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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-153 are the original claims filed 6/17/2022. In the Preliminary Amendment of 12/202022, claims 2, 23, 57, 61, 63, 80, 91-92, 94, 96-98, 110, 112, 114, 121, 126 and 127 are amended, claims 3-21, 24-56, 58-60, 62, 64-79, 81- 90, 95, 100-109, 111, 113, 115-120, 122, 124-125 and 128-153 are canceled and new claims 154-161 are added. In the Reply of 12/16/2025, Claims 61, 112 and 127 are amended.
Claims 1-2, 22-23, 57, 61, 63, 80, 91-94, 96-99, 110, 112, 114, 121, 123, 126-127 and 154-161 are the pending claims.
Priority
2. USAN 17/786,708, filed 12/20/2022, is a National Stage entry of PCT/CA2020/ 051753, International Filing Date: 12/18/2020, PCT/CA2020 /051753 Claims Priority from Provisional Application 62/951,701, filed 12/20/2019.
Election/Restriction
3. Applicant’s election without traverse of Group I in the reply filed on 12/16/2025 is acknowledged.
4. Claims 126-127, 154 and 160 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 12/16/2025.
5. Claims 1-2, 22-23, 57, 61, 63, 80, 91-94, 96-99, 110, 112, 114, 121, 123, and 155-159 and 161 are the claims under examination.
Information Disclosure Statement
6. As of 3/3/2026, a total of five (5) IDS are filed: 6/17/2022; 1/24/2023; 12/13/2023; 2/7/2025; and 12/16/2025. The corresponding initialed and dated 1449 forms are considered and of record.
7. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 12/21/2022.
Required response – Applicant must provide:
A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter and
An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3))
If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide:
A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and
Statement according to item 2) a) or b) above.
Specification
9. The disclosure is objected to because of the following informalities:
a) The use of the term ATCC, Tween, Tris, nanobody, DART, NOG MOUSE, AKTA PURE, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) Amend the specification to include sequence identifiers for those peptides > 4 amino acids in length pursuant to 37 CFR 1.821-1.825. See page 16, line 10; page 73, lines 9-13.
Appropriate correction is required.
Claim Objections
10. Claims 1-2, 22-23, 57, 61, 63, 80, 91-94, 96-99, 110, 112, 114, 121, 123, and 155-159 and 161 are objected to because of the following informalities:
a) Amend Claims 1-2, 57, 61, 63, 80, 91-94, and 96-97 in claim 1 to recite “A polypeptide comprising from an N- to C-terminus an amino acid sequence of formula Ib.” Use of the term “fashion” is colloquial.
b) Amend claims 22-23 in claim 22 to recite “A polypeptide comprising from an N- to C-terminus an amino acid sequence of formula Ic.”
c) Amend claims 98, 110, 112, 114, 121, 123, 155-159 in claim 98 to recite “wherein the polypeptide comprises from an N- to C-terminus an amino acid sequence of formula Ib.” Use of the term “fashion” is colloquial.
d) Amend claim 99 for proper punctuation, i.e., insert a colon after “comprising:.”
e) Amend claim 161 to recite “wherein the first and second polypeptide are identical or different and comprise from an N- to C-terminus an amino acid sequence of formula Ic.” Use of the term “fashion” is colloquial.
f) Amend claims 2 and 155 to replace the conditional term “favor” with a definitive and positive term: “or CH3 mutations that form a heterodimer
g) Claim 57 is objected to for failure to comply with the sequence listing of record. A reasonable search of the sequences (SEQ ID NOS: 27 and 29) is not permissible based on the defective sequence listing filed 12/20/2022. Claim 57 is not further examined on the merits.
h) Claims 1-2, 61, 98, 112 and 161 are confusing for reciting an identical formula “X-[(Aba)-(Lb)] m-(DD)-(Lc)-(Abd)]n -Y” but which is referred to as “formula Ib” in claims 1 and 98, and “formula Ic” in claims 2 and 161, respectively. The formulas contain no apparent differences so the distinction in formula number is unclear. More confusing is why formula Ib in claims 1 and 98 is renamed formula II in dependent claims 61 and 112, respectively. The formulas Ib and II are no different in scope between the generic and dependent claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
11. Claims 63 and 156 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 63 and 156 recite the broad recitation “a single domain antibody (sdAb)”, and the claims also recite VHH which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
12. Claim(s) Claims 1, 61, 63, 80, 91-94, and 96-97 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (WO 2016192613); 1/24/2013; IDS 6/17/2022).
