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 .
1. Claims 1-27 are pending and being examined.
Claim Objections
2. Claim 3 is objected to because of the following informalities: Claim 3 part (xiv) recite a typo of “an d16” that should be corrected to “and 16”. Claim 3 part (xv) recites a typo of “and16” that should be corrected to “and 16”.
Appropriate correction is required.
3. Claim 14 is objected to because of the following informalities: Claim 14 contains a grammatical typo where the conjunction “and” is used twice in listing the SEQ ID NOs. Examiner suggests amending the claim to recite: “…any one of SEQ ID NOs:481-503, 515, 522, 524, and 509.” Appropriate correction is required.
4. Claim 20 is free of the art but is 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.
Claim Rejections - 35 USC § 112
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.
5. Claims 1-19 and 21-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an antibody or fragment thereof that specifically binds to stem cell factor SCF248 and comprises the claimed heavy and light chain CDR SEQ ID NOs, does not reasonably provide enablement for an antibody or fragment thereof that specifically binds to any stem cell factor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The claims broadly encompass an antibody or fragment thereof that specifically binds to any stem cell factor (SCF), wherein the antibody comprises a heavy chain and light chain, each chain comprising the claimed CDR SEQ ID NOs.
The instant specification discloses there are at least three isoforms of SCF: SCF248, SCF220, and SCF165, wherein each play distinct, non-redundant roles in regulating hematopoietic stem cells, mast cells, and inflammatory responses, with SCF248 isoform implicated in chronic fibrosis and allergic diseases. The specification discloses that the claimed antibodies are derived from parental monoclonal antibody 5H10 that binds to a soluble isoform of SCF that is identified as SCF248:
[0089] The present disclosure provides antibodies having modified CDR regions that surprisingly resulted in improved affinity for SCF relative to the parental murine antibody 5H10 as well as the parental humanized antibody 5H10 VK3/VH1. Modifications in the CDR regions of the parental antibodies were identified that surprisingly result in significantly enhanced affinity for SCF. Table 5 provides consensus sequences representing the modified CDRs.
[0104] In some embodiments, the antibodies described herein bind to a polypeptide comprising the amino acid sequence of SEQ ID NO: 479. The 5H10 VK3/VH1 humanized antibody of Table 1 binds to a C-terminal biotinylated polypeptide of SEQ ID NO: 479 with a KD of about 165.6. The 5H10 VK3/VH1 humanized antibody of Table 1 binds to an N-terminal biotinylated polypeptide of SEQ ID NO: 479 with a KD of about 229.6.
[0105] Binding of the antibodies may be evaluated via ELISA, for example, as described in Example 3 of this disclosure. The absorbance values for binding of the humanized 5H10 VK3/VH1 antibody of Table 1 to the polypeptide of SEQ ID NO: 479 (a peptide of SCF248) at various antibody concentrations are below.
[0119] The SCF248 isoform of SCF includes exon 6, which comprises a cleavage site between two alanine residues (amino acids 16 and 17 of SEQ ID NO: 473, which provides the amino acid sequence of exon 6). Previous anti-SCF antibodies were generated by immunizing mice with a peptide spanning exon 6 and part of Exon 7 (see, e.g., U.S. Pat. No. 8,911,729, which is hereby incorporated by reference in its entirety for all purposes). Since SCF220 is associated with homeostatic activities, any cross-reactivity with SCF220 would be detrimental as it would result in various off-target effects in subjects. Advantageously, the antibodies provided in the present disclosure bind to SCF248 with very high specificity. In some embodiments, the antibodies provided herein are specific for SCF248 and do not bind to SCF220. Thus, the antibodies provided herein are capable of specifically inhibiting the interaction between SCF248 and c-Kit that induces and perpetuates chronic inflammatory responses and fibrosis. Moreover, the antibodies provided herein are capable of specifically inducing the internalization of SCF and thereby reducing the interaction between SCF248 and c-Kit. Accordingly, in some embodiments the present disclosure provides antibodies that are specific for SCF248 and are safe and effective in various inflammatory and fibrotic diseases discussed herein and known in the art.
