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
1. Applicant’s election without traverse of (iii) antibody or fragment thereof for species A and (a) Immune checkpoint molecule for species B in the reply filed on May 26, 2026 is acknowledged. Applicant indicates that claims 1-2, 5 and 12-14 read upon the elected species.
2. Claims 1, 5 and 13 have been amended and claims 3-4 and 6-11 have been canceled as requested in the amendment filed May 26, 2026. Accordingly, claims 1-2, 5 and 12-14 are pending and under examination in the present application.
Information Disclosure Statement
3. The information disclosure statements (IDSs) filed 11/01/2023, 10/31/2024, 02/26/2025 and 04/07/2026 have been considered. The IDS filed 04/07/2026 is a duplicate of the 02/26/2026 IDS, and therefore the references cited on the 04/07/2026 IDS have been lined through.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
4. Claim(s) 1-2, 5 and 12-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nam et al. (US 2019/0216947 A1) and Jeon et al. (Biomaterials, Jan 2021; 270:120685, 15 pages; listed on 10/31/2024 IDS) in view of Montemiglio et al. (Nat. Comm. 2019, 10(1121), pp. 1-8; listed on 11/01/2023 IDS) and Di Rienzo et al. (Comp. Struct. Biotech J. 2020, 18:2678-2686).
The teachings of Nam et al. and Jeon et al. are commensurate and thus will be presented together because both references are concerned with the production and application of ferritin nanocage complexes for cancer immunotherapy. In particular, Nam et al. teach a fusion protein comprising a self-assembling protein, such as ferritin, and an antibody or antibody fragment targeting an immune checkpoint molecule, such as PD-1 or PD-L1 (see [0006], [0014], FIG. 1B and [0041]-[0043]). The antibody fragment is defined as a single chain-based antibody, such as a scFv, a sdAb, a diabody, a nanobody, etc. ([0043]). Nam also teaches that the PD-1/PD-L1 interaction inhibitor may be pembrolizumab (anti-PD-1), nivolumab (anti-PD-1), atezolizumab (anti-PD-L1) or avelumab (anti-PD-L1) ([0058]). Accordingly, such teachings address the ferritin protein and foreign peptide of present claim 1.
Regarding claim 2, the anti-PD1 or anti-PD-L1 antibody or antibody fragment of Nam all meet the limitation of a pharmacologically active peptide.
Regarding claim 5, an antibody or single chain-based antibody as taught by Nam would all contain antigen-binding region CDRs.
Regarding claim 14, Nam teaches that the ferritin protein is a human ferritin heavy chain protein ([0045]).
Consistent with the teachings of Nam, Jeon et al. also teach a nanocage complex that comprises ferritin protein monomers, wherein the ferritin protein monomers are fused to a peptide that is capable of binding the immune checkpoint molecule PD-L1. Jeon teaches that the PD-L1 binding peptide was ligated to multiple surface-exposed positions of human ferritin heavy chain, including the N-terminus (PpNF), the loop between the fourth and fifth helices (corresponding to the D-E loop) (PpLF), and the C-terminus (PpCF) (see Fig. 1A and 1C, and Materials and Methods section 2.1). Such teachings are on point to claim 1 reciting the position where the foreign peptide is fused to ferritin (i.e., the N-terminus, the D-E loop, the C-terminus).
Jeon further teaches that monoclonal antibodies directed against immune checkpoint inhibitors such as pembrolizumab and nivolumab (anti-PD-1), and atezolizumab and durvalumab (anti-PD-L1), have been demonstrated to be effective in the treatment of cancer (see p. 1). Jeon further notes that while PD-L1 binding peptides were developed as therapeutic alternatives anti-PD-L1 antibodies, atezolizumab and durvalumab have far greater affinities to PD-L1 (p. 2, left column).
However, neither Nam nor Jeon teaches that the ferritin protein is a mutated ferritin protein in which amino acid positions 15, 16, 23, 82 and 84 of SEQ ID NO: 1 are each substituted with alanine as in claim 1.
Montemiglio et al. teach heavy chain ferritin (H-Ft) binds to the human transferrin receptor (CD71 or hTfR1) in a virus-like fashion (p. 2, H-Ft binds the CD71 receptor in a virus-like fashion). Montemiglio teaches the production of engineered H-Ft variants having mutations in various contact regions, and particularly a variant (mutant C) that contains substitutions Q14A, D15A, R22A, F81A and Q83A (p. 4, Mutations at common contacts tune ferritin-CD71 interaction). Montemiglio demonstrates that binding to CD71 was significantly reduced in mutant C compared to wild-type ferritin (Fig. 3).
It is noted that Montemiglio’s numbering of the ferritin amino acid sequence is that of the mature ferritin sequence and does not include the initiator methionine residue that is present in the sequence of instant SEQ ID NO: 1. Therefore, the numbering of amino acid residues in the instant claims is shifted by one position relative the residues of Montemiglio. As such, Montemiglio’s substitutions of Q14A, D15A, R22A, F81A and Q83A correspond to the claimed substitutions at positions 15, 16, 23, 82 and 84 of SEQ ID NO: 1, respectively.
