Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendments filed 09/15/2025 are acknowledged.
Claims 3-5, 7, 9, 11-20, 22-33, 35, 37-45, 47-49, 51-52, 55-58, 60-73, 75-78 and 81-108 are canceled.
Claims 1, 2, 6, 8, 10, 21, 34, 36, 46, 50, 53-54, 59, 74, 79-80 and 109-110 are currently pending.
Claims 1, 10, 21, 46 and 109-110 are amended.
Claims 74 and 79-80 are withdrawn from consideration under 37 CFR 1.142(b) as being drawn to nonelected invention as specified in the election response filed 11/13/2024.
Claims 1, 2, 6, 8, 10, 21, 34, 36, 46, 50, 53-54, 59 and 109-110 are currently under examination.
Examiner notes in response to the species election requirement (response filed 04/23/2025) applicant elected one species of a single Fc-based chimeric protein complex set forth in SEQ ID NO: 58, with a corresponding targeting moiety set forth in SEQ ID NO: 2 and a signaling agent set forth in SEQ ID NO: 6; as well as a cDC-1 cell targeted by the targeting moiety and a L234A modification in the Fc region.
3. Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/US20/25421 filed 03/27/2020, which claims benefit of US provisional application 62/825,580 filed 03/28/2019. Claims 1, 2, 6, 8, 10, 21, 34, 36, 46, 50, 53-54, 59 and 109-110 have an effective filing date of 03/28/2019.
4. In view of applicant’s claim amendments, previous rejection of claims 1-2, 6, 8, 10-11, 34, 36 and 46, under 35 U.S.C. 102(a)(1) as being anticipated by LYMAN et al. (US Pat No. 5,554,512; of record) are hereby withdrawn because newly amended claim 1 recites limitations that are not specified by the prior art.
Previous provisional rejections of claims 1, 2, 6, 8, 10-13, 21, 23, 34 and 36 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 18, 30 and 32 of copending Application No. 17/442,772 in view of KLEY et al (WO 2017134305 A1) are hereby withdrawn as the instant claims are drawn to patentably distinct chimeric protein comprising Fc domain(s); further, the newly amended claims recite several limitations making the instant claims patentable distinct from the copending reference application.
5. In view of applicant’s claim amendments, the following rejection are set forth. Applicant’s arguments regarding the obviousness rejections detailed below are addressed in section 13 below.
Claim Objections
6. Claims 1, 2, 6, 8, 10, 21, 34, 36, 46, 50, 53-54, 59 and 109-110 are objected to because of the following informalities: independent claims 1 and 109 recite “FLT3L”; while the acronym FLT3 is defined as FMS-like kinase 3, the “L” is not properly defined in the claims as being a designator for the term “ligand”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
7. 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.
8. Claims 1, 2, 6, 8, 10, 21, 34, 36, 46, 50, 53-54, 59 and 109-110 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.
This is a new grounds of rejection necessitated by Applicant’s amendment.
Amended base claim 1 recites “An Fc-based chimeric protein complex comprising: (i) one or more targeting moieties which specifically bind to FMS-like tyrosine kinase 3 (FLT3), wherein the one or more targeting moieties comprise the extracellular domain of FLT3L, or a portion thereof, and the extracellular domain is a single chain dimer”. This claim is indefinite because it is not clear how an Fc-based chimeric protein complex comprising only one targeting moiety would make a single chain dimer. Claims 2, 6, 8, 10, 21, 34, 36, 46, 50, 53-54 and 59 depend from claim 1 and are included in this rejection for incorporating the indefiniteness of claim 1 by dependency.
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 109 recites the broad recitation, “the one or more targeting moieties comprise the extracellular domain of FLT3L”, and the claim also recites “or a portion thereof” and “any one of SEQ ID NOs: 2-4” which are narrower statements of the range/limitation further defining a specific portion of the extracellular domain of FLT3L. 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. Specifically, it is unclear whether the substitution at position L27 would be applicable to the extracellular domain of FLT3L or if it would only apply to the “portion thereof” seemingly defined by SEQ ID NOs: 2-4. Claim 110 is included in this rejection for incorporating the indefiniteness of claim 109 by dependency.
