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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05MAY2026 has been entered.
Notice of Change of Examiner
The Examiner of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Examiner Samantha Lake Hopkins in Art Unit 1641.
Claim Status
Applicant’s amendments received 05MAY2026 are acknowledged.
Claims 2-7, 9, 11-20, 22-33, 35, 37-45, 47-49, 51-52, 55-58, 60-73, 75-78, and 81-108 have been canceled.
Claims 1, 8, and 109 have been amended.
Claims 1, 8, 10, 21, 34, 36, 46, 50, 53-54, 59, 74, 79-80, and 109-110 are pending in the instant application (i.e., Claims 1 and 109 are independent).
Claims 74 and 79-80 remain withdrawn.
Claims 1, 8, 10, 21, 34, 36, 46, 50, 53-54, 59, and 109-110 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2020/025421, filed 27MAR2020, which claims the benefit of US Provisional Patent Application No. 62/825580, filed 28MAR2019. Applicant’s claim for the benefit of prior-filed application is acknowledged. Examiner notes that the newly added limitations to claim 1 (i.e., the ECD is a single chain dimer and wherein the at least two targeting moieties are attached to one Fc chain of the Fc domain) and dependent claims 8, 10, 21, 34, 36, 46, 50, 53-54, and 59 have an effective filing date of 27MAR2020. Claims 109-110 have an effective filing date of 28MAR2019.
Nucleotide and/or Amino Acid Sequence Disclosures
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 – Nucleotide and/or amino acid sequences appearing in the specification (see for example, p 80 and 83) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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 sequence identifiers, 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.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures of 10*GGS are located on p 79.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Objections
Applicant’s arguments, see p 5, Response to claim objections section, filed 05MAY2026, with respect to objections to of claim(s) 1, 2, 6, 8, 10, 21, 34, 36, 46, 50, 53-54, 59 and 109-110 (i.e., objection to claim(s) 2 and 6 are moot because claims have been cancelled) for informalities have been fully considered and said objections to claim(s) 1, 8, 10, 21, 34, 36, 46, 50, 53-54, 59, and 109-110 have been withdrawn in view of claim amendments filed as part of said response.
Amendments to the claims has resulted in new claim objections. Claims 21, 34, and 53 are objected to because of the following informalities:
Claim 21 should include “of the signaling agent” between “…affinity or activity” and “is restorable….” for the purpose of clarity.
Claim 34 should be amended from “Flt3+” to “FLT3+” or “FLT3-positive” for the purpose of clarity.
Claim 53 is missing punctuation (“.”) at the end of the claim. Appropriate correction is required.
Withdrawn Rejections
Indefiniteness
Applicant’s arguments, see p 5-6, Response to rejection under 35 USC §112(b) section, filed 05MAY2026, with respect to the rejection(s) of claim(s) 1, 2, 6, 8, 10, 21, 34, 36, 46, 50, 53-54, 59 and 109-110 (i.e., rejection of claim(s) 2 and 6 are moot because claims have been cancelled) under 35 USC §112(b) have been fully considered and said rejections of claim(s) 1, 8, 10, 21, 34, 36, 46, 50, 53-54, 59, and 109-110 have been withdrawn in view of the claim amendments filed as part of said response.
35 USC §103
Applicant’s arguments, see p 6-9, Response to rejections under 35 USC §103 section, filed 05MAY2026, with respect to the rejection(s) of claim(s) 1-2, 6, 8, 10, 21, 34, 36, and 46 (i.e., rejection of claim(s) 2 and 6 are moot because claims have been cancelled) under 35 USC §103 have been fully considered and are fully persuasive because of the claim amendments which add limitations not taught in the cited art. As such, said rejections of claim(s) 1, 8, 10, 21, 34, 36, and 46 have been withdrawn.
Claim Rejections - 35 USC § 112
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 1, 8, 10, 34, and 36 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.
Claim 1 appears to recite a Markush group, but the group of alternatives are not closed as required by a proper Markush group in MPEP §2173.05(h). In this instance, claim 1 recites Markush-type claims without reciting proper Markush-type language such as “selected from the group consisting of” and an “and” between the last two species. For example, in claim 1, an “and” should replace the ‘or’ between “…SEQ ID NO: 38” and “a mutant human IL-1ß….”
