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 .
Claims Status
Claims 1-25 are pending and presented for examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/19/2023, 07/10/2024, and 03/23/2026 has been considered by the Examiner. An initialed copy of the form PTO-1449 is attached to the office action.
Drawings
The drawings are objected to because of the following informalities:
Figures 1-7 and Figures 9-10 are non-compliant with 37 CFR 1.84 (a)(1), which requires India ink, or its equivalent that “secures solid black lines” to be used for drawings. Because black/white ink is not used in Figures 1-7 and Figures 9-10, some of the symbols in certain figures, such as the symbol for SD-611534 in Figure 3A, cannot be distinguished.
Appropriate correction is required.
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The y-axis is unlabeled on the graph entitled “1:25, Multi-sample: P2” of Figure 2.
Appropriate correction is required.
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Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Sequence Listing file name in paragraph [0003] in the specification does not match the file name for the Sequence Listing that was filed on 19 October 2023. The specification states that the file name is “IBO:1037.xml,” but in the USPTO patent electronic filing system, the file name is “IBIO1037.xml” with no colon. The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is defective. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
The specification recites “SEQ ID NO: 5” on pages 2-3 and 34 in paragraphs [0008], [0010], and [0104] and in Table 1 on pages 23-24 and “SEQ ID NOS: 47, 53, 59, 65, 71, 77, 83, and 89” on pages 2-3 and 34 in paragraphs [0008], [0010], and [0104] and in Table 4 on pages 32-33. However, because the instant application was filed after July 1, 2022, the rules governing sequence disclosures are dictated by WIPO ST.26 which do not permit amino acid sequences of less than 4 amino acids being included in the Sequence Listing. Therefore, SEQ ID NOs: 5, 47, 53, 59, 65, 71, 77, 83, and 89 are technically “skipped sequences” and are not associated with the sequences “RMS” (i.e., SEQ ID NOs: 5 and 47), “KVE” (i.e., SEQ ID NOs: 53, 59, and 71), “GLT” (i.e., SEQ ID NO: 77), “KAN” (i.e., SEQ ID NOs: 65 and 83), and “QVK” (i.e., SEQ ID NO: 89) in the sequence listing. Deletion of “SEQ ID NOs: 5 and 47” from the specification and replacement with “RMS,” deletion of “SEQ ID NOs: 53 59, and 71,” deletion of “SEQ ID NO: 77” from the specification and replacement with “GLT,” deletion of “SEQ ID NOs: 65 and 83” from the specification and replacement with “KAN,” and deletion of “SEQ ID NO: 89” from the specification and replacement with “QVK” would be remedial (if it is not already present). Upon amendment, Applicant should point to the original sequence listing in the parent application as basis for inserting “RMS” in place of “SEQ ID NOs: 5 and 47,” inserting “KVE” in place of “SEQ ID NOs: 53, 59, and 71,” inserting “GLT” in place of “SEQ ID NO: 77,” inserting “KAN” in place of “SEQ ID NOs: 65 and 83,” and inserting “QVK” in place of “SEQ ID NO: 89” if there is not currently literal support for the amendment.
Appropriate correction is required.
The specification contains a trademarked term (i.e., “IBIOLAUNCHTM” in paragraph [0073]), but does not provide the generic terminology:
The use of the term “IBIOLAUNCHTM” in paragraph [0073], which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
Claims 1-3 and 14 are objected to because of the following informality:
Claim 1, lines 4-11 recite: “any one of the following SEQ ID NOS:...”
Claim 2, lines 3 and 5 recite: “any one of the following SEQ ID NOS:...”
Claim 3, lines 4 and 7 recite: “any one of the following SEQ ID NOS:...”
Claim 14, lines 5-13 recite: “any one of the following SEQ ID NOS:...”
The recitation of “the following” is unnecessary because the sequences are not being provided in a list such that use of “the following” would be necessary. It is suggested that the claim merely recite “any of SEQ ID NOs:..”.
Appropriate correction is required.