Claim Rejections - 35 USC § 103
9. 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.
10. 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.
11. Claims 1-2, 6, 8, 10, 21, 34, 36 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over LYMAN et al. (US Pat No. 5,554,512; of record) in view of KLEY et al. (WO 2017134305 A1; of record).
Regarding base claim 1, the teachings of LYMAN made of record (office action mailed 06/16/2025) are as follows:
LYMAN discloses fusion proteins and methods for targeting FMS-like tyrosine kinase 3 (FLT3) (e.g. abstract and background sections). The fusion proteins taught by LYMAN comprise a targeting moiety that includes a soluble portion of FLT3 ligand (FLT3-L) fused to a constant domain of an immunoglobulin protein (FLT3L:Fc) (column 3, ¶5). The fusion proteins taught by LYMAN are constructed on fragment crystallizable regions (Fc) which comprise at least the hinge region allowing interchain disulfide bond formation; LYMAN reasons the Fc dimers are advantageous for promoting a greater binding affinity of FLT3-L (last ¶ of column 7 through first ¶ of column 8). The fusion proteins taught by LYMAN may comprise native signal peptides or be modified to comprise one or more heterologous signal peptides (column 8, ¶5).
Regarding the new limitation recited in amended claim 1(i), which recites, “wherein the one or more targeting moieties comprise the extracellular domain of FLT3L, or a portion thereof, and the extracellular domain is a single chain dimer…”, LYMAN teaches an alternative limitation wherein two soluble FLT3L domains are linked via a peptide linker (column 13, lines 34-35), thus forming a single chain dimer.
The teachings of LYMAN differ from amended claim 1 by not reciting the specific species of signaling agents recited in claim 1(iii).
KLEY, in the field of chimeric proteins to recruit effector cells (page 1, ¶2), discloses Fc-based chimeric proteins having two or more targeting moieties that recognize and specifically bind to target of interest (antigens, receptors, etc) (page 2, ¶1). The chimeric proteins taught by KLEY further comprise modified signaling agent (e.g. immune modulating agent) (page 2, ¶1). KLEY teaches these signaling agents are modified to provide improved safety compared to an un-modified (wild-type) form (page 2, ¶1). KLEY discloses a wide range of these modified signaling agents including interleukins (reciting IL-1, as well as any fragment, variant or analog thereof) (e.g., page 85, lines 15-23) and interferons such as IFNα2, IFNα1, IFNβ (page 85, lines 24-26). KLEY also discloses amino acid sequences with greater than 95% sequence identity to SEQ ID NOs: 6, 7, 38 and 39. Example sequence alignments are provided below, showing the SEQ ID NOs claimed in instant claim 13 (Qy) compared to the sequences disclosed by KLEY (Db) for each cytokine.
IFNa2
Qy: Sequence 6, instant application
Db: Sequence 336, WO-2017134305-A1
Query Match 100.0%; Score 851; DB 1; Length 165;
Best Local Similarity 100.0%;
Matches 165; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMI 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMI 60
Qy 61 QQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 QQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVR 120
Qy 121 KYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE 165
|||||||||||||||||||||||||||||||||||||||||||||
Db 121 KYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE 165
IL-1β
Qy: Sequence 39, instant application
Db: Sequence 343, WO-2017134305-A1
Query Match 97.3%; Score 768.5; DB 1; Length 152;
Best Local Similarity 98.7%;
Matches 151; Conservative 0; Mismatches 1; Indels 1; Gaps 1;
Qy 1 APVRSLNCTLRDSQQKSLVMSGPYELKALHLQGQDMEQQVVFSMSFVQGEESNDKIPVAL 60
||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||
Db 1 APVRSLNCTLRDSQQKSLVMSGPYELKALHLQGQDMEQQ-WFSMSFVQGEESNDKIPVAL 59
Qy 61 GLKEKNLYLSCVLKDDKPTLQLESVDPKNYPKKKMEKRFVFNKIEINNKLEFESAQFPNW 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 60 GLKEKNLYLSCVLKDDKPTLQLESVDPKNYPKKKMEKRFVFNKIEINNKLEFESAQFPNW 119
Qy 121 YISTSQAENMPVFLGGTKGGQDITDFTMQFVSS 153
|||||||||||||||||||||||||||||||||
Db 120 YISTSQAENMPVFLGGTKGGQDITDFTMQFVSS 152
LYMAN et al. and KLEY et al. are both directed to chimeric/fusion proteins for immune cell modulation. Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was filed, to modify the Fc-based fusion protein of LYMAN with the modified cytokine-based signaling moiety to achieve the predictable result of obtaining a composition suitable for activation of effector cells. One of ordinary skill in the art would have been motivated to do so because KLEY teach that the modified cytokine signaling moiety allows for the cytokine to be active on target cells while being substantially inactive in the protein’s transient form, i.e., en route to the target cell, thus providing a substantial advantage by greatly reducing undesired side effects or off-target activation (page 87, last ¶). As such, amended base claim 1 is obvious over LYMAN et al., in view of KLEY et al.
