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 .
Priority
The instant application, filed on 07 December, 2023, is a 371 of PCT/US2022/032855 filed 09 June, 2022 and which claims domestic benefit to US provisional application no. 63/209,671, filed on 11 June, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 18 September, 2025 has been considered by the examiner.
The information disclosure statement (IDS) submitted on 07 December, 2023 has been considered by the examiner.
Status of Application, Amendments, and/or Claims
The response filed on 08 July, 2024 has been entered in full. These are the amended claims of the original claim set received on 07 December, 2023. In the amendment, claims 4, 7, 10, 11, 13, 18, 21, 22, 24, 29, and 32-35 are amended and claims 2, 5, 6, 8, 9, 12, 17, 19, 20, 23, 25, 26, 28, 30, 31, and 36-40 are canceled. Therefore, claims 1, 3, 4, 7, 10, 11, 13-16, 18, 21, 22, 24, 27, 29, and 32-35 are pending and are the subject of this Office Action.
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 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.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the Tables of 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.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description:
The description of figure 4 recites 4a -4f, however 4f is not labeled.
The description of figure 12 recites 12a - 12d, however the graphs of figure 12 are not labeled a) – d).
The description of figure 14 recited 14a and 14b, however the graphs of figure 12 are not labeled a) and b).
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. 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 Objections
Claim 13 is objected to because of the following informalities: the claim recites “the antibody of any one of claim 8.” The recitation of only one claims make the “any one of” unnecessary.
Appropriate correction is required.
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.
Claims 1, 4, 7, 10, 11, and 13-15 are rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement. The claim 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, at the time the application was filed, had possession of the claimed invention.
Claim 1 recites “An antibody that specifically binds to human Natural Cytotoxicity Triggering Receptor 3 (NCR3), wherein the antibody comprises at least…(2) a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR) 1 comprising SEQ ID NO: 14, a HCDR2 comprising SEQ ID NO: 15, and a HCDR3 comprising SEQ ID NO: 41,” SEQ ID NO: 41 (HCDR3) recites a sequence containing wildcards in which positions 2, 5, and 7 can be any amino acid, and positions 3, 6, 8, and 18 can be selected from a list. As such, claim 1 encompasses a genus of antibody structures which are limited by as little as a random combination of amino acids at positions 2, 5 and 7.
The instant disclosure, however, does not describe a representative number of species of the claimed genus performing the claimed function, nor does the disclosure identify a structure function relationship that could be used to predictably identify what amino acid selections could be used in order to arrive at an antibody with the claimed function.
The samples of the instant disclosure studied the combinations as listed in the chart below based on the specification. The examples do not describe the use of any other species of the claimed genus of antibodies nor do the examples demonstrate a predictable structure function correlation between antibody structure and binding function.
Examiner Table 1: Antibodies supported in specification
Name
LCDRs 1,2,3 respectively
HCDRs 1, 2, 3, respectively
NRC3.12
SEQ ID NOs: 2, 3, and 4
SEQ ID NOs: 6, 7, and 8
NRC3.19
SEQ ID NOs: 18, 19, and 20
SEQ ID NOs: 22, 23, and 24
NCR3.18
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 16
NCR3.18.1
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 42
NCR3.18.3
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 43
NCR3.18.4
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 44
NCR3.18.6
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 45
NCR3.18.7
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 46
NCR3.18.8
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 47
NCR3.18.9
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 48
NCR3.18.10
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 49
NCR3.18.11
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 50
NCR3.18.12
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 51
NCR3.18.13
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 52
NCR3.18.14
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 53
NCR3.18.15
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 54
NCR3.18.17
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 55
NCR3.18.18
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 56
NCR3.18.19
SEQ ID NOs: 10, 11, and 12
SEQ ID NOs: 14, 15, and 57
The state of the art around the effective filling 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 et al. (2019) Antibody Structure and Function: Basis for Engineering Therapeutics Antibodies 8(55); 1-80 teaches, that the antigen binding site is formed by the pairing of the Fab VH and VL with the N-terminal region designed as the Fv region and that the VL region is composed of CDR-L1, CDR-L2, and CDR-L3 and the VH region is composed of CDR-H1, CDR-H2, and CDR-H3. The CDR loops are determined by variability analysis and brought together form the antigen-binding site (page 4, paragraph 2). Chiu also teaches a canonical structure is defined by the loop length, the conformation of the loop, and the conserved amino acid residues within the hypervariable loop and FRs (page 5, paragraph 2). Further Chiu teaches “despite the obvious development in algorithms and computer power, the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody-antigen docking are also disappointing” (pg.11, lines 12-14). Based on these teachings, and person of ordinary skill in the art would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function.