The claimed polypeptide is prima facie obvious over Wang.
Claims 1 and 61 (formula II) recite formula Ib comprising “X-[(Aba)-(Lb)] m-(DD)-(Lc)-(Abd)]n -Y” for what is construed a single polypeptide, where Ab(a or b) are antigen binding domains; L(c or d) are linkers; DD is a dimerization domain, and X- and/or Y- are any other amino acid sequence that may or may not be present.
Wang discloses in Figure 1b an antibody structure comprising two polypeptides and each of which comprises from N- to C- terminus the formula of claim 1, namely, VH (Aba)-L-CH1 (DD)-L-VHH (Abd) and VL(Aba)-L-CL(DD)-VHH’ (Abd). The Wang model excludes the X- and Y- amino acid sequences which is permissive according to claim 1 and Wang teaches a flexible linker sequence (not a cleavable sequence).
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Claim 63 recites the antigen binding domain is sdAb or VHH or VH that is taught and shown above in Wang.
Claim 80 recites the polypeptide comprising antigen binding domains that bind a tumor antigen, immunomodulator and/or immune cell for recruitment that is taught and claimed in Wang as the tumor antigen is selected from the group consisting of CEA, EGFR, Her2, EpCAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX , PSMA, folate binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin, αVβ3, α5β1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP and Tenascin; as specific for immune cell such as mammalian T cells or mammalian NK cells; and as immunomodulators such as CD3, CD16, CD19, CD28 and CD64.
Claim 91 recites a pharmaceutical composition for the polypeptide that is taught in Wang as a pharmaceutical composition comprising an antigen binding polypeptide of the invention.
Claims 92-94 recite nucleic acids, vectors and cells for expressing the polypeptide as taught in Wang:
The invention also provides an isolated polynucleotide or nucleic acid molecule encoding a bispecific antibody, a variant or derivative thereof.
Accordingly, in one embodiment, the invention provides a host cell comprising one or more polynucleotides encoding two strands of a bispecific antibody of the invention. In one aspect, a single nucleotide construct (eg, a plasmid) includes two coding sequences. In another aspect, the invention provides two different polynucleotide constructs, each encoding one of the polynucleotide strands. In one embodiment, the invention also provides a host cell comprising two polypeptide chains of a bispecific antibody of the invention.
Claims 96-97 recite kits comprising the polypeptide or the nucleic acid as taught in Wang:
The components are usually provided, either alone or in combination, in unit dosage form, for example, as a lyophilized powder or a water-free concentrate in a closed container, such as an ampoule or sachette indicating the amount of active agent.
Wang provides the motivation to generate single domain antibody fragments is for increased manufacturing efficiency, retention of immunogenicity, and maintenance of half-life. Wang teaches it is unexpected that a steric effect has a limited effect on the function of the antibodies of the invention. Moreover, the overall affinity of this antibody (which does not require an Fc fragment) is comparable to that of a conventional antibody. Another surprise is that VHH binds efficiently to its target, whether it is in the same orientation (ie, the N-terminus of VHH is attached to the N-terminus of the heavy or light chain of the Fab fragment) or in the opposite direction (ie The C-terminus of VHH is linked to the N-terminus of the heavy or light chain of the Fab fragment) to the Fab fragment. Wang provides further motivation teaching that “Although these disclosed bispecific antibodies are heterodimers which are known to be detrimental to expression and production, they are also unexpectedly capable of being readily expressed in bacterial cells (eg E. coli).” Where Wang provides the structure of a polypeptide that overcomes problems for convention bispecific antibodies, whereby the POSA is placed in a position of predictable and reasonable success.
