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 .
Status of Claims
The amended claims filed 12/04/2005 are acknowledged and entered.
Claims 1, 9 and 78 have been amended
Claims 2, 7, 14, 15, 20-22, 33-34, 47, 49, 51, 58-61 and 82-83 are cancelled
Claims 67, 78-79 are withdrawn
Claims 85-91 are new
Claims 1, 8-10, 24, 26-27, 41-42, 84 and 85-91 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Objections
Specification - Withdrawn
The disclosure was objected to because of the following informalities:
a) The use of the term(s), which are a trade name or a mark used in commerce,
Applicant has corrected the informalities in the substitute specification and the objection is withdrawn.
Claim Rejections - 35 USC § 112 withdrawn
1. The rejections for claims 1-2, 8, 24, 26-27 and 41-42 under 35 U.S.C. 112(a) because of lack of enablement is withdrawn in view of Applicant’s amendment of claim 1 and cancellation of claim 2. Claims 8, 24, 26, 27, 41 and 42 depend from claim 1 as amended
New Rejections Based on Amendments
Claim Rejections - 35 USC § 112
Claims 1, 24, 26-27, 41-42, 84 and 85-91 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for some binding proteins, or antibodies, with six well-defined CDRs capable of binding a TAT protein transduction domain (PTD), does not reasonably provide enablement for any framework to support binding to this specific target antigen .The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Claims 1 and 41-42 are drawn to a binding protein, or an antibody, comprising an antigen binding domain, said antigen binding domain comprising:
1) a VH CDR3 domain comprising SEQ ID NO: 4; a VH CDR2 domain comprising SEQ ID NO: 3; and a VH CDR1 domain comprising SEQ ID NO: 2; and
2) a VL comprising a VL CDR3 domain comprising SEQ ID NO: 8, a VL CDR2 domain comprising SEQ ID NO: 7, and a VL CDR1 domain SEQ ID NO: 6; or a VL comprising a VL CDR3 domain comprising SEQ ID NO: 12, a VL CDR2 domain SEQ ID NO: 11, and a VL CDR1 domain comprising SEQ ID NO: 10, wherein said binding protein is capable of binding a TAT protein transduction domain Claim 2 is drawn to the binding protein of claim 1, wherein said antigen binding domain further comprises a light chain CDR3 domain comprising the amino acid sequence selected from SEQ ID NO: 8 and SEQ ID NO: 12;
wherein said binding protein is capable of binding a TAT protein transduction domain
Claims 89, 90-91 are drawn to the binding protein, wherein said antigen binding domain comprises a VL region comprising SEQ ID NO: 1 or SEQ ID NO: 14 with at least 90% identity for SEQ ID NO: 1.
Claim 85, 86, 87, 88, is drawn to the binding protein, wherein said antigen binding domain comprises a VL comprising SEQ ID NO: 5, VL comprising SEQ ID NO: 9, or a VL comprising SEQ ID NO: 13, with at least 90% identity for SEQ ID NOs: 1, 13
Claims 10 and 84 are drawn to the binding protein, wherein said antigen binding domain comprises (1) a VH comprising SEQ ID NO: 1 and VL comprising SEQ ID NO: 5, (2) a VH comprising SEQ ID NO: 1 and VL comprising SEQ ID NO: 9, (3) a VH comprising SEQ ID NO: 1 and VL comprising SEQ ID NO: 13, (4) a VH comprising SEQ ID NO: 14 and VL comprising SEQ ID NO: 5 with at least 95% identity for SEQ ID NO: 1 and 95% identity for SEQ ID NO: 5.
Claims 24 and 26-27 are drawn to the binding protein of claim 1, wherein the TAT PTD comprises SEQ ID NO: 23 and maybe is covalently linked to a cargo moiety.(a polypeptide, a frataxin polypeptide, an antibody, a nucleic acid, a small molecule, a liposome enclosing protein, a radionuclide or radionuclide labeled compound, or any combination thereof).
