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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-24, 26, and 29 in the reply filed on 6/22/206 is acknowledged.
Claims 25 and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/22/2026.
Applicant's election with traverse of the following species:
Claim 1: SEQ ID NO: 53 ((G4Q)3) and SEQ ID NOs: 214-216;
Claim 5: SEQ ID NOs: 304-309;
Claim 8: SEQ ID NO: 34;
Claim 9: SEQ ID NO: 594, SEQ ID NO: 595, and SEQ ID NO: 53 with SEQ ID NO: 34 and SEQ ID NO: 624 and SEQ ID NO: 625 and SEQ ID NO: 53 with SEQ ID NO: 34 and SEQ ID NO: 594, SEQ ID NO: 595, and SEQ ID NO: 53;
Claim 10: CD33;
Claim 13: SEQ ID NO: 850;
Claim 14: SEQ ID NO: 850 and SEQ ID NO: 72;
Claim 15: SEQ ID NO: 850;
Claim 16: SEQ ID NO: 850;
Claim 17: SEQ ID NO: 624, SEQ ID NO: 625, and SEQ ID NO: 53 with SEQ ID NO: 1, SEQ ID NO: 850, SEQ ID NO: 72, SEQ ID NO: 1, SEQ ID NO: 594, SEQ ID NO: 595, SEQ ID NO: 53 with SEQ ID NO: 34, SEQ ID NO: 702, SEQ ID NO: 703, and SEQ ID NO: 53.
in the reply filed on 6/22/2026 is acknowledged.
After further consideration of the Applicant’s arguments and examination of the available prior art, Examiner agrees that the species election should be withdrawn. The species formulae S(G4X)n and (G4X)n were searched in general. The most relevant matches are discussed below.
Consequently, the invention election is maintained (it was not traversed) and the species election is withdrawn.
Priority
Priority to US 63/110,840, filed 11/6/2020, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 7/28/2023, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-26 and 28-29 are pending. Claims 25 and 28 are withdrawn. Claims 1-24, 26, and 29 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Specifically, the specification recites amino acids of four amino acids or longer in paragraphs [1], [3], [51], [52], [53], [55], [56], [59], [61], [62], [77], [79], [80], [81], [82], [85], [86], [87], [89], [91], [125], [126], [206], [262], [271], [272], [274], and [278] that lack sequence identifiers.
Furthermore, claims 1, 4, 11, 12, and 18 contain amino acid sequences of four or more that lack sequence identifiers.
Note: The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, 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.
Specification
The disclosure is objected to because of the following informalities: the specification recites amino acids of four amino acids or longer in paragraphs [1], [3], [51], [52], [53], [55], [56], [59], [61], [62], [77], [79], [80], [81], [82], [85], [86], [87], [89], [91], [125], [126], [206], [262], [271], [272], [274], and [278] that lack sequence identifiers.
Appropriate correction is required.
Note: The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The use of the term “Cytiva”, on page 69, para. [216], 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.
The use of the term “Skyline”, on page 74, para. [233], 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.
Claim Objections
Claims 1, 4, 11, 12, and 18 are objected to because of the following informalities: claims 1, 4, 11, 12, and 18 contain amino acid sequences of four or more that lack sequence identifiers.
Patent Rule 1.831(b)(1) states: “An unbranched sequence or linear region of a branched sequence containing 4 or more specifically defined amino acids, wherein the amino acids form a single peptide backbone.”
The peptides in claim 1 claimed as SG4X and G4X both possess at least 4 specifically defined amino acid sequences and therefore require sequence identifiers as described above.
Appropriate correction is required.
Claims 12 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 102/103
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 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.
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.
Claims 1-2, 5-7, 22-24, and 26 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Miller et al. WO2012088461, published 6/28/2012.
Regarding claim 1, Miller discloses a polypeptide comprising a VH and VL domain connected by a peptide linker:
“An scFv molecule comprising a VH and a VL region, wherein the VH and VL region are genetically linked by a linker peptide, wherein the linker peptide comprises the amino acid sequence (GGGXX)3 or (GGGXX)4, wherein X is an amino acid which reduces or eliminates the addition of xylose residues to the linker peptide upon expression in a host cell and wherein the linker peptide lacks the sequence GSG.” (Miller et al., claim 28).
Miller also discloses that this linker may be (GGGGA)3, which reads on Applicant claim 1 in the case wherein X=A and n=3:
“The scFv molecule of claim 28, wherein the VH and the VL region are genetically linked by a linker peptide comprising the amino acid sequence selected from the group consisting of (GGGGA)3 and (GGGGA)4.” (Miller et al., claim 29).
In this scenario, Miller anticipates Applicant claim 1.
Miller also discloses the following linker:
“A linker peptide comprising the amino acid sequence (GGGGQ)2GGGGS.” (Miller et al., claim 42).
This linker differs from Applicant SEQ ID NO: 53 by a single substitution. Furthermore, Applicant SEQ ID NO: 53 also fits within the formula in Miller claim 28 listed above.
Also, Xiong et al. discloses that the GGGGQ motif cannot be glycosylated: “However, the linker used in this Example cannot be glycosylated (e.g., G4Q) or was shorter (G4S instead of (G4S)4), to reduce glycosylation.” (Xiong et al., page 45, line 31).
Xiong also discloses the linker of Applicant SEQ ID NO: 53 in the case wherein the linker of Xiong is (G4Q)n and n=3:
“The fusion protein of any one of claims 1-6, wherein the linker is a (G4S)n or (G4Q)n linker, wherein n is greater than 0.” (Xiong et al., claim 7).
“The fusion protein of claim 7 or 9, wherein the n is 3 or 4.” (Xiong et al., claim 10).
Wang discloses that the (G4S) motif is the most common base linker: “The most commonly used linker contains a 15-combination of glycine and serine residues (GGGGS)3 that provides flexibility and enhances the hydrophilicity of the peptide backbone. (8) ScFvs are predominantly monomeric when the linker is at least 12 residues.” (Wang et al., page 998, col. 1, para. 1).
