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 .
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 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.
Priority
The instant application, filed 05/06/2023, is a continuation of PCT/CN2021/134134, filed 11/29/2021, which is a continuation in part of PCT/CN2020/132111, filed 11/27/2020.
Status of Application, Amendments, and/or Claims
Applicant’s amendment of 06/18/2026 is acknowledged. Claims 1, 3, 10, 12, and 15 are amended and claims 2 and 11 are cancelled. Claims 1, 3-10, and 12-15 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 12/18/2025,
The sequence disclosure was objected to. Applicant’s amendment to the specification to recite the ASCII size in bytes has overcome the first objection and the objection is withdrawn.
Claim 11 was rejected under 35 USC 101. The cancellation of the claim has rendered the rejection moot and the rejection is withdrawn.
Claim 10 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to recite “one or more” in place of “two or more” has overcome the rejection and the rejection is withdrawn.
Claim 11 was rejected under 35 USC 112(b). The cancellation of the claim has rendered the rejection moot and the rejection is withdrawn.
Claim 3 was rejected under 35 USC 112(d). Applicant’s amendment to claim 3 to change the claim from a dependent to independent claim has overcome the rejection and the rejection is withdrawn.
Claims 11-15 were rejected under 35 USC 112(a) Scope of enablement. The cancellation of claim 11 and the amendments to claims 12 and 15 to remove limitations concerning prevention has overcome the rejections and the rejections are withdrawn.
Claims 2 and 11 were rejected under 35 USC 112(a) Written description. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
Claims 1-2 and 9 were rejected under 35 USC 102(a)(2) over US’157. Applicant’s amendment to claim 1 to limit the sequence identity to at least 98% or at least 99% has overcome the rejections and the rejections are withdrawn.
Claims 1-2, 4-6, 9, and 11-15 were rejected under 35 USC 103 over US’157. Applicant’s amendment to claim 1 to limit the sequence identity to at least 98% or at least 99% has overcome the rejections and the rejections are withdrawn.
The following grounds of objections and/or rejections are either maintained or modified as necessitated by applicant’s amendment to the claims.
Nucleotide and/or Amino Acid Sequence Disclosures
In the specification “G4S” is recited in the following locations without an appropriate SEQ ID NO: [0026], line 3; and Table 2, description column, all rows.
Claim 5 recites “G4S”, representing the sequence GGGGS, without an appropriate SEQ ID NO.
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:
In the specification “G4S” is recited in the following locations without an appropriate SEQ ID NO: [0026], line 3; and Table 2, description column, all rows.
Claim 5 recites “G4S”, representing the sequence GGGGS, without an appropriate SEQ ID NO.
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).
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.
Response to Arguments
In the response filed 06/18/2026, applicant has not provided any response specifically concerning the recitation of “G4S” in Table 2 of the specification or in claim 5.
Applicant is reminded that sequences comprising four or more specifically defined amino acids, such as G4S, which has 5 specifically defined amino acids, are required to be listed in the sequence listing and accompanied by a SEQ ID NO where recited in the disclosure/claims.
Claim Rejections - 35 USC § 112(a) – Written Description
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, 3-10, and 12-15 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.
Claim 1 is drawn to a single domain anti-LAG3 antibody that specifically binds LAG3 and encompasses sequences comprising an amino acid sequence selected from the group of SEQ ID NOs: 1-19, 80-86, and 89-97, or an amino acid sequence that is “at least 98%, or at least 99% identical” to a sequence selected from the group of SEQ ID NOs: 1-19, 80-86, and 89-97. Claims 12-15 further claim methods of administering the antibodies in treating cancer. Based on the claimed identity percentages, claim 1 encompasses a genus of single domain anti-LAG3 antibodies with modifications to the recited sequences, including modifications that can be made in the antibody CDRs, all of which are claimed to function in specifically binding to human LAG3 and being capable of treating cancer when used in the claimed methods.
Claim 3 has been amended to recite a single domain anti-LAG3 antibody that specifically binds to human LAG3, wherein the antibody comprises a CDR1, a CDR2, and a CDR3, respectively, having the amino acid sequences shown in the table provided. The table in the claim recites sequences for CDR1, CDR2, and CDR3; however, the claim also recites the optional limitation that one or more DG of one or more CDRs is mutated to DA and/or EG, and or one or more NG of one or more CDRs are mutated to NA and/or DG. As such, claim 3 encompasses a genus of antibodies in which the CDRs encompass the modifications as recited, all of which are claimed as performing the function of specifically binding to human LAG3.
Claim 8 is drawn to a single domain antibody fusion comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 58-76, or an amino acid sequence that is “at least 85%, at least 90%, at least 95%, at least 98%, or at least 90% identical” to a sequence selected from the group of SEQ ID NOs: 58-76. Based on the claimed identity percentages, claim 8 encompasses a genus of single domain antibody fusions all of which are claimed as functioning as an antibody fusion which indicates that the claimed fusion must bind to something.
The instant claims are drawn to a genus of anti-LAG3 antibodies and fusion antibodies all of which are claimed as having the recited functions as discussed in detail above. The instant disclosure, however, does not demonstrate a representative number of species of the claimed genus performing the claimed functions. The disclosure also does not provide a structure-function correlation that could be used to predictably identify which species of the claimed genus would be capable of performing the claimed function, particularly in the absence of a full complement of CDRs (three for single domain antibodies), which are the art recognized binding sites of antibodies.
