nucleic acids, and pharmaceutical compositions and conjugates in the reply filed on 18 June 2026 is acknowledged.
Claims 60 and 6 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 June 2026.
Applicant’s election without traverse of the species polypeptide complex comprising, by EU numbering: a) n1:n2 of V173C:Q160C; n3:n4 is A141D:F116K; n5:n6 is C220S:C214S; n7:n8 is wildtype; b) n1':n2'; n3':n4'; n5':n6'; and n7':n8' are all wildtype; c) the first Fc polypep in the reply filed on 18 June 2026 is acknowledged.
First, the examiner notes that the Applicant described this election as the antibody DIC010. However, the specification teaches that the sequences of DIC010 are SEQ ID NOs: 4, 8, 22, and 23; and the examiner notes that in these sequences the n3:n4 pair is A141K:F116D. Because the opposite charge mutant A141D:F116K was explicitly recited in the election, only A141D:F116K is being examined as the elected species.
The Examiner notes that although the applicant recites that n7:n8 is wildtype, no position pair is recited for n7:n8 or n7':n8' that is wildtype and therefore the election is not completely responsive because it cannot be determined which position is wildtype for the elected species. The Examiner will interpret, for the purposes of expedited prosecution, that n7:n8 is wildtype may read at least one additional residue of the CH domain and one additional residue of the CL domain at any position. Therefore, claims that recite substitutions at a particular position pair for n7:n8 or n7’:n8’ do not encompass the elected species (e.g. claim 18) and are withdrawn.
Claims 18, 20, 28, and 32 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 June 2026.
Claim Status
Claims 1, 2, 6, 9, 16, 18, 20, 22, 27-28, 30, 32, 34-36, 40, 43, 49, 53-60, and 62 are pending. Claims 18, 20, 28, 32, 60 and 62 are withdrawn as described in the Restriction/Election section above. Claims 1, 2, 6, 9, 16, 22, 27, 30, 34-36, 40, 43, 49, and 53-59 are under Examination in the instant office action.
Claim Objections
Claims 30, 34 objected to because of the following informalities:
Claim 30 is objected to for a missing period at the end of the claim. See MPEP§604.01(m).
Claim 34 is objected to because t.
Claim 35 is objected to for the recitation of “or either the first polypeptide fragment or the second polypeptide fragment is absent from the polypeptide fragment is absent from the polypeptide complex”. This language obscures the meaning of the claim because the claim recites comprising a first polypeptide fragment and/or a second polypeptide fragment; since at least one of the polypeptide fragments is optional, the claim is not indefinite, but it is informal to recite that one of the polypeptide fragments is both optional and “absent”.
Claim 36 is objected to for the recitation of “or either the third polypeptide fragment or the fourth polypeptide fragment is absent from the polypeptide fragment is absent from the polypeptide complex”. This language obscures the meaning of the claim because the claim recites comprising a third polypeptide fragment and/or a fourth polypeptide fragment; since at least one of the polypeptide fragments is optional, the claim is not indefinite, but it is informal to recite that one of the polypeptide fragments is both optional and “absent”.
Claim 53 is objected to for the list starting with item c). It is informal to start a list in the middle of the alphabet rather than with “a)”.
Claim 40 is objected to for the recitation “wherein the first antigen-binding domain and/or the second antigen-binding domain is contained within an antibody”. “Is contained within” is informal language that obscures the meaning of the claim limitation. The Examiner suggests that Applicant amend the claim to “is comprised by” or “wherein the polypeptide complex comprises an antibody which comprises the first antigen-binding domain and/or the second antigen-binding domain”.
Claim 54 is objected to for the recitation of “A nucleic acid comprising a nucleotide sequence encoding the polypeptide complex or a part thereof” because it is not clear whether “a part thereof” is intended to modify the polypeptide complex or the nucleic acid.
