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 Group I (claims 1-18) and the below-listed species in the reply filed on 06/18/2026 is acknowledged.
Elected Species (Formulas (I) and (II)):
X is Ph-S;
La is ethylene;
Lb is m-phenylene;
W is an oxygen atom; and
Y is an affinity peptide (A) of SEQ ID NO: 2.
Applicant is advised that while the currently elected species is rendered obvious over the cited prior art references (see the 103 section below), the cited prior art references further disclose species that anticipate the genus as instantly claimed (i.e., the art anticipates non-elected species). Some exemplary, non-elected species disclosed by the cited prior art references that anticipate the instantly claimed genus are provided below.
US 2021/0139549 A1: See Table 9 Examples 104-105 (Pages 202-204).
Claim Status
Claims 1-46 are pending in the instant application.
Claims 19-46 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 06/18/2026, there being no allowable generic or linking claim.
Claims 1-18 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, it is noted that no English translation of the foreign priority document has been received, and as such the claim to foreign priority has not been perfected.
Claims 1-18 have an effective filing date of January 17, 2022 corresponding to PCT/JP22/01358, because the claim to foreign priority has not been perfected.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/18/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Figures 7-8, 13-14, 18-27, and 31-34 comprise labels/text that are blurry and difficult to read. See, for example, the x-axis labels of the recited Figures. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at Page 22. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to for the use of the terms, for example, Xcalibur, Orbitrap Fusion, and BioPharma Finder, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
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
Claim 7 is objected to because of the following informalities: the claim lists limitations using (A), (B) ... (E), (f); the list should be amended such that the list is formatted consistently using (A), (B) ... (E), and (F) or (a), (b) ... (e), and (f). Appropriate correction is required.
Claim Interpretation
With regard to the sequence limitations of claims 6-7, the following are noted:
The recitation of, for example, “comprising the amino acid sequence of CQRRFYEALHDPNLNEEQRNARIRSIKDDC (SEQ ID NO :1) is interpreted as closed sequence language, wherein for a reference sequence to meet the limitation it must comprise and/or consist of full-length SEQ ID NO: 1. This interpretation is pertinent to claims 6 and 7.
In claim 6, the recitation of “comprising an amino acid sequence comprising a mutation of 1 to 5 amino acid residues which is selected from the group consisting of substitution, insertion, deletion, and addition of amino acid residues in the amino acid sequence SEQ ID NO: 1, wherein the lysine residue at position 27 and the two cysteine residues at positions 1 and 30 are maintained” is being interpreted such that for a reference sequence to meet the limitation, the reference sequence may comprise, at most, 5 mutations relative to full-length SEQ ID NO: 1, so long as the lysine residue at position 27 and the two cysteine residues at positions 1 and 30 are maintained.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 and 8-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are generally drawn to (i) a compound or salt thereof represented by Formula (I) or (ii) an antibody intermediate comprising a structural unit represented by Formula (II); specifically it is noted that Formula (I) and Formula (II) comprise the element “Y”, which is an affinity peptide having a binding region to a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains.
Thus, the claims identify the affinity peptide by the function of binding a CH2 domain in an immunoglobulin. Claim 6 further limits the affinity peptide, wherein the affinity peptide may (i) comprise the amino acid sequence of SEQ ID NO: 1, or (ii) comprising an amino acid sequence comprising a mutation of 1 to 5 amino acid residues which is selected from the group consisting of substitution, insertion, deletion, and addition of amino acid residues in the amino acid sequence SEQ ID NO: 1, wherein the lysine residue at position 27 and the two cysteine residues at positions 1 and 30 are maintained. Thus, the claims encompass a vast genus of affinity peptides, and affinity peptide variants comprising variable sequences and that are required to bind a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains.
The instant specification describes a total of seven affinity peptides, adequately described by their full-length sequences, corresponding to SEQ ID NOs: 1-7 (see Pages 34-35).
Thus, the instant specification discloses seven structurally similar affinity peptides that all function to bind a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains. The specification fails to disclose any other affinity peptide sequence variants having from 1 to 5 mutations relative to full-length SEQ ID NO: 1 that retain the function of binding a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains.
To provide adequate written description and evidence of possession of the claimed affinity peptide genus, the instant specification can structurally describe representative affinity peptide variants that function to bind a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of the affinity peptide function, to binding a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains. The instant specification fails to describe structural features common to the members of the affinity peptide genus, which features constitute a substantial portion of the genus, because the instant specification fails to disclose representative affinity peptide variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the affinity peptide does, rather than what it is. Other than for the seven affinity peptides disclosed at Pages 34-35, the specification fails to provide the structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of affinity peptide sequence variants for the genus of affinity peptides that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed compound or salt thereof.
The claims broadly encompass any sequence variant comprising as many as 5 amino acid mutations relative to SEQ ID NO: 1 that functions to bind a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains. Applicants have not established any reasonable structure-function correlation with regards to the animo acid positions in the affinity peptides that can be altered and still maintain the recited binding function. The skilled artisan would not have been in possession of the vast repertoire of affinity peptides encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single affinity peptide comprising SEQ ID NOs: 1 to the structure of any variants required to bind a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for affinity peptides that bind a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The BCMA antigen provides no information about the structure of an antibody that binds to it.
Given the lack of representative examples to support the full scope of the claimed affinity peptide and variants thereof, and lack of reasonable structure-function correlation with regards to the unknown variable amino acid residues in the affinity peptide that provide the function of binding a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of affinity peptide variants that bind a CH2 domain in an immunoglobulin unit containing two heavy chains and two light chains and comprise a sequence that is mutated relative to SEQ ID NO: 1 required to practice the claimed invention.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 8 fails to further limit the subject matter of the claim(s) from which it depends; claim 8 recited the compound or salt thereof of claim 6, wherein the N-terminal and C-terminal amino acid residues in the affinity peptide may be protected, and the two thiol groups in side chains of the two cysteine residues in the affinity peptide may be linked by a disulfide bond or via a linker (emphasis added). The recitation of “may be” indicates that the limitations either are or are not required. Thus, if not required, claim 8 fails to further limit the subject matter of the claim(s) from which it depends. For the purpose of applying art, claim 8 is being interpreted such that the N-terminal and C-terminal amino acid residues in the affinity peptide are protected, and the two thiol groups in side chains of the two cysteine residues in the affinity peptide are linked by a disulfide bond or via a linker. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 12,024,549 (equivalent to WO 2018/199337 A1, foreign citation number 16 on 07/18/2023 IDS; herein after referred to as “Yamada”).