The examples disclose the generation and optimization of anti-LAG3 single domain antibodies (Examples 1-6 and 8-9). The examples further demonstrate the effects of single domain antibodies on Jurkat T cells overexpressing human LAG3 and Raji B cells (Example 7) and on hLAG3-His protein (Example 10). The specification provides sequences of single domain antibodies, and their 3 CDRs, in Table 1 (pages 6-9), Table 13 (pages 29-32), and Table 19 (pages 38-40) as well as sdAb fusion sequences in Table 2 (pages 9-13).
These single domain antibodies and fusion sequences, with the full complement of 3 CDRs with 100% identity in the CDRs, represents the single domain antibodies and fusions thereof that applicant was in possession of at the time of the effective filing date.
The prior art also does not provide a representative number of species of the claimed genus nor does the prior art provide a structure function correlation that can be used to predictably identify which species of the claimed genus would perform the functions claimed. Rather, the state of the art suggests that antibody structure-function is not predictable, particularly in the absence of a full complement of CDRs.
Bathula, N.V., et al (2021) Nanobodies: The future of antibody-based immune therapeutics Cancer biotherapy and radiopharmaceuticals 36; 109-122 teaches that crystallography studies revealed many dynamic features of VHH domain antibodies, such as it is composed of four framework regions (FR) with nine β-sheets separated by loops, which include three hypervariable regions, or CDRs (page 110, right column). The CDR1, located towards the N-terminal region, has high variability, but nonetheless contributes to the binding strength of the domain in collaboration with CDR2, particularly by formation of an interloop disulfide bond with CDR3. The CDR3 is mainly engaged in antigen recognition and is longer than in the conventional VH domain. The longer CD3 gives increased flexibility for antigen binding and specificity variations. Furthermore, in many nanobodies, CDR3 domains have protruding ends, which improves their ability to reach and interact with the epitopes located in protein crevices and enzyme-active domains. All of these properties contribute to the convex surface of VHH, which supplements its ability to interact with the antigen cavities (page 111, left column, paragraph 3).
Hoey, R.J., et al (2019) Structure and development of single domain antibodies as modules for therapeutics and diagnostics Experimental biology and medicine 244; 1568-1576 teaches that VHH domains typically rely heavily on CDR3 for interactions with antigens. Notably, an elongated CDR3 loop provides VHH significant versatility in its ability to interact with target molecules. Unlike conventional antibodies, VHH domains have been observed to interact with antigens in protruding/extended conformations, which allow the antibody to bind protein clefts/pockets, including enzyme active sites. In addition, the CDR3 loop can produce a structurally flat paratope using CDR1/3, CDR1/2/3, and CDR2/3/FW, with some possessing more convex or concave paratopes (paragraph bridging columns, page 1569).
The teachings of Bathula and Hoey demonstrate that antigen binding specificity and strength of single domain antibodies depends on the full complement 3 CDRs all of which, together, form the paratope of the binding domain.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published approximately two years after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable years after the effective filing date. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1). Teachings which demonstrate that, even years after the effective filing date of the claimed invention, modifications, even those using conservative substitutions, were not predictable.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of single domain anti-LAG3 antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable modification of the claimed sequences while maintaining LAG3 binding function. Therefore, the instant claims are found to not meet the written description requirement.
It is noted that there would be support for variation in the framework regions if the full complement of 3 CDRs were limited to 100% identity.
Response to Arguments
In the response filed 06/18/2026, with regards to the rejection of the claims under 35 USC 112(a), applicant argues that claim 1 has been amended to recite an amino acid sequence that is “at least 98%, or at least 99% identical” to the recited sequences and claim 3 has been amended to recite CDR1, CDR2, and CDR3 sequences and to recite that the antibody comprises a CDR 1, 2, and 3.
While independent claims 1 and 3 have been amended, as discussed in detail in the rejection above, the claims still encompass a genus of antibody structures, in which the CDRs of the single domain antibody can be modified with the claimed function of binding specifically to human LAG3 and, in the case of instant claims 12-15, treat cancer. It is noted that claim 8 has not been amended and claims fusion proteins with sequences that are “at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical” to SEQ ID NOs: 58-76.
As discussed in the rejection, independent claims 1, 3, and 8 all encompass embodiments in which the CDRs of the claimed antibody can be modified. Due to unpredictability in the antibody art, it is not clear that applicant was in possession of a representative number of species of the claimed antibody nor is a structure-function correlation provided in the instant disclosure or the prior art that could be used to identify what CDRs in the claimed antibodies could be modified in what way while still resulting in an antibody that specifically binds human LAG3 and treats cancer.
As discussed in the rejection, the specification provides sequences of single domain antibodies, and their 3 CDRs, in Table 1 (pages 6-9), Table 13 (pages 29-32), and Table 19 (pages 38-40) as well as sdAb fusion sequences in Table 2 (pages 9-13).
These single domain antibodies and fusion sequences, with the full complement of 3 CDRs with 100% identity in the CDRs, represents the single domain antibodies and fusions thereof that applicant was in possession of at the time of the effective filing date.
It is noted that applicant does not provide any specific arguments concerning the rejection other than to state that the claims have been amended.
To overcome the rejection, it is suggested that the claims be amended to limit the claimed single domain antibodies to species of antibody that each comprise at least a full combination of 3 specific CDRs, with 100% identity, which were characterized together in a single antibody shown to bind LAG3 in the disclosure.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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