Claim 56 is objected to for the recitation of “A host cell comprising the nucleic acid of claim 54 or a vector comprising the nucleic acid” because it is opaque whether the claim requires a host cell in both list items separated by the “or”, or if an isolated vector may read on “a vector comprising the nucleic acid”. The Examiner suggests adding punctuation such as a colon after “A host cell comprising” to clarify the claim scope.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2, 6, 9, 16, 22, 30, 34-36, 40, 43, 49, and 53 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 is indefinite for:
The recitation of “optionally”, wherein the optional limitations lead to indefiniteness in the claim (See MPEP §2173.05(h)). The optional limitations in this case are indefinite because the second optional limitation finds antecedent basis for “the […] second target binding domain” in the first optional limitation and the third optional limitation finds antecedent basis for “the second CH1 region” and “the second CL region” in the first optional limitation. Additionally, there is no conjunction ‘and’ or ‘or’ between the optional limitations. Therefore, it is unclear whether the optional limitations are grouped together or are individually optional.
Claim 9 is indefinite for:
the recitation of “wherein the second CH1 region” and “the second CL region” because the second CH1 region and the CL region find antecedent basis in two separate optional limitations of claim 2. It is unclear, therefore, whether claim 9 requires one or both optional limitations of claim 2 which may provide antecedent basis for the terms.
The parentheticals (for IgG1) and (for IgG2 and IgG4) in lines 8-10, 15, 19, 22, and 25, because the parentheticals are exemplary language and it is unclear whether the limitations in the parenthetical are required by the claim (See MPEP §2173.05(d)).
It is unclear whether the “wherein” clause in line 24 is optional because it follows the optionally in line 13, or whether it is an alternate required limitation because it is not given a letter in the list like parts (a) and (b) in lines 14 and 18 and does not start with the word “optionally” like in line 21.
The Examiner requests both amendment of claim 9 and reformatting of the claim to further clarify the nested optional and alternate limitations.
Claim 22 is indefinite for:
the recitation of “the fifth corresponding amino acid residue at EU position n5’ and the sixth corresponding amino acid residue at EU position n6’” because the fifth and sixth corresponding positions lack antecedent basis in claim 1.
The parentheticals in lines 8-12 because the parentheticals are exemplary language and it is unclear whether the limitations in the parenthetical are required by the claim (See MPEP §2173.05(d)).
The second CH1 region in line 10 and the second CL region in line 11 lack antecedent basis in claim 1.
It is unclear whether the “wherein” clause in line 10 is an optional limitation because it is recited in the alternate but it does not start with the phrase “optionally” like the limitations in lines 3, 4, and 8.
Claim 34 is indefinite for:
the recited of “the second target-binding domain comprises a second combination of substitutions at (n5’+n6’)(n7’+n8’) positions”. There is a lack of antecedent basis in claim 1 for a second target-binding domain and for the (n5’+n6’)(n7’+n8’) positions and therefore the claim is indefinite.
The parentheticals within the first set of parenthesis e.g. “(Q160C (or E160C) […]” are indefinite because it is unclear whether the limitation in the second parenthesis is required by the claim.
Claim 35 is indefinite for the recitation of “the second target-binding moiety comprises a second polypeptide fragment operably linked to the second CL region”. There is a lack of antecedent basis in claim 1 for a second target-binding domain and a second CL region and therefore the claim is indefinite.
Claim 36 is indefinite for the recitation of “the second target-binding moiety comprises a fourth polypeptide fragment operably linked to the second CL region”. There is a lack of antecedent basis in claim 1 for a second target-binding domain and a second CL region and therefore the claim is indefinite.
Claim 36 is indefinite for the recitation of “wherein the first target-binding moiety further comprises a third polypeptide fragment operably linked to the first CH1 region, and/or […] comprises a fourth polypeptide fragment”. Because the first and/or second polypeptide fragments of claim 35 are recited in the alternate, it is unclear whether the claim requires the alternate limitation of the second polypeptide fragment operably linked to the second CL region, wherein the first polypeptide fragment has a different amino acid sequence from the second polypeptide fragment of claim 35, because that is the only mention of a second polypeptide fragment in claim 35 in order to make the fragment of claim 36 a third polypeptide fragment. Thus, it is uncertain whether any polypeptide fragment linked to the CH1 domain of the first antigen-binding domain may be considered a third polypeptide fragment, or whether it requires all of the limitations of the second polypeptide fragment limitation of claim 35. For the purposes of expedited prosecution, any polypeptide fragment linked to the CH1 domain of the first antigen binding region will be considered to by a third polypeptide fragment.