Yamada teaches a compound comprising an affinity substance to a soluble protein, a cleavable portion, and a reactive group represented by Formula (I): A-L-B-R, or a salt thereof, wherein A is an affinity substance to a soluble protein, L is a cleavable linker which is a divalent group comprising a cleavable portion, B is (a) a divalent group comprising a bioorthogonal
functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody (Column 67, Lines 44-57). A is an affinity substance to a soluble protein, the affinity substance is a substance having binding ability through a noncovalent bond to a target (Column 67, Lines 65-67); the affinity substance used in the present invention targets
a soluble protein, also called a secretory protein, wherein examples of such a soluble protein include antibodies (Column 68, Lines 1-3). The affinity substance to the soluble protein may be an affinity peptide comprising an amino acid sequence (a) in which any amino acid residue is substituted with one amino acid residue selected from the group consisting of a lysine residue, an aspartic acid residue, a glutamic acid residue, a 2-amino suberic acid residue, and a diaminopropionic acid residue (an amino acid residue which can be easily modified with a cross-linking agent) (preferably a lysine residue, an aspartic acid residue, or a glutamic acid residue, and more preferably a lysine residue) in the amino acid sequence of SEQ ID NO: 92, and (b) having 90% or more identity to the amino acid sequence of SEQ ID NO: 92 (Column 87, Lines 50-62). The affinity peptide can have affinity to human IgG (e.g., human IgG1) and the affinity peptide may form a cyclic peptide through a disulfide bond by the cysteine residues at position 5 and position 34 (Column 88, Lines 18-21). The amino acid sequence having the characteristics of (a) and (b) may be more preferably an amino acid sequence selected from the group comprising, for example, SEQ ID NO: 68. It is specifically noted that Yamada SEQ ID NO: 68 is an exact match to instant SEQ ID NO: 2. When the affinity substance is a peptide, the amino group and the carboxy group at the ends of the peptide may be protected by protecting groups and when the affinity substance is a peptide comprising two or more cysteine residues, a disulfide bond may be formed through thiol residues at the side chains of the cysteine residues (Column 90, Lines 9-
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30). The cleavable portion may correspond to the structure below:
wherein a wavy line orthogonal to a bond indicates a cleavage site and wherein the symbol of "white circle" indicates a bond to A (or La described below), and a symbol of "black circle"
indicates a bond to B (or Lb described below); when a chemical structure is asymmetrical with respect to the cleavage site, a symbol of "black circle" may indicate a bond to A (or La described below), and a symbol of "white circle" may indicate a bond to B (or Lb described below) (Columns 92-94). In a specific embodiment, the cleavable linker (L) may be
represented by: (i) La-C-Lb, (ii) La-C, or (iii) C-Lb wherein La and Lb are each a divalent group and C is a cleavable portion (Column 97, Lines 36-47). Exemplary divalent groups are provided, and include a divalent hydrocarbon group optionally having a substituent, a divalent heterocyclic group optionally having a substituent, -C(=O)-, -NRa- (Ra indicates a hydrogen atom or a substituent), -O-, -S-, -C(=S)-, and a group consisting of a combination of two or more (e.g., two to eight, preferably two to six, and more preferably two to four) of these (Column 97, Lines 48-55). The divalent hydrocarbon group is a linear, branched, or cyclic divalent hydrocarbon group and preferably a linear or branched divalent hydrocarbon group including alkylene, alkenylene, alkynylene, and arylene (Column 97, Lines 56-60); an arylene is preferably C6-24 arylene, more preferably C6-18 arylene, even more preferably C6-14 arylene, and still even more preferably C6-10 arylene, wherein examples of arylene include phenylene, naphthylene, and anthracenylene (Column 98, Lines 18-23). It is acknowledged that Yamada does not explicitly designate that a phenylene group (or any other cyclic ring) as a divalent group is m-phenylene, however Yamada suggests that ortho, meta, and para attachments are permissible. Specifically, Yamada teaches that the length of the main chain linking A and R can also be defined as the number of atoms forming the main chain (except hydrogen atoms and substituents), wherein the number of atoms of the main chain may be e.g., 20 (about 30 angstroms) or smaller, preferably 16 (about 23 angstroms) or smaller, and more preferably 12 (about 16.5 angstroms) or smaller (e.g., 4 to 20, preferably 6 to 16, and more preferably 8 to 12) (Column 115, Lines 19-30). Yamada further teaches that when the main chain is a structure comprising a cyclic structure, the number of atoms of the main chain in such a case can be determined by counting the number of atoms of the shortest route connecting two bonds in the cyclic structure in addition to the number of atoms in a chain structure comprising no divalent cyclic structure in the main chain:
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wherein in the case of (a), (b), and (c), the shortest route, and thus the number of atoms in the divalent cyclic structure counted as the number of atoms of the main chain, are two, three, and four, respectively (Columns 115-116). Thus, Yamada suggests that ortho, meta, and para cyclic groups are permissible, so long as their inclusion meets the main chain limitations. Thus, from the above, the invention of Yamada reads on, for example:
wherein -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups) wherein the S atom is connected to B of Formula (I) and m-phenylene-(C=O) connects to A of Formula (I), A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. In a specific embodiment, B may be represented by the following Formula (B-1):
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wherein Y is -NH-, -O-, -CH2-, or Formula (B-2) (see Column 106), further wherein Z is an oxygen atom, a sulfur atom, or a hydrogen atom (when Z is a hydrogen atom, -C(=Z)- indicates
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-CH2-), and a symbol of "white circle" in Formula (B-1) indicates a bond to an L-side portion, and a symbol of "black circle" indicates a bond to an R-side portion (Column 106, Lines 16-54). Thus, in view of the above, Yamada further reads on, for example:
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wherein -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. The reactive group (R) specific to a side chain of a lysine residue (of a soluble protein) may correspond to:
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wherein R5c are each a hydrogen or a substituent and j is any integer of 1 to 5 (Columns 110-111). Thus, in view of the above, Yamada further reads on, for example:
wherein Ph-S-(C=O)- corresponds to R, -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. The above structure thus reads on the instantly elected species of Formula (I) of instant claim 1, wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68) having a binding region to a CH2 domain in an immunoglobulin unit comprising two heavy chains and two light chains (i.e., a full-length, human IgG antibody) and wherein the total number of atoms constituting a main chain in La and a main chain in Lb is 5. Furthermore, Yamada provides exemplary embodiments that show the relationship between compound having affinity substance to soluble protein, cleavable portion, and reactive group, and soluble protein (antibody) having bioorthogonal functional groups which can be produced by using the same (see, for example, Table 3; Example 2-1 reproduced below):
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From the above example, the reactive group reacts with the NH2 group(s) of the antibody, wherein the reactive group is effectively a leaving group that serves to facilitate the formation of the amide bond, and the cleavage of the cleavable portion in L detaches the affinity peptide leaving the HS-CH2-CH2-(C=O) attached to the antibody. Thus, one of ordinary skill in the art
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would recognize that an intermediate associated with Example 2-1 is as shown below:
Thus, with regard to the instantly elected species that Yamada reads on, it is noted that the intermediate associated with such a compound when reacted with an antibody would be as follows:
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wherein A is an affinity substance, such as Yamada SEQ ID NO: 68. It is further noted that Yamada teaches that chemical conjugation by affinity peptide (C-CAP) has succeeded in
regioselectively modifying an antibody Fc region with practically favorable results [reaction time: 30 minutes, yield: 70% (for DAR 1), and regioselectivity: 100%] have been determined. It has been demonstrated that control with a DAR of 2 can be achieved by adding about five
equivalents of the peptide reagent (Column 2, Lines 16-32). Furthermore, an Example of such a reaction using trastuzumab, a compound of the invention, and DM1 yielded an antibody-drug conjugate with an average drug-to-antibody ratio (DAR) of 2 (i.e., two compounds of the invention react with the antibody allowing for the attachment of two DM1 molecules) (Column 166, Example 9, Figure 23).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine the identified structural elements of Yamada to arrive at the instantly elected structure of Formula (I) and the antibody intermediate of Formula (II), wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68, instant SEQ ID NO: 2) having a binding region to a CH2 domain in an immunoglobulin unit comprising two heavy chains and two light chains (i.e., a full-length, human IgG antibody) and wherein the total number of atoms constituting a main chain in La and a main chain in Lb is 5. One would have been motivated to combine said structural elements as Yamada explicitly suggests their combination, wherein the resultant structure would reasonably be expected to be useful in regioselectively modifying an antibody, as suggested by and exemplified by Yamada.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 12,428,450 (equivalent to WO 2020/090979 A1; herein after referred to as “Matsuda”) in view of US 12,024,549 (equivalent to WO 2018/199337 A1, foreign citation number 16 on 07/18/2023 IDS; herein after referred to as “Yamada”).
