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 1, 2, 28, 30, 31, 57, 59, 60, 86, 88-91, 98-103 are pending and being examined on the merit.
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 – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Specifically, page 50 recite a sequence for CDR2 on paragraph 0247 that is not accompanied by a sequence identifiers.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because paragraph [00248] of the instant specification contains an embedded hyperlink and/or other form of browser-executable code. 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.
Claim Objections
Claims 1, 2, 28, 30, 31, 57, 59, 60, 86, 88-91, 98-103 are objected to because of the following informalities: Claims 1, 30, 59, 88, 98, 102 and 103 recite “vhhCDRl,vhhCDR2 and said vhhCDR3 is” when the it should be “vhhCDRl,vhhCDR2 and said vhhCDR3 are” . Appropriate correction is required.
Claim 100 is objected to because of the following informalities: A conjunction of “or” or “and” is missing between “404” and “436-441” on line 4 . Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 28, 30, 57, 59, 86, 88-91, and 98-103 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.
Claims 1, 30, 59, 88, 98, 99, and 101-103 are referencing sequences recited in figures 13, 15, or 25. Claims 28, 57, 86, 89-91, and 100 are dependent from these claims. The instant claims attempt to incorporate by reference to a specific table or figure; however, such incorporation is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. In the instant case, there is a practical way to define the invention in words. Incorporation by reference is a necessity doctrine, not for applicant' s convenience. See MPEP 2173.05(s).
Claims 57 and 86 recite the limitation "said sdABD" in line 2. Claim 57 is dependent from claim 30, and claim 86 is dependent from claim 57. Base claim 30 does not recite sdABD. Thus, there is insufficient antecedent basis for this limitation in the claim.
Claims 99 and 101 recite the limitation "the trimeric Spike protein" in line 2 and 1, respectively. There is no previous recitation of the term. Thus, there is insufficient antecedent basis for this limitation in the claim.
Claim 99 is directed to an antigen binding domain (ABD) that binds to a sequence on the spike protein, and binding to a first epitope of a first monomer and second epitope of a second monomer. The claims do not state what the first monomer and second monomer are referring to. Thus, the claimed ABD binding properties are unclear. Thus, the metes and bounds of the claims are unclear.
Claim 100 recite “said second epitope comprises residues 342, 343, 367, 371-375, 404, 436-441” on line 4 without a reference protein or sequence. Thus, the metes and bounds of the claims are unclear.
For the purpose of expedited prosecution, claims 99-101 is interpreted as:
A composition comprising an antigen binding domain (ABD) that binds a first and second monomer of the trimeric Spike protein comprising SEQ ID NO:300, wherein the ABD binds to a first epitope on the first monomer comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and a second epitope on the second monomer comprising residues 342, 343, 367, 371-375, 404, and 436-441.
Claims 1, 28, 30, 57, 59, 86, 88-91, 98, 102-103 are directed to a Marksuh group of distinct single domain antigen binding domains (scABDs) comprising distinct CDR1, CDR2, and CDR3 sequences (figure 13), that are isolated independently (example 1), and have different binding properties (table 1).
MPEP 2117 states that a “Markush grouping is proper if the members of a group share a single structural similarity and a common use.” An improper Markush group contains:
(1) the members of the Markush group do not share a "single structural similarity" or
(2) the members do not share a common use.
The instant claims are directed to different scABDs that do not share a single structural similarity. Although all 24 scADBs (figure 13) were identified with the same yeast surface displayed nanobody assay, they are distinct different sdABDs, each comprising 3 distinct CDR sequences, (Example 1a and figure 13) and have different binding properties (table 1). A proper Markush group comprising different scABD should share the same binding properties, including binding to the same epitopes, and are derived from the same parental scABD. Thus, the scABD disclosed on figure 13 of the instant speciation an improper Markush group.
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 99-101 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.
The claimed invention. The instant claims are directed to a genus of antigen binding domain (ABD) that binds a first and second monomer of the trimeric Spike protein comprising SEQ ID NO:300, wherein the ABD binds to a first epitope on the first monomer is comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and a second epitope on the second monomer comprising residues 342, 343, 367, 371-375, 404, and 436-441. The claims further requires that binding of the claimed ABD results in the RBD of the spike protein being locked into the non-extended position. Thus, the claims are directed to a genus of antibodies, including variable heavy chain antibodies (VHH), that binds to specific epitopes on the trimeric Spike protein to lock the RBD into an extended position.
State of the prior art.
Single domain antibody, variable heavy chain antibody (VHH), heavy chain antibody or nanobody is an antibody that is comprised of a variable heavy (VH) chain comprising three distinct CDR sequences, CDR1, CDR2, and CDR3 domains that form the antigen binding domain that mediates binding to a cognate epitope on an antigen (Bannas et al., Frontiers in Immunology, 2017, 8: 1603, pages 1-13; abstract; figure 2; page 2, right column, paragraphs 1 and 2). VHH CDR3 region is generally longer than a conventional VH CDR3 domain (Bannas et al, page 3, left column) and provides major contribution to antibody diversity and specificity (Bannas et al.; figure 2; page 2, right column, paragraph 2). Vishwakarma et al. (Internation Journal of Molecular Science, 2022, 23:3721, pages 1-32) teaches that the paratope region of VHH directly interacts with antigens in the nanomolar to micromolar range (page 2).