Claims 8, 10, 34, and 36 recite the limitation "wherein the targeting moiety further comprises" which are dependent on claim 1 which recites “at least two targeting moieties….” In this instance, it is unclear whether it is one of the two targeting moieties or both of the targeting moieties. Therefore, there is insufficient antecedent basis for this limitation in the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 36 and 59 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 36 is dependent on claim 34, which recites “wherein the targeting moiety is directed to a DC selected from cDC-1, migratory DC, and FLT3+ DC” or a narrower subset of cells compared to “HSC, early progenitor cell, immature thymocyte, or steady state dendritic cells” as recited in claim 36 and therefore fails to further limit the claim upon which it depends.
In the instance of claim 59, dependent on claim 1, the SEQ ID NOs: 40-41 and 46-57 comprise at least two targeting moieties which comprise the ECD of FLT3L or a portion thereof; however, SEQ ID NOs: 40-41 and 46-57 fail to include the limitations of the ECD is a single-chain dimer and the at least two targeting moieties comprising the ECD are attached to one Fc chain of the Fc domain as presently recited in claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 8, 10, 21, 34, 36, 46, 50, 53-54, 59, and 109-110 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 and having support for:
“A Fc-based chimeric protein complex comprising:
two targeting moieties, which specifically bind to FLT3;
a Fc domain; and
a signaling agent;
wherein the two targeting moieties comprise a single-chain dimer comprising a) a first targeting moiety comprising the ECD of FLT3L or a portion thereof, b) a linker, and c) a second targeting moiety comprising the ECD of FLT3L or a portion thereof; wherein the ECD of FLT3L or a portion thereof comprises the amino acid sequences set forth in SEQ ID NOs: 3-5 and the linker comprises the amino acid sequence set forth in SEQ ID NO: 12;
wherein the Fc domain comprises a heterodimer comprising a first and second polypeptide chain, wherein the heterodimer is IgG1 and wherein one polypeptide chain comprises L234A, L235A, and K322Q substitutions and the other polypeptide chain comprises Y349C, T366S, and Y407V substitutions or one polypeptide chain comprises L234A, L235A, and K322Q substitutions and the other polypeptide chain comprises S345C and T366W substitutions;
wherein the signaling agent is a mutant human IFNα2 comprising the amino acid substitutions of T106E and R149A as related to SEQ ID NO: 6; and
wherein the single-chain dimer is located trans of the signaling agent with relation to the Fc heterodimer polypeptide chains and wherein the amino acid sequence of the linker between the single-chain dimer and one of the Fc polypeptide chains is set forth in SEQ ID NO: xx and the amino acid sequence of the linker between the signaling agent and the other Fc polypeptide chain is SEQ ID NO: 12.” (Claims 1, 8, 46, and 54) (See the discussion supra regarding amino acid sequence deficiencies, with regard to 10*GGS, which requires a SEQ ID NO);
-AND-
“The Fc-based chimeric protein complex of claim 1, wherein the at least two targeting moieties further comprise a mutation that reduces intermolecular extracellular domain dimerization, wherein the mutation is a substitution at position L27D as related to SEQ ID NOs: 3-5.” (Amended claim 1 and claim 10);
-AND-
“The Fc-based chimeric protein complex of claim 1, wherein the amino acid sequences of the first and second polypeptide chains are set forth in:
SEQ ID NOs: 58 and 59,
SEQ ID NOs: 60 and 66,
SEQ ID NOs: 61 and 66,
SEQ ID NOs: 62 and 66,
SEQ ID NOs: 63 and 66,
SEQ ID NOs: 64 and 66, or
SEQ ID NOs: 65 and 66, respectively.” (Amended claim 1 and claim 59)
-AND-
“A Fc-based chimeric protein complex comprising:
two targeting moieties, which specifically bind to FLT3;
a Fc domain; and
a signaling agent;
wherein the two targeting moieties comprise a single-chain dimer comprising a) a first targeting moiety comprising the ECD of FLT3L or a portion thereof, b) a linker, and c) a second targeting moiety comprising the ECD of FLT3L or a portion thereof; wherein the ECD of FLT3L or a portion thereof comprises a mutation that reduces intermolecular extracellular domain dimerization, wherein the mutation is a substitution at position L27D of SEQ ID NOs: 3-5; wherein the linker comprises the amino acid sequence set forth in SEQ ID NO: 12;
wherein the Fc domain comprises a heterodimer comprising a first and second polypeptide chain, wherein the heterodimer is IgG1 and wherein one polypeptide chain comprises L234A, L235A, and K322Q substitutions and the other polypeptide chain comprises Y349C, T366S, and Y407V substitutions or one polypeptide chain comprises L234A, L235A, and K322Q substitutions and the other polypeptide chain comprises S345C and T366W substitutions;
wherein the signaling agent is a mutant human IFNα2 comprising the amino acid substitutions of T106E and R149A as related to SEQ ID NO: 6; and