Claim 3 is objected to because of the following informalities:
Lines 6-7 recite: “a VL encoded by a nucleic acid sequence having at least 95, 96, 97, 98, 99, or 100% sequences identity to any one of the following SEQ ID NOs: 34, 35, 36, 37, 18, 29, 40, 41, or 42.” The recitation of SEQ ID NO: 18 and SEQ ID NO: 29 in line 7 appear to be typographical errors, as SEQ ID NO: 18 is not a nucleic acid sequence and SEQ ID NO: 29 is indicated in the same claim in line 4 as encoding a VH molecule.
Applicant should review their disclosure and make the appropriate correction.
Lines 3 and 6 recite: “a VH encoded by a nucleic acid sequence” and “a VL encoded by a nucleic acid sequence,” respectively. A nucleic acid sequence is not a nucleic acid molecule; it is merely a characteristic of a nucleic acid molecule. Lines 3 and 6 should recite: “a VH encoded by a nucleic acid molecule which has a nucleic acid sequence having at least…,”and “a VL encoded by a nucleic acid molecule which as a nucleic acid sequence having at least…,”respectively.
Appropriate correction is required.
Claim 9 is objected to because of the following informalities:
Lines 1-2 recite: “wherein the heavy chain CDRs are SEQ ID NOS: 1, 2 and 3…”. Since the CDRs comprise amino acid sequences wherein the amino acid sequences are SEQ ID NOs: 1-3, etc., they are not sequence identifiers. Therefore, Applicant should revise the claim language in lines 1-2 to state: “wherein the heavy chain CDRs comprising the amino acid sequences of SEQ ID NOs: 1, 2 and 3, and the light chain CDRs comprise the amino acid sequences of SEQ ID NOs: 4, 5, and 6.” As set forth above, “SEQ ID NO: 5” in line 2 should be replaced with the 3 amino acid sequence “RMS” because “SEQ ID NO: 5” is a skipped sequence.
Appropriate correction is required.
Claim 19 is objected to because of the following informality:
Claim 19 recites “sequence identify” in lines 4 and 6. This appears to be a typographical error and that the term “identity” is most likely the terminology that was intended.
Appropriate correction is required.
Claim 25 is objected to because of the following informality:
The recitation of “host cell comprising nucleic acid the vector of claim 24” is grammatically incorrect and unclear. Claim 24 is directed to a vector which comprises a nucleic acid. Therefore, claim 25 could recite “a host cell comprising the vector of claim 24”, which would be remedial.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 4-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 and 14, lines 10-12 recite VL CDR2 variable light chain sequences as set forth in SEQ ID NOs: 5, 53, 59, 65, 71, 77, 83, and 89, which are “skipped sequences.” Because the instant application was filed after July 1, 2022, the application falls under the ST26 version of the Sequence rules. 37 CFR 1.831(j) states that a “Sequence listing XML” must not include any sequences having fewer than 10 specifically defined nucleotides, or fewer than 4 specifically defined amino acids. Because these sequences have fewer than 4 specifically defined amino acids, they are “skipped” in the sequence listing and therefore, there is no information in the Sequence listing for SEQ ID NOs: 5, 53, 59, 65, 71, 77, 83 and 89, and therefore, the claims are indefinite as the amino acid sequences intended by reference to these identifiers cannot be determined. Replacement of the sequence identifier with the actual amino acid sequence that the identifier was to represent would be remedial.
Regarding claims 4 and 16, these claims recite: “antibody or antigen binding fragment of claim 1” and “antibody or antigen binding fragment of claim 14,” respectively, and then limit the antibody to “binding fragments thereof” (e.g., instant claim 4) or “fragments thereof” (e.g., instant claim 16). The metes and bounds of these recitations are unclear and indefinite because for claim 4, there is no statement as to what the fragment is binding, and it appears to be something different than just the antigen binding fragment. For claim 16, a fragment in this context can read on a single amino acid and this does not appear to be what would reasonably be intended. A recitation of “antigen-binding fragment” would be remedial.
Claims 4 and 16 are also dependent upon claims 1 and 14, respectively, without resolving the issue(s) identified above and are therefore included in the rejection. Amendment to claims 1 and 14 as set forth above would be remedial.
Regarding claims 5-13, these claims are dependent upon claim 1 without resolving the issue identified above and are therefore included in the rejection. Amendment to claim 1 as set forth above would be remedial.