Teixeira and Erasmus et al. (2021) Drug-like antibodies with high affinity, diversity and developability directly from next-generation antibody libraries mAbs 13(1) discusses similar teachings about how improving the stability and developability of a lead antibody is typically achieved by modifying the sequence which can be time consuming and often results in reduced affinity and how sequence-based liabilities may affect one or more characteristics (abstract). Further, Teixeria and Erasmus teaches antibody libraries needed to determine affinity binding (abstract). Based on these teaching, a person of ordinary skill in the art at the time of filing would have not been able to identify which species of the claimed genus would be capable of the claimed function.
Claims 4, 7, 11, and 13-15 are rejected due to their dependency on claim 1.
For the purpose of further examination, the claims will only be interpreted in light of the antibodies supported by the specification.
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.
Claims 3, 13, 24, 32, and 35 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 3 recites dependence to “the antibody of claim 2,” claim 2 however is cancelled rendering the claim indefinite. For the purpose of further examination and in light of the specification which recites the sequences listed in claim 3 are embodiments of the wild card containing sequence SEQ ID NO: 41 (pg.14, paragraph 0066), claim 3 will be interpreted to depend on antibody (2) of claim 1.
Claim 13 recites dependence to “the antibody of any one of claim 8,” claim 8 however is cancelled rendering the claim indefinite for the purpose of further examination and in light of the specification which recites “a method of stimulating natural killer (NK) cell-mediated cytotoxicity in a human in need thereof. In some embodiments, the method comprises administering the antibody as described above to the human in an amount sufficient to stimulate NK cell-mediated cytotoxicity,” (pg.4, paragraph 0014) the claim will be interpreted to depend on claim 1.
Claim 24 recites dependence to “the antibody of claim 19,” claim 19 however is cancelled rendering the claim indefinite for the purpose of further examination and in light of the specification which recites “a method of stimulating natural killer (NK) cell-mediated cytotoxicity in a human in need thereof. In some embodiments, the method comprises administering the antibody as described above to the human in an amount sufficient to stimulate NK cell-mediated cytotoxicity,” (pg.4, paragraph 0019) the claim will be interpreted to depend on claim 16.
Claim 32 recites “a polynucleotide encoding the antibody of claim 27 any one of claims 27-31” it is unclear which of the statements “antibody of claim 27” or “any one of claims 27-31” governs the claim. Further claims 28, 30, and 31 are cancelled and the claim cannot depend on them rendering the claim indefinite. For the purpose of further examination the claim will be interpreted to read “a polynucleotide encoding the antibody of claim 27.”
Claim 35 recites dependence to “the antibody of any one of claim 30,” claim 30 however is cancelled rendering the claim indefinite for the purpose of further examination and in light of the specification which recites “a method of stimulating natural killer (NK) cell-mediated cytotoxicity in a human in need thereof. In some embodiments, the method comprises administering the antibody as described above to the human in an amount sufficient to stimulate NK cell-mediated cytotoxicity,” (pg.5, paragraph 0026) the claim will be interpreted to depend on claim 27.
Prior Art of Record
The prior art of record does not disclose an antibody that binds to NCR3 having a variable light and variable heavy chain with the enabled (outlined above) CDR combinations recited in claim 1. Dependent claims 3, 4, 7, 10, 11, and 13-15 are therefore also free of the prior art.
Claim 1 recites claim to three antibodies ((1), (2), and (3)) which bind to Natural Cytotoxicity Triggering Receptor (NCR) 3.
In regards to antibody (1) the antibody comprises at least a light chain variable region comprising LCDRs 1 , 2, and 3 of SEQ ID Nos: 2, 3, and 4 respectively and heavy chain variable region comprising HCDRs 1 , 2, and 3 of SEQ ID Nos: 6, 7, and 8 respectively. The prior art of record does not disclose a light chain variable region comprising LCDRs of SEQ ID NOs: 2, 3, and 4, and therefore does not disclose the antibody binding to NCR3. The following is considered the closest prior art.
Wells et al. (US Pat No. 11,603,412, priority date: 10/25/2017)
Wells teaches the light chain variable region SEQ ID NO: 64 which shares the following alignment with the instant CDRs SEQ ID NOs: 2, 3, and 4:
PNG
media_image1.png
236
623
media_image1.png
Greyscale
As shown in the alignment, the sequence comprises mismatches in CDR3. Further the light chain variable region is part of an antibody which binds to CUB domain containing protein 1 (CDCP1) and thus does not disclose the antibody of the instant application.
