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 .
Election/Restrictions
Applicant’s election without traverse of Group I and antibody species which is 12D6 in the reply filed on 09/26/2025 is acknowledged.
The restriction requirement is made final.
Nucleotide and/or Amino Acid Sequence Disclosures
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
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 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
The size of the sequence text file is required to be in bytes instead of KB or kilobytes (see 37 CFR 1.52(e)(5)).
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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.
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 7-9 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.
Independent claim 1 is drawn to an antibody that specifically binds to human CD40 and comprises a heavy chain constant region selected from SEQ ID NO:159-170. The specification defines “specifically binds” on p. 17, second full paragraph, as “[A]n antibody that “specifically binds to human CD40” refers to an antibody that binds to soluble or cell bound human CD40 with a KD of 10-7 M or less, such as approximately less that 10-8 M, 10-9 M or 10-10 M or even lower.” Dependent claim 7 is drawn to wherein the antibody of claim 1 further comprises an antigen binding domain that competes for binding to human CD40 in a cross-blocking assay with antibody 12D6 comprising SEQ ID NO:3 and 4 (the elected antibody species). Note that use of the word “further” in claim 7 means that the antibody of 1 that binds CD40 further, i.e., additionally, comprises a distinct antigen binding domain that competes for binding to human CD40 as set forth in the claim. Dependent claim 8 further limits the cross-blocking assay used to determine if the antibody metes the particular competition parameters. Dependent claim 9 requires the antibody to bind the epitope comprising or consisting of amino acids 11-35 of human CD40 of SEQ ID NO:1 as drawn to the elected antibody species of 12D6.
The specification discloses antibody 12D6, which has the variable heavy region (VH) and variable light region (VL) of SEQ ID NO: 3 and 4, respectively. Humanized versions of 12D6 are referred to as 12D6-03, -22, -23 and -24, comprising the respective VH/VL pairs of sequences of SEQ ID NO: 5/6, 7/8, 9/10 and 11/8. An antibody comprising any of these VH/VL sequence pairs would be expected to meet the functional requirements of claims 7-9 and, therefore, meet the written description provision of 35 USC 112(a). However, the claims are directed to or encompass antibodies with sequences different than these. Because it is generally accepted that the CDR1-3 regions of the variable domains of an antibody are predominantly responsible for antigen-binding, the functional properties of competing for human CD40 binding and binding to a particular epitope of CD40 are dependent on the antibody CDR sequences (see, e.g., p. 10, third paragraph of the specification). Anti-CD40 antibody clones 19G3 and 5G7 bind epitopes that are within the epitope of 12D6 (see Table 7 of WO 2017/004006, cited in the IDS filed 3/10/2023) and, therefore, would reasonably be expected to compete with antibody 12D6 and its disclosed derivatives. No other antibodies aside from 12D6, 19G3, 5G7 and the disclosed humanized versions thereof in claim 13 meet the written description provision of 35 USC 112(a).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
It is stated in AbbVie Deustschland GmbH v. Janssen Biotechnology, Ltd., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., Inc., 323 F.3d at 964, “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date…” In the instant situation, only antibody 12D6 having the VH and VL sequence of SEQ ID NO:3/4, 5/6, 7/8, 9/10 or 11/8 have been shown to possess the properties required by claims 7-9. Because antibodies 5G7 and 19G3 have been shown to bind the same or significantly overlapping human CD40 epitope as 12D6, these also appear the meet the limitations of the claims. It is noted that not all 5G7 or 19G3 humanized antibodies bound human CD40 (see Table 6 of WO 20170004006). These two antibodies have different CDRs than 12D6 and the specification provides no structure-function correlation to allow the skilled artisan to readily envision antibodies other than those indicated above which would meet the competition limitations of the claims.