13. Claim(s) Claims 1-2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sasisekharan et al (USPN 11459405 B2; issued 2022-10-04; priority 2016-12-28) in view of DE KRUIF et al (AU 2018201326 B2; published 2020-02-06; filed 2018-02-23).
The claimed polypeptide is prima facie obvious over Sasisekharan in view of DE KRUIF.
Claim 1 recites formula Ib comprising “X-[(Aba)-(Lb)] m-(DD)-(Lc)-(Abd)]n -Y” for what is construed a single polypeptide, where Ab(a or b) are antigen binding domains; L(c or d) are linkers; DD is a dimerization domain, and X- and/or Y- are any other amino acid sequence that may or may not be present.
Claim 2 is drawn to the polypeptide of claim 1 where the DD comprises a CH2-CH3 domain with the CH3 domain comprising mutations that promote the formation of heterodimers.
Sasisekharan teaches bispecific antibodies drawn to two polypeptides of claim 1 having as a DD, a CH2-CH3 mutated in the CH3 region in order to promote heterodimerization.
(111) Other aspects of the invention relate to newly identified CH3 mutations which favor heterodimerization of Fc domains in a bispecific antibody. Certain amino acids within the CH3 domain were identified as described herein as facilitating the formation of heterodimers. These CH3 residues in human IgG1 include, but are not limited to, L351, P352, P353, D356, E357, L365, T366, K370, K392, P395, V397, D399, F405, Y407, K409, and K439. In certain embodiments, the residue important for CH3 heterodimer formation is E357, K370 or K409, or combination thereof. In certain embodiments, any one or more of these residues are replaced in a heterodimeric polypeptide or a bispecific antibody with any other amino acid suitable for use. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes one or more of the following substitutions in the CH3 domain: E357K, K370E and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having an amino acid substitution at residue K370. In certain embodiments the substitution is K370E. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes CH3′ domain having an amino acid substitution at residues E357 and K409. In certain embodiments the substitutions are E357K and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having an amino acid substitution at residue K370. In certain embodiments the substitution is K370E. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having an amino acid substitution at residues E357 and K409. In certain embodiments the substitutions are E357K and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having a K370E substitution, and a CH3″ having E357K and K409R substitutions. In certain embodiments, the heterodimeric polypeptide or bispecific antibody has a CH3′ domain as set forth in SEQ ID NO: 13, and a CH3″ domain as set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ having E357K and K409R substitutions, and a CH3″ domain having a K370E substitution. In certain embodiments, the heterodimeric polypeptide or bispecific antibody has a CH3′ domain as set forth in SEQ ID NO: 14, and a CH3″ domain as set forth in SEQ ID NO: 13.
CH3 positions taught in Sasisekharan that are overlapping with DE KRUIF and as corresponding to “mutations in the CH3 domains of heavy chains wherein naturally occurring charged amino acid contact residues are replaced by amino acid residues of opposite charge (i.e. a charge reversal strategy). This creates an altered charge polarity across the Fc dimer interface such that co-expression of electrostatically matched Fc chains support favorable attractive interactions thereby promoting desired Fc heterodimer formation, whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation. It was described that within the CH3-CH3 interface four unique charges residue pairs are involved in the domain-domain interaction. These are D356/K439', E357/K370', K392/D399'and D399/K409' (numbering according to Kabat (1991) where residues in the first chain are separated from residues in the second chain by'' and where the prime (') indicates the residue numbering in the second chain). As the CH3-CH3 interface displays a 2-fold symmetry, each unique charge pair is represented twice in intact IgG (i.e., also K439/D356', K370/E357', D399/K392'and K409/D399' charge interactions are present in the interface).”
Applicants have not shown original data for unexpected or surprising results using the claimed CH3 mutations much less those limited to that taught in Sasisekharan or DE KRUIF. MPEP 716.02(a).