Matsuda teaches a compound comprising an affinity substance to a soluble protein, a cleavable portion, and a reactive group represented by Formula (I): A-L-B-R, or a salt thereof, wherein A is an affinity substance to an antibody, L is a cleavable linker which is a divalent group comprising a cleavable portion, B is (a) a divalent group comprising a bioorthogonal
functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody (Column 35, Lines 29-47). A is an affinity substance to a soluble protein, the affinity substance is a substance having binding ability through a noncovalent bond to an antibody (Column 35, Lines 49-51). The affinity substance to an antibody is an affinity substance to a monoclonal antibody; more preferred is an affinity substance to a chimeric antibody, a humanized antibody, or a human antibody (e.g., IgG including IgG1, IgG2, IgG3, and IgG4) as a full-length monoclonal antibody (Column 40, Lines 23-33). In a preferred embodiment, the antibody-affinity polypeptide is a variant of a fragment of protein A having affinity to an antibody with a glutamine residue (Q) or QET added to an N-terminal; examples of such a variant include, for example, SEQ ID NO: 23 (Column 47, Lines 31-67). It is specifically noted that Matsuda SEQ ID NO: 23 is an exact match for instant SEQ ID NO: 2. At least two cysteine residues separated from each other in each amino acid sequence of the affinity polypeptide can form a cyclic peptide through a disulfide bond (Column 48, Lines 11-13). A terminal amino group and a carboxy group at the ends of the peptide may be protected by protecting groups (Column 48, Lines 55-67). The cleavable portion may correspond to the
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structure below:
wherein a wavy line orthogonal to a bond indicates a cleavage site and wherein the symbol of "white circle" indicates a bond to A (or La described below), and a symbol of "black circle"
indicates a bond to B (or Lb described below); when a chemical structure is asymmetrical with respect to the cleavage site, a symbol of "black circle" may indicate a bond to A ( or La described below), and a symbol of "white circle" may indicate a bond to B (or Lb described below) (Columns 51-52). In a specific embodiment, the cleavable linker (L) may be
represented by: (i) La-C-Lb, (ii) La-C, or (iii) C-Lb wherein La and Lb are each a divalent group and C is a cleavable portion (Column 54, Lines 55-65). Exemplary divalent groups are provided, and include a divalent hydrocarbon group optionally having a substituent, a divalent heterocyclic group optionally having a substituent, -C(=O)-, -NRa- (Ra indicates a hydrogen atom or a substituent), -O-, -S-, -C(=S)-, and a group consisting of a combination of two or more (e.g., two to eight, preferably two to six, and more preferably two to four) of these (Column 55, Lines 66-67 and Column 55, Lines 1-6). The divalent hydrocarbon group is a linear, branched, or cyclic divalent hydrocarbon group and preferably a linear or branched divalent hydrocarbon group including alkylene, alkenylene, alkynylene, and arylene (Column 55, Lines 7-11); an arylene is preferably C6-24 arylene, more preferably C6-18 arylene, even more preferably C6-14 arylene, and still even more preferably C6-10 arylene, wherein examples of arylene include phenylene, naphthylene, and anthracenylene (Column 55, Lines 35-40). It is acknowledged that Matsuda does not explicitly designate that a phenylene group (or any other cyclic ring) as a divalent group is m-phenylene, however Matsuda suggests that ortho, meta, and para attachments are permissible. Specifically, Matsuda teaches that the length of the main chain linking A and R can also be defined as the number of atoms forming the main chain (except hydrogen atoms and substituents), wherein the number of atoms of the main chain may be e.g., 20 (about 30 angstroms) or smaller, preferably 16 (about 23 angstroms) or smaller, and more preferably 12 (about 16.5 angstroms) or smaller (e.g., 4 to 20, preferably 6 to 16, and more preferably 8 to 12) (Column 72, Lines 37-48). Matsuda further teaches that when the main chain is a structure comprising a cyclic structure, the number of atoms of the main chain in such a case can be determined by counting the number of atoms of the shortest route connecting two bonds in the cyclic structure in addition to the number of atoms in a chain structure comprising no divalent
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cyclic structure in the main chain:
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wherein in the case of (a), (b), and (c), the shortest route, and thus the number of atoms in the divalent cyclic structure counted as the number of atoms of the main chain, are two, three, and four, respectively (Columns 72-73). Thus, Matsuda suggests that ortho, meta, and para cyclic groups are permissible, so long as their inclusion meets the main chain limitations. Thus, from the above, the invention of Matsuda reads on, for example:
wherein -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups) wherein the S atom is connected to B of Formula (I) and m-phenylene-(C=O) connects to A of Formula (I), A corresponds to the affinity substance which, as provided above, may be Matsuda SEQ ID NO: 23. In a specific
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embodiment, B may be represented by the following Formula (B-1):
wherein Y is -NH-, -O-, -CH2-, or Formula (B-2) (see Column 63), further wherein Z is an oxygen atom, a sulfur atom, or a hydrogen atom (when Z is a hydrogen atom, -C(=Z)- indicates
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-CH2-), and a symbol of "white circle" in Formula (B-1) indicates a bond to an L-side portion, and a symbol of "black circle" indicates a bond to an R-side portion (Columns 63-64). Thus, in view of the above, Matsuda further reads on, for example:
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wherein -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Matsuda SEQ ID NO: 23. The reactive group (R) specific to a side chain of a lysine residue (of a soluble protein) may correspond to:
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wherein R5b are each an electron withdrawing group and j is any integer of 1 to 5 (Columns 110-111). Thus, in view of the above, Matsuda further reads on, for example:
wherein Ph((R5b)j)-S-(C=O)- corresponds to R, -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Matsuda SEQ ID NO: 23.
However, Matsuda does not teach an R group that is Ph-S, absent an electron withdrawing group. This deficiency is remedied by Yamada.
Yamada teaches a compound comprising an affinity substance to a soluble protein, a cleavable portion, and a reactive group represented by Formula (I): A-L-B-R, or a salt thereof, wherein A is an affinity substance to a soluble protein, L is a cleavable linker which is a divalent group comprising a cleavable portion, B is (a) a divalent group comprising a bioorthogonal
functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody (Column 67, Lines 44-57). A is an affinity substance to a soluble protein, the affinity substance is a substance having binding ability through a noncovalent bond to a target (Column 67, Lines 65-67); the affinity substance used in the present invention targets
a soluble protein, also called a secretory protein, wherein examples of such a soluble protein include antibodies (Column 68, Lines 1-3). The affinity peptide can have affinity to human IgG (e.g., human IgG1) and the affinity peptide may form a cyclic peptide through a disulfide bond by the cysteine residues at position 5 and position 34 (Column 88, Lines 18-21). The amino acid sequence having the characteristics of (a) and (b) may be more preferably an amino acid sequence selected from the group comprising, for example, SEQ ID NO: 68. It is specifically noted that Yamada SEQ ID NO: 68 is an exact match to instant SEQ ID NO: 2. When the affinity substance is a peptide, the amino group and the carboxy group at the ends of the peptide may be protected by protecting groups and when the affinity substance is a peptide comprising two or more cysteine residues, a disulfide bond may be formed through thiol residues at the side chains of the cysteine residues (Column 90, Lines 9-30). The cleavable portion may correspond
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to the structure below:
wherein a wavy line orthogonal to a bond indicates a cleavage site and wherein the symbol of "white circle" indicates a bond to A (or La described below), and a symbol of "black circle"
indicates a bond to B (or Lb described below); when a chemical structure is asymmetrical with respect to the cleavage site, a symbol of "black circle" may indicate a bond to A ( or La described below), and a symbol of "white circle" may indicate a bond to B (or Lb described below) (Columns 92-94). In a specific embodiment, the cleavable linker (L) may be
represented by: (i) La-C-Lb, (ii) La-C, or (iii) C-Lb wherein La and Lb are each a divalent group and C is a cleavable portion (Column 97, Lines 36-47). Exemplary divalent groups are provided, and include a divalent hydrocarbon group optionally having a substituent, a divalent heterocyclic group optionally having a substituent, -C(=O)-, -NRa- (Ra indicates a hydrogen atom or a substituent), -O-, -S-, -C(=S)-, and a group consisting of a combination of two or more (e.g., two to eight, preferably two to six, and more preferably two to four) of these (Column 97, Lines 48-55). The divalent hydrocarbon group is a linear, branched, or cyclic divalent hydrocarbon group and preferably a linear or branched divalent hydrocarbon group including alkylene, alkenylene, alkynylene, and arylene (Column 97, Lines 56-60); an arylene is preferably C6-24 arylene, more preferably C6-18 arylene, even more preferably C6-14 arylene, and still even more preferably C6-10 arylene, wherein examples of arylene include phenylene, naphthylene, and anthracenylene (Column 98, Lines 18-23). It is acknowledged that Yamada does not explicitly designate that a phenylene group (or any other cyclic ring) as a divalent group is m-phenylene, however Yamada suggests that ortho, meta, and para attachments are permissible. Specifically, Yamada teaches that the length of the main chain linking A and R can also be defined as the number of atoms forming the main chain (except hydrogen atoms and substituents), wherein the number of atoms of the main chain may be e.g., 20 (about 30 angstroms) or smaller, preferably 16 (about 23 angstroms) or smaller, and more preferably 12 (about 16.5 angstroms) or smaller (e.g., 4 to 20, preferably 6 to 16, and more preferably 8 to 12) (Column 115, Lines 19-30). Yamada further teaches that when the main chain is a structure comprising a cyclic structure, the number of atoms of the main chain in such a case can be determined by counting the number of atoms of the shortest route connecting two bonds in the cyclic structure in addition to the number of atoms