Finally, Seitz discloses that glycosylation must occur at serine, threonine, or asparagine residues:
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(Seitz, et al., page 216, col. 1, para. 1)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the final serine residue with another glutamine residue in the linker disclosed by Miller to arrive at Applicant claim 1, specifically the case wherein the linker is Applicant SEQ ID NO: 53 because the linker of Miller has already replaced two of the common serines with glutamines, Xiong discloses a linker in which all serines are replaced with glutamines, and Seitz discloses that glycosylation can’t occur at glutamines.
A person of ordinary skill in the art would modify the final serine in the linker of Miller so that no unwanted glycosylation could occur at any point in the linker. A person of ordinary skill in the art would retain the length of the linker at fifteen residues to keep the ScFV monomeric as disclosed by Wang.
A person of ordinary skill in the art would have a reasonable expectation of success because Xiong already contemplates the usage of this linker in a similar but not identical context of a GDF15 region joined to an Fc region. Wang discloses that the most common 15-mer linker is (GGGGS)3 and Miller already has a linker that replaces two of the three serines of this common motif. Seitz discloses that serine, threonine, or asparagine is required for glycosylation, so replacing the final serine would reasonably be expected to eliminate that possibility. Finally, at least in the case of Xiong, the substitution of G4S to G4Q did not in and of itself affect activity: “Though whether the linker is a G4S or G4Q does not affect activity, the length of the linker is important for activity.” (Xiong et al., page 46, line 29).
Consequently, claim 1 is anticipated by Miller et al.
Regarding claim 2, claim 1 is anticipated as described above. The (GGGGA)3 linker of Miller reads on claim 2 in the case wherein n=3.
Consequently, claim 2 is anticipated by Miller et al..
Regarding claim 5, claim 1 is anticipated as described above. Miller discloses the usage of disclosed polypeptides as homodimers or heterodimers:
“Polypeptides which comprise a linking peptide of the invention may be either monomeric or multimeric. For example, in one embodiment, a protein of the invention is a dimer. In one embodiment, the dimers of the invention are homodimers, comprising two identical monomeric subunits or polypeptides. In another embodiment, a dimeric polypeptide of the invention is a heterodimer, comprising two non-identical monomeric subunits or polypeptides (e.g., comprising two different biologically active moieties or one biologically active moiety only).” (Miller et al., page 11, para. 2).
Consequently, claim 5 is anticipated by Miller et al.
Regarding claim 6, claim 1 is anticipated as described above. Miller discloses the usage of disclosed polypeptides as homodimers:
“Polypeptides which comprise a linking peptide of the invention may be either monomeric or multimeric. For example, in one embodiment, a protein of the invention is a dimer. In one embodiment, the dimers of the invention are homodimers, comprising two identical monomeric subunits or polypeptides. In another embodiment, a dimeric polypeptide of the invention is a heterodimer, comprising two non-identical monomeric subunits or polypeptides (e.g., comprising two different biologically active moieties or one biologically active moiety only).” (Miller et al., page 11, para. 2).
Consequently, claim 6 is anticipated by Miller et al.
Regarding claim 7, claim 1 is anticipated as described above. Miller discloses the case wherein the binding polypeptide has one target:
“In one embodiment, a polypeptide of the invention is a binding molecule, i.e., a polypeptide that comprises a binding domain or binding site. The terms "binding domain" or "binding site", as used herein, refer to the portion, region, or site of polypeptide that mediates specific binding with a target molecule (e.g. an antigen, ligand, receptor, substrate or inhibitor).”
(Miller et al., page 11, para 3).
Consequently, claim 7 is anticipated by Miller et al.
Regarding claim 22, claim 1 is anticipated as described above. Miller discloses: “In another embodiment, the invention pertains to a nucleic acid molecule encoding a polypeptide comprising a linker peptide of the invention. In one embodiment, the nucleic acid molecule is in a vector. In another embodiment, the invention pertains to a host cell comprising the nucleic acid molecule of the invention. (Miller et al., page 3, para. 6).
Consequently, claim 22 is anticipated by Miller et al.
Regarding claim 23, claim 22 is anticipated as described above. Miller discloses: “In another embodiment, the invention pertains to a nucleic acid molecule encoding a polypeptide comprising a linker peptide of the invention. In one embodiment, the nucleic acid molecule is in a vector. In another embodiment, the invention pertains to a host cell comprising the nucleic acid molecule of the invention. (Miller et al., page 3, para. 6).
Consequently, claim 23 is anticipated by Miller et al.
Regarding claim 24, claim 23 is anticipated as described above. Miller discloses: “In another embodiment, the invention pertains to a nucleic acid molecule encoding a polypeptide comprising a linker peptide of the invention. In one embodiment, the nucleic acid molecule is in a vector. In another embodiment, the invention pertains to a host cell comprising the nucleic acid molecule of the invention. (Miller et al., page 3, para. 6).
Consequently, claim 24 is anticipated by Miller et al.
Regarding claim 26, claim 1 is anticipated as described above. Claim 26 recites a composition comprising the polypeptide of claim 1 with no other limitations. Because claim 1 is anticipated, claim 26 is as well.
Consequently, claim 26 is anticipated by Miller et al.
Regarding claim 29, claim 1 is anticipated as described above. MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004)”.
Consequently, claim 29 is anticipated by Miller et al.
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.
Claims 1-2, 5-7, 22-24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)).
Regarding claim 1, Miller discloses a polypeptide comprising a VH and VL domain connected by a peptide linker:
“An scFv molecule comprising a VH and a VL region, wherein the VH and VL region are genetically linked by a linker peptide, wherein the linker peptide comprises the amino acid sequence (GGGXX)3 or (GGGXX)4, wherein X is an amino acid which reduces or eliminates the addition of xylose residues to the linker peptide upon expression in a host cell and wherein the linker peptide lacks the sequence GSG.” (Miller et al., claim 28).
“The scFv molecule of claim 28, wherein the VH and the VL region are genetically linked by a linker peptide comprising the amino acid sequence selected from the group consisting of (GGGGA)3 and (GGGGA)4.” (Miller et al., claim 29).
Miller also discloses the following linker:
“A linker peptide comprising the amino acid sequence (GGGGQ)2GGGGS.” (Miller et al., claim 42).