Sasisekharan and DE KRUIF provide the motivation by teaching that mutations in the CH3 constant regions contribute to more favorable contacts, as evaluated by the structural analysis and connectivity network, for the specific and limited number of amino acid residues which potentially mediate new or improved contacts. DE KRUIF provides the motivation to change naturally occurring charged amino acid contact residues with amino acid residues of opposite charge (i.e. a charge reversal strategy), thus the scope of a limited number of possible variants falls within the decision of K.S.R. (the “obvious to try” concept, which applies when an inventor chooses from a finite number of identified, predictable solutions with a reasonable expectation of success). The POSA is assured of predictable and reasonable assurance of success because the CH3 mutations are well-accepted in the field of art for yielding heterodimer formation.
14. Claim(s) Claims 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sasisekharan et al (USPN 11459405 B2; issued 2022-10-04; priority 2016-12-28) in view of DE KRUIF et al (AU 2018201326 B2; published 2020-02-06; filed 2018-02-23).
The claimed polypeptide is prima facie obvious over Sasisekharan in view of DE KRUIF.
Claim 22 recites formula Ic comprising “X-[(Aba)-(Lb)] m-(DD)-(Lc)-(Abd)]n -Y” for what is construed a single polypeptide, where Ab(a or b) are antigen binding domains; L(c or d) are linkers; DD is a dimerization domain, and X- and/or Y- are any other amino acid sequence that may or may not be present, where the DD comprises a CH2-CH3 domain with the CH3 domain comprising mutations that promote the formation of heterodimers.
Sasisekharan teaches bispecific antibodies drawn to two polypeptides of claim 22 having as a DD, a CH2-CH3 mutated in the CH3 region in order to promote heterodimerization.
(111) Other aspects of the invention relate to newly identified CH3 mutations which favor heterodimerization of Fc domains in a bispecific antibody. Certain amino acids within the CH3 domain were identified as described herein as facilitating the formation of heterodimers. These CH3 residues in human IgG1 include, but are not limited to, L351, P352, P353, D356, E357, L365, T366, K370, K392, P395, V397, D399, F405, Y407, K409, and K439. In certain embodiments, the residue important for CH3 heterodimer formation is E357, K370 or K409, or combination thereof. In certain embodiments, any one or more of these residues are replaced in a heterodimeric polypeptide or a bispecific antibody with any other amino acid suitable for use. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes one or more of the following substitutions in the CH3 domain: E357K, K370E and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having an amino acid substitution at residue K370. In certain embodiments the substitution is K370E. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes CH3′ domain having an amino acid substitution at residues E357 and K409. In certain embodiments the substitutions are E357K and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having an amino acid substitution at residue K370. In certain embodiments the substitution is K370E. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having an amino acid substitution at residues E357 and K409. In certain embodiments the substitutions are E357K and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having a K370E substitution, and a CH3″ having E357K and K409R substitutions. In certain embodiments, the heterodimeric polypeptide or bispecific antibody has a CH3′ domain as set forth in SEQ ID NO: 13, and a CH3″ domain as set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ having E357K and K409R substitutions, and a CH3″ domain having a K370E substitution. In certain embodiments, the heterodimeric polypeptide or bispecific antibody has a CH3′ domain as set forth in SEQ ID NO: 14, and a CH3″ domain as set forth in SEQ ID NO: 13.
Claim 23 recites residue substitutions for CH3 positions taught in Sasisekharan that are overlapping with DE KRUIF and as corresponding to “mutations in the CH3 domains of heavy chains wherein naturally occurring charged amino acid contact residues are replaced by amino acid residues of opposite charge (i.e. a charge reversal strategy). This creates an altered charge polarity across the Fc dimer interface such that co-expression of electrostatically matched Fc chains support favorable attractive interactions thereby promoting desired Fc heterodimer formation, whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation. It was described that within the CH3-CH3 interface four unique charges residue pairs are involved in the domain-domain interaction. These are D356/K439', E357/K370', K392/D399'and D399/K409' (numbering according to Kabat (1991) where residues in the first chain are separated from residues in the second chain by'' and where the prime (') indicates the residue numbering in the second chain). As the CH3-CH3 interface displays a 2-fold symmetry, each unique charge pair is represented twice in intact IgG (i.e., also K439/D356', K370/E357', D399/K392'and K409/D399' charge interactions are present in the interface).”