Claims 40 and 43 are dependent upon a canceled base claim, and are therefore incomplete as there is no antecedent basis for the limitations in the canceled base claims. MPEP 608.01(n): “If the base claim has been canceled, a claim which is directly or indirectly dependent thereon should be rejected as incomplete”. It was unable to be determined upon which claim claims 40 and 43 should depend for expedited prosecution, and therefore they are unable to be examined further on the merits.
Claim 43 is indefinite because it is unclear whether the limitation starting “and/or wherein the first antigen-binding domain is a first Fab domain […] in lines 9-14 is optional because it follows the “optionally” in line 7, or whether it is “and/or” with the alternate limitations starting in lines 4 and 6.
Claim 49 is indefinite for:
the recitation of “the second target-binding domain”. There is a lack of antecedent basis in claim 1 for a second target-binding domain therefore the claim is indefinite.
The limitations “wherein the Fc region is heterodimeric; or wherein the heterodimeric Fc region comprises one or more mutations […]” in lines 5-7 because they follow the “optionally” in line 4, but it is unclear whether then are optional or if they are separate alternate limitations following the limitation of lines 2-3. For the purposes of expedited prosecution, the limitations of lines 4-7 are all being read as alternative optional limitations.
Dependent claims are rejected for failing to resolved the indefiniteness as described.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 54 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the claimed genus
Claim 54 recites a “nucleic acid comprising a nucleotide sequence encoding the polypeptide complex of claim 1 or a part thereof”. As explained in the objections above, claim 54 can read on either “a part thereof” of a nucleic acid comprising a nucleotide sequence encoding the polypeptide complex of claim 1 or of the polypeptide complex. The instant specification does not define “a part”. The instant specification, regarding nucleic acids states “As used herein, the term "nucleic acid," "nucleic acid molecule," "nucleotide," "polynucleotide" or alike, is construed to refer to a nucleotide polymer of any length, and can include both DNA and RNA, and can be single-stranded or double-stranded. Herein, nucleotides in a nucleic acid can include deoxyribonucleotides, ribonucleotides, modified nucleotides (e.g., methylated nucleotides) or bases, or analogs thereof. […] Herein, the terms also refer to synthetic and/or non-naturally occurring nucleic acid molecules (e.g., comprising nucleotide analogues or modified backbone residues or linkages). The terms encompass nucleic acids containing analogues of natural nucleotides. The terms also encompass nucleic acid-like structures with synthetic backbones. Unless otherwise indicated, a particular polynucleotide sequence also implicitly encompasses conservatively modified variants thereof (e.g. degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated” [00106]. Therefore, the claim reads on any part of a nucleotide sequence, or any nucleotide sequence encoding any part of the polypeptide complex of claim 1. The claim therefore encompasses a vast genus including a) single nucleotides (part of a nucleic acid encoding) and b) nucleic acids comprising polypeptide sequences encoding any single codon. Because claim 1 recites an undefined first target-binding domain, the claims also include any nucleic acid encoding any target-binding domain or portion thereof encoding, for example, any of the 1018 antibodies a human is expected to be able to produce. This claim, therefore, is directed towards a truly enormous genus of nucleic acids.
State of the Relevant Art
The “central dogma” of molecular biology is the encoding of proteins by triplet codes of nucleic acids. mRNA serves as a copy of chromosomal DNA and specifies the amino acids in proteins (Smith, A. (2008) Nucleic acids to amino acids: DNA specifies protein. Nature Education 1(1):126). Smith teaches that, even as early as 1962, scientists Nirenberg and Matthaei made artificial mRNA and identified the polynucleotide encoded from it (“Decoding the Genetic Code” section, ¶2).