Further, while the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, there is no evidence and no correlation that any unspecified changes in the framework can still retain binding to TAT PTD. Lastly, the specification does not establish any additionally framework changes. The teachings of the art also fail to indicate that, without such evidence, those in the art would have expected the full scope of the claimed VH and VL with undefine framework changes would confer the claimed biding to TAT PTD. For example, a search of the art indicates that modifications to biological molecules such as proteins are unpredictable, and require experimentation regarding the relationships between alterations in sequence bases/side chains and the function and structure of the protein in order to determine the actual effects of the modifications as discussed by Bowie et al. (Bowie JU, Reidhaar-Olson JF, Lim WA, Sauer RT. Deciphering the message in protein sequences: tolerance to amino acid substitutions. Science. 1990 Mar16;247(4948):1306-10; See page 1306). The art also shows that single amino acid mutations in the antibodies can greatly affect the ability of said antibody to bind to its target antigen (Winkler K, Kramer A, Küttner G, Seifert M, Scholz C, Wessner H, Schneider-Mergener J, Höhne W. Changing the antigen binding specificity by single point mutations of an anti-p24 (HIV-1) antibody. J Immunol. 2000 Oct 15;165(8):4505-14.; See also Kussie PH, Parhami-Seren B, Wysocki LJ, Margolies MN. A single engineered amino acid substitution changes antibody fine specificity. J Immunol. 1994 Jan 1;152(1):146-52.) When single amino acid mutations are generated, or when the combination or order of CDRs within an antibody is altered, it affects the neutralizing capability of the resulting antibody or fragment thereof (Chen Z, Wang J, Bao L, Guo L, Zhang W, Xue Y, Zhou H, Xiao Y, Wang J, Wu F, Deng Y, Qin C, Jin Q. Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus. Nat Commun. 2015 Mar 30;6:6714.) The art has further highlighted the importance of the order of CDRs, the interaction of non-CDR domains with respect to antigen/epitope binding, and that antigen-antibody algorithms or epitope prediction software/rational antibody design is highly inaccurate (Sela-Culang I, Kunik V, Ofran Y. The structural basis of antibody-antigen recognition. Front Immunol. 2013 Oct 8;4:302.) Computational in silico methods have traditionally struggled to predict the effect of mutations in antibody–antigen complexes on binding affinity, and generation of actual mutants in vitro of antibodies is the preferred and reliable method to determine the effect of mutations on antigen-antibody binding (Sirin S, Apgar JR, Bennett EM, Keating AE. AB-Bind: Antibody binding mutational database for computational affinity predictions. Protein Sci. 2016 Feb;25(2):393-409. Epub 2015 Nov 6.) The CDR positions are also vital, as it is shown the length and sequence of the CDR in the H3 position can affect the overall binding capability of the antibody (Tsuchiya Y, Mizuguchi K. The diversity of H3 loops determines the antigen-binding tendencies of antibody CDR loops. Protein Sci. 2016 Apr;25(4):815-25. Epub 2016 Jan 20.) The antigen itself can determine what lengths of CDRs are tolerated (Collis AV, Brouwer AP, Martin AC. Analysis of the antigen combining site: correlations between length and sequence composition of the hypervariable loops and the nature of the antigen. J Mol Biol. 2003 Jan 10;325(2):337-54.). Further, CDRs may vary depending on the numbering system utilized. The Chothia, Kabat, Martin, IMGT, Honneger, and Gelfand numbering schemes all differ, and depending on the numbering system utilized, one may end up with wildly different antibodies with functional differences distinct from the original antibody (See e.g. Dondelinger M, Filée P, Sauvage E, Quinting B, Muyldermans S, Galleni M, Vandevenne MS. Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition. Front Immunol. 2018 Oct 16;9:2278.) Regardless of the choice of CDRs, about 20% of the residues that bind the antigen fall outside the CDRs. Moreover, these residues are at least as important to antigen binding as residues within the CDRs, and in some cases, they are even more important energetically. Therefore, for CDR grafting, the CDR definition is a good starting point, but the framework residues interacting with the antigen must be considered. Typically, for shorter CDRs, more FR residues, and for longer CDRs, fewer FR residues will need to be considered for back mutations. (Chiu ML, Goulet DR, Teplyakov A, Gilliland GL. Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). 2019 Dec 3;8(4):55. Page 12). Structurally, the complementarity-determining regions (CDRs) from both heavy and light chains form a paratope, while framework regions (FWRs) of each chain form a 2-layered β-sandwich to present and stabilize the conformations of CDRs. SHMs in CDRs undergo frequent antigen-specific selection to optimize the physical non-covalent interactions between paratope and epitope. FWRs are more conserved than CDRs; however, new evidence demonstrates the critical roles of FWR SHMs in both in vivo and in vitro affinity maturation. In contrast to SHMs in CDRs, many beneficial SHMs in FWRs modulate antibody features remotely by altering the stability and conformations of CDRs, the pairing of specific VH-VL interactions, and the elbow angles between the variable and constant domains (VH-CH1 or VL-CL). Because many FWR residues are conserved among germline genes, a FWR SHM could affect antibody features consistently among antibodies with different gene origins, and we thus refer to such consistent affects as a common mechanism of modulation (Sheng Z, Bimela JS, Katsamba PS, Patel SD, Guo Y, Zhao H, Guo Y, Kwong PD, Shapiro L. Structural Basis of Antibody Conformation and Stability Modulation by Framework Somatic Hypermutation. Front Immunol. 2022 Jan 3;12:811632, page 2, second paragraph). These results highlight the pitfalls in attempting to describe an antibody functionally and/or with a percent identity to known structural characteristics.
Thus, in view of the above, there would have been significant uncertainty as to which framework changes that are possible will be able confer the claimed binding to TAT PTD without undue experimentation. In view of this uncertainty, the claims are rejected for lack of adequate enablement.
Conclusion
1, 24, 26-27, 41-42, 84 and 85-91 claims are not allowed
Claims 8, 9 and 10 are objected to because they depend on a rejected claim.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IMMA BARRERA whose telephone number is (571) 272-0674. The examiner can normally be reached Monday - Friday 9 to 5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached on (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IMMA BARRERA/
Examiner, Art Unit 1671
/RACHEL B GILL/Primary Examiner, Art Unit 1671