Applicants have not shown original data for unexpected or surprising results using the claimed CH3 mutations much less those limited to that taught in Sasisekharan or DE KRUIF. MPEP 716.02(a).
Sasisekharan and DE KRUIF provide the motivation by teaching that mutations in the CH3 constant regions contribute to more favorable contacts, as evaluated by the structural analysis and connectivity network, for the specific and limited number of amino acid residues which potentially mediate new or improved contacts. DE KRUIF provides the motivation to change naturally occurring charged amino acid contact residues with amino acid residues of opposite charge (i.e. a charge reversal strategy), thus the scope of a limited number of possible variants falls within the decision of K.S.R. (the “obvious to try” concept, which applies when an inventor chooses from a finite number of identified, predictable solutions with a reasonable expectation of success). The POSA is assured of predictable and reasonable assurance of success because the CH3 mutations are well-accepted in the field of art for yielding heterodimer formation.
15. Claim(s) Claims 98, 110, 112, 114, 121, 123, and 156-159 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (WO 2016192613); 1/24/2013; IDS 6/17/2022).
The claimed polypeptides are prima facie obvious over Wang.
Claims 98 and 112 (formula II) recite formula Ib comprising “X-[(Aba)-(Lb)] m-(DD)-(Lc)-(Abd)]n -Y” for what is construed a single polypeptide, where Ab(a or b) are antigen binding domains; L(c or d) are linkers; DD is a dimerization domain, and X- and/or Y- are any other amino acid sequence that may or may not be present.
Wang discloses in Figure 1b an antibody structure comprising two polypeptides and each of which comprises from N- to C- terminus the formula of claim 1, namely, VH (Aba)-L-CH1 (DD)-L-VHH (Abd) and VL(Aba)-L-CL(DD)-VHH’ (Abd). The Wang model excludes the X- and Y- amino acid sequences which is permissive according to claim 1.
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Claim 110 recites the properties of the linkers that are taught by Wang for a flexible linker sequence.
Claim 114 recites the complex being multispecific that Wang also teaches:
Antibodies, antigen binding polypeptides, variants or derivatives thereof of the invention include, but are not limited to, polyclonal, monoclonal, multispecific,
Claim 121 recites a composition comprising the protein as taught by Wang: The invention also provides pharmaceutical compositions.
Claim 123 recites the percent of heterodimer and homodimers in a composition as taught by Wang:
Similar to Fab, this S-Fab was purified as a heterodimer. Immunoblotting (Fig. 2c, 2d) revealed that the half antibody did fold into a complete Fab. After a second Ni-NTA affinity purification, the purity of this protein exceeded 90% (Fig. 2e).
Claim 156 recites the antigen binding domain is sdAb or VHH or VH that is taught and shown above in Wang.
Claim 157 recites the polypeptide comprising antigen binding domains that bind a tumor antigen, immunomodulator and/or immune cell for recruitment that is taught and claimed in Wang as the tumor antigen is selected from the group consisting of CEA, EGFR, Her2, EpCAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX , PSMA, folate binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin, αVβ3, α5β1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP and Tenascin; as specific for immune cell such as mammalian T cells or mammalian NK cells; and as immunomodulators such as CD3, CD16, CD19, CD28 and CD64.
Claim 158 recites the polypeptide(s) being conjugated as taught by Wang:
an antigen binding polypeptide comprises an amino acid sequence or one or more portions that are not normally associated with an antibody. Exemplary modifications are described in detail below. For example, a fragment of the invention may comprise a flexible linker sequence or may be modified to add a functional moiety (eg, PEG, drug, toxin or marker)
Claim 159 recites a composition for the complex that is taught in Wang as a pharmaceutical composition comprising an antigen binding polypeptide of the invention.