The instant specification discloses that the claimed antibody does not bind to the membrane-bound SCF (mSCF) isoform identified as SCF220:
Stem Cell Factor
[0079] In humans, there are at least two forms of SCF, which have different structures and activities. SCF220 functions in several homeostatic functions, including hematopoiesis and spermatogenesis and is found in bone marrow, testis, and other tissues and organs. SCF220 is slowly cleavable and sometimes called “membrane SCF.” In contrast, SCF248 is rapidly cleavable and comprises a cleavage site in exon 6, located between the N-terminal c-kit binding domain and the transmembrane domain. SCF248 may be referred to as “soluble SCF”. Exon 6 is excluded from SCF220 via alternative splicing, and SCF220 thus lacks this cleavage site. A monomeric, extracellular domain (SCF165) is the cleavage product and serves as a biomarker in plasma for chronic inflammatory diseases. Plasma may also contain detectable levels of SCF extracellular domain that comes from SCF220, but the majority of detectable extracellular domain is expected to be SCF165. SCF248 is the isoform found on myofibroblasts, activated epithelial cells, and other cells, which activates immune cells during inflammation and contributes to perpetuation of fibrosis. More specifically, SCF248 binds to c-Kit on immune cells, initiating production of cytokines that activate fibroblasts to become myofibroblasts, which secrete extracellular matrix proteins, collagen, and fibronectin. The activated myofibroblasts as well as activated epithelia, endothelia, macrophages, eosinophils, mast cells, monocytes, and other cells also express SCF on the cell surface, activating more c-Kit+ immune cells, resulting in further cytokine release and immune activation and fibrotic responses.
[0080] The antibodies and antigen-binding fragments thereof disclosed herein are specific for SCF. In some embodiments, the antibodies and fragments thereof are specific for human SCF. In some embodiments, the antibodies and fragments thereof are specific for SCF248. In some embodiments, the antibodies bind SCF248 and do not bind other isoforms of SCF. In some embodiments, the antibodies bind SCF248 and do not bind to SCF220.
Example 6 of the instant specification demonstrates the parental antibody does not bind to SCF220:
[0180] Controls are run with the ATCC cell line SL/SL3 hSCF220 (CRL-2453) that only expresses SCF220 as well as ATCC cell line SL/SL2 control (CRL-2452). ATCC cell line SL/SL2 control cells do not express any SCF isoforms. Neither of these cell lines show internalization and demonstrate specificity for the parental antibody.
Thus, the instant specification demonstrates that the parental 5H10 antibody cannot bind to stem cell factor SCF220 form, and it is reasonably expected that the instantly claimed antibodies derived from parental 5H10 antibody have the same binding characteristics as 5H10 and are unable to bind SCF220. The instant antibodies are not enabled to bind to any stem cell factor as broadly claimed. The instantly claimed methods for treating chronic inflammatory disease or a fibrotic disease in a subject would not be enabled unless the administered antibody binds to and inhibits SCF248 that is specifically linked to these diseases.
Examiner Suggestion: Amend the limitation of claim 20 into claim 1
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
6. Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 7 is dependent from claim 1. Claim 1 is limited to an antibody that binds to SCF and comprises a heavy chain and a light chain, wherein the heavy and light chain CDRs are defined in claim 1. Claim 7 recites the antibody is a single domain antibody (sdAb), which is an antibody that contains only the heavy chain variable domain CDRs and excludes any light chain sequences, therefore a sdAb is outside the scope of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
7. Claims 12, 13, and 14 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 12, 13, and 14 depend from claim 1. Claim 1 is limited to an antibody that binds to SCF and comprises a heavy chain and a light chain, wherein the heavy and light chains each comprise CDRs1-3 as defined in claim 1.
Claim 12 recites the antibody “comprising a heavy chain amino acid sequence of any one of SEQ ID NOs:892-914, 926, 933, 935, and 920 and a light chain amino acid sequence of any one of SEQ ID NOs:…” Claim 12 is interpreted as an antibody that comprises any heavy chain amino acid sequence of (found in) any of SEQ ID NOs:892-914, 926, 933, 935, and 920 as few as two consecutive amino acids found within the listed SEQ ID NOs. Similarly, claim 12 is interpreted as an antibody that comprises any light chain amino acid sequence of (found in) any of SEQ ID NOs:1029-1051, 1063, 1070, 1072, and 1057, as few as two consecutive amino acids found within the SEQ ID NOs. Therefore, the antibody of claim 12 is not required to comprise the full six CDR SEQ ID NOs from the heavy and light chains recited in claim 1, and falls outside the scope of claim 1.