Di Rienzo et al. provide additional information on the amino acid residues involved in the protein-protein interactions between ferritin and transferrin receptor (CD71). Di Rienzo created ferritin mutants with increased (H-C-mut) or decreased (L-C-mut) complementarity to CD71 (Table 1 at p. 2682). Di Rienzo indicates that ferritin mutants with increased or decreased complementarity would provide a powerful tool to fine tune the therapeutic/diagnostic cargo transport and delivery of engineered ferritin molecules (i.e., ferritin nanocages) to cancer cells (p. 2679, right column). Di Rienzo also teaches that at least residues Q14, D15, R22, F81 and Q83 (i.e., the instant Q15, D16, R23, F82 and Q84) are important binding site residues of ferritin for binding with CD71 (Fig. 1 at p. 2680).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the present application to have modified the ferritin protein of Nam and Jeon to have included the substitutions taught by Montemiglio and Di Rienzo and thereby arrive at the presently claimed invention. Given the teachings of Di Rienzo, the artisan would have been aware that modifying the affinity of ferritin for CD71 may be useful in the development of engineered ferritin nanoparticles. Additionally, Montemiglio teaches that the combined substitution of residues 15, 16, 23, 82 and 84 with alanine residues preserved ferritin nanoparticle assembly while substantially reducing CD71 interaction/binding. Therefore, the skilled artisan would have been motivated to have made such modifications to the ferritin monomers to reduce non-specific uptake by healthy tissues of ferritin, thereby prolonging circulation half-life and reducing off-target binding of the ferritin nanocage. Reducing ferritin complementarity to CD71 would also augment the ability for the expressed PD-1/PD-L1 antibody fused to the ferritin nanoparticle to successfully bind and interact with target tumor tissues.
Furthermore, given that Montemiglio teaches the same ferritin mutant recited in claim 1 and that the mutant has significantly reduced binding to CD71, the result ferritin engineered according to the combined prior art references would have a binding force K greater than or equal to 10 nM (as in claim 12) as evidenced by Montemiglio (see Supplementary Table 5). Therefore, the combined references teachings render obvious the presently recited invention of claims 1-2, 5 and 12-14.
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.
5. Claims 1-2, 5 and 12-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 11-12 and 14-15 of copending Application No. 18/289,152 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims encompass a ferritin protein fused to an immune checkpoint molecule of PD1, PD-L1 or TIGIT, wherein the immune checkpoint molecule is an antibody or fragment thereof having binding affinity for the immune checkpoint molecule, wherein the ferritin protein comprises a sequence in which amino acids at positions 15, 16, 23, 82 and 84 of SEQ ID NO: 1 are each substituted with alanine, and wherein the antibody is fused at one or more of the same positions of the ferritin monomer. Regarding present claim 2, the co-pending claims recite that the antibody or fragment thereof is capable of binding to an immune checkpoint molecule, and thus would be considered a pharmacological active peptide as defined by the instant application. The claims of the co-pending ‘152 application further recite that: the antibody binding fragment is an antigen binding region (CDR) of the antibody (which is on point to present claim 5); the binding force (K) to the transferrin receptor satisfies Equation 1: K ≥10 nM (addressing present claim 12); the transferrin receptor is a human transferrin receptor (addressing present claim 13); the ferritin is a human ferritin heavy chain (addressing present claim 14).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
6. Claims 1-2, 5 and 12-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-10 and 12-13 of copending Application No. 17/773,266 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims are directed to a fusion protein comprising ferritin an a molecule that binds PD1, PD-L1 or TIGIT, wherein the molecule is fused at one or more of the same positions of the ferritin monomer, and wherein the binding molecule is an antibody (which would inherently comprise CDRs). The ‘266 claims further recite that the ferritin protein is mutated to reduce binding force to a human transferrin receptor, wherein the recited mutations (substitutions) are consistent with those of present claim 1, the binding force to a transferrin receptor is defined by the same equation, and the ferritin is a human ferritin heavy chain.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
7. Claims 1-2, 5 and 12-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-13, 25 of copending Application No. 18/034,193 in view of Montemiglio et al. (Nat. Comm. 2019, 10(1121), pp. 1-8; listed on 11/01/2023 IDS) and Di Rienzo et al. (Comp. Struct. Biotech J. 2020, 18:2678-2686).
The claims of the ’193 co-pending application recite a ferritin monomer fused to a CDR, wherein the CDR comprises at least a heavy chain CDR 3 (HCDR3) of an antibody and the HCDR3 comprises an amino acid sequence selected from SEQ ID NOs: 2, 5-7 and 26-29. It is noted that the specification of the ‘193 application teaches that these sequences are the HCDR3 sequences of PD-1, PD-L1 and TIGIT antibodies, among others. These CDRs are also all pharmacologically active peptides, as in present claim 2. Co-pending claim 5 also recites that the CDR is fused to a human ferritin heavy chain monomer, as in present claim 14. The co-pending claims further recite that the CDR is fused at one or more positions within the ferritin protein that are the same as those recited in present claim 1. Thus, the co-pending claims recite a ferritin protein having all elements of present claim 1 except for the substitutions at positions 15, 16, 23, 82 and 84.
The teachings of Montemiglio et al. and Di Rienzo et al. are discussed above and provide for a mutated ferritin protein comprising the instantly recited mutations and having a reduced binding force to human transferrin receptor (CD71).
Therefore, the presently claimed ferritin protein is obvious in view of the claims of the ‘193 application in view the teachings of Montemiglio and Di Rienzo because modifying the complementarity of ferritin for CD71 to reduce binding force would have been desirable for reducing potential off-target binding of the ferritin nanoparticle, which simultaneously would have allowed for better binding and interaction of the PD-1, PD-L1 or TIGIT CDRs with their target molecules.
This is a provisional nonstatutory double patenting rejection.
Conclusion
8. No claims are allowed.
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. This prior art includes:
Calisti L et al. Engineered ferritin for lanthanide binding. PLoS ONE, 2018, 13(8):e0201859.
Jin Y et al. Ferritin variants: inspirations for rationally designing protein nanocarriers. Nanoscale, 2019, 11, 12449-12459.
Truffi M et al. Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer. Pharmacological Res. 2016, 107:57-65.
Advisory Information
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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