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 06/12/2023, is a 371 filing of PCT/CN2021/136952, filed 12/10/2021, and claims foreign priority to PCT/CN2020/135594, filed 12/11/2020.
Status of Claims/Application
The preliminary amendment of 06/11/2023 is acknowledged. Claims 2, 9, 23-24, 31, 38, 42-43, 67-68, 73-78, and 80-82 are amended and claims 3-8, 10-22, 25-30, 32-37, 39-41, 44-66, 69-72, 79, and 83-85 are cancelled. Claims 1-2, 9, 23-24, 31, 38, 42-43, 67-68, 73-78, and 80-82 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/11/2023 and 08/16/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing in the specification. See item 1) a) or 1) b) below.
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 Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. 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.
Drawings
The drawings are objected to because the figures are low resolution and are difficult to read.
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.
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 1-2, 9, 23-24, 31, 38, 42-43, 67-68, 73-78, and 80-82 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.
Instant claim 1 is drawn to an antibody or an antigen binding fragment thereof capable of specifically binding to TNFR2 which comprises a heavy chain variable region (VH), light chain variable region (VL) “or both”, wherein the VH comprises “at least one” heavy chain complimentary determining region (HCDR) selected from the group consisting of the amino acid sequences set forth in SEQ ID NOs: 13, 15, and 17.; and wherein the VL comprises “at least one” LCDR selected from the group consisting of the amino acid sequences set forth in SEQ ID NOs: 25, 27, and 29.
Based on the recitation of “or both” and “at least one” in the claim, the claim is drawn to a genus of antibodies or antigen binding fragments thereof that are limited by as little as a single CDR and are claimed with the function of being capable of specifically binding TNFR2. Claims 73 and 82 recite further functions for the antibody or antigen binding fragments thereof including that the TNFR2 is a human and/or cynomolgus TNFR2 (claim 73) and the application of the antibody or antigen binding fragment thereof in a method of treating a tumor and/or for inhibiting the growth of tumor cells expressing TNFR2 (claim 82).
Claim 2 depends on claim 1 and further limits the antibody or antigen binding fragment thereof to comprising one, two, or three of the HCDRs as recited; however, the claim remains drawn to a genus of antibodies or antigen binding fragments thereof that specifically bind to TNFR2 and are limited by as little as a single CDR.
Claim 23 depends on claim 1 and further limits the antibody or antigen binding fragment thereof to comprising one of the recited VH sequences. The claim; however, remains drawn to a genus of antibodies or antigen binding fragments thereof in which the recited VH regions are paired with any VL region and function in binding to TNFR2.
Claim 31 depends on claim 1 and further limits the antibody or antigen binding fragment thereof to comprising one, two, or three of the LCDRs as recited; however, the claim remains drawn to a genus of antibodies or antigen binding fragments thereof that specifically bind to TNFR2 and are limited by as little as a single CDR.
Claim 42 depends on claim 1 and further limits the antibody or antigen binding fragment thereof to comprising one of the recited VL sequences. The claim; however, remains drawn to a genus of antibodies or antigen binding fragments thereof in which the recited VL regions are paired with any VH region and function in binding to TNFR2.
Claim 43 depends on claim 1 and recites further structural limitations for the antibody or antigen binding fragment thereof, however, the claim remains drawn to a genus of antibodies or antigen binding fragments there of that specifically bind to TNFR2 and are limited by as little as a single CDR.
As such, the claims are drawn to a genus of antibodies, or antigen binding fragments thereof, all of which are claimed as having the recited function(s).
The instant disclosure, however, does not describe a representative number of species of the claimed genus performing the claimed function(s), nor does the disclosure identify a structure-function relationship that could be used to predictably identify which of the claimed CDRs or sequences could be used in combination with what other CDRs/sequences while arriving at an antibody or antigen-binding fragment thereof with the claimed functions. This is particularly the case as the claims do not require a full complement of 6 CDRs, specifically 3 from the heavy chain variable region and 3 from the light chain variable region, which are the art recognized binding region of antibodies.
The examples of the instant disclosure detail generation of anti-TNFR2 rabbit polyclonal antibodies (Examples 1 and 2; pages 31-32) and details the identification of the antibody VH and VL of TN1-36_VH and TN1-36_VL as set forth in instant SEQ ID NOs: 1 and 2, respectively. Examples 5-6 detail the generation of chimeric antibodies and the humanization of the chimeric antibodies (pages 32-33). Example 6 discloses humanized VH constructs of AL2, AL3, AL4, AL5, and AL6, having SEQ ID NOs: 3-7, respectively, as well as humanized VL constructs of AL8, AL9, AL10, and AL11, having SEQ ID NOs: 8-11, respectively (page 33, [0269]-[0270]). The examples discloses the formation of anti-TNFR2 antibody candidates comprising the following light and heavy chains (Table 1, pages 33-34):
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The examples further confirm that the antibodies produced bind to target TNFR2 with various binding affinity.
The antibodies produced all comprise HCDR 1-3 of instant SEQ ID NOs: 13, 15, and 17, respectively and LCDRs 1-3 of instant SEQ ID NOs: 25, 27, and 29, respectively.
These antibodies, with a full complement of 6 CDRs, specifically 3 from the heavy chain variable region and three from the light chain variable region, with 100% identity in the CDRs, represent the antibodies that applicant was in possession of at the time of the effective filing date of the claimed invention.
The state of the art around the effective filing date of the claimed invention also does not provide a representative number of species or a predictable structure-function relationship to support the full scope of the claimed genus.
For example, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed functions. This is particularly the case in the absence of a full complement of heavy and light chain CDRs.
Rabia, L., et al (2018) Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility Biochem Eng. J. 15(137); 365-374 discusses similar challenges faced during antibody optimization. Rabia discusses the challenges with optimizing antibody properties and states that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity… antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 – page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations in the antibody structure, particularly in the CDR regions, is not a predictable task and requires experimentation following mutation to ensure that the binding affinity is maintained and a specific, stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and teaches that these methods are not robust enough yet to yield predictable results. These teachings demonstrate that a modification to even one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that is not suitable for binding to TNFR2 as claimed.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published 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 even modifications using conservative substitution in known CDRs 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 antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and function which would allow for the predictable modification of the claimed sequences while maintaining TNFR2 specific binding and the claimed functions. See MPEP 2163 II.A.3.(a).ii. Therefore, the instant claims were found to not meet the written description requirement.
It is noted that there would be support for variation in the heavy and light chain variable regions, specifically the framework regions, if the full complement of 6 CDRs were limited to 100% identity.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached on 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693