This linker differs from Applicant SEQ ID NO: 53 by a single substitution. Furthermore, Applicant SEQ ID NO: 53 also fits within the formula in Miller claim 28 listed above.
Also, Xiong et al. discloses that the GGGGQ motif cannot be glycosylated: “However, the linker used in this Example cannot be glycosylated (e.g., G4Q) or was shorter (G4S instead of (G4S)4), to reduce glycosylation.” (Xiong et al., page 45, line 31).
Xiong also discloses the linker of Applicant SEQ ID NO: 53 in the case wherein the linker of Xiong is (G4Q)n and n=3:
“The fusion protein of any one of claims 1-6, wherein the linker is a (G4S)n or (G4Q)n linker, wherein n is greater than 0.” (Xiong et al., claim 7).
“The fusion protein of claim 7 or 9, wherein the n is 3 or 4.” (Xiong et al., claim 10).
Wang discloses that the (G4S) motif is the most common base linker: “The most commonly used linker contains a 15-combination of glycine and serine residues (GGGGS)3 that provides flexibility and enhances the hydrophilicity of the peptide backbone. (8) ScFvs are predominantly monomeric when the linker is at least 12 residues.” (Wang et al., page 998, col. 1, para. 1).
Finally, Seitz discloses that glycosylation must occur at serine, threonine, or asparagine residues:
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(Seitz, et al., page 216, col. 1, para. 1)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the final serine residue with another glutamine residue in the linker disclosed by Miller to arrive at Applicant claim 1, specifically the case wherein the linker is Applicant SEQ ID NO: 53 because the linker of Miller has already replaced two of the common serines with glutamines, Xiong discloses a linker in which all serines are replaced with glutamines, and Seitz discloses that glycosylation can’t occur at glutamines.
A person of ordinary skill in the art would modify the final serine in the linker of Miller so that no unwanted glycosylation could occur at any point in the linker. A person of ordinary skill in the art would retain the length of the linker at fifteen residues to keep the ScFV monomeric as disclosed by Wang.
A person of ordinary skill in the art would have a reasonable expectation of success because Xiong already contemplates the usage of this linker in a similar but not identical context of a GDF15 region joined to an Fc region. Wang discloses that the most common 15-mer linker is (GGGGS)3 and Miller already has a linker that replaces two of the three serines of this common motif. Seitz discloses that serine, threonine, or asparagine is required for glycosylation, so replacing the final serine would reasonably be expected to eliminate that possibility. Finally, at least in the case of Xiong, the substitution of G4S to G4Q did not in and of itself affect activity: “Though whether the linker is a G4S or G4Q does not affect activity, the length of the linker is important for activity.” (Xiong et al., page 46, line 29).
Consequently, claim 1 is obvious over Miller et al. in view of Xiong et al., Wang et al., and Seitz et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. The (GGGGQ)3 linker of Miller, Xiong, Wang, and Seitz reads on claim 2 in the case wherein n=3.
Consequently, claim 2 is obvious over Miller et al. in view of Xiong et al., Wang et al., and Seitz et al. and rejected.
Regarding claim 5, claim 1 is anticipated/obvious as described above. Miller discloses the usage of disclosed polypeptides as homodimers or heterodimers:
“Polypeptides which comprise a linking peptide of the invention may be either monomeric or multimeric. For example, in one embodiment, a protein of the invention is a dimer. In one embodiment, the dimers of the invention are homodimers, comprising two identical monomeric subunits or polypeptides. In another embodiment, a dimeric polypeptide of the invention is a heterodimer, comprising two non-identical monomeric subunits or polypeptides (e.g., comprising two different biologically active moieties or one biologically active moiety only).” (Miller et al., page 11, para. 2).
Consequently, claim 5 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Regarding claim 6, claim 1 is anticipated/obvious as described above. Miller discloses the usage of disclosed polypeptides as homodimers:
“Polypeptides which comprise a linking peptide of the invention may be either monomeric or multimeric. For example, in one embodiment, a protein of the invention is a dimer. In one embodiment, the dimers of the invention are homodimers, comprising two identical monomeric subunits or polypeptides. In another embodiment, a dimeric polypeptide of the invention is a heterodimer, comprising two non-identical monomeric subunits or polypeptides (e.g., comprising two different biologically active moieties or one biologically active moiety only).” (Miller et al., page 11, para. 2).
Consequently, claim 6 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Regarding claim 7, claim 1 is anticipated/obvious as described above. Miller discloses the case wherein the binding polypeptide has one target:
“In one embodiment, a polypeptide of the invention is a binding molecule, i.e., a polypeptide that comprises a binding domain or binding site. The terms "binding domain" or "binding site", as used herein, refer to the portion, region, or site of polypeptide that mediates specific binding with a target molecule (e.g. an antigen, ligand, receptor, substrate or inhibitor).”
(Miller et al., page 11, para 3).
Consequently, claim 7 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Regarding claim 22, claim 1 is anticipated/obvious as described above. Miller discloses: “In another embodiment, the invention pertains to a nucleic acid molecule encoding a polypeptide comprising a linker peptide of the invention. In one embodiment, the nucleic acid molecule is in a vector. In another embodiment, the invention pertains to a host cell comprising the nucleic acid molecule of the invention. (Miller et al., page 3, para. 6).
Consequently, claim 22 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Regarding claim 23, claim 22 is anticipated/obvious as described above. Miller discloses: “In another embodiment, the invention pertains to a nucleic acid molecule encoding a polypeptide comprising a linker peptide of the invention. In one embodiment, the nucleic acid molecule is in a vector. In another embodiment, the invention pertains to a host cell comprising the nucleic acid molecule of the invention. (Miller et al., page 3, para. 6).
Consequently, claim 23 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Regarding claim 24, claim 23 is anticipated/obvious as described above. Miller discloses: “In another embodiment, the invention pertains to a nucleic acid molecule encoding a polypeptide comprising a linker peptide of the invention. In one embodiment, the nucleic acid molecule is in a vector. In another embodiment, the invention pertains to a host cell comprising the nucleic acid molecule of the invention. (Miller et al., page 3, para. 6).