In regards to antibody (2) the antibody comprises at least a light chain variable region comprising LCDRs 1 , 2, and 3 of SEQ ID Nos: 10, 11, and 12 respectively and heavy chain variable region comprising HCDRs 1 , 2, and 3 of SEQ ID Nos: 14, 15, and all enabled HCDR3s (see above) respectively. The prior art of record does disclose a light chain variable region comprising LCDRs of SEQ ID NOs: 10, 11, and 12, however the light chain variable region is not attached to a heavy chain variable region with HCDRs of SEQ ID NOs: 14, 15, or any enabled HCDR3s and therefore does not disclose the antibody binding to NCR3. The following is considered the closest prior art.
Burden et al. (US Pat No. 11,492,401, priority date: 04/16/2021)
Burden teaches the light chain variable region SEQ ID NO: 98 which shares the following alignment with the instant CDRs SEQ ID NOs: 10, 11, and 12:
PNG
media_image2.png
238
624
media_image2.png
Greyscale
As shown in the alignment, the sequence comprises all the CDR sequences of the instant application. However, the heavy chain variable region associated with the light chain variable region is represented by SEQ ID NO: 97 which shares the following alignment with the instant CDRs SEQ ID NOs: 14, 15, and 16:
PNG
media_image3.png
218
662
media_image3.png
Greyscale
As shown in the alignment, the sequence is missing the first amino acid residue of CDR1, and further the light chain variable region with the heavy chain variable region is part of an antibody which binds to MuSK and thus does not disclose the antibody of the instant application.
In regards to antibody (3) the antibody comprises at least a light chain variable region comprising LCDRs 1 , 2, and 3 of SEQ ID Nos: 18, 19, and 20 respectively and heavy chain variable region comprising HCDRs 1 , 2, and 3 of SEQ ID Nos: 22, 23, and 24 respectively. The prior art of record does not disclose a light chain variable region comprising LCDRs of SEQ ID NOs: 18, 19, and 20, and therefore does not disclose the antibody binding to NCR3. The following is considered the closest prior art.
Moffat et al. (WO 2020/102904)
Moffat teaches the light chain variable region SEQ ID NO: 158 which shares the following alignment with the instant CDRs SEQ ID NOs: 18, 19, and 20:
PNG
media_image4.png
233
618
media_image4.png
Greyscale
As shown in the alignment, the sequence comprises mismatches in CDR3. Further the light chain variable region is part of an antibody which binds to Protocadherin-1 and thus does not disclose the antibody of the instant application.
Claims 24 and 35 are clear of prior art as outlined below in allowable subject matter but are not allowable due to the 112b rejections described above.
Allowable Subject Matter
Claims 16, 18, 21, 22, 27, 29, and 32-34 are allowed.
The following is a statement of reasons for the indication of allowable subject matter.
Independent claim 16 recites claim to an antibody that binds to NRC1 wherein the antibody comprises at least a light chain variable region comprising LCDRs 1 , 2, and 3 of SEQ ID Nos: 26, 27, and 28 respectively and heavy chain variable region comprising HCDRs 1 , 2, and 3 of SEQ ID Nos: 30, 31, and 32 respectively. It is noted that instant application SEQ ID Nos: 26, 27, and 28 are identical to instant application SEQ ID Nos: 10, 11, and 12 respectively, and the as discussed above for antibody (2) of claim 1 above, the light chain variable region is taught by the art, however no art was found for a heavy chain variable region comprising HCDRs of SEQ ID NOs: 30, 31, and 32 and further all of the art none show any similar HCDRs to the claimed HCDRs.
Claims 18, 21, and 22 are allowed due to their dependence on claim 16.
Independent claim 27 recites claim to an antibody binding to CD-16 wherein the antibody comprises at least a light chain variable region comprising LCDRs 1 , 2, and 3 of SEQ ID Nos: 34, 35, and 36 respectively and heavy chain variable region comprising HCDRs 1 , 2, and 3 of SEQ ID Nos: 38, 39, and 40 respectively. The prior art of record does not disclose a light chain variable region comprising LCDRs of SEQ ID NOs: 34, 35, and 36, and therefore does not disclose the antibody binding to CD-16. The following is considered the closest prior art:
Burden et al. (US Pat No. 11,492,401, priority date: 04/16/2021)
Burden teaches the light chain variable region SEQ ID NO: 98 which shares the following alignment with the instant CDRs SEQ ID NOs: 34, 35, and 36:
PNG
media_image5.png
302
777
media_image5.png
Greyscale
As shown in the alignment, the sequence comprises mismatches in CDR3. Further the light chain variable region is part of an antibody which binds to MuSK and thus does not disclose the antibody of the instant application.
Claims 29 and 32-34 are allowed due to their dependence on claim 27.
Further the state of the art around the effective filing date of the claimed invention also does not provide a predictable structure-function relationship to support mismatches in antibody sequences, or mismatching CDRs as discussed by Chiu and, Teixeira and Erasmus above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Friday from 8:30am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (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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/D.A.A/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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