Regarding nucleic acids encoding polypeptide complexes comprising CH1 and CH2 regions, these are also known in the art. For example, WO8900999 to Robinson et. al. published 9 February 1989 teaches a mouse variable region conjugated to the CH1 region of human IgG1 (Example II); WO2014081955 to Kannan et. al. published 30 May 2014 teaches CH1/CL regions with substitutions of charged residues at the CH1/CL contact positions (e.g. Fig. 8) and nucleic acids encoding the polypeptides (e.g. [0097]).
Summary of Species disclosed in the original specification
The instant specification prophetically teaches nucleic acids encoding the polypeptide complexes of the instant invention (e.g. [00310-00311]). In all cases the nucleic acids encode a complete polypeptide complex.
The instant specification is directed at polypeptide comprising the CH-CL domains of an antibody. The inventors examined the CH-CL interface for interacting residues (Examples 1 and 2) and looked for residues that are points of contact between the heavy and the light chain for mutation in order to drive preferred CH-CL pairings (e.g. in the context of a bispecific antibody with two different VH-VLs to prevent mispairing) (Example 3). The specification teaches exemplary bispecific antibodies comprising an anti-PD-1 antibody and an anti-TGFBR antibody (Example 5). The specification discloses specific antibody embodiments DIC002 and DIC007 and control DIC0014 (e.g. [00398]). The specification teaches DNA sequencing encoding each of the four chains of those antibodies [00400]. The specification teaches additional examples DIC003, DIC004, DIC005, DIC006, DIC009, and DIC010 (Table 7 and 8) and teaches DNA sequences encoding the four chains of each transfected into CHO cells to express the bispecific antibodies [00410]. There are no examples of parts of polypeptide complexes or parts of nucleic acid sequences discloses by the claims.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for any part of a nucleic acid or any nucleic acid encoding a part of the claimed polypeptide complex of claim 54. There are not sufficient examples of alternate nucleic acids, nucleic acids of different portions or sizes, or nucleic acids encoding only a portion of the instant polypeptide complex in order to demonstrate possession of such a vast genus of nucleic acids. The Examiner suggests this rejection may be obviated by amending the claims to recite a nucleic acid or multiple nucleic acids encoding the polypeptide complex of claim 1.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 54 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by WO8900999 to Robinson et. al. published 9 February 1989.
Claim 54 is directed towards a nucleic acid comprising a nucleotide sequence encoding the polypeptide complex of claim 1 or a part thereof. As described in the 112(a) written description rejection above, the instant specification does not define what is meant by “part” therefore, “part” is interpreted as any part of any size of a nucleic acid comprising a nucleotide sequence encoding the polypeptide complex of claim 1.
Robinson et. al. teaches a vector (reads on nucleic acid) comprising an antibody V-region fused to a human IgG1 CH1 region (Example II (3), see p. 62, Fig. 9A). The nucleic acid encoding the wild-type CH1 region would inherently comprise a part of the nucleic acid sequence of the polypeptide complex of instant claim 1 because it would comprise a nucleic acid encoding all of the wild-type residues of the polypeptide complex of instant claim 1 (e.g. a nucleic acid encoding CH1 residues according to EU number 118-140), which reads on a part of the nucleic acid encoding the polypeptide complex of claim 1 and a nucleic acid encoding a part of the polypeptide complex of claim 1 (a part of the CH1 domain).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 2, 6, 9, 16, 22, 27, 30, 34, 35, 36, 49, 53, 54, 55, 56, 57, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over WO2017205014 to Yan et. al. published 30 November 2017 (IDS dated 10/21/2023) in view of WO2014081955 to Kannan et. al. published 30 May 2014.