Consequently, claim 24 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Regarding claim 26, claim 1 is anticipated/obvious as described above. Claim 26 recites a composition comprising the polypeptide of claim 1 with no other limitations. Because claim 1 is anticipated obvious, claim 26 is as well.
Consequently, claim 26 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Regarding claim 29, claim 1 is anticipated/obvious as described above. MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004)”.
Consequently, claim 29 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)).
Regarding claim 3, claim 1 is obvious as described above. The linker of Miller, Xiong, Wang, and Seitz has X as Q.
Consequently, claim 3 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Regarding claim 4, claim 1 is obvious as described above. The linker of Miller, Xiong, Wang, and Seitz is (G4Q)3.
Consequently, claim 4 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Claims 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), as applied to claim 1 above, further in view of Rudnick et al. (Rudnick, et al. Cancer Biotherapy and Radiopharmaceuticals 24.2: 155-161 (2009)).
Regarding claim 8, claim 5 is anticipated/obvious as described above.
Miller, Xiong, Wang, and Seitz do not specifically disclose the construct recited in claim 8.
However, Rudnick discloses that a system of scFV dimers will result in the recited construct:
“Dimers of scFv (scFv2 ) differ from diabodies in that the two monomers are typically tethered by peptides on the C-termini, and the interaction between VH and VL domains remains intramolecular. This scaffold was used to address directly whether decreasing first-pass renal clearance or increasing avidity is more important for dimer retention in tumors compared to scFv. 44 For comparison to the monomeric anti-Her2 scFv 741F8-1, a scFv homodimer was produced that is divalent for Her2.
For comparison to the monomeric anti-Her2 scFv 741F8-1, a scFv homodimer was
produced that is divalent for Her2. To test the same molecular weight, and therefore renal clearance rate, with only a monovalent binding with Her2, a heterodimer was made by
pairing 741F8-1 with the antidigoxin scFv 26-10.44 Homodimerization decreased the in vitro KD of the scFv monomer from to 4.8_10_8M to 9.2_10_9 M, while the heterodimer had no change.44 After 24 hours, 741F8-1 scFv and the 741F8-1=26-10 heterodimer had the same retention in the tumor (1.25 and 1.13 %ID=g respectively), using a small-cell SCID xenograft. However, 3.57 %ID=g of 741F8-1 scFv2 was retained in the tumor. These observations demonstrate that the increased valency and avidity, and not reduction in clearance from an increase in mass, is responsible for the increased tumor-targeting ability of scFv2.44” (Rudnick et al., page 158, col. 1, para. 3, emphasis added)
Given the disclosure of Rudnick, the construct becomes two copies of the scFV construct of Miller, Xiong, Wang, and Seitz tether as described by Rudnick (the middle linker) to result in the construct of claim 8.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to tether two scFVs of Miller, Xiong, Wang, and Seitz with the tether disclosed by Rudnick to arrive at the claimed invention because Rudnick discloses the usage of such dimers to test retention properties of constructs against tumors.
A person of ordinary skill in the art would be motivated to create this construct to either increase avidity as disclosed by Rudnick or to perform the measurements disclosed by Rudnick.
A person of ordinary skill in the art would have a reasonable expectation of success because Rudnick was able to observe increased avidity in the construct.
Consequently, claim 8 is obvious over Miller, Xiong, Wang, and Seitz as applied to claim 5 above, further in view of Rudnick et al. and rejected.
Regarding claim 11, claim 8 is obvious as described above. The linker of Miller, Xiong, Wang, and Seitz is (G4Q)3.
Consequently, claim 11 is obvious over Miller, Xiong, Wang, and Seitz and rejected.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), and Rudnick et al. (Rudnick, et al. Cancer Biotherapy and Radiopharmaceuticals 24.2: 155-161 (2009)) as applied to claim 8 above, further in view of Deyev et al. (Deyev, et al. Bioessays 30.9: 904-918 (2008)).
Regarding claim 9, claim 8 is obvious as described above. Miller, Xiong, Wang, Seitz and Rudnick do not specifically disclose a trimer construct.
However, Deyev discloses the usage of multimers for additional avidity:
“The most-important advantage of multivalent mini-antibodies over monovalent ones is the enhancement of specific binding avidity towards antigens. Theoretically, the resulting binding constant (avidity) can approach the product of original binding constants (affinities).” (Deyev et al., page 914, col. 1, para. 1).
Other advantages include multiple binding targets:
“In special cases, multivalency is exploited in different selection technologies, that is, multivalent phage displays.(98,99) It allows detection of antibodies with low intrinsic affinity per binding site(100) and rapid isolation of pairs of interacting polypeptides. (Deyev et al., page 914, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add another scFV of Miller, Xiong, Wang, Seitz, and Rudnick to form a trimer as recited by claim 9 because Deyev discloses that increasing avidity can increase binding and binding multiple targets has selection applications.
A person of ordinary skill in the art would be motivated to create a trimer to take advantage of the benefits disclosed by Deyev above and would have a reasonable expectation of success because Deyev discloses how increased avidity can increase binding and binding multiple targets has selection applications.
Consequently, claim 9 is obvious over Miller, Xiong, Wang, Seitz, and Rudnick as applied to claim 8 above, further in view of Deyev et al. and rejected.
Claims 10, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), and Rudnick et al. (Rudnick, et al. Cancer Biotherapy and Radiopharmaceuticals 24.2: 155-161 (2009)) as applied to claim 8 above, further in view of Kortt et al. (Kortt, et al. Biomolecular engineering 18.3: 95-108 (2001)).
Regarding claim 10, claim 8 is obvious as described above. Miller, Xiong, Wang, Seitz and Rudnick do not specifically disclose binding to CD3 and an additional cell surface antigen.
However, Kortt et al. discloses the usage of a dimer targeted to CD3 and a cell surface antigen:
“Most recent examples have focused on T-cell recruitment; using one Fv module targeted to CD3 on T-cells and with a second Fv module targeted to a cancer marker such as EP-CAM, CEA or CD19, in one case via NIP-tagged ligands. There are also numerous diagnostic applications (immunoassays) that require bispecific cross-linking reagents.” (Kortt et al., page 105, col. 2, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the dimer construct of Miller, Xiong, Wang, Seitz and Rudnick to target CD3 and an additional cell surface marker as disclosed by Kortt because each scFV of Miller, Xiong, Wang, Seitz and Rudnick can be engineered to target CD3 and a cell surface marker.
