BIOENGINEERED IMMUNOMODULATORY FUSION PROTEIN COMPOSITIONS

§102 §112

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 of Group I and species of conjugation agent which is a fluorescent compound and species of cytokine which is IL-12 in the reply filed on 07/28/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 1-21 and 25 are under examination as drawn to the elected invention. The restriction requirement is made final. Information Disclosure Statement Non-Patent Literature reference #33, Ausubel et al., of the IDS filed 7/28/2026 was only submitted in part (1,257/4755 pages). As a result, it has been lined-through on the IDS and not considered. It is noted that cited US 2010/0028637 A1 is titled “Multi-Layer Film Comprising A Barrier Layer And An Antistatic Layer”. Cited US Patent 5,122,946 is titled “Quasi Push-pull Single Switch Current-fed Fly-back Converter”. Specification The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: SINGLE CHAIN TRIMERIC CD40L IMMUNOMODULATORY FUSION PROTEIN COMPOSITIONS The use of the term RoboColumn and Superdex ([00327]), Beckman (lines 1 and 4 of [00367]), each of which is a trade name or a mark used in commerce, has been noted in this application. The 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. The disclosure is objected to because of the following informalities: In [00362], line 6, “incubate” should be “incubated”. Appropriate correction is required. Claim Interpretation The specification defines in [0094], “Unless otherwise stated, any numerical values, such as a concentration or a concentration range described herein, are to be understood as being modified in all instances by the term “about.”” Therefore, this applies to the numerical range of amino acids in a linker (e.g., claim 9). The extra breadth, however, is not being applied to “three CD40L subunits” (e.g., claim 1) because the specification is specific about the exact number of CD40L subunits present in the claimed polypeptide (see also Figs. 1A and 1B). Claim Rejections - 35 USC § 112(b) The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 11 and 15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 11 recites the broad recitation in (g) and (h) of a minimal percentage of “about 10%”, and the claim also recites “about 20%,… or about 99%”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claim 15 is indefinite because it depends from nonexistant claim number 113. Because this appears to be a typographical error, in the interest of compact prosecution it is being assumed that claim 15 depends from claim 13. 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, 5-9, 12-16, 19, 21 and 25 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 wherein the CD40L submit binds CD40, does not reasonably provide enablement for wherein the CD40L subunit does not bind CD40. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Independent claim 1 is drawn to “A polypeptide comprising a single chain trimer CD40 ligand (CD40L) fusion protein,… comprising three CDL subunits…” As defined in the specification ([00131]), “As used herein, the term "single chain trimeric CD40L Fc fusion protein" refers to a protein comprising a monomeric Fc region (mFc), generally linked (optionally through a peptide tether, as described herein) to three CD40L subunits, as described herein and shown in Figure 1.” While CD40 ligand or CD40L refers to a protein that acts as a ligand to CD40 ([00129]), a CD40L subunit is referred to merely as an individual CD40L component ([00129]). In the claim itself, there is no requirement for any activity, and the only structural limitation is that of comprising three covalently linked CD40L subunits. Even if the subunit comprises a portion of the CD40L extracellular domain, there is no limitation related to how much of the extracellular domain is present or what activity that portion imparts. That is, “a portion” may be two consecutive amino acids, which would not reasonably be expected to provide any CD40L-specific activity. If the claimed polypeptide does not bind CD40, one skilled in the art would not know how to use it. The invention is based on the finding that a CD40L trimer according to Fig. 1A or 1B and which has the full CD40L extracellular domain. It is reported in the specification ([00324]) that “the activity of CD40L is located to the extracellular domain, and this domain was chosen for Fc fusion construct generation. CD40L ECDs (Uniprot ID. P29965) were fused together with flexible linkers….” Karnell et al. (Adv. Drug Deliv. Rev., 141:92-103, 2019, p. 93, col. 1) discusses the role of CD40L in activating its receptor, CD40. The working examples of the specification (e.g., [00366[) show that the disclosed CD40L trimer “is a stable and functionally superior CD40 agonist.” The claims have significant breadth because the CD40L trimer-comprising the polypeptide of claim 1 and dependent claims are not required to activate CD40 nor comprise the extracellular domain of CD40L. There is no direction or guidance in the specification for how to use the claimed polypeptide which does not at least bind CD40. The only working examples are directed to activating CD40 by binding with the trimeric CD40L-Fc polypeptide. It would require undue experimentation to use the claimed invention commensurate in