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in a chain structure comprising no divalent cyclic structure in the main chain:
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wherein in the case of (a), (b), and (c), the shortest route, and thus the number of atoms in the divalent cyclic structure counted as the number of atoms of the main chain, are two, three, and four, respectively (Columns 115-116). Thus, Yamada suggests that ortho, meta, and para cyclic groups are permissible, so long as their inclusion meets the main chain limitations. Thus, from the above, the invention of Yamada reads on, for example:
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wherein -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups) wherein the S atom is connected to B of Formula (I) and m-phenylene-(C=O) connects to A of Formula (I), A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. In a specific embodiment, B may be represented by the following Formula (B-1):
wherein Y is -NH-, -O-, -CH2-, or Formula (B-2) (see Column 106), further wherein Z is an oxygen atom, a sulfur atom, or a hydrogen atom (when Z is a hydrogen atom, -C(=Z)- indicates
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-CH2-), and a symbol of "white circle" in Formula (B-1) indicates a bond to an L-side portion, and a symbol of "black circle" indicates a bond to an R-side portion (Column 106, Lines 16-54). Thus, in view of the above, Yamada further reads on, for example:
wherein -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. The reactive group (R) specific to a side chain of a lysine residue (of a soluble protein) may correspond to:
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wherein R5c are each a hydrogen or a substituent and j is any integer of 1 to 5 (Columns 110-111). Thus, in view of the above, Yamada further reads on, for example:
wherein Ph-S-(C=O)- corresponds to R (and does not comprise an electron withdrawing group),
-CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. Furthermore, Yamada provides exemplary embodiments that show the relationship between compound having affinity substance to soluble protein, cleavable portion, and reactive group, and soluble protein (antibody) having bioorthogonal functional groups which can be produced by using the same (see, for example, Table 3; Example 2-1 reproduced below):
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From the above example, the reactive group reacts with the NH2 group(s) of the antibody, wherein the reactive group is effectively a leaving group that serves to facilitate the formation of the amide bond, and the cleavage of the cleavable portion in L detaches the affinity peptide leaving the HS-CH2-CH2-(C=O) attached to the antibody. Thus, one of ordinary skill in the art would recognize that an intermediate associated with Example 2-1 is as shown below:
Thus, with regard to the instantly elected species that Yamada reads on, it is noted that the intermediate associated with such a compound when reacted with an antibody would be as follows:
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wherein A is an affinity substance, such as Yamada SEQ ID NO: 68. It is further noted that Yamada teaches that chemical conjugation by affinity peptide (C-CAP) has succeeded in
regioselectively modifying an antibody Fc region with practically favorable results [reaction time: 30 minutes, yield: 70% (for DAR 1), and regioselectivity: 100%] have been determined. It has been demonstrated that control with a DAR of 2 can be achieved by adding about five
equivalents of the peptide reagent (Column 2, Lines 16-32). Furthermore, an Example of such a reaction using trastuzumab, a compound of the invention, and DM1 yielded an antibody-drug conjugate with an average drug-to-antibody ratio (DAR) of 2 (i.e., two compounds of the invention react with the antibody allowing for the attachment of two DM1 molecules) (Column 166, Example 9, Figure 23). Thus, Yamada teaches structures highly similar to Matsuda, comprising the same or similar components, wherein Yamada suggests the use of an R group that is Ph-S, which does not require an electron withdrawing group.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compound of Matsuda to arrive at the instantly elected structure of Formula (I) and the antibody intermediate of Formula (II), wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Matsuda SEQ ID NO: 23, Yamada SEQ ID NO: 68, instant SEQ ID NO: 2) having a binding region to a CH2 domain in an immunoglobulin unit comprising two heavy chains and two light chains (i.e., a full-length, human IgG antibody) and wherein the total number of atoms constituting a main chain in La and a main chain in Lb is 5. One would have been motivated to modify the R group of Matsuda to an R group of Yamada wherein the Ph-S group does not have an electron withdrawing group, and would have had a reasonable expectation of success, because Matsuda and Yamada both teach the same general compounds for regioselectively modifying soluble proteins/antibodies, wherein replacing the R group of Matsuda with the R group of Yamada would reasonably be expected to yield a compound capable of regioselectively modifying an antibody, as suggested by Yamada.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 2021/0139549 A1 (equivalent to WO 2019/240287 A1, foreign citation number 17 on 07/18/2023 IDS; herein after referred to as “Fuji”) in view of US 12,024,549 (equivalent to WO 2018/199337 A1, foreign citation number 16 on 07/18/2023 IDS; herein after referred to as “Yamada”).
Fuji teaches a compound comprising an affinity substance to a soluble protein, a cleavable portion, and a reactive group represented by Formula (I): A-L-B-R, or a salt thereof, wherein A is an affinity substance to an antibody, L is a cleavable linker which is a divalent group comprising a cleavable portion, B is (a) a divalent group comprising a bioorthogonal
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functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody (Paragraphs 0549-0554). A is an affinity substance to an antibody, the affinity substance is a substance having binding ability through a noncovalent bond to an antibody (Paragraph 0557). preferred embodiment, the affinity substance to an antibody is an affinity substance to a chimeric antibody, a humanized antibody, or a human antibody (e.g., IgG including IgG1, IgG2, IgG3, and IgG4) as a full-length monoclonal antibody (Paragraph 0604). The cleavable portion may correspond to the structure below:
wherein a wavy line orthogonal to a bond indicates a cleavage site and wherein the symbol of "white circle" indicates a bond to A (or La described below), and a symbol of "black circle"
indicates a bond to B (or Lb described below); when a chemical structure is asymmetrical with respect to the cleavage site, a symbol of "black circle" may indicate a bond to A ( or La described below), and a symbol of "white circle" may indicate a bond to B (or Lb described below) (Paragraphs 0682-0688). In a specific embodiment, the cleavable linker (L) may be
represented by: (i) La-C-Lb, (ii) La-C, or (iii) C-Lb wherein La and Lb are each a divalent group and C is a cleavable portion (Paragraphs 0702-0705). Exemplary divalent groups are provided, and include a divalent hydrocarbon group optionally having a substituent, a divalent heterocyclic group optionally having a substituent, -C(=O)-, -NRa- (Ra indicates a hydrogen atom or a substituent), -O-, -S-, -C(=S)-, and a group consisting of a combination of two or more (e.g., two to eight, preferably two to six, and more preferably two to four) of these (Paragraph 0706). The divalent hydrocarbon group is a linear, branched, or cyclic divalent hydrocarbon group and preferably a linear or branched divalent hydrocarbon group including alkylene, alkenylene, alkynylene, and arylene (Paragraph 0707); an arylene is preferably C6-24 arylene, more preferably C6-18 arylene, even more preferably C6-14 arylene, and still even more preferably C6-10 arylene, wherein examples of arylene include phenylene, naphthylene, and anthracenylene (Paragraph 0711). It is acknowledged that Fuji does not explicitly designate that a phenylene group (or any other cyclic ring) as a divalent group is m-phenylene, however Fuji suggests that ortho, meta, and para attachments are permissible. Specifically, Fuji teaches that the length of the main chain linking A and R can also be defined as the number of atoms forming the main chain (except hydrogen atoms and substituents), wherein the number of atoms of the main chain may be e.g., 20 (about 30 angstroms) or smaller, preferably 16 (about 23 angstroms) or smaller, and more preferably 12 (about 16.5 angstroms) or smaller (e.g., 4 to 20, preferably 6 to 16, and more preferably 8 to 12) (Paragraph 0872). Fuji further teaches that when the main chain is a structure comprising a cyclic structure, the number of atoms of the main chain in such a case can be determined by counting the number of atoms of the shortest route connecting two bonds in the cyclic structure in addition to the number of atoms in a chain structure comprising no divalent cyclic structure in the main chain:
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wherein in the case of (a), (b), and (c), the shortest route, and thus the number of atoms in the divalent cyclic structure counted as the number of atoms of the main chain, are two, three, and four, respectively (Paragraphs 0874-0877). Thus, Fuji suggests that ortho, meta, and para cyclic groups are permissible, so long as their inclusion meets the main chain limitations. Thus, from the above, the invention of Fuji reads on, for example:
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wherein -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups) wherein the S atom is connected to B of Formula (I) and m-phenylene-(C=O) connects to A of Formula (I), and A corresponds to the affinity substance. In a specific embodiment, B may be represented by the following Formula (B-1):
wherein Y is -NH-, -O-, -CH2-, or Formula (B-2) (see Page 40), further wherein Z is an oxygen atom, a sulfur atom, or a hydrogen atom (when Z is a hydrogen atom, -C(=Z)- indicates
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-CH2-), and a symbol of "white circle" in Formula (B-1) indicates a bond to an L-side portion, and a symbol of "black circle" indicates a bond to an R-side portion (Paragraphs 0797-0806). Thus, in view of the above, Fuji further reads on, for example:
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wherein -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance. The reactive group (R) specific to a side chain of a lysine residue (of a soluble protein) may correspond to:
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wherein R5c are each a hydrogen or a substituent and j is any integer of 1 to 5 (Paragraphs 0843-0847). Thus, in view of the above, Fuji further reads on, for example:
wherein Ph-S-(C=O)- corresponds to R, -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance.