A person of ordinary skill in the art would be motivated to make this construct because it can be used to direct T-cells to cancer as disclosed by Kortt or as diagnostic searching for treatments related to CD3 as disclosed by Kortt.
A person of ordinary skill in the art because Kortt references Fv modules that target CD3 and an additional marker and the VH/VL of Miller, Xiong, Wang, Seitz and Rudnick form Fv molecules.
Consequently, claim 10 is obvious over Miller, Xiong, Wang, Seitz, and Rudnick as applied to claim 8 above, further in view of Kortt et al. and rejected.
Regarding claim 20, claim 10 is obvious as described above. The additional cellular marker of Kortt is a cancer cell marker.
Consequently, claim 20 is obvious over Miller, Xiong, Wang, Seitz, and Rudnick as applied to claim 8 above, further in view of Kortt et al. and rejected.
Regarding claim 21, claim 20 is obvious as described above. Kortt recites CD19 as a potential target:
“Most recent examples have focused on T-cell recruitment; using one Fv module targeted to CD3 on T-cells and with a second Fv module targeted to a cancer marker such as EP-CAM, CEA or CD19, in one case via NIP-tagged ligands. There are also numerous diagnostic applications (immunoassays) that require bispecific cross-linking reagents.” (Kortt et al., page 105, col. 2, para. 3).
Consequently, claim 21 is obvious over Miller, Xiong, Wang, Seitz, and Rudnick as applied to claim 8 above, further in view of Kortt et al. and rejected.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), as applied to claim 1 above, further in view of Zhou et al. (Zhou, Li, et al. "Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery." Biomaterials 117: 24-31. (2017))
Regarding claim 13, claim 1 is anticipated/obvious as described above. Miller, Xiong, Wang, and Seitz disclose a half-life extending domain:
“In one embodiment, a biologically active moiety comprises an Fc region, or domain or moiety thereof. As used herein, the term "Fc region" shall be defined as the portion of a polypeptide which corresponds to the Fc region of native immunoglobulin, i.e., as formed by the dimeric association of the respective Fc domains (or Fc moieties) of its two heavy chains. A native Fc region is homodimeric and comprises two polypeptide chains. In contrast, the term "genetically-fused Fc region" or "single-chain Fc region" (scFc region), as used herein, refers to a synthetic dimeric Fc region comprised of Fc domains (or Fc moieties) genetically linked within a single polypeptide chain (i.e., encoded in a single contiguous genetic sequence).” (Miller et al., page 12, para. 2).
Zhou confirms this motif as half-life extending domain:
“The strategy of engineering Fc conjugates takes advantage of this characteristic to prolong the plasma half-life of protein drugs.” (Zhou et al., page 24, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an Fc region as a half-life extending domain as disclosed by Miller to the polypeptide of Miller, Xiong, Wang, and Seitz because Zhou discloses that Fc regions prolong the plasma half-life of protein drugs.
A person of ordinary skill in the art would art this domain to extend the half-life of the polypeptide of Miller, Xiong, Wang, and Seitz as described by Zhou and have a reasonable expectation of success because Zhou discloses that Fc domains extend plasma half-life.
Consequently, claim 13 is obvious over Miller, Xiong, Wang, and Seitz as applied to claim 1 above, further in view of Zhou et al. and rejected.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)), Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), and Zhou et al. (Zhou, Li, et al. "Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery." Biomaterials 117: 24-31. (2017)).
Regarding claim 14, claim 13 is obvious as described above. Miller discloses ““In one embodiment, a biologically active moiety comprises an Fc region, or domain or moiety thereof. As used herein, the term "Fc region" shall be defined as the portion of a polypeptide which corresponds to the Fc region of native immunoglobulin, i.e., as formed by the dimeric association of the respective Fc domains (or Fc moieties) of its two heavy chains. A native Fc region is homodimeric and comprises two polypeptide chains. In contrast, the term "genetically-fused Fc region" or "single-chain Fc region" (scFc region), as used herein, refers to a synthetic dimeric Fc region comprised of Fc domains (or Fc moieties) genetically linked within a single polypeptide chain (i.e., encoded in a single contiguous genetic sequence).” (Miller et al., page 12, para. 2).
Miller also discloses usage of a complete Fc domain: “In other embodiments, an Fc moiety comprises a complete Fc domain (i.e., a hinge domain, a CH2 domain, and a CH3 domain). “ (Miller et al., page 14, para. 2).
The result of implementing single-chain Fc region of Miller as disclosed by Miller would result in the formula of claim 14.
Furthermore, Zhou discloses a production weakness of traditional Fc moieties that are expressed as a dimer: “However, their main limitation is production, which requires dual expression plasmids containing the drug-Fc and the Fc sequences. This production protocol generates a mixture of multiple fusion products including (drug-Fc)2, drug-(Fc)2 and (Fc)2, creating issues of impurity. Further, formation of homodimers (i.e. (drug-Fc)2 and (Fc)2) are favored over the Monomeric drug-(Fc)2 products, resulting in low production yields and instability.” (Zhou et al., page 25, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art to use a complete Fc moiety in a single chain as disclosed by Miller to implement a half-life extending domain because Miller discloses this exact domain and Zhou discloses that the domain is easier to produce when implemented in this way.
A person of ordinary skill in the art would use a single chain Fc region to create beneficial production conditions and have a reasonable expectation of success because Miller discloses this exact format and Zhou discloses that single chain Fc regions are known to be easier to produce.
Consequently, claim 14 is obvious over Miller, Xiong, Wang, and Seitz as applied to claim 1 above, further in view of Zhou et al. and rejected.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), and Rudnick et al. (Rudnick, et al. Cancer Biotherapy and Radiopharmaceuticals 24.2: 155-161 (2009)) as applied to claim 8 above, further in view of Zhou et al. (Zhou, Li, et al. "Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery." Biomaterials 117: 24-31. (2017)).