Regarding claim 7, line 1 recites: “the nucleic acid.” Because claim 7 is dependent on claim 1 and there is no nucleic acid recited in claim 1, there is insufficient antecedent basis for this limitation in the claim. Introduction of a nucleic acid element earlier in claim 1 would be remedial.
Regarding claims 15-18, these claims are dependent upon claim 14 without resolving the issue identified above and are therefore included in the rejection. Amendment to claim 14 as set forth above would be remedial. Regarding claim 19, line 1 recites: “a nucleic acid comprising an anti-CCR8 antibody or antigen binding fragment,” which is not possible because antibodies are proteins made of amino acids, and not nucleic acids. Therefore, a nucleic acid cannot comprise an antibody. Thus, claim 19 fails to delineate the metes and bounds of the subject matter that Applicant regards as the invention with the requisite clarity and particularity to permit the skilled artisan to know or determine the infringing subject matter. Accordingly, claim 19 is indefinite for failing to particularly point out and distinctly claim the subject matter which the Applicant regards as the invention. Amending claim 19 to recite “encoding” instead of “comprising” would be remedial.
Regarding claims 20-25, these claims are dependent upon claim 19 without resolving the issue(s) identified above and are therefore included in the rejection. Amendment to claim 19 as set forth above would be remedial.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-8 and 10-18 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.
Claimed Invention
Claims 1 and 14 are directed to an antibody or antigen-binding fragment thereof that binds to and inhibits CCR8 comprising sequences for CDRH1-H3 and CDRL1-L3, wherein:
CDRH1 comprises the amino acid sequence of SEQ ID NOs: 1, 49, 67, 73, 79, or 85;
CDRH2 comprises the amino acid sequence of SEQ ID NOs: 2, 50, 68, 74, 80, or 86;
CDRH3 comprises the amino acid sequence of SEQ ID NOs: 3, 51, 69, 75, 81, or 87;
CDRL1 comprises the amino acid sequence of SEQ ID NOs: 4, 52, 55, 58, 61, 64, 70, 76, 82, or 88;
CDRL2 comprises the amino acid sequence of SEQ ID NOs: 5 (RMS), 53 (KVE), 56, 59 (KVE), 62, 65 (KAN), 71 (KVE), 77 (GLT), 83 (KAN), or 89 (QVK);
CDRL3 comprises the amino acid sequence of SEQ ID NOs: 6, 54, 57, 60, 63, 66, 72, 78, 84, or 90.
However, the claim limitations as written fail to provide an adequate written description for such antibodies and antigen-binding fragments thereof that specifically bind and inhibit CCR8 because while the claims recite CDR structures for the VH and VL regions of the antibody, the claims also encompass mixing and matching VH/VL CDRs to arrive at a functional antibody that specifically binds and inhibits CCR8.
Claims 2-8, 10-13, and 15-18 are dependent on the anti-CCR8 antibody or antigen-binding fragment thereof disclosed in claims 1 and/or 14 and have the same written description issue.
Scope of Disclosed Species
The instant specification teaches an anti-CCR8 antibody or antigen binding fragment, wherein the antibody or antigen binding fragment comprises a VH CDR1 comprises the amino acid sequence of SEQ ID NO: 1, the VH CDR2 comprises the amino acid sequence of SEQ ID NO: 2, and the VH CDR3 comprises the amino acid sequence of SEQ ID NO: 3; and wherein the VL CDR1 comprises the amino acid sequence of SEQ ID NO: 4, the VL CDR2 comprises the amino acid sequence of SEQ ID NO: 5, and the VL CDR3 comprises the amino acid sequence of SEQ ID NO: 6 (e.g., pages 23-24, Table 1).
However, the instant specification also teaches antibodies which mix and match CDRs of the heavy and light chain variable domains which also have the ability to bind their respective targets, but these antibodies do not have written description (e.g., pages 32-33, Table 4).