Claim 13 recites the antibody comprises “a heavy chain amino acid sequence of any one of SEQ ID NOs:618-640, 6522, 659, 661, and 646, and a light chain amino acid sequence of any one of SEQ ID NOs:755-777, 789, 796, 798, and 783.” Claim 13 is interpreted as an antibody that comprises any heavy chain amino acid sequence of (found in) any of SEQ ID NOs:618-640, 6522, 659, 661, and 646, as few as two consecutive amino acids long. Similarly, claim 13 is interpreted as an antibody that comprises any light chain amino acid sequence of (found in) any of SEQ ID NOs:755-777, 789, 796, 798, and 783 as few as two consecutive amino acids long. Therefore, the antibody of claim 13 is not required to comprise the full six CDR SEQ ID NOs from the heavy and light chains recited in claim 1, and falls outside the scope of claim 1.
Claim 14 recites the antibody comprises an amino acid sequence of any of SEQ ID NOs:481-503, 515, 522, 524, and 509. Claim 14 is interpreted as an antibody that comprises any amino acid sequence of (found in) the claimed SEQ ID NOs, as few as two consecutive amino acid long. Therefore, the antibody of claim 14 is not required to comprise the full six CDR SEQ ID NOs from the heavy and light chains recited in claim 1, and falls outside the scope of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Alternatively, Applicants may amend the claims to recite:
Claim 12. The antibody or fragment thereof of claim 1 comprising the heavy chain amino acid sequence of any one of SEQ ID NO:892-914, 920, 926, 933, and 935 and the light chain amino acid sequence of any one of SEQ ID NOs:1029-1051, 1057, 1063, 1070, and 1072.
Claim 13. The antibody or fragment of claim 1 comprising the heavy chain amino acid sequence of any one of SEQ ID NOs:618-640, 646, 652, 659, and 661.
Claim 14. The antibody or fragment thereof of claim 1 comprising the amino acid sequence of any one of SEQ ID NOs:481-503, 509, 515, 522, and 524.
8. Conclusion: Claims 1-19 and 21-27 are rejected. Claim 20 is objected to. The closest prior art made of record but not relied upon are US Patent 11,939,373, Phillips, claiming priority to September 2019, and WO 2012/096960, Lukacs et al, published July 2012.
US Patent 11,939,373, Phillips teaches the parental anti-SCF antibody 5H10. Antibody 5H10 comprises VH and VL CDR SEQ ID NOs 1-6 that fall within the scope of the instantly claimed CDR SEQ ID NOs:1-6 except the VL CDR1 SEQ ID NO:4 of US Patent 11,939,373 comprises a Lys (K) at position 12 instead of a Asn (N) as recited in the instant claims:
SEQ ID NO
Instant Application 18/550,438
US Patent
11,939, 373
VH CDR1
1
SXXMN
SYWMN
VH CDR2
2
QIYPXDXDXHXNXKFXX
QIYPGDGDTHYNGKFKG
VH CDR3
3
XNWXGSY
SNWVGSY
VL CDR1
4
XXSQSLLXXDGNTYLN
KSSQSLLESDGKTYLN
VL CDR2
5
LVXRXDX
LVSRLDS
VL CDR3
6
WQGXXLPQT
WQGTHLPQT
US Patent 11,939,373 does not teach or suggest the VL CDR1 sequence instantly claimed that results in antibodies having improved affinity to SCF248. It is also noted on the record that US Patent Application Publication 2022/0324957 and US Patent 12,410,246, both teach the same anti-SCF sequences as US Patent 11,939,373 and claim the same priority to September 2019.
WO 2012/096960, Lukacs, teaches monoclonal anti-SCF antibody and fragments thereof that are administered to subjects to treat inflammation and fibrosis, wherein the antibody inhibits binding of SCF to c-kit (sections 1, 2 and 4; claims 1-7, 9-30). Lukacs does not teach or suggest the anti-SCF antibody comprises the instantly claimed CDR SEQ ID NOs.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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