Wang provides the motivation to generate single domain antibody fragments is for increased manufacturing efficiency, retention of immunogenicity, and maintenance of half-life. Wang teaches it is unexpected that a steric effect has a limited effect on the function of the antibodies of the invention. Moreover, the overall affinity of this antibody (which does not require an Fc fragment) is comparable to that of a conventional antibody. Another surprise is that VHH binds efficiently to its target, whether it is in the same orientation (ie, the N-terminus of VHH is attached to the N-terminus of the heavy or light chain of the Fab fragment) or in the opposite direction (ie The C-terminus of VHH is linked to the N-terminus of the heavy or light chain of the Fab fragment) to the Fab fragment. Where Wang provides the structure of a successful polypeptide that overcomes problems for convention bispecific antibodies, the POSA is placed in a position of predictable and reasonable success.
16. Claim(s) 99 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sasisekharan et al (USPN 11459405 B2; issued 2022-10-04; priority 2016-12-28) in view of DE KRUIF et al (AU 2018201326 B2; published 2020-02-06; filed 2018-02-23).
The claimed polypeptide is prima facie obvious over Sasisekharan in view of DE KRUIF.
Claim 99 is drawn to a first dimerization domain (DD1) comprising a CH3 domain comprising one or more mutations at positions corresponding to D399, D/E356 and/or K370 in accordance with EU numbering;and a second polypeptide comprising one or more antigen binding domains and a second dimerization domain (DD2) comprising a CH3 domain comprising one or more mutations at positions corresponding to D399, E357 and/or K439 in accordance with EU numbering wherein the first and second polypeptides form a dimer.
Sasisekharan teaches bispecific antibodies drawn to two polypeptides of claim 22 having as a DD, a CH2-CH3 mutated in the CH3 region in order to promote heterodimerization.
(111) Other aspects of the invention relate to newly identified CH3 mutations which favor heterodimerization of Fc domains in a bispecific antibody. Certain amino acids within the CH3 domain were identified as described herein as facilitating the formation of heterodimers. These CH3 residues in human IgG1 include, but are not limited to, L351, P352, P353, D356, E357, L365, T366, K370, K392, P395, V397, D399, F405, Y407, K409, and K439. In certain embodiments, the residue important for CH3 heterodimer formation is E357, K370 or K409, or combination thereof. In certain embodiments, any one or more of these residues are replaced in a heterodimeric polypeptide or a bispecific antibody with any other amino acid suitable for use. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes one or more of the following substitutions in the CH3 domain: E357K, K370E and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having an amino acid substitution at residue K370. In certain embodiments the substitution is K370E. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes CH3′ domain having an amino acid substitution at residues E357 and K409. In certain embodiments the substitutions are E357K and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having an amino acid substitution at residue K370. In certain embodiments the substitution is K370E. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having an amino acid substitution at residues E357 and K409. In certain embodiments the substitutions are E357K and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having a K370E substitution, and a CH3″ having E357K and K409R substitutions. In certain embodiments, the heterodimeric polypeptide or bispecific antibody has a CH3′ domain as set forth in SEQ ID NO: 13, and a CH3″ domain as set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ having E357K and K409R substitutions, and a CH3″ domain having a K370E substitution. In certain embodiments, the heterodimeric polypeptide or bispecific antibody has a CH3′ domain as set forth in SEQ ID NO: 14, and a CH3″ domain as set forth in SEQ ID NO: 13.