State of the Prior Art
At the time of the filing of the instant application, it is well established in the art, specifically in Almagro & Fransson (Frontiers in Bioscience, 01 January 2008, 13:1619-33; hereinafter “Almagro”), that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three complementarity determining regions (CDRs) which provide the majority of the contact residues for the binding of the antibody to its target epitope (e.g., Section 3, “Antibody Structure and the Antigen Binding Site”; Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (e.g., page 3, “The IgG Molecule,” paragraphs 2-3), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. Chiu et al. (Antibodies, 16 October 2019, 8(55):1-80; hereinafter “Chiu”) teaches the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (e.g., page 5, paragraph 1). Thus, it might be difficult to predict binding of a CDR to an epitope or difficult to determine what amino acids would be required in a CDR to bind to an epitope. Chiu further teaches that antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (e.g., page 6, paragraph 2). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (e.g., page 6, paragraph 2). Chiu teaches the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody-antigen docking are also disappointing (e.g., page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa et al. (MAbs, July 2017, 9(5):854-873; hereinafter “Hasegawa”) teaches a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (e.g., page 866, last sentence, left column). Hasegawa teaches the 2 monoclonal antibodies (mAbs) differed only by one amino acid in the light chain’s CDR1 and that despite the near-identity of their primary sequences, the parental mAb secretes copious amounts of IgG to the culture media, while the variant mAb induces RB phenotypes extensively and secretes 20-fold less IgG (e.g., page 866, right column, paragraph 1). Importantly, the two model IgGs are by no means abnormal or defective as mAbs, but demonstrate a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (e.g., page 866, right column, paragraph 1).
Based on the state of the art, mixing and matching HCDR1-3 and LCDR1-3 amino acid sequences does not guarantee an antibody will bind a specific antigen. Altering one amino acid within the CDR sequences of the VH and VL regions can change, particularly within the CDR sequences, can alter the antigen binding domain and disrupt antigen binding. Therefore, mixing and matching CDR sequences will not form a proper antigen binding domain that will bind to CCR8 as required by the instant claims.
Conclusion
As indicated by the art, mixing and matching VH CDR1-3 and VL CDR1-3 amino acid sequences does not guarantee an antibody will bind a specific antigen (i.e., CCR8). Antibody-antigen binding requires highly precise molecular fitting. Therefore, one of ordinary skill in the art cannot envision randomly combining VH CDR1-3 and VL CDR1-3 amino acid sequences to result in a functional antibody that binds to and inhibits CCR8.
Applicant can overcome the rejection of claims 1 and 14 by stating a specific SEQ ID NO for each of the amino acid sequences comprising CDR1-3 in the VH region of the anti-CCR8 antibody, in addition to stating a specific SEQ ID NO for each of the amino acid sequences comprising CDR1-3 in the VL region of the anti-CCR8 antibody. Claims 2-8, 10-13, and 15-18 are dependent on the anti-CCR8 antibody or antigen-binding fragment thereof disclosed in claims 1 and/or 14 and have the same written description issue. Amendment to claims 1 and 14 as set forth above would be remedial.
Claims 19-25 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.
Claimed Invention
Claim 19 is directed to a nucleic acid encoding an anti-CCR8 antibody or antigen binding fragment comprising:
a heavy chain variable domain encoding polynucleotide having at least 95, 96, 97, 98, 99, or 100% sequence identity to SEQ ID NOs: 25, 26, 27, 28, 29, 30, 31, 32, or 33; and
a light chain variable domain encoding polynucleotide having at least 95, 96, 97, 98, 99, or 100% sequence identity to SEQ ID NOs: 34, 35, 36, 37, 38, 39, 40, 41, or 42.
However, the claim limitations as written fail to provide adequate written description for such nucleic acids encoding antibodies and antigen-binding fragments thereof that specifically bind and inhibit CCR8 because while the claims recite polynucleotide sequences encoding the VH and VL domains of the antibody, the claims also encompass 1-5% variability in the sequence identity of the polynucleotide sequences encoding the VH and VL domains, wherein the domains comprise of three CDRs (i.e., VH CDR1-3 and VL CDR1-3) that are also encoded by polynucleotide sequences, to arrive at a functional antibody that specifically binds and inhibits CCR8.
Claims 20-25 are dependent on the nucleic acid encoding the anti-CCR8 antibody or antigen binding fragment disclosed in claim 19 and have the same written description issue.