scope with the claims. Claims 1-21 and 25 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 “A polypeptide comprising a single chain trimer CD40 ligand (CD40L) fusion protein,… comprising three CDL subunits…” As defined in the specification ([00131]), “As used herein, the term "single chain trimeric CD40L Fc fusion protein" refers to a protein comprising a monomeric Fc region (mFc), generally linked (optionally through a peptide tether, as described herein) to three CD40L subunits, as described herein and shown in Figure 1.” While CD40 ligand (CD40L) refers to a protein that acts as a ligand to CD40 ([00129]), a CD40L subunit is referred to merely as an individual CD40L component ([00129]). In the claim itself, there is no requirement for any activity, and the only structural limitation is that of comprising three covalently linked CD40L subunits. Even if the subunit comprises a portion of the CD40L extracellular domain, there is no limitation related to how much of the extracellular domain is present. That is, “a portion” may be two consecutive amino acids, which would not reasonably be expected to provide any CD40L-specific activity. Further, claims reciting a full sequence of a single chain trimeric CD40L Fc fusion state the particular sequence is optional (e.g., claim 10) and, therefore, no required. Example 1 of the specification reports ([00324]), “The activity of CD40L is located to the extracellular domain, and this domain was chosen for Fc fusion construct generation. CD40L ECDs (Uniprot ID. P29965) were fused together with flexible linkers….” The intra-CD40L linkers were “either 9 or 12 amino acids and chosen for flexibility….” “The tether between the last CD40L and the Fc was chosen to promote flexibility and ranged from 0-20 amino acids…. The C-terminal trimeric CD40L Fc fusions were constructed on effector silenced human IgG1 and IgG2A isotypes.” Initial constructs with the CD40L trimer fused to human IgG (huIgG) led to high molecular weight species after protein A purification and were unsuitable. “The biophysical and functional properties of the protein were optimized by redesigning the protein with structure based rationale. The proteins were designed with various intra-subunit linkers, tethers and Fc attachment points (FIG. 1A).” Paragraph [00331] sets forth the basic polypeptide structure as: CD40L-LINKER-CD40L-LINKER-CD40L-TETHER-HUMAN-IgG Fc. This structure agrees with the prior art fusion protein MEDI5083 (FP6) set forth in Fig. 1 of WO 2017/197231 (Baca, cited in the IDS) showing three CD40L subunits separated by (G4S)2 linkers, which linker is also used to connect the C-terminal subunit to an IgG4 Fc region. Baca showed MEDI5083 specifically bound and activated CD40 (Examples 2-5). Note that IgG2 and IgG4 isotypes have low or no effector function (e.g., Irani et al., Mol. Immunol. 67:171-182, 2015, e.g., p. 172, col. 2, first paragraph). The acknowledgement is made of the definition of “Fc region” in the specification ([00121]): The term "Fc region" refers to the carboxy terminal portion of an antibody's constant region and encompasses the CH2 and CH3 regions of the heavy chains. The two CH3 domains interact with each other to form a homodimer resulting in dimerization of Fc. The specification discloses a polypeptide comprising a single chain trimeric CD40L fusion protein comprised of three CD40L subunits, each of which is the CD40L extracellular domain linked with a flexible linker of 9-12 amino acids, wherein the terminal CD40L subunit is tethered to an effector silenced IgG Fc region by a tether of 0-20 amino acids. This polypeptide meets the written description provision of 35 USC 112(a). However, the claims are directed to or encompass CD40L subunits that do not bind CD40, including that do not comprise a portion of the CD40L extracellular domain sufficient to bind CD40, that have no or unspecified intra-CD40L peptide linkers which may or may not be flexible, are tethered to an Fc region which does not have silenced effector function and which tether is not flexible and/or is longer than 20 amino acids. None of these sequences meets the written description provision of 35 USC 112(a). The specification does not disclose a representative number of species to support the claimed genus. 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). With the exception of the polypeptide comprising the single chain trimeric CD40L Fc fusion protein 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 product 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). Therefore, only a polypeptide comprising a single chain trimeric comprising three CD40L extracellular domains linked by a flexible linker of 9-20 amino acids, further fused directly to or linked by a flexible tether of 1-20 amino acids to an IgG Fc region that has silenced effector function, but not the full breadth of the claim 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 § 102 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claim(s) 1-21 and 25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017197231 (Baca, cited in the IDS). Baca teaches a polypeptide comprising a single chain CD40L trimeric fusion protein comprised of three CD40L linked by a peptide linker, e.g., (G4S)2 or G3SG2S) and linked to an Fc monomer (IgG4P Fc) (Table 