Regarding claim 1, Yan et. al. teaches antibodies and mixtures of antibodies wherein the heavy and light chains of the antibodies contain at least one LC-partner-directing alternation and at least one HC-partner directing alteration (Abstract, e.g. Example 3). The antibodies comprise, for example, an anti-PD-1 binding domain, anti-HER2 binding domain, or anti-CTLA-4 binding domain (reads on a first-target binding moiety; e.g. p. 74 lines 25-32). Yan et. al. teaches that the antibodies comprise a CH1 domain and a CL domain, wherein the CH1 and the CL domain comprise a contacting pair of cysteine residues, wherein the cysteine residues are at positions selected from a group including position 173 and 160 (see e.g. claim 95, p. 24 lines 4-9). Yan et. al. also discloses that the antibodies further comprise a set of charge mutants in the CH1 and CL domains at a second position (e.g. Table 20; reads on n3:n4 non-covalent bond).
Regarding claim 2 and 27, Yan et. al. teaches a that the n3 and n4 mutations are a pair of oppositely charged amino acids (e.g. p. 59 lines 20-p. 60 line 3; p. 69 lines 19-36); wherein the charge pair is a positively charged and a negatively changed amino acid.
Regarding claim 22, Yan et. al. teaches that the cysteines at positions 173 and 160 form a disulfide bond (e.g. p. 76 lines 10-20; see also p. 85 line 36-p. 86 line 4; p. 88 lines 10-21; p. 90 lines 7-20).
Regarding claim 30, the alterations of the residues are made by substitution (see e.g. p. 77 lines 14-16).
Regarding claim 34, Yan et. al. teaches the particular substitutions include V173C and Q160C (e.g. p. 60 lines 13-14).
Regarding claim 35, Yan et. al. teaches an anti-PD-1 VL linked to the CL (reads on a polypeptide fragment operably linked to the first CL region) (Fig. 1, e.g. p. 59 lines 20-21; p. 69 lines 2-3).
Regarding claim 36, Yan et. al. teaches that the PD-1 antibodies are monospecific, and therefore the first antigen-binding site and the second target-binding site (the two Fab domains of the monospecific antibody) bind to the same target molecule.
Regarding claim 49, Yan et. al. teaches that the anti-PD-1 antibody further comprises a CH2 and CH3 domain (reads on “Fc region”; e.g. Fig. 1, p. 31 lines 3-10).
Regarding claim 53, the Examiner notes that although the claim requires a heterodimer Fc region, the claim recites that the first Fc polypeptide and/or the second Fc polypeptide comprise an Fc mutation. Additionally, while the species election reads D399K and E356K, the claim in part d) requires only “the first Fc mutation comprises D399K or E356K, and the second Fc mutation comprises K392D, or K409D”. Thus, the claim only requires either the mutation in the first Fc domain or the second Fc domain, and the mutations in each chain are recited in the alternate, so only one of the recited mutations per chain is required by the claim. Yan et. al. teaches CH3 mutations to direct pairing between the Fc domains of the desired antibodies at position D399 in the first heavy chain with K409 in the second heavy chain, and E356 of first heavy chain and , wherein the mutations include D399K paired with a mutation at K409 among D/E (See e.g. p. 39 lines 3-5).
Regarding claims 54-56 Yan et. al. teaches nucleic acids encoding the antibodies, vectors comprising the nucleic acids, and host cells comprising the vectors or nucleic acids (reads on the polypeptide complex of claim 1, as above; e.g. p. 52 lines 16-17; p. 64 line 30-p. 66 line 37).
Regarding claims 57 and 59, Yan et. al. teaches the antibody in composition with a pharmaceutically acceptable buffer and/or excipient (reads on pharmaceutically acceptable carrier; e.g. p. 52 lines 16-25).
Yan et. al. teaches that a partner-directing substitution of a single amino acid in the HC/LC interface with a VL or CL; and that the partner-directing substitutions are made in the residues at contacting residues between CH1 and CL; which includes CH1 residue 141 paired with 116 of CL (See Table 12, p. 47 lines 10-29).
Regarding claim 1, Yan et. al. does not teach the antibody wherein the charge pair n3:n4 forming a noncovalent bond is at the position 141:116 (elected species).
