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
This application is a U.S. national phase of International Application No. PCT/KR2021/015795, filed on 11/03/2021. This application claims priority to REPUBLIC OF KOREA Application No. KR10-2020-0147716, filed 11/06/2020; KR10-2020-0147845, filed 11/06/2020; KR10-2020-0147590, filed 11/06/2020; KR10-2021-0135095, filed 10/12/2021; and KR10-2021-0135094, filed 10/12/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
The Amendment, filed on 05/05/2023, is acknowledged in which:
Claims 21-30 are canceled.
Claims 1-20 are original.
Claims 1-20 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/05/2023 and 07/28/2026 have being considered by the examiner.
Drawings
The drawings are objected to because Figures 3, 7 and 13 do not comply with the standards for drawings as recited in 37 CFR 1.84 (see MPEP 608.02(V)).
(l) Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction. This requirement applies to all lines however fine, to shading, and to lines representing cut surfaces in sectional views. Lines and strokes of different thicknesses may be used in the same drawing where different thicknesses have a different meaning.
(p) Numbers, letters, and reference characters.
(3) Numbers, letters, and reference characters must measure at least .32 cm. (1/8 inch) in height. They should not be placed in the drawing so as to interfere with its comprehension. Therefore, they should not cross or mingle with the lines…
Specific issues:
Figures 3, 7, and 13 characters are too small
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.
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:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that Figure 13 includes amino acid sequence “GGGGS” without proper disclosure. Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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 replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o 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 of the following informalities: “neurodegerative” should read “neurodegenerative” (pg 35, line 8; pg 40, line 10; pg 41, line 10).
Appropriate correction is required.
The use of the term “Alexa488” (i.e. Alexa Flour) (pg 42, line 19; pg 43, line 12; pg 52, line 1; pg 54 line 8; pg 55, line 1; pg 56, line 4) and “1-Step” (pg 53, line 19; pg 58, line 1; pg 59, line 22; pg 61, line 4), which are trade names or marks used in commerce, have been noted in this application. Each 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.
Claim Rejections - Improper Markush
Claim 20 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of cell surface antigens is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: several antigens listed (i.e. adenovirus fiber knob and HN/NDV) are virus associated antigens, and therefore would not be considered of cellular origin by a person of ordinary skill in the art as evidenced by Taylor (Viruses and Man: A History of Interactions. 2014;23-40):
“Viruses do not contain ribosomes, mitochondria or other cell-like organelles, and are thus completely parasitic. Since they cannot replicate without the metabolic processes of the host cell, they are genetic parasites. This differentiates viruses from bacteria or other single-cell microorganisms (e.g., protozoa), most of which can replicate in culture on their own, although they can also be parasitic.” (pg, ¶ 1)
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 1-20 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 anti-Fc alpha receptor antibody or immunologically active fragment thereof comprising, (a) a VH domain including HCDRs from any one selected from SEQ ID NOs:1-3 for CDR1, SEQ ID NOs: 4-7 for CDR2, and SEQ ID NOs: 8-15 for CDR3; and/or (b) a VL domain including LCDRs from any one selected from SEQ ID NOs:16-21 for CDR1, SEQ ID NOs: 22-27 for CDR2, and SEQ ID NOs: 28-32 for CDR3. This claim encompass a genus of antibody formulations which suggests interchangeability of CDRs from any one of the sequences provided, and encompasses that either a VH or VL fragment as described would be sufficient for Fc alpha receptor binding (i.e. binding does not require a full complement of 6 CDRs).
Instant claims 2-13 (dependent on claim 1) are drawn to the antibody of claim 1, comprising VH domain including various sequences and/or VL domain including various sequences. These claims encompass a genus of antibody formulations which suggests fragments with either the 3 HCDR sequences or fragments with the 3 LCDR sequences are sufficient for active Fc alpha receptor binding (i.e. binding does not require a full complement of 6 CDRs).
Instant claim 7 further claims an antibody species comprising a compliment of 6 CDRs (SEQ ID NOs: 1, 4, 10, 17, 23, and 29) not disclosed in the specification.
MPEP 2163.I1.A.3.a.ii. states that the written description requirement for claimed genus may be satisfied through a sufficient description of a representative number of species by actual reduction to practice, or 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 inventor was in possession of the claimed genus.