Regarding claim 2, LYMAN in view of KLEY render the fusion protein of claim 1 obvious; further, LYMAN teaches the fusion proteins may be constructed as oligomers (covalently linked dimers) or dimeric proteins comprising two FLT3-L:Fc proteins linked by cysteine residues on the Fc region (column 13, ¶2). Alternatively, LYMAN discloses that two soluble FLT3-L domains may be joined by a peptide linker, ultimately allowing for a FLT3-L:Fc oligomer with as many as four FLT3-L moieties (column 13, ¶2). Therefore, claim 2 is obvious over LYMAN in view of KLEY.
Regarding claim 6, LYMAN in view of KLEY render the fusion protein of claim 1 obvious; further, LYMAN teaches that the targeting moiety of the fusion protein is the soluble domain of the FLT3 ligand (FLT3-L); LYMAN discloses that the soluble flt3-L polypeptides encompassed by the invention retain the ability to bind the FLT3 receptor (column 8, ¶2). Therefore, claim 6 is obvious over LYMAN in view of KLEY.
Regarding claim 8, LYMAN in view of KLEY render the fusion protein of claim 1 obvious; further, the FLT3-L targeting moiety amino acid sequence disclosed by LYMAN (Db) comprises the amino acid sequence of SEQ ID NO: 2 of instant claim 8 (Qy) with 100% sequence identity (see SEQ ID alignment below).
Sequence 6, US/08243545
Patent No. 5,554,512
Query Match 100.0%; Score 841; DB 1; Length 235;
Best Local Similarity 100.0%;
Matches 158; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TQDCSFQHSPISSDFAVKIRELSDYLLQDYPVTVASNLQDEELCGGLWRLVLAQRWMERL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 27 TQDCSFQHSPISSDFAVKIRELSDYLLQDYPVTVASNLQDEELCGGLWRLVLAQRWMERL 86
Qy 61 KTVAGSKMQGLLERVNTEIHFVTKCAFQPPPSCLRFVQTNISRLLQETSEQLVALKPWIT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 87 KTVAGSKMQGLLERVNTEIHFVTKCAFQPPPSCLRFVQTNISRLLQETSEQLVALKPWIT 146
Qy 121 RQNFSRCLELQCQPDSSTLPPPWSPRPLEATAPTAPQP 158
||||||||||||||||||||||||||||||||||||||
Db 147 RQNFSRCLELQCQPDSSTLPPPWSPRPLEATAPTAPQP 184
Therefore, claim 8 is obvious over LYMAN in view of KLEY.
Regarding claim 10, LYMAN in view of KLEY render the fusion protein of claim 1 obvious; further, LYMAN teaches the FLT3-L polypeptides may further comprise various additions or substitutions of amino acid residues, or deletions of terminal or internal residues or sequences not needed for biological activity or binding, including deletions of the Cys residues to prevent aggregation or formation of incorrect intramolecular disulfide bridges (column 10, ¶3-4). Therefore, claim 10 is obvious over LYMAN in view of KLEY.