wherein the single-chain dimer is located trans of the signaling agent with relation to the Fc heterodimer polypeptide chains and wherein the amino acid sequence of the linker between the single-chain dimer and one of the Fc polypeptide chains is set forth in SEQ ID NO: xx and the amino acid sequence of the linker between the signaling agent and the other Fc polypeptide chain is SEQ ID NO: 12.” (Claims 109 and 110) (See the discussion supra regarding amino acid sequence deficiencies, with regard to 10*GGS, which requires a SEQ ID NO);
does not reasonably provide enablement or support for more. Claims 21, 34, 36, 50, and 53 are also rejected since they depend upon claim 1 but do not remedy the deficiencies. 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 nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
With regard to the structure and function of the FLT3L ECD, the prior art supports that amino acid residues 115-132 of the FLT3L within the ECD (i.e., amino acid residues 27-184 comprise the ECD of FLT3L) are necessary to bind to FLT3, but that the 18 amino acid peptide is not sufficient by itself to bind FLT3 (Mwangi, et al., J Immuno, 2000, 165, 6966-6974, see discussion section and Fig 3). Furthermore, the single point mutation of W144D in the FLT3L-Fc chimeric protein (i.e., within the ECD) introduced new T cell epitopes and induced promiscuous T cell response with high immunogenicity potential (Qin, et al., Front Immunol, 2025, 16, 1-16, see section 4). Therefore, without any defining structure (i.e., specific sequences) it is unclear whether essentially any portion comprising essentially any length of the ECD of FLT3L would function to bind and target FLT3 or that 10% mutation of SEQ ID NOs: 2-5 would result in effective binding/targeting of FLT3 without potential adverse effects upon administration. Additionally, in the instance of Fc-based fusion proteins comprising an Fc domain, it is well known in the art that specific point modifications (i.e., mutations/substitutions/deletions) to one or both Fc chains which make up the Fc domain result in improved pairing (e.g., knob-in-hole) (Liu, et al., Front Immunol, 2017, 8, 1-15, see entire document, specifically see Table 1) and/or modulate antibody effector function (Wang, et al., Protein & Cell, 2018, 9, 63-73, see entire document, specifically see Table 1) and therefore require a specific structure (i.e., combination of mutations) to function (i.e., improve pairing, modify effector function, etc.). With regard to signaling agents or signaling molecules, it is known in the art that all of these signaling molecules act as ligands that bind to receptors expressed by their target cells; however, there is considerable variation in the structure and function of the different types of molecules that serve to transmit signals, for example, hormones, cytokines, gases, neurotransmitters, growth factors, eicosanoids, etc. (Cooper, G.M., The Cell: A Molecular Approach, 2nd ed, 2000). Thus, it is difficult for one to imagine the full breadth of signaling agents given specific sequences which have one or more mutation which confers reduced affinity or activity as compared to the wt signaling agent and then the reduced affinity or activity of said signaling agent is restored upon incorporation into an Fc-based chimeric protein complex, much less essentially any signaling agent or modified form thereof which would appropriately function in combination with FLT3 binding. Lastly, chimeric protein complexes are considered engineered constructs in which two or more components are linked to form a novel biological agent and generally comprise one component that targets the molecule to a specific cell and a second component that exerts a pharmacological activity (Borsari, et al., J Med Chem, 2020, 63, 1908-1928, see section 1). In the instance of fusion proteins, it has been shown that the choice of N- or C-terminal deletions in combination with distinct mutations at the termini of the ligand and appropriate linker sequences (i.e., type and length) results in optimized fusion proteins with increased thermal stability, solubility, and production rate (Siegemund, et al., MAbs, 2016, 8, 879-891, see last paragraph of introduction section). Therefore, the art supports that for any ligand binding to a protein, there are necessary structural features to maintain functional binding; in a fusion protein that comprises an Fc region, the art supports that it is specific point mutations in one or both of the Fc chains within the Fc domain, which provides specific pairing results or modulates effector function; the structure and function of signaling agents (i.e., any ligand that bind to receptors expressed by their target cells, for example FLT3L could be considered a signaling agent) is considerably broad and varied; and the structure of the overall fusion protein must be better defined as with any engineered structure for biological applications the structures of the targeting moiety, the linkers, and the pharmacological activity moiety are necessary for the fusion protein to function (i.e., target and provide biological efficacy).