The instant specification discloses 9 species of anti-Fc alpha receptor antibodies with sufficient written description, summarized in the table below. However, guidance for arriving at additional variations encompassed by the genus of anti-Fc alpha receptor antibodies as currently claimed is not sufficient to allow one of ordinary skill in the art to envision all potential CDR combinations within claimed genus that predictably retain Fc alpha receptor binding.
SEQ ID NOs
Clone
HCDR1
HCDR2
HCDR3
LCDR1
LCDR2
LCDR3
VH
VL
JS9
2
6
12
18
25
31
73
74
JS19
1
4
15
21
27
32
79
80
JS30
3
7
13
19
26
30
75
76
JS40
1
4
11
16
24
28
81
82
JS41
3
7
14
20
23
30
77
78
JS48
1
4
11
17
23
30
83
84
JS116
1
4
8
16
22
28
85
86
JS144
1
4
9
16
22
28
87
88
JS140
1
5
10
17
23
29
89
90
The state of the art near the effective filing date of the claimed invention demonstrates that antibody functionality is dependent on amino acid structure, particularly regarding complementarity of the CDR domains. It is understood by one of ordinary skill in the art that mutations to CDRs is unpredictable and that each construct requires function testing.
Rabia (Rabia LA et al. Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility. Biochem Eng J. 2018 Sep 15;137:365-374.) teaches that antibody-antigen binding specificity is primarily mediated by the six CDRs within the sequences of variable heavy and variable light chains (Introduction, paragraph 1). Given the chemical diversity possible within combined CDRs alone (~20 different amino acids at ~60 sites), not all combinations can result in viable antibodies suitable for therapeutic applications. An outstanding challenge in the field is that optimizing antibodies based on antigen affinity can lead to defects in other properties such as stability, specificity, and solubility (page 366, column 1, ¶ 2). Even natural antibody maturation, which relies on random somatic mutations, is followed by clonal selection for antibodies with improved affinity and/or with mutations that compensate for destabilizing affinity enhancing mutations (page 366, column 2, paragraph 2). It is expected that most somatic mutations that increase affinity, such as those that increase hydrophobicity or charge, can also reduce specificity. Based on these teachings, introducing variation in antibody structure, particularly in the arrangement of CDR regions, requires thorough testing to ensure suitable binding specificity and antibody stability.
Herold (Herold EM, John C, Weber B, et al. Determinants of the assembly and function of antibody variable domains. Sci Rep. 2017;7(1):12276) teaches antigen binding is "affected by each CDR loop differently" and changes thereto "can in principle affect antigen binding affinity in an unpredictable way" (pg. 14, ¶ 2). Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex (pg. 14, ¶ 3).
Regarding recombinantly-produced single domain antibodies (sdAbs) or heavy chain with 3 CDRs instead of 6 CDRs, Wagner (Int J Mol Sci. 2018 Nov 2;19(11):3444) teaches that design of nanobody grafts with CDRs derived from conventional antibodies (VH CDRs) requires careful consideration because conventional antibodies utilize both VH and VL domains for antigenic recognition (page 2, last ¶). A direct CDR grafting approach was observed to produce weak antigen binders (abstract). A second step was required, in which additional affinity maturation steps by panning of synthetic phage libraries was performed generate nanobodies with sufficient antigen binding, resulting several changes in grafted CDR residues (Abstract; Figure 6B). Therefore, based on these teachings it would be unlikely that direct CDR grafting from conventional VH or VL CDRs to a sdAb format without modifications (e.g. as suggested with “or” statements between claimed VH and VL sequences) would predictably generate a functional immunoglobin binding fragment.
Moreover, Zabetakis (PLoS One. 2013;8(10):e77678) teaches the highly-variable CDRs embody the specific binding interaction of the antigen-antibody complex (introduction ¶ 2). Through CDR swapping experiments in sdAbs comprising 3 CDRs, Zabetakis observed that while swapping framework regions and CDRs will work in some cases to increase thermal stability this can cause unpredictable variability in affinity (i.e. swapping CDRs within sdAbs can change target specificity) (Abstract; Table 1; page 5, column 2, last ¶ ).
In summary, making changes to the CDR sequences of an antibody is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding swapping CDR domains with any reasonable expectation of success nor envisage the breadth of CDR combinations as claimed that would still possess claimed anti-Fc alpha receptor binding. Therefore, instant claims 1-13, and subsequent dependent claims 14-20 that do not rectify these issues, were determined not to meet the written description requirement of 35 USC 112(a).
Allowable Subject Matter
Anti-Fc alpha receptor antibody species with sufficient written description, summarized in the table above, are free from prior art.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (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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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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