Regarding claim 21, LYMAN in view of KLEY render the fusion protein of claim 1 obvious; additionally, KLEY recites a catalogue of amino acid modifications that substantially reduce or ablate binding of these signaling agents. KLEY also disclose that this reduced binding affinity is restorable when bound to the fusion protein comprising a targeting moiety (page 88, ¶s 1-2). Therefore, claim 21 is obvious over LYMAN in view of KLEY.
Regarding claims 34 and 36, LYMAN in view of KLEY render the fusion protein of claim 1 obvious; LYMAN also discloses the use of FLT3-L:Fc fusion proteins for treating myelodysplastic syndrome, aplastic anemia, HIV infection (AIDS) and cancers by stimulating or expanding cell populations in either myeloid and lymphoid lineages (column 1, background paragraphs) which includes conventional dendritic cells (cDC-1). Additionally, it is common logic that following the administration of a FLT3-L:Fc protein, comprising a FLT3-L targeting domain, would be directed, not only to Flt3+ dendritic cells, but also cDC-1 and migratory dendritic cells because FLT3 signaling is required for dendritic cell development, differentiation and mature dendritic cell functions including cytokine production. LYMAN further discloses how FLT3-L:Fc protein is used to stimulate and expand early progenitor cells and hematopoietic stem cells collected from a patient ex vivo (column 3, last ¶). Therefore, claims 34 and 36 are obvious over LYMAN in view of KLEY.
Regarding claim 46, LYMAN in view of KLEY render the fusion protein of claim 1 obvious; LYMAN also discloses the Fc regions may originate from IgA or IgG, including Fc regions of the human or murine IgG1 regions (column 7, last ¶). Therefore, claim 46 is obvious over LYMAN in view of KLEY.
12. Claims 1, 50, and 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over LYMAN et al. (US Pat No. 5,554,512; of record) in view of KLEY et al. (WO 2017134305 A1; of record) as applied to claims 1-2, 6, 8, 10, 21, 34, 36 and 46 above, and further in view of JOHNSON et al. (WO 2017106061 A1; of record).
As discussed above, amended claim 1 is obvious over LYMAN in view of KLEY. Further, LYMAN discloses fusion proteins comprising Fc domain derived polypeptides allowing for the formation of non-covalently linked heterologous dimers (column 13, ¶1-2).
The teachings of LYMAN and KLEY differ from the instant claims by not specifically reciting that the Fc chain pairing is promoted by ionic pairing and/or a knob-in-hole pairing. The teachings of LYMAN and KLEY also differ from the instant invention by not being explicit in reciting that the Fc domain mutations result in a reduction of Fc effector function, nor the trans orientation of a heterodimeric construct.
JOHNSON et al, in the field of therapeutic bispecific binding molecules, discloses a variety of approaches for engineering antibodies (and antibody-like molecules), including the knob-into-hole approach, which is well known in the art and allows for the construction of heterodimeric and/or asymmetric fusion proteins (¶0159-0160). JOHNSON also discloses several embodiments comprising point mutations to the Fc region to achieve reduced effector function (e.g. ¶0150-0151). Finally, JOHNSON teaches bispecific binding molecules and diabodies with a “trans” binding capability sufficient to co-ligate and/or co-localize different cells that express different epitopes in addition to the a "cis" binding capability sufficient to co-ligate and/or co-localize different molecules expressed by the same cell (¶0094).
LYMAN et al., KLEY et al. and JOHNSON et al. are all directed to Fc-based fusion proteins or binding agents comprising Fc domains. Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was filed, to modify the FLT3-L:Fc fusion protein of LYMAN and KLEY with the bispecific modified Fc domains taught by JOHNSON to achieve the predictable result of obtaining a heterodimeric fusion protein capable of targeting and engaging two separate ligands simultaneously. One of ordinary skill in the art would have been motivated to do so because JOHNSON teaches that trans-binding bispecific fusion proteins are advantageous in their wide-ranging applications for therapy and immunodiagnostics, offering flexibility in the design and engineering of the diabody in various applications, providing enhanced avidity to multimeric antigens, the cross-linking of differing antigens, and directed targeting to specific cell types relying on the presence of both target antigens (¶0094-0095). One would have been further motivated to combine the teachings of LYMAN, KLEY and JOHNSON because JOHNSON teaches that Fc region mutations that reduce effector function is desirable in certain cases, for example in the case of fusion proteins whose mechanism of action involves blocking or antagonism, but not killing of the cells bearing a target antigen (¶0146).