This deficiency is resolved by Kannan et. al.
Kannan et. al. teaches a method of steering pairing between heavy and light chains to form heterodimeric antibodies by substitution amino acids in the CH1-domain or the CL-domain to amino acids with positive and negative charge, respectively [0009]. The charges are electrostatically favorable to heterodimer formation and guide HC/LC pairing ([0007], [0046], [0057], [0059]), and the positively and negatively charged amino acids encourage heterodimer formation by attraction ([00322], reads on non-covalent bond). Kannan teaches that the CH1 domain has a substitution at an EU position selected from a group of contact residues including 141 replaced with a charged amino acid [0077] and its CL contact residue F116 [00336] (Also see Table 2).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the charge mutations at positions F116 and A141 in place of the charge mutations in other contact pairs as taught in Yan to promote cognate heavy chain/light chain pairing as taught by both Yan and Kannan. This would result in a polypeptide complex comprising a first CH1 domain and a first CL domain with a V173C CH1 : Q160C CL substitution to form a disulfide bond as taught by Yan et. al. and a A141D CH1: F116K CL substitution as taught by Kannan in one heavy/light chain pair. This would have a reasonable expectation of success because both Yan and Kannan teach substitutions at the contact residues of the CH:CL interface to steer desired pairing of heavy and light chains in making antibodies.
Regarding claim 27, Yan in view of Kannan as described above comprises negative charged amino acid D (A141D) at position n3 and positively charged amino acid K (F116K) at position n4.
Regarding claim 34, Yan in view of Kannan as described above comprises the first combination of substitutions at (n1 + n2):(n3 + n4) positions (V173C + A141D):(Q160C + F116K).
Regarding claim 6, Yan et. al. teaches that the introduced cysteine bonds combined with breaking of the native cysteine bond by introducing C220S and C214S to HC1 and LC1 (p. 13 line 33-37; Fig. 5 p. 27 line 17-29; Table 1). Yan et. al. teaches that the proper heavy and light chain pairs are formed when you use different contact pairs for the different HC1/LC1 and HC2/LC2 pairings or when only one antibody comprises the partner-directing mutations (e.g. Example 3; p. 56 lines 21-33; 57 lines 15-17).
Yan et. al. does not explicitly teach the polypeptide complex further comprising a second antigen binding domain, wherein the second CH1 region comprises a first corresponding amino acid residue at EU position n1’, and the second CL region comprises a second corresponding amino acid residue at EU position n2’, wherein the n1’:n2’ position pair is identical to the n1:n2 position pair, and with the first corresponding amino acid residue at EU position n1’ does not form a covalent bond with the second amino acid residue at EU position n2 (optionally recited in claim 2; claim 6). As described above, Yan et. al. is teaching modification of the contact residues of CH-CL to discourage the formation of heterodimers in mixtures of antibodies; therefore, the expected antibody is a monoclonal antibody and the n1’ and n1 residues would be the same, and interact in the same way with both the n2’ and n2 residues.
This deficiency is resolved by Kannan et. al.
Kannan et. al. teaches methods of making heterodimeric bispecific antibodies as described above. Kannan et. al. teaches charge pair substitutions in the first and second CH3 domains and CH1 and CL domains at the interface between binding in order to favor heterodimer formation between the heavy chain and steer away from Fab mispairing between the heavy/light chain variable and CH1/CL regions (See e.g. Examples 3 and 4). Kannan teaches particular embodiments of an anti-DKK and anti-sclerostin bispecific antibody (See e.g. Examples 3 and 4).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the combination of CH1/CL cysteine mutations (e.g. V173C/Q160C) of Yan et. al. and CH1/CL mutations (e.g. A141D/F116K) of Kannan et. al. as described above to make a bispecific antibody as taught by Kannan et. al. to benefit from making a linker-free bispecific antibody with increased heterodimer formation as taught by Kannan et. al. The combination would result in a bispecific antibody comprising a first antigen binding domain comprising V173C CH1 : Q160C CL and A141D CH1: F116K CL for proper pairing of one arm of the bispecific, wherein the second arm of the bispecific is wildtype at those positions and therefore n1’ and n2’ would not form a covalent bond. This would have a predictable effect because a person of ordinary skill in the art would understand that the same scientific effect that allows proper pairing of CH/CL domains into monoclonal antibodies as taught by Yan et. al. would also be effective for driving proper light/heavy chain pairing for bispecific heterodimerization as taught by Kannan et. al.; a person of ordinary skill in the art would be able to pick and choose the desired pairings of CH3:CH3 between the heavy chains and between CH1-VH:CL-VL in order to benefit from increased pairing of the desired domains as taught by both Yan and Kannan.
