DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed 02/27/2023, has been entered.
Claims 1-25 have been canceled.
Claims 26-43 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 26-36) and species H5 antibody with VH and VL sequences of SEQ ID NOs: 3 and 5, respectively, in the reply filed on 11/17/2025 is acknowledged.
Claims 37-43 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 26-36 are currently under examination as they read on an anti-hepsin antibody.
Independent claim
26. (New) An antibody or antigen-binding fragment thereof that comprises:
a. a variable heavy chain, wherein the variable heavy chain comprises a reconstructed polypeptide consensus sequence selected from any one of SEQ ID NOS: 1-3; or
b. a variable light chain, wherein the variable light chain comprises a reconstructed polypeptide consensus sequence selected from any one of SEQ ID NOS: 4-5.
Claim Rejections - 35 USC § 112
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.
Claims 33-36 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.
Base claim 26 is drawn 3 VH or 3 VL. Dependent claims 33 and 34 recite CDRs, the smaller fragments residing in a VH or VL. A genus in claims 33 and 34, for example, a VH comprising those CDRs in claim 33 and 34 does not have the FR1-4 in a VH sequence of the base claim, for example SED NO:1 in claim 26. Therefore claim 33 and 34 do not further limit the base claim. They are broader since the genus included in claims 33 and 34 do not include the FR sequences in the base claim. Further, mixing CDRs would not further limit claim 26. Regarding both CDRs and FRs, the dependent claims are broader in scope. Claims 35 and 36 have the same problem as claims 33 and 34.
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. Please see Allowable Subject Matter below for suggestion for claim amendment.
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.
Claims 26-36 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
A) The following Grounds of Rejection are based on an antibody without antigen specificity (claims 26, 28-36).
Antibodies are glycoproteins that possess the ability to react in vitro and in vivo specifically and selectively with the antigenic determinants or epitopes eliciting their production or with an antigenic determinant closely related to the homologous antigen.
Antibodies are immunoglobulins that are formed in response to immunogens or that are screened for specificity an antigen / immunogen.
It has been well established in the art that the antigen binding specificity is critical to how the skilled artisan would employ antibodies in various modalities (e.g., affinity purification, detection or diagnostic assays, bioassays, treatment), including those consistent with the instant disclosure (see specification, including the Summary of the Invention).
However, the instant claims do not recite an antigen specificity for hepsin. The specification provides insufficient direction or guidance regarding how to make and use antibodies comprising the claimed sequences in the absence of an antigen specificity for hepsin and yet retain substantially the same binding specificity of the anti-hepsin antibodies and antigen-binding fragments thereof, which are enabling consistent with the disclosed utilities of the instant disclosure.
Given the well-known polymorphism of antibodies, it would have been undue experimentation to make and use the vast repertoire of antibodies encompassed by the claimed invention in the absence of binding specificity for hepsin to enable the scope of the claimed antibodies encompassed by the claimed invention.
Without sufficient guidance and given the well-known complexity and unpredictability of using antibodies with no particular antigen specificity as well the well-known polymorphism of antibodies; it would be unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue to make and use the vast repertoire of antibodies broadly encompassed by the claimed invention in order to make and use the anti-hepsin antibodies consistent with the instant disclosure.
Applicant is invited to amend the claims by reciting the antigen-specificity, hepsin.
B) The following Grounds of Rejection are based on an antibody with fewer than all of the six CDRs; having mismatched VH and VL, or VH CDR and VL CDR (claims 26-36).
The breadth of the instant claims encompasses an anti-hepsin antibody in which fewer than all of the six CDRs (three from the heavy chain variable region and three from the light chain variable region) and mismatching of CDRs from VH and VL found in the heavy plus light chain pair that forms the binding region of a referenced antibody are defined. Therefore, the following grounds of rejection have been set forth.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. MacCallum et al. J. Mol. Biol. (1996) 262, 732-745, analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology (2002) 169, 3076-3084) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (BBRC 2003, 307:198-205), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.). Vajdos et al. (J. Mol. Biol. (2002) 320, 415-428), additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Chen et al. (J. Mol. Bio. (1999) 293, 865-881) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol. (1999) 294, 151-162) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. Padlan et al. (PNAS 1989, 86:5938-5942) described the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen. Lastly, Lamminmaki et al. (JBC 2001, 276:36687-36694) describe the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen (even CDR2 of VL, which is rarely directly involved in hapten binding).
Thus, the state of the art recognized that it would be highly unpredictable that an antibody comprising less than all six CDRs from both the VH and VL regions with a desired specificity would bind the same antigen. Likewise, variations in the heavy and light chains that read on variations in the CDRs also would provide unpredictablity in the antigen-binding capability of the antibody. Thus, the minimal structure which provides the function of hepsin-binding appears to include six CDRs (three in the heavy chain variable region and three in the light chain variable region) from the same antibody.
The instant disclosure enabled the antibodies with both heavy and light chain chains for binding hepsin. For example, H5 antibody disclosed in the instant specification comprises all six CDRs from the heavy and light chain set forth in SEQ ID NOs: 3 and 6 (Table 1, page 51). The specification as filed did not provide any evidence showing that either the heavy chain CDRs or the light chain CDRs of the H5 antibody alone can bind hepsin and efficiently detect hippuric acid, a feature that is critical for the present antibody.
Without sufficient guidance, and in view of the unpredictability of the art, it would require undue experimentation of the skilled artisan to make or use the claimed antibodies with less than all six CDRs or having variations in the heavy and light chains that read on the CDRs in order to bind selectively hepsin commensurate in scope with the instant disclosure.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary, the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Allowable Subject Matter
Anti-Hepsin antibodies H5 and H2 with the VH and VL sequences as disclosed in the instant specification (Table 1 and 2) are free of prior art.
Applicant is invited to amend the independent claim in the following format to recite a claimed antibody in order to obviate the above rejections:
An anti-Hepsin antibody or antigen binding fragment thereof, comprising:
(a) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 19;
(b) a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 14;
(c) a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 9;
(d) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20;
(e) a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 15; and
(f) a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 10.
Claims reciting VH/VL should depend on the above suggested claim in order to be further limiting.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHARON X WEN whose telephone number is (571)270-3064. The examiner can normally be reached Mon-Fri 8-5.
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/SHARON X WEN/Primary Examiner, Art Unit 1641