Regarding claim 15, claim 8 is obvious as described above. Miller, Xiong, Wang, Seitz, and Rudnick disclose a half-life extending domain:
“In one embodiment, a biologically active moiety comprises an Fc region, or domain or moiety thereof. As used herein, the term "Fc region" shall be defined as the portion of a polypeptide which corresponds to the Fc region of native immunoglobulin, i.e., as formed by the dimeric association of the respective Fc domains (or Fc moieties) of its two heavy chains. A native Fc region is homodimeric and comprises two polypeptide chains. In contrast, the term "genetically-fused Fc region" or "single-chain Fc region" (scFc region), as used herein, refers to a synthetic dimeric Fc region comprised of Fc domains (or Fc moieties) genetically linked within a single polypeptide chain (i.e., encoded in a single contiguous genetic sequence).” (Miller et al., page 12, para. 2).
Zhou confirms this motif as half-life extending domain:
“The strategy of engineering Fc conjugates takes advantage of this characteristic to prolong the plasma half-life of protein drugs.” (Zhou et al., page 24, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to attach the HLE domain to the C-terminal of the construct of Miller, Xiong, Wang, Seitz, and Rudnick because in a single chain construct, said domain would have to be on the N-terminal side or C-terminal side and therefore a finite number of choices exist.
A person of ordinary skill in the art would art this domain to extend the half-life of the polypeptide of Miller, Xiong, Wang, Seitz, and Rudnick as described by Zhou and have a reasonable expectation of success because Zhou discloses that Fc domains extend plasma half-life.
Consequently, claim 15 is obvious over Miller, Xiong, Wang, Seitz, and Rudnick as applied to claim 8 above, further in view of Zhou et al. and rejected.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), Rudnick et al. (Rudnick, et al. Cancer Biotherapy and Radiopharmaceuticals 24.2: 155-161 (2009) and Deyev et al. (Deyev, et al. Bioessays 30.9: 904-918 (2008)) as applied to claim 9, further in view of Zhou et al. (Zhou, Li, et al. "Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery." Biomaterials 117: 24-31. (2017)).
Regarding claim 16, claim 9 is obvious as described above. Miller, Xiong, Wang, Seitz, Rudnick, and Deyev disclose a half-life extending domain:
“In one embodiment, a biologically active moiety comprises an Fc region, or domain or moiety thereof. As used herein, the term "Fc region" shall be defined as the portion of a polypeptide which corresponds to the Fc region of native immunoglobulin, i.e., as formed by the dimeric association of the respective Fc domains (or Fc moieties) of its two heavy chains. A native Fc region is homodimeric and comprises two polypeptide chains. In contrast, the term "genetically-fused Fc region" or "single-chain Fc region" (scFc region), as used herein, refers to a synthetic dimeric Fc region comprised of Fc domains (or Fc moieties) genetically linked within a single polypeptide chain (i.e., encoded in a single contiguous genetic sequence).” (Miller et al., page 12, para. 2).
Zhou confirms this motif as half-life extending domain:
“The strategy of engineering Fc conjugates takes advantage of this characteristic to prolong the plasma half-life of protein drugs.” (Zhou et al., page 24, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to attach the HLE domain to the C-terminal of the construct of Miller, Xiong, Wang, Seitz, Rudnick, and Deyev because in a single chain construct, said domain would have to be on the N-terminal side or C-terminal side and therefore a finite number of choices exist.
A person of ordinary skill in the art would art this domain to extend the half-life of the polypeptide of Miller, Xiong, Wang, Seitz, Rudnick, and Deyev as described by Zhou and have a reasonable expectation of success because Zhou discloses that Fc domains extend plasma half-life.
Consequently, claim 15 is obvious over Miller, Xiong, Wang, Seitz, and Rudnick as applied to claim 8 above, further in view of Zhou et al. and rejected.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)) and Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), and Rudnick et al. (Rudnick, et al. Cancer Biotherapy and Radiopharmaceuticals 24.2: 155-161 (2009)) and Zhou et al. (Zhou, Li, et al. "Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery." Biomaterials 117: 24-31. (2017)), as applied to claim 15 above, further in view of Deyev et al. (Deyev, et al. Bioessays 30.9: 904-918 (2008)), Kortt et al. (Kortt, et al. Biomolecular engineering 18.3: 95-108 (2001)), and Mullard et al. (Mullard, Asher. "Trispecific antibodies take to the clinic." Nat Rev Drug Discov 19.10: 657-8. (2020))
Regarding claim 17, claim 15 is obvious as described above.
Miller, Xiong, Wang, Seitz, Rudnick, and Zhou do not specifically disclose the construct of claim 17.
However, Kortt discloses constructs that target CD3 and another cellular target:
“Most recent examples have focused on T-cell recruitment; using one Fv module targeted to CD3 on T-cells and with a second Fv module targeted to a cancer marker such as EP-CAM, CEA or CD19, in one case via NIP-tagged ligands. There are also numerous diagnostic applications (immunoassays) that require bispecific cross-linking reagents.” (Kortt et al., page 105, col. 2, para. 3).
Furthermore, Mullard discloses an antibody construct that targets CD3 and two other cellular targets:
PNG
media_image2.png
216
752
media_image2.png
Greyscale
(Mullard et al., page 657, Table 1).
Mullard continues:
“ Naive T cells need at least two signalling events to become activated, and so Sanofi’s approach was to design an antibody that would bind both CD3 and CD28 on the T cell, providing activating and co-stimulatory signalling at the same time. CD38, for its part, is highly expressed on multiple myeloma cells.” (Mullard et al., page 657, col. 3, para. 4).
Deyev discloses the usage of multimers for additional avidity:
“The most-important advantage of multivalent mini-antibodies over monovalent ones is the enhancement of specific binding avidity towards antigens. Theoretically, the resulting binding constant (avidity) can approach the product of original binding constants (affinities).” (Deyev et al., page 914, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to generate the construct of claim 17 by arranging the polypeptides of Miller, Xiong, Wang, Seitz, Zhou and Rudnick to result in polypeptide with two CD3 binding domains as disclosed by Deyev for avidity purposes and binding motifs for two other cell surface targets as disclosed by Mullard. Furthermore, a finite number of ways to arrange these motifs exists and therefore the claimed arrangement is obvious.