Regarding claim 9, and Yan et. al. teaches breaks of the wildtype covalent bond at positions CH1 C220 and CL C214 wherein the other antibody CH1/CL is wildtype (e.g. see Table 3); therefore the second target-binding domain n5’:n6’ position pair of the bispecific Yan in view of Kannan as described for claim 6 above would further comprise the n5’:n6’ position pair 220:214 comprising a disulfide (reads on covalent) bond.
Regarding claim 16, Yan et. al. teaches that the introduced cysteine bonds combined with breaking of the native cysteine bond by introducing C220S and C214S to HC1 and LC1 (p. 13 line 33-37; Fig. 5 p. 27 line 17-29; Table 1). Therefore, the bispecific antibody of Yan in view of Kannan as taught for claims 6 and 9 above would have the C220S and C214S in the HC1/LC1 and have wildtype C220 and C214, forming a hydrogen bond, in HC2/LC2 of the bispecific to facilitate pairing of the non-native V173C:Q160C disulfide bond and discourage formation of HC2/LC1 and HC1/LC2 pairs through C220:C214 double bond formation as taught by Yan et. al. This would have a reasonable expectation of success because Yan et. al. teaches using a non-native cysteine bond at the CH1/CL interface combined with disruption of the C220:C214 bond in one heavy chain to avoid mispairing in the scenario of two heavy/light chain pairs and a person of ordinary skill in the art would understand that driving the pairs of cognate LC:HC would also apply to bispecific antibodies as in Kannan.
Claim(s) 58 is rejected under 35 U.S.C. 103 as being unpatentable over WO2017205014 to Yan et. al. published 30 November 2017 in view of WO2014081955 to Kannan et. al. published 30 May 2014, and in further view of Iwata, Tomomi Nakayama, et al. "A HER2-targeting antibody–drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model." Molecular cancer therapeutics 17.7 (2018): 1494-1503.
The teachings of Yan et. al. in view of Kannan et. al. are in regard to claim 1 are in the 103 rejection above.
Yan et. al. in view of Kannan et. al. does not teach the polypeptide complex wherein the polypeptide complex is conjugated to a payload, wherein the payload is e.g. an anticancer drug.
This deficiency is resolved by Iwata et. al.
Iwata et. al. teaches a method of treating cancer comprising administering a combination of an anti-HER2 antibody drug conjugate conjugated to the exatecan derivative (DX-8951) and an anti-PD-1 antibody (Abstract). Iwata et. al. teaches that the anti-HER2 ADC was more effective at treating cancer than the anti-HER2 antibody alone (Fig. 1B), and that the combination of the anti-HER2/anti-PD-1 antibodies had the strongest anti-cancer effect (Fig. 6)
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to modify the antibody comprising the modified CH1/CL domains as taught by Yan in view of Kannan above by conjugating to an exatecan derivative as taught by Iwata et. al. in order to benefit from the increase in anti-cancer activity of and the increased cognate pairing of HER2 antibodies as taught by Yan in view of Kannan for making antibody mixtures to treat cancer. A person of ordinary skill in the art would have a reasonable expectation of success because as taught by Iwata, both antibody-drug conjugates and mixing antibodies known for anticancer treatment would be expected to result in an improved anticancer therapy.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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