With the exception of the sequences referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only antibody clones 12D6, 19G3, 5G7 and the disclosed humanized versions thereof as set forth in claims 7 and 13, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-14 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/004006 A1 (“Barnhart”, cited in the IDS filed 3/10/2023) in view of WO 2018218056 A1 (“Yamniuk”, cited in the IDS filed 3/10/2023), WO 2018146317 A1 (“Beurskens”) and Diebolder et al. (Science, 343:1260-1263, 2014, cited in the IDS filed 3/10/23).
Barnhart teaches agonistic anti-human CD40 antibodies,12D6 (SEQ ID NO:3 and 4), 5F11 (SEQ ID NOs: 23 and 24), 8E8 (SEQ ID NOs: 40 and 41), 5G7 (SEQ ID NOs: 52 and 53), and 19G3 (SEQ ID NOs: 58 and 59) (e.g., p. 1, lines 31-33, and p. 94). It is taught that antibody 12D6 binds CD40 epitope WGCLLTAVHPEPPTACRE, residues 11 - 28 of SEQ ID NO: 1 (p. 2, first paragraph). It also teaches that antibodies 12D6, 5G7 and 19G3 all bind CD40 amino acids 21-25 of SEQ ID NO:1 (EPPTACREKQYLINS). Further (p. 2, lines 11-16), it is disclosed that the CDR sequences of antibody 12D6 are “derived at least in part from murine V region germline VH1-39_01 and J region germline IGHJ4 and light chain CDR sequences derived at least in part from murine V region germline VK1-110_01 and J region germline IGKJ1).” (See also Table 3) The CDRs of 12D6-derived antibodies include (p. 3, lines 1-13), “the CDRs of antibody 12D6-03 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO:5 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively; the CDRs of antibody 12D6-22 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO:7 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:9; the CDRs of antibody 12D6-23 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO: 10 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO: 11; the CDRs of antibody 12D6-24 wherein CDRH1, CDRH2 and CDRH3 comprise residues 31-35, 50-66 and 99-108, respectively, of SEQ ID NO: 12 and CDRL1, CDRL2 and CDRL3 comprise residues 24-39, 55-61 and 94-102, respectively, of SEQ ID NO:9….” These 12D6-derived antibodies have the respective VHs of amino acids 1-119 of SEQ ID NO:4, 7, 10 and 12 (12D6-03, -22, -23 and -24) and the respective VLs of amino acids 1-117 of SEQ ID NO:6, 9, 11 and 9 (p. 4, lines 19, 20, 27-32). Table 2 lists positions of the CDRs in the antibody variable regions. Hybrid IgG isotypes are discussed which can increase antibody serum half-life, such as an IgG1/IgG3 hybrid variant (p. 43, lines 19-22). Use of disclosed anti-CD40 antibodies for the treatment of cancer and enhancement of immune response is discussed (p. 69, lines 28-32, and p. 71, lines 17-22). Barnhart et al. does not teach wherein the heavy chain constant region comprises one of instant SEQ ID NO:159-185.
Yamniuk teaches antibodies comprising modified IgG heavy chain constant regions. The antibody may bind to any one of a variety of costimulatory receptors that are a member of the TNF receptor super family (TNFRSF), including CD40 (p. 8, last paragraph). When an antibody costimulatory receptor such as CD40 comprises a modified heavy chain that may be selected from SEQ ID NO:181, 241-245 and 256-262, the antibody exhibits enhanced or altered agonist activity (p. 9, first full paragraph). Table 22 shows that the IgG1 and IgG2 mutations resulted in significantly reduced FcR binding, with addition of L235 added to the P238K-containing isotype having greatly reduced CD64 binding, wherein L235E was more effective than L235A. Adding the P238K mutation to IgG2(IgG2.3-P238K) abolished CD64 binding. (see Example 13) Example 14 shows elimination of effector function with an IgG1 domain modified to IgG1.3 of an anti-CD40 antibody (IgG1.3f of SEQ ID NO:78, e.g., Table 30). The different mutated heavy chain constant regions are shown in Table 33. The sequences shown in the Table that are identical with the instant sequences are as follows (SEQ ID NO: of Yamniuk/instant SEQ ID NO:):241/159; 243/160; 180/161; 253/162; 244/163; 254/164; 256/165; 245 or 258/166; 259/167; 260/168; and 262/170.