The specification discloses seven constructs which comprise two polypeptide chains comprising specific amino acid sequences. The first polypeptide chain comprises from N- to C-terminus i) single-chain dimer of FLT3L wherein each monomer of FLT3L is linked via a peptide linker of specific length, ii) a peptide linker, and iii) a first Fc chain with specific mutations to improve pairing (i.e., SEQ ID NOs: 58 and 60-65). The second polypeptide chain comprises from N- to C-terminus i) a second Fc chain with specific mutations to improve pairing, ii) a peptide linker of specific length, and iii) a specific mutant of human IFNα2 (i.e., SEQ ID NOs: 59 and 66). Despite the specification teaching seven constructs, these do not provide a representative number of species or a clear structure/function correlation as recited in the breadth of claims 1 and 109 and furthermore would require undue experimentation for one of ordinary skill in the art to make and/or use the invention. Therefore, claims 1, 8, 10, 21, 34, 36, 46, 50, 53-54, 59, and 109-110 as presently claimed are rejected because 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 nor does it provide sufficient description to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed had possession of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 109 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,583,898, herein referred to as “’898 in view of Graddis, et al., (J Biol Chem, 1998, 273, 17626-17633, included in IDS), herein referred to as “Graddis.”
The issued claims of the ‘898 patent drawn to a chimeric protein complex comprising a targeting moiety comprising the FLT3L, an Fc domain having one or more mutations that reduce or eliminate one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, or stabilizes a hinge region in the Fc domain, and a human mutant IFNα1 of SEQ ID NO: 1 is an obvious variant of the Fc-based chimeric protein complex comprising one or more targeting moieties which specifically bind FLT3, wherein the one or more targeting moieties comprise the ECD of FLT3L of SEQ ID NOs: 2-4 and comprises a substitution at position L27D, an Fc domain having one or more mutations that reduce or eliminate one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, or stabilizes a hinge region in the Fc domain, and a signaling agent or a modified form thereof of the instant application.
The issued claims of the ‘898 patent recite:
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In this instance, because claim 1 of the ‘898 patent is silent on the structure of the targeting moiety comprising the FLT3L, the specification was consulted to determine the scope of the generic term of the targeting moiety. Per the specification of the ‘898 patent, the structure of the FLT3L targeting moiety is the natural ligand or a truncated version thereof, which is able to bind FLT3, the ECD of FLT3 as observed in SEQ ID NO: 289 of Example 5, which is 100% query match to the instant application SEQ ID NO: 3 (see OA.APPENDIX—Application No. 17/813985 corresponds to the ‘898 patent), and may be a single chain dimer of FLT3L, wherein the FLT3L domain is connected to a second FLT3L domain via a linker (see col 52, lines 35-51 and Example 5).
However, they do not claim: wherein the FLT3L comprises a mutation that reduces the intermolecular ECD dimerization, wherein the mutation is a substitution at position L27 with reference to any one of SEQ ID NOs: 2-4.
Nevertheless, Graddis teaches a mutation library of FLT3L and screening thereof to determine binding with FLT3 (see entire document). Specifically, Graddis teaches that the L27P mutation disrupts the FLT3L dimerization interface and therefore reduces the biological activity of the mutant protein (i.e., (see Discussion section and Figs 6A-B).
It would have been obvious to artisans to modify the issued the chimeric protein complex comprising a targeting moiety comprising the FLT3L, wherein the FLT3L in SEQ ID NO: 289 comprises SEQ ID NO: 3 of the instant application, an Fc domain having one or more mutations that reduce or eliminate one or more effector functions of the Fc domain, promotes Fc chain pairing in the Fc domain, or stabilizes a hinge region in the Fc domain, and a human mutant IFNα1 of SEQ ID NO: 1 as claimed by the ‘898 patent to include a L27P substitution in the FLT3L to reduce the potential for intermolecular dimerization, as taught by Gaddis. This is because Gaddis teaches that disruption of dimerization by a hot spot mutation of L27P results in reduced biological activity (i.e., retains FLT3 binding while reducing the dimerization of the FLT3L therefore reducing the signaling activation upon binding two FLT3 molecules). One would have been motivated to do so, given the direction by the ‘898 patent that the FLT3L could be a single-chain dimer wherein one FLT3L domain is connected to a second FLT3L domain via a linker, which could result in unwanted dimerization and therefore signaling activation. There would have been a reasonable expectation of success, given the knowledge that by modifying the chimeric protein comprising i) a targeting moiety comprising an FLT3L, which may comprise a single chain dimer of the FLT3L ECD, ii) a mutated Fc domain, and iii) a signaling agent taught by ‘898 by introducing a mutation at position 27 of the FLT3L in a single chain dimer, would allow for binding FLT3 and reduce the potential for intermolecular dimerization and therefore biological activation of FLT3 signaling, which could be used to specifically target FLT3 without inducing activation, as taught by Gaddis.