13. Claims 1 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over LYMAN et al. (US Pat No. 5,554,512; of record) in view of KLEY et al. (WO 2017134305 A1; of record) as applied to claims 1-2, 6, 8, 10, 21, 34, 36 and 46 above, and further in view of MA et al. (US 20040254108 A1; of record).
As discussed above, amended claim 1 is obvious over LYMAN in view of KLEY.
LYMAN in view of KLEY differs from instant claim 59 by not disclosing an Fc-based fusion protein comprising a polypeptide having an amino acid sequence with at least 95% identity with any one of SEQ ID NOs: 40, 41 or 46-66.
MA et al, in the field of anti-tumor bifunctional fusion proteins (¶0004), discloses chimeric proteins comprising a FLT3 ligand or biologically active fragment thereof and a proteinuous or peptidyl tumoricidal agent (abstract) such as TNF-α or TNF-related apoptosis-inducing ligand (TRAIL) (e.g. ¶102). In a specific embodiment, MA discloses a fusion protein comprising an active TRAIL moiety fused to human IgG1 Fc regions, in turn fused to FLT3 ligand. This Fc-based FLT3-L containing fusion protein disclosed by MA (SEQ ID NO: 68) (Db) has greater than 95% sequence identity to SEQ ID NO: 48 (Db) of the instant application (see sequence alignment below).
US2004254108-A1
Claim 23; SEQ ID NO 68
Query Match 97.3%; Score 2020; Length 582;
Best Local Similarity 97.2%;
Matches 377; Conservative 3; Mismatches 6; Indels 2; Gaps 1;
Qy 1 TQDCSFQHSPISSDFAVKIRELSDYLLQDYPVTVASNLQDEELCGGLWRLVLAQRWMERL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 27 TQDCSFQHSPISSDFAVKIRELSDYLLQDYPVTVASNLQDEELCGGLWRLVLAQRWMERL 86
Qy 61 KTVAGSKMQGLLERVNTEIHFVTKCAFQPPPSCLRFVQTNISRLLQETSEQLVALKPWIT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 87 KTVAGSKMQGLLERVNTEIHFVTKCAFQPPPSCLRFVQTNISRLLQETSEQLVALKPWIT 146
Qy 121 RQNFSRCLELQCQPDSSTLPPPWSPRPLEATAPTAPQPS--DKTHTCPPCPAPEAAGGPS 178
||||||||||||||||||||||||||||||||||||:| ||||||||||||| ||||
Db 147 RQNFSRCLELQCQPDSSTLPPPWSPRPLEATAPTAPEPKSCDKTHTCPPCPAPELLGGPS 206
Qy 179 VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST 238
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 207 VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST 266
Qy 239 YRVVSVLTVLHQDWLNGKEYKCQVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELT 298
||||||||||||||||||||||:|||||||||||||||||||||||||| ||||||||||
Db 267 YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT 326
Qy 299 KNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQ 358
||||||:| |||||||||||||||||||||||||||||||||||||| ||||||||||||
Db 327 KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ 386
Qy 359 GNVFSCSVMHEALHNHYTQKSLSLSPGK 386
||||||||||||||||||||||||||||
Db 387 GNVFSCSVMHEALHNHYTQKSLSLSPGK 414
LYMAN et al., KLEY et al. and MA et al. are all directed to Fc-based fusion proteins comprising an FLT3 ligand and a cytokine. Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was filed, to modify the Fc-based fusion protein of LYMAN and KLEY with the Fc domain structure and bispecific activity of an added cytokine moiety to achieve the predictable result of obtaining a chimeric protein that is active against cancer cells while simultaneously stimulating a lasting and effective anti-tumor immune response. One of ordinary skill in the art would have been motivated to do so because MA et al teach that this dual activity is advantageous as tumor antigens released by the dying tumor cells then can be processed and presented by FL-activated DCs, that then effectively serve as antigen presenting cells for a specific anti-tumor immune response. In this way, the chimeric protein simultaneously effects direct and indirect tumor cell elimination while eliciting an effective active immune response against the tumor cells that prevents the recurrence of tumor growth (¶0010-0011).