However, Fuji does not teach or suggest an affinity substance that is a peptide comprising instant SEQ ID NO: 2. This deficiency is remedied by Yamada.
Yamada teaches a compound comprising an affinity substance to a soluble protein, a cleavable portion, and a reactive group represented by Formula (I): A-L-B-R, or a salt thereof, wherein A is an affinity substance to a soluble protein, L is a cleavable linker which is a divalent group comprising a cleavable portion, B is (a) a divalent group comprising a bioorthogonal
functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody (Column 67, Lines 44-57). A is an affinity substance to a soluble protein, the affinity substance is a substance having binding ability through a noncovalent bond to a target (Column 67, Lines 65-67); the affinity substance used in the present invention targets
a soluble protein, also called a secretory protein, wherein examples of such a soluble protein include antibodies (Column 68, Lines 1-3). The affinity peptide can have affinity to human IgG (e.g., human IgG1) and the affinity peptide may form a cyclic peptide through a disulfide bond by the cysteine residues at position 5 and position 34 (Column 88, Lines 18-21). The amino acid sequence having the characteristics of (a) and (b) may be more preferably an amino acid sequence selected from the group comprising, for example, SEQ ID NO: 68. It is specifically noted that Yamada SEQ ID NO: 68 is an exact match to instant SEQ ID NO: 2. When the affinity substance is a peptide, the amino group and the carboxy group at the ends of the peptide may be protected by protecting groups and when the affinity substance is a peptide comprising two or more cysteine residues, a disulfide bond may be formed through thiol residues at the side chains of the cysteine residues (Column 90, Lines 9-30). The cleavable portion may correspond
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to the structure below:
wherein a wavy line orthogonal to a bond indicates a cleavage site and wherein the symbol of "white circle" indicates a bond to A (or La described below), and a symbol of "black circle"
indicates a bond to B (or Lb described below); when a chemical structure is asymmetrical with respect to the cleavage site, a symbol of "black circle" may indicate a bond to A ( or La described below), and a symbol of "white circle" may indicate a bond to B (or Lb described below) (Columns 92-94). In a specific embodiment, the cleavable linker (L) may be
represented by: (i) La-C-Lb, (ii) La-C, or (iii) C-Lb wherein La and Lb are each a divalent group and C is a cleavable portion (Column 97, Lines 36-47). Exemplary divalent groups are provided, and include a divalent hydrocarbon group optionally having a substituent, a divalent heterocyclic group optionally having a substituent, -C(=O)-, -NRa- (Ra indicates a hydrogen atom or a substituent), -O-, -S-, -C(=S)-, and a group consisting of a combination of two or more (e.g., two to eight, preferably two to six, and more preferably two to four) of these (Column 97, Lines 48-55). The divalent hydrocarbon group is a linear, branched, or cyclic divalent hydrocarbon group and preferably a linear or branched divalent hydrocarbon group including alkylene, alkenylene, alkynylene, and arylene (Column 97, Lines 56-60); an arylene is preferably C6-24 arylene, more preferably C6-18 arylene, even more preferably C6-14 arylene, and still even more preferably C6-10 arylene, wherein examples of arylene include phenylene, naphthylene, and anthracenylene (Column 98, Lines 18-23). It is acknowledged that Yamada does not explicitly designate that a phenylene group (or any other cyclic ring) as a divalent group is m-phenylene, however Yamada suggests that ortho, meta, and para attachments are permissible. Specifically, Yamada teaches that the length of the main chain linking A and R can also be defined as the number of atoms forming the main chain (except hydrogen atoms and substituents), wherein the number of atoms of the main chain may be e.g., 20 (about 30 angstroms) or smaller, preferably 16 (about 23 angstroms) or smaller, and more preferably 12 (about 16.5 angstroms) or smaller (e.g., 4 to 20, preferably 6 to 16, and more preferably 8 to 12) (Column 115, Lines 19-30). Yamada further teaches that when the main chain is a structure comprising a cyclic structure, the number of atoms of the main chain in such a case can be determined by counting the number of atoms of the shortest route connecting two bonds in the cyclic structure in addition to the number of atoms
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in a chain structure comprising no divalent cyclic structure in the main chain:
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wherein in the case of (a), (b), and (c), the shortest route, and thus the number of atoms in the divalent cyclic structure counted as the number of atoms of the main chain, are two, three, and four, respectively (Columns 115-116). Thus, Yamada suggests that ortho, meta, and para cyclic groups are permissible, so long as their inclusion meets the main chain limitations. Thus, from the above, the invention of Yamada reads on, for example:
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wherein -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups) wherein the S atom is connected to B of Formula (I) and m-phenylene-(C=O) connects to A of Formula (I), A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. In a specific embodiment, B may be represented by the following Formula (B-1):
wherein Y is -NH-, -O-, -CH2-, or Formula (B-2) (see Column 106), further wherein Z is an oxygen atom, a sulfur atom, or a hydrogen atom (when Z is a hydrogen atom, -C(=Z)- indicates
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-CH2-), and a symbol of "white circle" in Formula (B-1) indicates a bond to an L-side portion, and a symbol of "black circle" indicates a bond to an R-side portion (Column 106, Lines 16-54). Thus, in view of the above, Yamada further reads on, for example:
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wherein -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. The reactive group (R) specific to a side chain of a lysine residue (of a soluble protein) may correspond to:
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wherein R5c are each a hydrogen or a substituent and j is any integer of 1 to 5 (Columns 110-111). Thus, in view of the above, Yamada further reads on, for example:
wherein Ph-S-(C=O)- corresponds to R (and does not comprise an electron withdrawing group),
-CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. Furthermore, Yamada provides exemplary embodiments that show the relationship between compound having affinity substance to soluble protein, cleavable portion, and reactive group, and soluble protein (antibody) having bioorthogonal functional groups which can be produced by using the same (see, for example, Table 3; Example 2-1 reproduced below):
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From the above example, the reactive group reacts with the NH2 group(s) of the antibody, wherein the reactive group is effectively a leaving group that serves to facilitate the formation of the amide bond, and the cleavage of the cleavable portion in L detaches the affinity peptide leaving the HS-CH2-CH2-(C=O) attached to the antibody. Thus, one of ordinary skill in the art would recognize that an intermediate associated with Example 2-1 is as shown below:
Thus, with regard to the instantly elected species that Yamada reads on, it is noted that the intermediate associated with such a compound when reacted with an antibody would be as follows:
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wherein A is an affinity substance, such as Yamada SEQ ID NO: 68. It is further noted that Yamada teaches that chemical conjugation by affinity peptide (C-CAP) has succeeded in
regioselectively modifying an antibody Fc region with practically favorable results [reaction time: 30 minutes, yield: 70% (for DAR 1), and regioselectivity: 100%] have been determined. It has been demonstrated that control with a DAR of 2 can be achieved by adding about five
equivalents of the peptide reagent (Column 2, Lines 16-32). Furthermore, an Example of such a reaction using trastuzumab, a compound of the invention, and DM1 yielded an antibody-drug conjugate with an average drug-to-antibody ratio (DAR) of 2 (i.e., two compounds of the invention react with the antibody allowing for the attachment of two DM1 molecules) (Column 166, Example 9, Figure 23). Thus, Yamada teaches structures highly similar to Fuji, comprising the same or similar components, wherein Yamada suggests the use of an affinity substance that is a peptide comprising SEQ ID NO: 68, which is an exact match for instant SEQ ID NO: 2.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compound of Fuji to arrive at the instantly elected structure of Formula (I) and the antibody intermediate of Formula (II), wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68, instant SEQ ID NO: 2) having a binding region to a CH2 domain in an immunoglobulin unit comprising two heavy chains and two light chains (i.e., a full-length, human IgG antibody) and wherein the total number of atoms constituting a main chain in La and a main chain in Lb is 5. One would have been motivated to modify the affinity peptide of Fuji to an affinity peptide of Yamada (e.g., Yamada SEQ ID NO: 68) wherein said modification would have had a reasonable expectation of success, because Fuji and Yamada both teach the same general compounds for regioselectively modifying soluble proteins/antibodies, wherein replacing the affinity peptide of Fuji with the affinity peptide of Yamada would reasonably be expected to yield a compound capable of regioselectively modifying an antibody, as suggested by Yamada.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5-6 of U.S. Patent No. 12,428,450 (reference patent) in view of US 12,024,549 (equivalent to WO 2018/199337 A1, foreign citation number 16 on 07/18/2023 IDS; herein after referred to as “Yamada”).