Zebetakis et al. (PLOS One, 2013, 8:e77678 pages 1-7) performed CDR swapping of different VHH to study the contributions of the VHH CDRs of VHH for thermal stability and antigen binding. Zebetakis et al. showed that altering the CDRs of VHHs dramatically reduce the thermal stability and antigen binding of the VHHs (abstract; table 1). Zebetakis et al. found that the CDR2 is a major contributor to VHH stability and that all three CDRs in the proper orders are required for antigen binding (page 4 and table 1). Asaadi et al. (Biomarker Research, 2021, 9:87, pages 1-20) teaches that all 3 CDR sequences of VHH contribute to antigen binding (page 3, left column, paragraph 2).
Screening phage display libraries comprising llama VHH monovalent antibodies have been used to isolate VHH antibodies that bind to a specific antigen. Groot et al. (Laboratory Investigation, 2006, 86:345-356) teaches screening a phage display library with 6X109 clones of VHH monovalent binding fragments to identify the VHH that bind to a specific antigen (entire document, specifically page 347, See “Selection of VHH”). Groot et al. identified five VHHs that bind to different regions of HIF-1α, the antigen of interest. This highlights one cannot simply predict which of the VHH out of the 6X109 VHH monovalent antibodies would bind to the specific antigen. Also, the phage library that is used for the screen can generate different antibodies.
Even post-filing review article, Vishwakarma et al. (Internation Journal of Molecular Science, 2022, 23:3721, pages 1-32), teaches that there are numerous modeling programs, but none can accurately predict the 3D structure of all the VHH antibodies (abstract). Vishwakarma et al. teaches that VHH CDRs are variable and flexible, which makes predicting the structure difficult (page 21, paragraph 1).
Bert (WO2021156490A2) further teaches specific VHH antibodies that binds to the RBD region of the Spike protein to neutralize SARS-CoV-2 (abstract; page 5) are comprised of 3 distinct CDR sequences (page 43). The antibodies of Bert are distinct from the instant disclosed ABD on Figures 13 and 15.
Scope of species disclosed in original specification.
Using yeast surface displayed nanobody assay, 24 different single domain (sdABD), each comprising 3 distinct CDR sequences, were isolated (Example 1a and figure 3). Even though the same screening assay was performed, only 13 of these sdABD antibodies bind to the trimeric spike protein comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and residues 342, 343, 367, 371-375, 404, and 436-441 (figure 13; Table1). This highlights the unpredictability in the arts to isolate scABDs that can bind to a specific epitope. Further, epitope mapping needs to be performed to determine the binding epitopes of scABDs.
The instant specification also disclosed different variants of pNbCOV0016A comprising SEQ ID NO:87 that are identified through affinity maturation (Example 2). All of these antibodies are also comprised of distinct 3 CDR sequences (figures 15).
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. While the disclosure appears to describe numerous heavy chain antibodies that binds to the trimeric spike protein comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and residues 342, 343, 367, 371-375, 404, and 436-441 to maintain the RBD region of the spike protein in the non-extended position, these antibodies are comprised of distinct combinations of CDR1, CDR2, CDR3 sequences. The disclosed sdABD on figure 13 is not representative of a genus of VHH, because they are distinct VHH. The disclosed sdABD on figures 15 cannot be considered representative because they are all highly structurally related, and can only be identified through complex screening process.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. In the present case, the disclosure does not describe and the prior art does not teach the common structural features of a genus of antibodies that binds to the trimeric spike protein comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and a second epitope on the second monomer comprising residues 342, 343, 367, 371-375, 404, and 436-441 to maintain the RBD region of the spike protein in the non-extended position as required by the claims.
Accordingly, the disclosure only provides adequate written description for VHH antibodies that are described in figures 13 and 15 of the instant specification that can bind to the trimeric spike protein comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and residues 342, 343, 367, 371-375, 404, and 436-441 to maintain the RBD region of the spike protein in the non-extended position as required by the claims.
Conclusion. For all of the reasons presented above, one of skill in the art cannot visualize a genus of antibodies that can bind to the trimeric spike protein comprising residues 446, 447, 449, 453, 455, 456, 483-486, 489-490, 493-496, 498, 501, and 505 within the ACE2 binding region of the SC2 spike RBD, and residues 342, 343, 367, 371-375, 404, and 436-441 to maintain the RBD region of the spike protein in the non-extended position. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of antibodies as broadly claimed at the time the application was filed.
Allowable Subject Matter
Claims 2, 31, and 60 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance: The instant claims are directed to single domain antibodies that bind to the spike protein comprising SEQ ID NOs:77-79, which is free of prior arts. Further, the instant claimed antibodies, which include variants of the single domain antibody comprising SEQ ID NO:87, are identified through affinity maturation of pNbCOV006A comprising SEQ ID NO: 87 (Example 2).
The closes prior art is Hultberg (US20110182897A1), which teaches an single chain antibody that binds to an envelope protein on a virus comprising the amino acid comprising SEQ ID NO:127, which has an 82.8% sequence identity to instant SEQ ID NO:165. It is not obvious to modify the antibody of Hultberg to arrive at the instant claimed antibodies.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 1, 28, 30, 57, 59, 86, 88-91, and 98-103 are rejected.
Claims 2, 31, and 60 are objected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIE WU whose telephone number is (571)272-5205. The examiner can normally be reached M-F 9-5PM.
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/JULIE WU/Supervisory Patent Examiner, Art Unit 1643