Scope of Disclosed Species
A nucleic acid encoding an antibody comprised of polynucleotide sequences having 100% sequence identity to a specific set of complementary polynucleotides encoding the VH/VL domains (wherein the domains comprise of a full set of polynucleotides encoding VH CDRs (i.e., HCDR1-3) and complementary VL CDRs (i.e., LCDR1-3)) has written description. The instant specification teaches a nucleic acid encoding an anti-CCR8 antibody or antigen binding fragment, wherein the amino acid sequence of the heavy chain variable domain of the anti-CCR8 antibody or antigen binding fragment is encoded by a polynucleotide having 100% sequence identity to SEQ ID NO: 25, and wherein the amino acid sequence of the light chain variable domain of the anti-CCR8 antibody or antigen binding fragment is encoded by a polynucleotide having 100% sequence identity to SEQ ID NO: 34 (e.g., page 2, paragraph [0008], lines 26-30; page 4, paragraph [0011], lines 1-6; pages 27-32, Tables 3A-3B). The polynucleotide sequences having 100% sequence identity to SEQ ID NOs: 25 and 34 encode the amino acid sequences of the VH and VL domains, respectively (comprising HCDR1-3 and LCDR1-3, respectively) of the anti-CCR8 antibody or antigen binding fragment (comprising the amino acid sequences set forth in SEQ ID NOs 1-3 and SEQ ID NOs: 4-6, respectively), as evidenced by a DNA sequence translation tool on Bioinformatics.org (e.g., https://www.bioinformatics.org/sms2/translate.html) (see results below).
Results from DNA sequence translation tool comprising the translation of the polynucleotide sequence having 100% sequence identity to SEQ ID NO: 25, which encodes the amino acid sequence of the VH domain (comprising HCDR1-3) of the anti-CCR8 antibody or antigen binding fragment set forth in SEQ ID NO: 7 (comprising the amino acid sequences of HCDR1-3 set forth in SEQ ID NOs: 1-3):
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Results from DNA sequence translation tool comprising the translation of the polynucleotide sequence having 100% sequence identity to SEQ ID NO: 34, which encodes the amino acid sequence of the VL domain (comprising LCDR1-3) of the anti-CCR8 antibody or antigen binding fragment set forth in SEQ ID NO: 16 (comprising the sequences of LCDR1-3 set forth in SEQ ID NOs: 4-6):
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However, the instant specification also teaches nucleic acids which mix and match polynucleotide sequences with 1-5% variability in sequence identity of the complementary polynucleotides encoding the VH/VL domains or VH CDR1-3/VL CDR1-3 which also have the ability to bind their respective targets, but these nucleic acids do not have written description (e.g., pages 27-32, Tables 3A-3B).
State of the Prior Art
At the time of the filing of the instant application, it is well established in the art, specifically in Almagro & Fransson (Frontiers in Bioscience, 01 January 2008, 13:1619-33; hereinafter “Almagro”) teaches that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three complementarity determining regions (CDRs) which provide the majority of the contact residues for the binding of the antibody to its target epitope (e.g., Section 3, “Antibody Structure and the Antigen Binding Site”; Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (e.g., page 3, “The IgG Molecule,” paragraphs 2-3), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. Chiu et al. (Antibodies, 16 October 2019, 8(55):1-80; hereinafter “Chiu”) teaches the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (e.g., page 5, paragraph 1). Thus, it might be difficult to predict binding of a CDR to an epitope or difficult to determine what amino acids would be required in a CDR to bind to an epitope. Chiu further teaches that antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (e.g., page 6, paragraph 2). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (e.g., page 6, paragraph 2). Chiu teaches the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody-antigen docking are also disappointing (e.g., page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa et al. (MAbs, July 2017, 9(5):854-873; hereinafter “Hasegawa”) teaches a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (e.g., page 866, last sentence, left column). Hasegawa teaches the 2 monoclonal antibodies (mAbs) differed only by one amino acid in the light chain’s CDR1 and that despite the near-identity of their primary sequences, the parental mAb secretes copious amounts of IgG to the culture media, while the variant mAb induces RB phenotypes extensively and secretes 20-fold less IgG (e.g., page 866, right column, paragraph 1). Importantly, the two model IgGs are by no means abnormal or defective as mAbs but demonstrate a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (e.g., page 866, right column, paragraph 1).