CH3 positions taught in Sasisekharan that are overlapping with DE KRUIF and as corresponding to “mutations in the CH3 domains of heavy chains wherein naturally occurring charged amino acid contact residues are replaced by amino acid residues of opposite charge (i.e. a charge reversal strategy). This creates an altered charge polarity across the Fc dimer interface such that co-expression of electrostatically matched Fc chains support favorable attractive interactions thereby promoting desired Fc heterodimer formation, whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation. It was described that within the CH3-CH3 interface four unique charges residue pairs are involved in the domain-domain interaction. These are D356/K439', E357/K370', K392/D399'and D399/K409' (numbering according to Kabat (1991) where residues in the first chain are separated from residues in the second chain by'' and where the prime (') indicates the residue numbering in the second chain). As the CH3-CH3 interface displays a 2-fold symmetry, each unique charge pair is represented twice in intact IgG (i.e., also K439/D356', K370/E357', D399/K392'and K409/D399' charge interactions are present in the interface).”
Applicants have not shown original data for unexpected or surprising results using the claimed CH3 mutations much less those limited to that taught in Sasisekharan or DE KRUIF. MPEP 716.02(a).
Sasisekharan and DE KRUIF provide the motivation by teaching that mutations in the CH3 constant regions contribute to more favorable contacts, as evaluated by the structural analysis and connectivity network, for the specific and limited number of amino acid residues which potentially mediate new or improved contacts. DE KRUIF provides the motivation to change naturally occurring charged amino acid contact residues with amino acid residues of opposite charge (i.e. a charge reversal strategy), thus the scope of a limited number of possible variants falls within the decision of K.S.R. (the “obvious to try” concept, which applies when an inventor chooses from a finite number of identified, predictable solutions with a reasonable expectation of success). The POSA is assured of predictable and reasonable success because the CH3 mutations are well-accepted in the field of art for yielding heterodimer formation.
17. Claim(s) Claim 161 is/are rejected under 35 U.S.C. 103 as being unpatentable over over Sasisekharan et al (USPN 11459405 B2; issued 2022-10-04; priority 2016-12-28) in view of DE KRUIF et al (AU 2018201326 B2; published 2020-02-06; filed 2018-02-23).
The claimed polypeptide is prima facie obvious over Sasisekharan in view of DE KRUIF.
Claim 161 recites formula Ic comprising “X-[(Aba)-(Lb)] m-(DD)-(Lc)-(Abd)]n -Y” for what is construed a single polypeptide, where Ab(a or b) are antigen binding domains; L(c or d) are linkers; DD is a dimerization domain, and X- and/or Y- are any other amino acid sequence that may or may not be present, where the DD comprises a CH2-CH3 domain with the CH3 domain comprising mutations that promote the formation of heterodimers.
Sasisekharan teaches bispecific antibodies drawn to two polypeptides of claim 22 having as a DD, a CH2-CH3 mutated in the CH3 region in order to promote heterodimerization.
(111) Other aspects of the invention relate to newly identified CH3 mutations which favor heterodimerization of Fc domains in a bispecific antibody. Certain amino acids within the CH3 domain were identified as described herein as facilitating the formation of heterodimers. These CH3 residues in human IgG1 include, but are not limited to, L351, P352, P353, D356, E357, L365, T366, K370, K392, P395, V397, D399, F405, Y407, K409, and K439. In certain embodiments, the residue important for CH3 heterodimer formation is E357, K370 or K409, or combination thereof. In certain embodiments, any one or more of these residues are replaced in a heterodimeric polypeptide or a bispecific antibody with any other amino acid suitable for use. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes one or more of the following substitutions in the CH3 domain: E357K, K370E and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having an amino acid substitution at residue K370. In certain embodiments the substitution is K370E. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes CH3′ domain having an amino acid substitution at residues E357 and K409. In certain embodiments the substitutions are E357K and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having an amino acid substitution at residue K370. In certain embodiments the substitution is K370E. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having the amino acid sequence set forth in SEQ ID NO: 13. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having an amino acid substitution at residues E357 and K409. In certain embodiments the substitutions are E357K and K409R. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3″ domain having the amino acid sequence set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ domain having a K370E substitution, and a CH3″ having E357K and K409R substitutions. In certain embodiments, the heterodimeric polypeptide or bispecific antibody has a CH3′ domain as set forth in SEQ ID NO: 13, and a CH3″ domain as set forth in SEQ ID NO: 14. In certain embodiments, the heterodimeric polypeptide or bispecific antibody includes a CH3′ having E357K and K409R substitutions, and a CH3″ domain having a K370E substitution. In certain embodiments, the heterodimeric polypeptide or bispecific antibody has a CH3′ domain as set forth in SEQ ID NO: 14, and a CH3″ domain as set forth in SEQ ID NO: 13.