Beurskens teaches induction of hexamerization with mutations in the heavy chain constant region, including E345R and E430G (p. 1, lines 13-16). These mutations enhance oligomerization of the antigen to produce Fc-Fc enhancement (p. 31, lines 3-8, and p. 153, lines 28-33: shown with an FAS-binding antibody). Similarly, a wildtype OX40 antibody did not induce an OX40 response, but the presence of Fc-Fc-enhancing mutation E345R resulted in a strong induction, while the presence of only the E430G mutation resulted in only a mild induction (p. 154, lines 31-35). A method of increasing agonistic activity of an antibody by introducing substitution of E345 in the Fc IgG1m(f) constant region with lysine (K) and also wherein the antibody comprises E430G and S440Y is taught in SEQ ID NO:78, which is the same as instant SEQ ID NO:173. However, Fc regions with a substitution at only one of those three positions is also taught, for example substitution of E345 with arginine (R ) or K or is also taught (e.g., p. 5, lines 11-15, p. 25, lines 33-34, and Example 16), which is the same as instant SEQ ID NO:172 and 171, respectively. This was shown when the activity of an agonistic anti-DR5 antibody was increased with a variety of constant region mutations (e.g., Examples 16 and 17). Example 30 evaluated Fc region mutations of an anti-CD40 antibody. All these antibodies are members of the TNFRSF that form trimeric complexes (paragraph bridging pp. 67-68).
Diebolder et al. explain (first sentence of Abstract), “Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease process, and immunotherapies.” It was shown that IgG antibodies activate complement-dependent cytotoxicity (CDC) by ordered clustering into hexamers through noncovalent Fc interactions. For example an E345R Fc mutation in an antibody led to significantly enhanced CDC (p. 1260, col. 3, first full paragraph, first two sentences). When that mutation was combined with E430G and S440Y, the antibodies readily formed hexamers in solution p. 1260, col. 3, first full paragraph, remainder of paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to have a CD40 antibody that comprised the prior art heavy chain constant region substitutions to increase Fc receptor-independent agonist activity. Specifically, as Yamniuk showed that elimination of effector function can be desirable and accomplished with the disclosed mutated antibody heavy chain constant regions, it would have been obvious and desirable for anti-CD40 agonist 12D6 antibody of Barnhart to have the heavy chain constant region comprising any of the mutations taught in Yamniuk, i.e., any corresponding to instant SEQ ID NO:159-170, that increase agonist activity and/or decrease FcR-binding activity. It further would have been obvious wherein the anti-CD40 antibody comprised instead of a P238K mutation e.g., in the IgG2.3 and IgG2.5 isotype of instant SEQ ID NO:159 or 165 (see Yamniuk), or the IgG1f or IgG1.3f isotype of instant SEQ ID NO:173 (see Beurskens), an E345R or -K mutation with or without an E430G and S440Y mutation (i.e., instant SEQ ID NO: 171-176 and 178-183) for the expected increase in hexamerization those mutations were shown to provide (Beurskens and Diebolder et al.). It would have been obvious wherein the anti-CD40 agonist antibody was 12D6 taught by Barnhart or an anti-CD40 taught by Barnhart that competes with 12D6, e.g., 19G3, or wherein the bivalent antibody has identical or different CD40-binding domains. Because it was stated by Barnhart that the anti-CD40 antibodies could be used therapeutically, it would have been obvious to have a pharmaceutical composition comprising the antibody and a carrier.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Kaufman, whose telephone number is (571) 272-0873. Examiner Kaufman can generally be reached Monday through Friday 7am-3:30pm, Eastern Time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached at (571) 272-0857.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Official papers filed by fax should be directed to (571) 273-8300. NOTE: If applicant does submit a paper by fax, the original signed copy should be retained by the applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
November 7, 2025