A person of ordinary skill in the art would be motivated to create this construct to get the avidity effects of Deyev for CD3 binding and the co-stimulatory effects described by Mullard.
A person of ordinary skill in the art would have a reasonable expectation of success because the avidity effects are known from Deyev and Mullard already discloses a trivalent CD3 therapeutic.
Consequently, claim 17 is obvious over Miller, Xiong, Wang, Seitz, Rudnick, and Zhou as applied to claim 15, further in view of Kortt, Mullard, and Deyev and rejected.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. WO2012088461, published 6/28/2012 in view of Xiong et al. WO2019199685, published 10/17/2019, Wang et al. (Wang, et al. Analytical Chemistry 78.4: 997-1004. (2006)), Seitz et al. (Seitz, et al. ChemBioChem 1.4: 214-246 (2000)), and Zhou et al. (Zhou, Li, et al. "Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery." Biomaterials 117: 24-31. (2017)) as applied to claim 14 above, further in view of Boone et al. WO 2004026329, published 4/1/2004.
Regarding claim 19, claim 14 is obvious as described above. Miller, Xiong, Wang, Seitz, and Zhou do not specifically disclose the linker G4.
However, Boone et al. discloses the following linkers for usage with Fc constructs:
“Linkers . Any "linker" group is optional. When present, its chemical structure is not critical, since it serves primarily as a spacer. The linker is preferably made up of amino acids linked together by peptide bonds. Thus, in preferred embodiments, the linker is made up of from 1 to 20 amino acids linked by peptide bonds, wherein the amino acids are selected from the twenty naturally occurring amino acids. Some of these amino acids may be glycosylated, as will be understood by those skilled in the art. In a more preferred embodiment, the 1 to 20 amino acids are selected from glycine, alanine, proline, asparagine, glutamine, and lysine. Even more preferably, a linker is made up of a majority of amino acids that are sterically unhindered, such as glycine and alanine. Thus, preferred linkers are polyglycines, particularly (Gly) 4 (SEQ ID NO: 284), (Gly)5 (SEQ ID NO: 285), (Gly)7 (SEQ ID NO: 286), as well as poly (Gly-Ala) and polyalanines . Other specific examples of linkers are: (Gly)3Lys(Gly)4 (SEQ ID NO: 123); (Gly)3AsnGlySer(Gly)2 (SEQ ID NO : 124); (Gly)3Cys(Gly)4 (SEQ ID NO: 125); and GlyProAsnGlyGly (SEQ ID NO : 126).” (Boone et al., page 40, para. 3).
“133. The composition of matter of Claim 132 comprising an amino acid sequence of the formula:
F-L-P wherein :
F is an Fc domain; L is a linker; and P is selected from the group consisting of: i. SEQ ID NOS: 8, 10, 23, and 24; ii. an analog of (i) ; and iii. a derivative of (i) or (ii) , and wherein said composition of matter is capable of modulating NGF activity.” (Boone et al., claim 133).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use any of the linkers, including GGGG, recited by Boone to connect the HLE domain (Fc domain) of the present invention to the rest of the polypeptide because Boone is also connecting an Fc domain to a polypeptide.
A person of ordinary skill in the art would use a linker to connect an HLE domain to the rest of the polypeptide so it can function as an HLE domain and have a reasonable expectation of success because Boone shows that these linkers can be used to link Fc domains to polypeptides.
Consequently, claim 19 is obvious over Miller, Xiong, Wang, Seitz, and Zhou as applied to claim 14, further in view of Boone et al. and rejected.
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.
To prevent truly excessive office action length, in this case, non-statutory double patenting will be addressed in a tabular format. The following patents and applications provide disclosures that result in non-statutory double patenting rejections:
Application/Patent
Linker Present
Claims
17/616,575
(GGGGQ)3-6
1,8-13,17-21, 24-31,33-34
18/251,196
(GGGGX)1-20
1-4,6,11,13-22(19),26-27,29-30,32-51,55,58,60
18/566,228
(GGGGQ)6-8
1-15 (8),17-18,38-44,58
18/862,282
(GGGGX)1-20 (Q)
1,3,5-6,9,13-16,20,31,39,41,43-44,49,51-52
18/251,120
(G4Q)1-?
5,16-25,27-29
16/689,793
(G4Q)
1-3,5-9,11,17-18,21,24-44 (28)
US 12,612,463
(G4Q)2-4
1-20(10)
19/421,479
(G4Q)2-4
1-30(10)
17/778,361
(G4Q)3-6
1-10(4),12,14-31
18/252,442
(G4Q)7
1-31(1)
18/035,054
G4Q
1,3-5,14-23,26,29,32-33,36-40 (33)
The claim in which the relevant linker appears is bolded for reference. An exemplary rejection is below. Rejections based off the other applications would be provisional but conceptually very similar.
Claims 1-5, 7, 13, 22-24, 26, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,612,463.
Regarding claim 1, the ‘463 patent discloses the following in claims 1 and 10:
“1. A multispecific antibody construct comprising:
(i) a first antibody comprising two light chains and two heavy chains, wherein
(a) the light chains comprise a first variable region (VL1) and a light chain constant region (CL);
(b) the heavy chains comprise a first heavy variable region (VH1) and CH1, hinge, CH2, and CH3 regions; and
(c) the heavy chains comprise at least one amino acid substitution that results in a reduced binding affinity of the heavy chain for Fc gamma RI receptor as compared with an unsubstituted heavy chain; and
(ii) a scFv comprising a second light chain variable region (VL2) and a second heavy chain variable region (VH2) of a second antibody, wherein the VL2 and the VH2 are connected via a first peptide linker,
wherein the scFv is fused at its amino terminus to the carboxyl terminus of each of the heavy chains through a second peptide linker such that a heavy chain fusion protein is formed; and wherein the first antibody specifically binds to and agonizes human CD40 comprising the amino acid sequence of SEQ ID NO:1, and the scFv specifically binds to human mesothelin (MSLN) comprising the amino acid sequence of SEQ ID NO:2; and…”
and
“10. The antibody construct of claim 1, wherein the first peptide linker is selected from the group consisting of SEQ ID NOs: 888-893.”
SEQ ID NO: 891 of the ‘463 patent is GGGGQGGGGQ.