Claim 1 of the reference patent is generally drawn to a compound having an affinity substance to an antibody, a cleavable portion, and a reactive group, or a salt thereof, the compound being represented by Formula (I): A-L-B-R, wherein A is the affinity substance to an antibody, L is a cleavable linker that is a divalent group comprising the cleavable portion, B is (a) a divalent group comprising a bioorthogonal functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody. Claim 5 of the reference patent further limits the compound of claim 1, wherein the affinity substance to an antibody comprises an amino acid sequence selected from a group that comprises, for example, SEQ ID NO: 23. It is specifically noted that reference patent SEQ ID NO: 23 is an exact match to instant SEQ ID NO: 2. Claim 6 of the reference patent drawn to a reagent of regioselectively modifying an antibody, the reagent comprising a compound generally having an affinity substance to antibody, a cleavable portion, and a reactive group, or a salt thereof, the compound being represented by Formula (I): A-L-B-R, wherein A is an affinity substance to an antibody, L is a cleavable linker that is a divalent group comprising the cleavable portion, B is (a) a divalent group comprising a bioorthogonal functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody.
However the reference patent does not disclose any associated structures nor any specific affinity peptides corresponding to a compound of instant Formula (I) or an antibody intermediate of instant Formula (II). This deficiency is remedied by Yamada.
Yamada teaches a compound comprising an affinity substance to a soluble protein, a cleavable portion, and a reactive group represented by Formula (I): A-L-B-R, or a salt thereof, wherein A is an affinity substance to a soluble protein, L is a cleavable linker which is a divalent group comprising a cleavable portion, B is (a) a divalent group comprising a bioorthogonal
functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody (Column 67, Lines 44-57). A is an affinity substance to a soluble protein, the affinity substance is a substance having binding ability through a noncovalent bond to a target (Column 67, Lines 65-67); the affinity substance used in the present invention targets
a soluble protein, also called a secretory protein, wherein examples of such a soluble protein include antibodies (Column 68, Lines 1-3). The affinity substance to the soluble protein may be an affinity peptide comprising an amino acid sequence (a) in which any amino acid residue is substituted with one amino acid residue selected from the group consisting of a lysine residue, an aspartic acid residue, a glutamic acid residue, a 2-amino suberic acid residue, and a diaminopropionic acid residue (an amino acid residue which can be easily modified with a cross-linking agent) (preferably a lysine residue, an aspartic acid residue, or a glutamic acid residue, and more preferably a lysine residue) in the amino acid sequence of SEQ ID NO: 92, and (b) having 90% or more identity to the amino acid sequence of SEQ ID NO: 92 (Column 87, Lines 50-62). The affinity peptide can have affinity to human IgG (e.g., human IgG1) and the affinity peptide may form a cyclic peptide through a disulfide bond by the cysteine residues at position 5 and position 34 (Column 88, Lines 18-21). The amino acid sequence having the characteristics of (a) and (b) may be more preferably an amino acid sequence selected from the group comprising, for example, SEQ ID NO: 68. It is specifically noted that Yamada SEQ ID NO: 68 is an exact match to instant SEQ ID NO: 2. When the affinity substance is a peptide, the amino group and the carboxy group at the ends of the peptide may be protected by protecting groups and when the affinity substance is a peptide comprising two or more cysteine residues, a disulfide bond may be formed through thiol residues at the side chains of the cysteine residues (Column 90, Lines 9-
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30). The cleavable portion may correspond to the structure below:
wherein a wavy line orthogonal to a bond indicates a cleavage site and wherein the symbol of "white circle" indicates a bond to A (or La described below), and a symbol of "black circle"
indicates a bond to B (or Lb described below); when a chemical structure is asymmetrical with respect to the cleavage site, a symbol of "black circle" may indicate a bond to A ( or La described below), and a symbol of "white circle" may indicate a bond to B (or Lb described below) (Columns 92-94). In a specific embodiment, the cleavable linker (L) may be
represented by: (i) La-C-Lb, (ii) La-C, or (iii) C-Lb wherein La and Lb are each a divalent group and C is a cleavable portion (Column 97, Lines 36-47). Exemplary divalent groups are provided, and include a divalent hydrocarbon group optionally having a substituent, a divalent heterocyclic group optionally having a substituent, -C(=O)-, -NRa- (Ra indicates a hydrogen atom or a substituent), -O-, -S-, -C(=S)-, and a group consisting of a combination of two or more (e.g., two to eight, preferably two to six, and more preferably two to four) of these (Column 97, Lines 48-55). The divalent hydrocarbon group is a linear, branched, or cyclic divalent hydrocarbon group and preferably a linear or branched divalent hydrocarbon group including alkylene, alkenylene, alkynylene, and arylene (Column 97, Lines 56-60); an arylene is preferably C6-24 arylene, more preferably C6-18 arylene, even more preferably C6-14 arylene, and still even more preferably C6-10 arylene, wherein examples of arylene include phenylene, naphthylene, and anthracenylene (Column 98, Lines 18-23). It is acknowledged that Yamada does not explicitly designate that a phenylene group (or any other cyclic ring) as a divalent group is m-phenylene, however Yamada suggests that ortho, meta, and para attachments are permissible. Specifically, Yamada teaches that the length of the main chain linking A and R can also be defined as the number of atoms forming the main chain (except hydrogen atoms and substituents), wherein the number of atoms of the main chain may be e.g., 20 (about 30 angstroms) or smaller, preferably 16 (about 23 angstroms) or smaller, and more preferably 12 (about 16.5 angstroms) or smaller (e.g., 4 to 20, preferably 6 to 16, and more preferably 8 to 12) (Column 115, Lines 19-30). Yamada further teaches that when the main chain is a structure comprising a cyclic structure, the number of atoms of the main chain in such a case can be determined by counting the number of atoms of the shortest route connecting two bonds in the cyclic structure in addition to the number of atoms in a chain structure comprising no divalent cyclic structure in the main chain:
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wherein in the case of (a), (b), and (c), the shortest route, and thus the number of atoms in the divalent cyclic structure counted as the number of atoms of the main chain, are two, three, and four, respectively (Columns 115-116). Thus, Yamada suggests that ortho, meta, and para cyclic groups are permissible, so long as their inclusion meets the main chain limitations. Thus, from the above, the invention of Yamada reads on, for example:
wherein -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups) wherein the S atom is connected to B of Formula (I) and m-phenylene-(C=O) connects to A of Formula (I), A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. In a specific embodiment,
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B may be represented by the following Formula (B-1):
wherein Y is -NH-, -O-, -CH2-, or Formula (B-2) (see Column 106), further wherein Z is an oxygen atom, a sulfur atom, or a hydrogen atom (when Z is a hydrogen atom, -C(=Z)- indicates
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-CH2-), and a symbol of "white circle" in Formula (B-1) indicates a bond to an L-side portion, and a symbol of "black circle" indicates a bond to an R-side portion (Column 106, Lines 16-54). Thus, in view of the above, Yamada further reads on, for example:
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wherein -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. The reactive group (R) specific to a side chain of a lysine residue (of a soluble protein) may correspond to:
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wherein R5c are each a hydrogen or a substituent and j is any integer of 1 to 5 (Columns 110-111). Thus, in view of the above, Yamada further reads on, for example:
wherein Ph-S-(C=O)- corresponds to R, -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. The above structure thus reads on the instantly elected species of Formula (I) of instant claim 1, wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68) having a binding region to a CH2 domain in an immunoglobulin unit comprising two heavy chains and two light chains (i.e., a full-length, human IgG antibody) and wherein the total number of atoms constituting a main chain in La and a main chain in Lb is 5. Furthermore, Yamada provides exemplary embodiments that show the relationship between compound having affinity substance to soluble protein, cleavable portion, and reactive group, and soluble protein (antibody) having bioorthogonal functional groups which can be produced by using the same (see, for example, Table 3; Example 2-1 reproduced below):
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From the above example, the reactive group reacts with the NH2 group(s) of the antibody, wherein the reactive group is effectively a leaving group that serves to facilitate the formation of the amide bond, and the cleavage of the cleavable portion in L detaches the affinity peptide leaving the HS-CH2-CH2-(C=O) attached to the antibody. Thus, one of ordinary skill in the art would recognize that an intermediate associated with Example 2-1 is as shown below:
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Thus, with regard to the instantly elected species that Yamada reads on, it is noted that the intermediate associated with such a compound when reacted with an antibody would be as follows:
wherein A is an affinity substance, such as Yamada SEQ ID NO: 68. It is further noted that Yamada teaches that chemical conjugation by affinity peptide (C-CAP) has succeeded in
regioselectively modifying an antibody Fc region with practically favorable results [reaction time: 30 minutes, yield: 70% (for DAR 1), and regioselectivity: 100%] have been determined. It has been demonstrated that control with a DAR of 2 can be achieved by adding about five
equivalents of the peptide reagent (Column 2, Lines 16-32). Furthermore, an Example of such a reaction using trastuzumab, a compound of the invention, and DM1 yielded an antibody-drug conjugate with an average drug-to-antibody ratio (DAR) of 2 (i.e., two compounds of the invention react with the antibody allowing for the attachment of two DM1 molecules) (Column 166, Example 9, Figure 23).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compound of the reference patent to arrive at the instantly elected structure of Formula (I) and the antibody intermediate of Formula (II), wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68, instant SEQ ID NO: 2) having a binding region to a CH2 domain in an immunoglobulin unit comprising two heavy chains and two light chains (i.e., a full-length, human IgG antibody) and wherein the total number of atoms constituting a main chain in La and a main chain in Lb is 5. One would have been motivated to modify the general structure of the reference patent to comprise the specific elements of instantly elected structure of Formula (I) and the antibody intermediate of Formula (II), wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68, instant SEQ ID NO: 2) because Yamada teaches the same general structure of the reference patent claims, wherein a compound of said general structure is useful in regioselective modification of soluble proteins (e.g., antibodies); one would have had a reasonable expectation of success because the specific structural elements of Yamada, matching the definitions of the structural elements of the reference patent, would reasonably be expected to be useful for regioselectively modifying soluble proteins/antibodies, as suggested by Yamada.
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-9, 10-11, and 16-17 of copending Application No. 17/119,786 (reference application) in view of US 12,024,549 (equivalent to WO 2018/199337 A1, foreign citation number 16 on 07/18/2023 IDS; herein after referred to as “Yamada”).
Reference application claim 1 is generally drawn to a compound having an affinity substance to antibody, a cleavable portion, and a reactive group, or a salt thereof, the compound being represented by Formula (I): A-L-B-R, wherein A is the affinity substance to an antibody, L is a cleavable linker that is a divalent group comprising the cleavable portion, B is (a) a divalent group comprising a bioorthogonal functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody, further wherein the affinity substance to an antibody is a peptide comprising an amino acid sequence selected from a group that comprises SEQ ID NOs: 5, 8-12, 16-26, 30-32, 34-53, 68-86 and wherein the cleavable portion comprises, for example, the structure below:
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wherein the white circle indicates a bond to A and the black circle represents a bond to B and when the structure is asymmetrical with respect to the cleavage site a black circle may indicate a bond to A and the white circle may indicate a bond to B. Reference application claim 7 further limits the compound of claim 1, wherein the reactive group is a reactive group specific to any one side chain of a lysine residue, a tyrosine residue, and a tryptophan residue. Reference application claim 8 further limits the compound of claim 1 wherein the compound of claim 1 has one or more characteristics selected from: (a) a main chain linking A and R has 4 to 20 atoms; (b) the main chain linking A and R comprises no cyclic structure; and (c) a partial structure represented by L-B comprises no peptide portion. Reference application claim 9 is drawn to A reagent of regioselectively modifying an antibody, the reagent comprising a compound generally having an affinity substance to an antibody, a cleavable portion, and a reactive group, represented by Formula (I): A-L-B-R, wherein A is the affinity substance to an antibody, L is a cleavable linker that is a divalent group comprising the cleavable portion, B is (a) a divalent group comprising a bioorthogonal functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody, further wherein the affinity substance to an antibody is a peptide comprising an amino acid sequence selected from a group that comprises SEQ ID NOs: 5, 8-12, 16-26, 30-32, 34-53, 68-86 and wherein the
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cleavable portion comprises, for example, the structure below:
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wherein the white circle indicates a bond to A and the black circle represents a bond to B and when the structure is asymmetrical with respect to the cleavage site a black circle may indicate a bond to A and the white circle may indicate a bond to B. Reference application claim 10 is drawn to an antibody comprising an affinity substance to the antibody and a cleavable portion, or salt thereof, represented by Formula (II): A-L-B-R’-T, wherein A is the affinity substance to the antibody, L is a cleavable linker which is a divalent group comprising the cleavable portion, B is (a) a divalent group comprising a bioorthogonal functional group or (b) a divalent group comprising no bioorthogonal functional group, R' is a portion formed by a reaction between the antibody and a reactive group, and T is the antibody, wherein the affinity substance to an antibody is a peptide comprising an amino acid sequence selected from SEQ ID NOs: 5, 8-12, 16-26, 30-32, 34-53, 68-86 and wherein the cleavable portion comprises, for example, the structure below:
wherein the white circle indicates a bond to A and the black circle represents a bond to B and when the structure is asymmetrical with respect to the cleavage site a black circle may indicate a bond to A and the white circle may indicate a bond to B. Claim 11 of the reference application further modifies the antibody of claim 10, wherein the antibody is a monoclonal antibody, or an IgG antibody, or the antibody is derived from a human. Reference application claim 16 further limits the antibody of claim 10, wherein the portion formed by a reaction between the antibody and a reactive group is a portion formed by a reaction of a reactive group specific to any one side chain of a lysine residue, a tyrosine residue, and a tryptophan residue to a lysine residue, a tyrosine residue, or a tryptophan residue. Claim 17 of the reference application further limits the antibody of claim 10, wherein the antibody in Formula (II) has a plurality of the structural units A-L-B-R'.
However the reference application does not disclose any specific structures for the full liker L, divalent group B, reactive group R, nor the portion formed by the reactive group and the antibody R’, nor any specific affinity peptides corresponding to a compound of instant Formula (I) or an antibody intermediate of instant Formula (II). This deficiency is remedied by Yamada.