Addressing Applicant Arguments:
14. Applicant's arguments filed 09/15/2025 have been fully considered but they are not persuasive.
Applicant’s arguments center upon newly amended claim 1, specifically pointing to the limitation that recites, “wherein the one or more targeting moieties comprise the extracellular domain of FL T3L, or a portion thereof, and the extracellular domain is a single chain dimer” (remarks beginning pgs. 5-6). Applicant argues that this modification is advantageous for simplifying the claimed constructs while simultaneously allowing for retained function and reduction in undesired dimerization and aggregation, thereby making the chimeric proteins safer and easier to produce (remarks pg. 6, last ¶). The Applicant bolsters this argument by highlighting data suggesting the single-chain format was less likely to dimerize or form high molecular weight species (remarks pg. 7, ¶2)(size exclusion chromatography data presented the specification example 4). The applicant also shows that the single-chain format retained anti-tumoral activity with and without a modified signaling agent (remarks pg. 7, ¶3 and reproduced figures). Applicant concludes this argument by asserting that none of the prior art references (LYMAN, KLEY, JOHNSON or MA), whether alone or in combination teach or suggest the presently claimed Fe-based chimeric protein complex comprising at least one targeting moiety comprising the extracellular domain of FLT3L, or a portion thereof, where the extracellular domain is a single chain dimer; (ii) a Fe domain; and (iii) a signaling agent, or modified form thereof, selected from a list of agents defined by particular amino acid sequences.
This argument was not persuasive because the primary reference LYMAN et al., does teach FLT3L moieties in single-chain dimer format (e.g., column 13, ¶2). Specifically, LYMAN recites, “… one can link two soluble FLT3-L domains with a peptide linker” (column 13, lines 34-35). The use of single-chain dimers draws on a long history of well-known prior art for producing fusion proteins comprising heterologous polypeptides fused to various portions of antibody-derived polypeptides (e.g., see LYMAN column 13, lines 21-28). LYMAN explains that the FLT3L fusion proteins are assembled much like antibody molecules and if proteins are made with both heavy and light chains of an antibody, it is possible to format an FLT3L oligomer with as many as four FLT3L extracellular regions (column 13, lines 21-34). Based on the disclosure as a whole, in conjunction with Applicant’s arguments, the amendment to claim 1(i) is merely reciting a limitation that is analogous to other Fc dimer based constructs that are well known in the art. As such, Applicant’s arguments are not persuasive.
Next, the applicant argues against each of the prior art documents in a piecemeal manner (see remarks, beginning on last ¶ of pg. 7 through ¶5 of pg. 8). For instance, contrary to Applicant’s assertions that that Lyman does not teach or suggest the inclusion of a modified signaling agent (pg. 7, last ¶), or that KLEY does not teach or suggest targeting moieties comprising extracellular domain of FLT3L (pg. 8, ¶2); LYMAN does indeed disclose that the FLT3L polypeptides may be modified to comprise one or more heterologous signal peptides (column 8, ¶5). LYMAN teaches several heterologous signaling agents capable of being used in the polypeptide construct disclosed in other prior art documents including IL-2, IL-7, IL-4 and type I IL-1 receptor signal peptide (e.g., column 16, ¶1). As discussed above, the differences between the teachings of LYMAN and the presently amended claim 1(iii) are made obvious by KLEY, which does in fact disclose the recited sequences.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As such, these arguments are not found to be persuasive.
Conclusion
15. No claim is allowed.
16. 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.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES L MCLELLAN whose telephone number is (703)756-1906. The examiner can normally be reached Monday - Thursday 7:30 am - 5:30 pm. *Compressed day off on first Friday of each Bi-week.
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, Misook Yu can be reached at (571) 272-0839. 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.
/JAMES LYLE MCLELLAN/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641