CH3 positions taught in Sasisekharan that are overlapping with DE KRUIF and are as corresponding to “mutations in the CH3 domains of heavy chains wherein naturally occurring charged amino acid contact residues are replaced by amino acid residues of opposite charge (i.e. a charge reversal strategy). This creates an altered charge polarity across the Fc dimer interface such that co-expression of electrostatically matched Fc chains support favorable attractive interactions thereby promoting desired Fc heterodimer formation, whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation. It was described that within the CH3-CH3 interface four unique charges residue pairs are involved in the domain-domain interaction. These are D356/K439', E357/K370', K392/D399'and D399/K409' (numbering according to Kabat (1991) where residues in the first chain are separated from residues in the second chain by'' and where the prime (') indicates the residue numbering in the second chain). As the CH3-CH3 interface displays a 2-fold symmetry, each unique charge pair is represented twice in intact IgG (i.e., also K439/D356', K370/E357', D399/K392'and K409/D399' charge interactions are present in the interface).”
Applicants have not shown original data for unexpected or surprising results using the claimed CH3 mutations much less those limited to that taught in Sasisekharan or DE KRUIF. MPEP 716.02(a).
Sasisekharan and DE KRUIF provide the motivation by teaching that mutations in the CH3 constant regions contribute to more favorable contacts, as evaluated by the structural analysis and connectivity network, for the specific and limited number of amino acid residues which potentially mediate new or improved contacts. DE KRUIF provides the motivation to change naturally occurring charged amino acid contact residues with amino acid residues of opposite charge (i.e. a charge reversal strategy), thus the scope of a limited number of possible variants falls within the decision of K.S.R. (the “obvious to try” concept, which applies when an inventor chooses from a finite number of identified, predictable solutions with a reasonable expectation of success). The POSA is assured of predictable and reasonable success because the CH3 mutations are well-accepted in the field of art for yielding heterodimer formation in bispecific antibodies.
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.
18. Claims 1-2, 22-23, 61, 63, 80, 91-94, 96-99, 110, 112, 114, 121, 123, and 155-159 and 161 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51, 62-63, 90-91, 98, 101-102, 128 and 133 of copending Application No. 18/283,579 (reference application US 20240166739). The reference claims are not afforded safe harbor under 35 USC 121 because they share no continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because each of the claim sets includes a core structure for formula Ib or Ic comprising “X-[(Aba)-(Lb)] m-(DD)-(Lc)-(Abd)]n -Y” for what is construed a single polypeptide, where Ab(a or b) are antigen binding domains; L(c or d) are linkers; DD is a dimerization domain, and X- and/or Y- are any other amino acid sequence that may or may not be present.
Ref claims recite:
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1480
1104
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1348
1086
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1134
1064
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1284
856
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582
1074
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
19. Claims 1-2, 61, 98, 110, and 112 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-22 and 54-55 of copending Application No. 19/098,348 (reference application US 20250313638). The reference claims are not afforded safe harbor under 35 USC 121 because they share no continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because each of the claim sets includes a core structure for formula Ib or Ic comprising “X-[(Aba)-(Lb)] m-(DD)-(Lc)-(Abd)]n -Y” for what is construed a single polypeptide, where Ab(a or b) are antigen binding domains; L(c or d) are linkers; DD is a dimerization domain, and X- and/or Y- are any other amino acid sequence that may or may not be present.
Ref claims recite:
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1410
1041
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528
1078
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
20. No claims are allowed.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643