Komar (Biochemistry (Mosc), 23 September 2021; 86(8):976-991; hereinafter “Komar“) teaches that polynucleotides encode the amino acid sequences of an antibody through groups of three nucleotides (i.e., codons) (e.g., page 976, Abstract), which dictate the order of amino acids for the antibody’s heavy and light chains, including their variable (antigen-binding) regions, which comprises VH CDRs (i.e., HCDR1-3) and VL CDRs (i.e., LCDR1-3), as further taught by Chailyan et al (FEBS J., August 2011; 278(16):2858-66; hereinafter “Chailyan”) (e.g., page 2858, Abstract). Thus, alterations to nucleotides within polynucleotide sequences encoding the heavy and light chain variable domains can change an antibody’s structure and biological function by modifying the codons responsible for encoding amino acid sequences within the VH/VL CDRs (e.g., page 2859, column 1, paragraph 4). Therefore, since CDRs form the antigen-binding site on the heavy and light chain variable domains of an antibody, nucleotide-level changes within the polynucleotide sequences encoding the heavy and light chain variable domains of an antibody, particularly within the CDR sequences, can alter the antigen binding domain and disrupt antigen binding (e.g., page 2859, column 1, paragraph 4).
Based on the state of the art, altering individual nucleotides within a polynucleotide sequence encoding VH and VL domains (wherein the VH and VL domains comprise of polynucleotide sequences encoding HCDR1-3 and LCDR1-3, respectively), in addition to mixing and matching polynucleotide sequences encoding VH and VL domains (wherein the VH and VL domains comprise of polynucleotide sequences encoding HCDR1-3 and LCDR1-3, respectively), does not guarantee a nucleic acid will encode an antibody that will bind a specific antigen. Altering individual nucleotides within a polynucleotide sequence has the ability to change a codon encoding a particular amino acid within the VH/VL domains and VH/VL CDR regions, which can prevent antigen binding. Therefore, altering nucleotides within the polynucleotide sequence encoding the VH/VL domains and mixing and matching the polynucleotide sequences encoding the VH and VL domains/VH CDR1-3 and VL CDR1-3 will not form a proper antigen binding domain that will bind to CCR8 as required by the instant claims.
Conclusion
As indicated by the art, having 1-5% variability or mixing and matching the polynucleotide sequences encoding the heavy chain variable domain and light chain variable domain of a particular antibody, which contain the VH CDR1-3 and VL CDR1-3 polynucleotide sequences, does not guarantee a nucleic acid encoding an antibody that binds a specific antigen (i.e., CCR8). Antibody-antigen binding requires highly precise molecular fitting. Therefore, one of ordinary skill in the art cannot envision randomly combining VH/VL polynucleotide sequences or VH CDR1-3/VL CDR1-3 polynucleotide sequences with 1-5% variability in the sequence identity to result in a functional nucleic acid that encodes an antibody that binds and inhibits CCR8.
Applicant can overcome the rejection of claim 19 by stating a specific SEQ ID NO that has 100% sequence identity to a polynucleotide encoding the heavy chain variable domain of a nucleic acid encoding an anti-CCR8 antibody, in addition to stating a specific SEQ ID NO that has 100% sequence identity to a polynucleotide encoding the complementary light chain variable domain of a nucleic acid encoding an anti-CCR8 antibody. Claims 20-25 are dependent on the nucleic acid encoding the anti-CCR8 antibody or antigen binding fragment disclosed in claim 19 and have the same written description issue. Amendment to claim 19 as set forth above would be remedial.
Claim Rejections - 35 USC § 112(d)
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.
Claims 8, 18, and 23 are 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. The specification clearly states that the antibodies of the specification do not bind to CCR4 (e.g., paragraph [0114]). Therefore, claims 8, 18 and 23 which recite that the antibodies do not bind to CCR4 do not limit the subject matter of the claims from which they depend. Because the antibodies already do not bind, these claims do not further limit the subject matter of the preceding claims. They do not limit the scope of the antibodies (since they already have this property), nor do they functionally add anything that results in the property. 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.
Conclusion
No claims are currently allowed.
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/MALIA NICOLE GREEN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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