Claims 1, 8, 21, 34, 36, 46, 50, and 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 198, 200-202, 206-213, 215-222, 226-233, and 235-237 of co-pending Application No. 17/042512, herein referred to as “reference application” in view of US Pat No. 5,554,512 (Lymann, et al., 10SEP1996, included in IDS), herein referred to as “’512.”
The co-pending claims of the reference application recite:
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In this instance, because claim 213 dependent upon claim 198 of the reference application is silent on the FLT3 targeting moiety, the specification was consulted to determine the scope of the generic term of FLT3 targeting moiety. Per the specification of the reference application, the Fc-based chimeric protein comprising the FLT3L-Fc of SEQ ID NO: 1528 and Fc-IFNα2 of SEQ ID NO: 1529 of example 30 encompasses 100% query match to the FLT3L of SEQ ID NO: 2 and 98.8% query match to human wt IFNα2 of SEQ ID NO: 6 of the instant application (i.e., the difference between sequence identity of the SEQ ID NO: 1529 and SEQ ID NO: 2 encompasses one or more mutations of wt IFNα2) (see OA.APPENDIX).
However, they do not claim: that the FLT3L ECD is a single chain dimer that are attached to one Fc chain of the Fc domain.
Nevertheless, ‘512 teaches fusion proteins and methods for targeting FMS-like tyrosine kinase 3 (FLT3) (see entire document, specifically see abstract and background sections). The fusion proteins taught by ‘512 comprising FLT3 targeting moieties which comprise FLT3L polypeptides which may exist as oligomers, such as covalently-linked dimers or trimers, wherein a dimer may comprise a fusion protein of a soluble portion of FLT3L (i.e., the ECD of FLT3L) fused to a constant domain of an immunoglobulin protein (FLT3L-Fc), or wherein two soluble FLT3L domains (i.e., the ECD) are linked with a peptide linker (i.e., forming a single chain dimer), which may further be combined to exist as a covalently linked oligomer (col 13, lines 11-34). Additionally, for use in the treatment of cancer, the constructs may be used alone or in combination with a cytokine (col 3, line 45 to col 4, line 14).
It would have been obvious to artisans to modify the issued Fc-chimeric protein comprising i) a FLT3 targeting moiety comprising the ECD of FLT3L, ii) a mutated Fc domain for improved pairing, reduced effector functions, or increased stabilization, and iii) a human mutant IFNα2 signaling agent as claimed by the reference application to include a single chain dimer comprising a ECD of FLT3L, a peptide linker, and a ECD of FLT3L, which then can be linked to an Fc region for example to in this instance form a trimer rather than a dimer, as taught by ‘512. This is because ‘512 teaches that such fusion proteins in combination with a cytokine (i.e., signaling agent) are useful and effective in the treatment of cancer. One would have been motivated to do so, given the open language of claim 213 dependent upon claim 198, wherein the targeting moiety binds to FLT3. There would have been a reasonable expectation of success, given the knowledge that by modifying the FLT3 targeting moiety comprising the ECD of FLT3L of the reference application to include a single-chain dimer with an Fc chain to form a trimer would lead to an effective cancer therapy, as taught by ‘512.
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
The following claim 59 drafted by the examiner and considered to distinguish patentably over the art of record in this application, is presented to applicant for consideration:
“An Fc-based chimeric protein complex comprising a first and second polypeptide chain, wherein the amino acid sequences of the first and second polypeptide chains comprise:
SEQ ID NOs: 58 and 59,
SEQ ID NOs: 60 and 66,
SEQ ID NOs: 61 and 66,
SEQ ID NOs: 62 and 66,
SEQ ID NOs: 63 and 66,
SEQ ID NOs: 64 and 66, or
SEQ ID NOs: 65 and 66, respectively.”
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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