Yamada teaches a compound comprising an affinity substance to a soluble protein, a cleavable portion, and a reactive group represented by Formula (I): A-L-B-R, or a salt thereof, wherein A is an affinity substance to a soluble protein, L is a cleavable linker which is a divalent group comprising a cleavable portion, B is (a) a divalent group comprising a bioorthogonal
functional group or (b) a divalent group comprising no bioorthogonal functional group, and R is a reactive group to the antibody (Column 67, Lines 44-57). A is an affinity substance to a soluble protein, the affinity substance is a substance having binding ability through a noncovalent bond to a target (Column 67, Lines 65-67); the affinity substance used in the present invention targets
a soluble protein, also called a secretory protein, wherein examples of such a soluble protein include antibodies (Column 68, Lines 1-3). The affinity substance to the soluble protein may be an affinity peptide comprising an amino acid sequence (a) in which any amino acid residue is substituted with one amino acid residue selected from the group consisting of a lysine residue, an aspartic acid residue, a glutamic acid residue, a 2-amino suberic acid residue, and a diaminopropionic acid residue (an amino acid residue which can be easily modified with a cross-linking agent) (preferably a lysine residue, an aspartic acid residue, or a glutamic acid residue, and more preferably a lysine residue) in the amino acid sequence of SEQ ID NO: 92, and (b) having 90% or more identity to the amino acid sequence of SEQ ID NO: 92 (Column 87, Lines 50-62). The affinity peptide can have affinity to human IgG (e.g., human IgG1) and the affinity peptide may form a cyclic peptide through a disulfide bond by the cysteine residues at position 5 and position 34 (Column 88, Lines 18-21). The amino acid sequence having the characteristics of (a) and (b) may be more preferably an amino acid sequence selected from the group comprising, for example, SEQ ID NO: 68. It is specifically noted that Yamada SEQ ID NO: 68 is an exact match to instant SEQ ID NO: 2. When the affinity substance is a peptide, the amino group and the carboxy group at the ends of the peptide may be protected by protecting groups and when the affinity substance is a peptide comprising two or more cysteine residues, a disulfide bond may be formed through thiol residues at the side chains of the cysteine residues (Column 90, Lines 9-
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30). The cleavable portion may correspond to the structure below:
wherein a wavy line orthogonal to a bond indicates a cleavage site and wherein the symbol of "white circle" indicates a bond to A (or La described below), and a symbol of "black circle"
indicates a bond to B (or Lb described below); when a chemical structure is asymmetrical with respect to the cleavage site, a symbol of "black circle" may indicate a bond to A ( or La described below), and a symbol of "white circle" may indicate a bond to B (or Lb described below) (Columns 92-94). In a specific embodiment, the cleavable linker (L) may be
represented by: (i) La-C-Lb, (ii) La-C, or (iii) C-Lb wherein La and Lb are each a divalent group and C is a cleavable portion (Column 97, Lines 36-47). Exemplary divalent groups are provided, and include a divalent hydrocarbon group optionally having a substituent, a divalent heterocyclic group optionally having a substituent, -C(=O)-, -NRa- (Ra indicates a hydrogen atom or a substituent), -O-, -S-, -C(=S)-, and a group consisting of a combination of two or more (e.g., two to eight, preferably two to six, and more preferably two to four) of these (Column 97, Lines 48-55). The divalent hydrocarbon group is a linear, branched, or cyclic divalent hydrocarbon group and preferably a linear or branched divalent hydrocarbon group including alkylene, alkenylene, alkynylene, and arylene (Column 97, Lines 56-60); an arylene is preferably C6-24 arylene, more preferably C6-18 arylene, even more preferably C6-14 arylene, and still even more preferably C6-10 arylene, wherein examples of arylene include phenylene, naphthylene, and anthracenylene (Column 98, Lines 18-23). It is acknowledged that Yamada does not explicitly designate that a phenylene group (or any other cyclic ring) as a divalent group is m-phenylene, however Yamada suggests that ortho, meta, and para attachments are permissible. Specifically, Yamada teaches that the length of the main chain linking A and R can also be defined as the number of atoms forming the main chain (except hydrogen atoms and substituents), wherein the number of atoms of the main chain may be e.g., 20 (about 30 angstroms) or smaller, preferably 16 (about 23 angstroms) or smaller, and more preferably 12 (about 16.5 angstroms) or smaller (e.g., 4 to 20, preferably 6 to 16, and more preferably 8 to 12) (Column 115, Lines 19-30). Yamada further teaches that when the main chain is a structure comprising a cyclic structure, the number of atoms of the main chain in such a case can be determined by counting the number of atoms of the shortest route connecting two bonds in the cyclic structure in addition to the number of atoms
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in a chain structure comprising no divalent cyclic structure in the main chain:
wherein in the case of (a), (b), and (c), the shortest route, and thus the number of atoms in the divalent cyclic structure counted as the number of atoms of the main chain, are two, three, and four, respectively (Columns 115-116). Thus, Yamada suggests that ortho, meta, and para cyclic groups are permissible, so long as their inclusion meets the main chain limitations. Thus, from the above, the invention of Yamada reads on, for example:
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wherein -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups) wherein the S atom is connected to B of Formula (I) and m-phenylene-(C=O) connects to A of Formula (I), A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. In a specific embodiment, B may be represented by the following Formula (B-1):
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wherein Y is -NH-, -O-, -CH2-, or Formula (B-2) (see Column 106), further wherein Z is an oxygen atom, a sulfur atom, or a hydrogen atom (when Z is a hydrogen atom, -C(=Z)- indicates
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-CH2-), and a symbol of "white circle" in Formula (B-1) indicates a bond to an L-side portion, and a symbol of "black circle" indicates a bond to an R-side portion (Column 106, Lines 16-54). Thus, in view of the above, Yamada further reads on, for example:
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164
426
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wherein -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. The reactive group (R) specific to a side chain of a lysine residue (of a soluble protein) may correspond to:
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120
447
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wherein R5c are each a hydrogen or a substituent and j is any integer of 1 to 5 (Columns 110-111). Thus, in view of the above, Yamada further reads on, for example:
wherein Ph-S-(C=O)- corresponds to R, -CH2-CH2- corresponds to B, -S-(C=O)- corresponds to the cleavable portion and m-phenylene-(C=O)- corresponds to La (i.e., a combination of two identified divalent groups), and A corresponds to the affinity substance which, as provided above, may be Yamada SEQ ID NO: 68. The above structure thus reads on the instantly elected species of Formula (I) of instant claim 1, wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68) having a binding region to a CH2 domain in an immunoglobulin unit comprising two heavy chains and two light chains (i.e., a full-length, human IgG antibody) and wherein the total number of atoms constituting a main chain in La and a main chain in Lb is 5. Furthermore, Yamada provides exemplary embodiments that show the relationship between compound having affinity substance to soluble protein, cleavable portion, and reactive group, and soluble protein (antibody) having bioorthogonal functional groups which can be produced by using the same (see, for example, Table 3; Example 2-1 reproduced below):
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414
976
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306
1673
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From the above example, the reactive group reacts with the NH2 group(s) of the antibody, wherein the reactive group is effectively a leaving group that serves to facilitate the formation of the amide bond, and the cleavage of the cleavable portion in L detaches the affinity peptide leaving the HS-CH2-CH2-(C=O) attached to the antibody. Thus, one of ordinary skill in the art would recognize that an intermediate associated with Example 2-1 is as shown below:
Thus, with regard to the instantly elected species that Yamada reads on, it is noted that the intermediate associated with such a compound when reacted with an antibody would be as follows:
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187
992
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wherein A is an affinity substance, such as Yamada SEQ ID NO: 68. It is further noted that Yamada teaches that chemical conjugation by affinity peptide (C-CAP) has succeeded in
regioselectively modifying an antibody Fc region with practically favorable results [reaction time: 30 minutes, yield: 70% (for DAR 1), and regioselectivity: 100%] have been determined. It has been demonstrated that control with a DAR of 2 can be achieved by adding about five
equivalents of the peptide reagent (Column 2, Lines 16-32). Furthermore, an Example of such a reaction using trastuzumab, a compound of the invention, and DM1 yielded an antibody-drug conjugate with an average drug-to-antibody ratio (DAR) of 2 (i.e., two compounds of the invention react with the antibody allowing for the attachment of two DM1 molecules) (Column 166, Example 9, Figure 23).
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compound of the reference application to arrive at the instantly elected structure of Formula (I) and the antibody intermediate of Formula (II), wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68, instant SEQ ID NO: 2) having a binding region to a CH2 domain in an immunoglobulin unit comprising two heavy chains and two light chains (i.e., a full-length, human IgG antibody) and wherein the total number of atoms constituting a main chain in La and a main chain in Lb is 5. One would have been motivated to modify the general structure of the reference application as in the instantly elected species, to comprise the specific elements of instantly elected structure of Formula (I) and the antibody intermediate of Formula (II), wherein X is Ph-S, La is ethylene, W is an oxygen atom, Lb is m-phenylene and Y is an affinity peptide (e.g., Yamada SEQ ID NO: 68, instant SEQ ID NO: 2) because Yamada teaches the same general structure of the reference application claims, wherein a compound of said general structure is useful in regioselective modification of soluble proteins (e.g., antibodies); one would have had a reasonable expectation of success because the specific structural elements of Yamada, matching the definitions of the structural elements of the reference application, would reasonably be expected to be useful for regioselectively modifying soluble proteins/antibodies, as suggested by Yamada.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-46 are pending in the instant application. Claims 19-46 are withdrawn. Claims 1-18 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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