1, and e.g., FP6 = MED15083, [00195], Fig. 1). The peptide linker may alternatively be (G3S)3 (SEQ ID NO:7 wherein n is 3, [0026]). The fusion polypeptides bound to and activated CD40 (Examples 1-5). A dimer comprising two of the single chain trimeric CD40L fusion protein that dimerize through their Fc regions is also taught (e.g., claim 2 and [00139]). The CD40L trimeric fusion induced a Th1 immune cytokine/chemokine response in monocyte-derived dendritic cells, increasing IFN γ and TNF-α, and activated T-cell proliferation (CD8+ memory T cells and Ki67; e.g., Fig. 8, [0092] and [00255]). It also stimulated B cell proliferation (Fig. 6) and has been shown to promote differentiation of B cells into antibody secreting cells and memory B cells ([00135]). CD40L is disclosed as binding antigen presenting cells and as expressed on T cells, mast cells, basophils and eosinophils ([0006]). The trimeric fusion can be used to treat cancer, induce B cell activation and Th1 cytokine response ([00185]). The fusion protein may be conjugated to fluorescent label, luminescent label or isotopic label (e.g., [00184]). It may be in a pharmaceutical composition (e.g., [0074]), which reasonably appears to have been with a pharmaceutically acceptable carrier in view of the route of administration shown as intravenous or subcutaneous (Example 8 and Table 7). SEQ ID NO:1 is the CD40L of the trimer and is identical to instant SEQ ID NO:20. SEQ ID NO:3 is the CD40L of the trimer and is identical to instant SEQ ID NO:21. The single chain trimeric CD40L fusion protein comprises a fragment of instant SEQ ID NO:35 as seen in the comparison below with SEQ ID NO:9. Comparison of SEQ ID NO:9 (Db) of Baca with instant SEQ ID NO:35 (Qy) Query Match 98.1%; Score 2226; Length 687; Best Local Similarity 98.2%; Matches 435; Conservative 0; Mismatches 8; Indels 0; Gaps 0; Qy 1 NPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFC 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 NPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFC 60 Qy 61 SNREASSQAPFIASLWLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVF 120 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 61 SNREASSQAPFIASLWLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVF 120 Qy 121 VNVTDPSQVSHGTGFTSFGLLKLEGKSSGSGSQIAAHVISEASSKTTSVLQWAEKGYYTM 180 ||||||||||||||||||||||| | || |||||||||||||||||||||||||||||| Db 121 VNVTDPSQVSHGTGFTSFGLLKLGGGGSGGGSQIAAHVISEASSKTTSVLQWAEKGYYTM 180 Qy 181 SNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLWLKSPGRFERILLRA 240 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 181 SNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLWLKSPGRFERILLRA 240 Qy 241 ANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKLEGKSSGS 300 ||||||||||||||||||||||||||||||||||||||||||||||||||||| | || Db 241 ANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKLGGGGSGG 300 Qy 301 GSQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFC 360 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 301 GSQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFC 360 Qy 361 SNREASSQAPFIASLWLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVF 420 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 361 SNREASSQAPFIASLWLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVF 420 Qy 421 VNVTDPSQVSHGTGFTSFGLLKL 443 ||||||||||||||||||||||| Db 421 VNVTDPSQVSHGTGFTSFGLLKL 443 Prior Art The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure. US Patent 10,464,981 B2 (’981) teaches 4-1BB and OX40 single chain trimers linked by (G4S)2 (Figs. 1A and 1B). It also teaches a trimer tethered to the N- or C-terminus of an Fc region (e.g., Figs. 2A-2B). It does not teach a single chain trimeric CD40L fusion protein. It is cited to show the state of the art as it relates to making and using single chain trimeric fusion polypeptides wherein the trimer is linked to an Fc region, which is optionally dimerized with a second Fc region. US Patent 10,975,155 B2 claims the same priority as and is by the same inventors and assignee as WO 2017/197231 A1 relied upon above and, therefore, is cumulative therewith. US Patent 9,724,390 teaches polypeptides comprising SEQ ID NO:90 and 92. These sequences are single chain CD40L trimers tethered to the N-terminus of an Fc region (col. 85, lines 28-31, see comparison immediately below). It also teaches linkers, including (GGGS)n where n=1-7 (col. 42, lines 43-49). The polypeptide enhances CD4+ and CD8+ T cell activity (col. 65, lines 32-59). This reference is cumulative with WO 2017197231 A1 relied upon above. Patent 9724390, SEQ ID NO 92 (Db) compared to instant SEQ ID NO:32 OTHER INFORMATION:Human single chain CD40L trimer-Fc (IgG2) amino acid sequence Query Match 96.9%; Score 3380; Length 676; Best Local Similarity 97.6%; Matches 653; Conservative 0; Mismatches 14; Indels 2; Gaps 2; Qy 1 IAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNR 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 10 IAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNR 69 Qy 61 EASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNV 120 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 70 EASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNV 129 Qy 121 TDPSQVSHGTGFTSFGLLKLEGKSSGSGSQIAAHVISEASSKTTSVLQWAEKGYYTMSNN 180 |||||||||||||||||||| | ||||||||||||||||||||||||||||||| Db 130 TDPSQVSHGTGFTSFGLLKLMQKGD-QNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNN 188 Qy 181 LVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANT 240 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 189 LVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANT 248 Qy 241 HSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKLEGKSSGSGSQ 300 |||||||||||||||||||||||||||||||||||||||||||||||||| | | Db 249 HSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKLMQKGD-QNPQ 307 Qy 301 IAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNR 360 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 308 IAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNR 367 Qy 361 EASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNV 420 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 368 EASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNV 427 Qy 421 TDPSQVSHGTGFTSFGLLKLVERKSCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPE 480 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 428 TDPSQVSHGTGFTSFGLLKLVERKSCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPE 487 Qy 481 VTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKE 540 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 488 VTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKE 547 Qy 541 YKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 600 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 548 YKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA 607 Qy 601 VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 660 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 608 VEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 667 Qy 661 KSLSLSPGK 669 ||||||||| Db 668 KSLSLSPGK 676 US Patent 10,793,616 B2 teaches agonist CD40 receptor polypeptides comprising SEQ ID NO:25 (e.g., col. 12, lines 60-62). The sequence is of a single chain CD40L trimer tethered to the N-terminus of an Fc region (col. 85, lines 28-31, see comparison immediately below). The disclosed CD40 agonists are formed from a single chain trimeric CD40L comprising three CD40L subunits linked together with one end tethered to the N- or C-terminus of an Fc region (Figs; 3 and 4, claims 1-8, and, e.g., col. 8, lines 3-7), with Fig. 4 showing dimerization of two single chain trimeric CD40L-Fc polypeptides. It also teaches linkers, including (GGGS)n where n=1-7 (e.g., col. 42, lines 43-49). The agonist induced more potent antigen presenting cells (Example 10). This reference is cumulative with WO 2017197231 A1 relied upon above. Patent No.10793616 SEQ ID NO:25 Comparison to instant NO:7 Query Match 94.9%; Score 3405.5; Length 700; Best Local Similarity 95.2%; Matches 661; Conservative 1; Mismatches 11; Indels 21; Gaps 3; Qy 1 NPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFC 60 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 19 NGQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFC 78 Qy 61 SNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVF 120 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 79 SNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVF 138 Qy 121 VNVTDPSQVSHGTGFTSFGLLKLGGGSGGGSGGGSNPQIAAHVISEASSKTTSVLQWAEK 180 |||||||||||||||||||||||| ||| || ||||||||||||||||||||||| Db 139 VNVTDPSQVSHGTGFTSFGLLKLGSGSGNGS------QIAAHVISEASSKTTSVLQWAEK 192 Qy 181 GYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFER 240 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 193 GYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFER 252 Qy 241 ILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKLGG 300 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 253 ILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKLGS 312 Qy 301 GSGGGSGGGSNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGL 360 ||| || |||||||||||||||||||||||||||||||||||||||||||||||| Db 313 GSGNGS------QIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGL 366 Qy 361 YYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGV 420 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 367 YYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGV 426 Qy 421 FELQPGASVFVNVTDPSQVSHGTGFTSFGLLKLEPKSS---------DKTHTCPPCPAPE 471 ||||||||||||||||||||||||||||||||| || ||||||||||||| Db 427 FELQPGASVFVNVTDPSQVSHGTGFTSFGLLKLGSGSSSSSSSSGSCDKTHTCPPCPAPE 486 Qy 472 AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVSVSHEDPEVKFNWYVDGVEVHNAKTKPRE 531 ||||||||||||||||||||||||||||| |||||||||||||||||||||||||||| Db 487 LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE 546 Qy 532 EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP 591 |||:|||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 547 EQYSSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP 606 Qy 592 SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD 651 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 607 SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD 666 Qy 652 KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 685 |||||||||||||||||||||||||||||||||| Db 667 KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 700 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. 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 . 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. Claire Kaufman /Claire Kaufman/ Primary Examiner, Art Unit 1674