Consequently, claim 1 is anticipated by the ‘463 patent and rejected.
Regarding claim 2, claim 1 is anticipated/obvious as described above. The (GGGGQ)2 linker of the ‘463 patent on claim 2 in the case wherein n=2.
Consequently, claim 2 is anticipated by the ‘463 patent and rejected.
Regarding claim 3, claim 1 is anticipated as described above. The linker of the ‘463 patent has X as Q.
Consequently, claim 3 is anticipated by the ‘463 patent and rejected.
Regarding claim 4, claim 1 is anticipated as described above. The linker of the ‘463 patent is (G4Q)2.
Consequently, claim 4 is anticipated by the ‘463 patent and rejected.
Regarding claim 5, claim 1 is anticipated as described above. The “first antibody” referenced by claim 1 of the ‘463 patent above constitutes one further binding domain.
Consequently, claim 5 is anticipated by the ‘463 patent and rejected.
Regarding claim 7, claim 5 is anticipated as described above. Claim 1 of the ‘463 application states: “…the first antibody specifically binds to and agonizes human CD40 comprising the amino acid sequence of SEQ ID NO:1, and the scFv specifically binds to human mesothelin (MSLN) comprising the amino acid sequence of SEQ ID NO:2…”
Consequently, claim 7 is anticipated by the ‘463 patent and rejected.
Regarding claim 13, claim 1 is anticipated as described above. The construct of the ‘463 patent includes a CH2 domain, a CH3 domain, and a hinge, which constitutes a half-life extending domain.
Consequently, claim 13 is anticipated by the ‘463 patent and rejected.
Claim 22 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,612,463 in view of Grantham et al. (Grantham, R., et al. "Codon catalog usage and the genome hypothesis." Nucleic acids research 8.1: 197-197 (1980)).
Regarding claim 22, claim 1 is rejected as described above. The ‘463 patent does not specifically disclose a nucleic acid.
However, Grantham discloses a codon table for nucleic acids. (Grantham et al., page 54, Fig. 1).
However, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the codon table of Grantham to create the desired nucleic acid because the codon table shows how nucleic acids get translated into amino acids.
Consequently, claim 22 is obvious over the ‘463 patent in view of Grantham and rejected.
Claims 23 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,612,463 in view of Grantham et al. (Grantham, R., et al. "Codon catalog usage and the genome hypothesis." Nucleic acids research 8.1: 197-197 (1980)) as applied to claim 22, further in view of van der Velden et al. (van der Velden, Alike W., Harry O. Voorma, and Adri AM Thomas. "Vector design for optimal protein expression." Biotechniques 31.3: 572-582 (2001)).
Regarding claim 23, claim 22 is obvious as described above. The ‘463 patent and Grantham do not specifically disclose a vector.
However, van der Velden discloses the creation of expression vectors in host cells: “We have discussed the presently known aspects in a mature mRNA important for efficient translation and mRNA stability. Literature and experimental data were predominantly based
on transfection of Cos-1 cells and injection of Xenopusembryos. Several literature examples can be found in which cell-specific translation was observed with picornaviral IRESs (3) and cellular
IRESs, as described for c-myc (36) and FGF-2 (5). This cell specificity must reside in the untranslated regions, as reporter genes were used in these studies. Nonetheless, we assume that the general ideas about constructing an expression vector are also applicable for other cell lines and embryos. In Figure 5, we summarize the mentioned suggestions by presenting the construction of a stable mRNA with high translational potential.” (van der Velden et al., page 580, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to transform the nucleic acid of the ‘463 patent and Grantham using the method of van der Velden to arrive at the claimed invention because van der Velden discloses using RNA to create vectors for expression of proteins.
Consequently, claim 23 is obvious over the ‘463 patent in view of Grantham as applied to claim 22 above, further in view of van der Velden and rejected.
Regarding claim 24, claim 23 is obvious as described above. The ‘463 patent and Grantham do not specifically disclose a host cell.
However, van der Velden discloses the creation of expression vectors in host cells: “We have discussed the presently known aspects in a mature mRNA important for efficient translation and mRNA stability. Literature and experimental data were predominantly based
on transfection of Cos-1 cells and injection of Xenopusembryos. Several literature examples can be found in which cell-specific translation was observed with picornaviral IRESs (3) and cellular
IRESs, as described for c-myc (36) and FGF-2 (5). This cell specificity must reside in the untranslated regions, as reporter genes were used in these studies. Nonetheless, we assume that the general ideas about constructing an expression vector are also applicable for other cell lines and embryos. In Figure 5, we summarize the mentioned suggestions by presenting the construction of a stable mRNA with high translational potential.” (van der Velden et al., page 580, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to transform the nucleic acid of the ‘463 patent and Grantham using the method of van der Velden to arrive at the claimed invention because van der Velden discloses using RNA to create vectors for expression of proteins in host cells.
Consequently, claim 24 is obvious over the ‘463 patent in view of Grantham as applied to claim 22 above, further in view of van der Velden and rejected.
Regarding claim 26, claim 1 is anticipated as described above. Claim 26 recites a composition comprising the polypeptide of claim 1 with no other limitations. Because claim 1 is anticipated, claim 26 is as well.
Consequently, claim 26 is anticipated by the ‘463 patent and rejected.
Regarding claim 29, claim 1 is anticipated as described above. MPEP 2112.01(III) states: “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004)”.
Consequently, claim 29 is anticipated by the ‘463 patent and rejected.
Free of the Prior Art
Claims 12 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claims 12 and 18, no reasonable teaching, suggestion, or motivation for utilizing the particular sequence of SGGGGQ as a peptide linker is present.
The closest available prior art is found in Xiong et al. WO2019199685A1 in claim 7:
“7. The fusion protein of any one of claims 1-6, wherein the linker is a (G4S)n or (G4Q)n linker, wherein n is greater than 0.”
In the case where n=1, this yields GGGGQ, but the leading serine is missing. There is no reason present in the prior art to add a serine in that position.
Conclusion
No claim is allowed.
Claims 1-11, 13-17, 19-24, 26, and 29 are rejected.
Claims 1, 4, 11, 12, and 18 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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