Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the invention of Group I, drawn to a spheromer MHC-peptide complex (claims 1-13) in the reply filed on 03/20/2026 is acknowledged. Applicant further elects the following species maxi-ferrtin, particularly Pyrococcus furiosus maxi-ferritin, and a biotin-streptavadin interaction between the self-assembling monomers and peptide-MHC complexes.
Claims 5-8,11 and 14-19 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/20/2026.
Claims 1-4, 9-10 and 12-13 are examined on the merits in the present Office Action.
Claim Interpretation
The term “biotinylation signal sequence” as recited in instant claim 10 is not specifically defined in the specification. Further, the art does not appear to recognize a ‘signal sequence’ for biotin. The specification, however, does state that “[b]iotinylation at the signal sequence allows the self-assembling polypeptide to bind to pMHC monomers at high affinity” (Para. 0010). It is known in the art that, unlike chemical biotinylation, enzymatic biotinylation with E. coli biotin ligase (BirA) is highly specific in covalently attaching biotin to the 15 amino acid AviTag peptide, giving a homogeneous product with high yield (emphasis added) (Fairhead et al, Summary). As such, AviTag can act as a ‘signal sequence’ that the BirA enzyme recognizes and covalently attaches a biotin molecule to the lysine (K) residue within the tag (Fairhead, see Figure 1 caption). Thus, without further definition, the term ‘biotinylation signal sequence’ is interpreted as a peptide sequence that servers as a recognition site for enzymatic biotinylation (e.g. an AviTag sequence).
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.
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al (KR101831483B1, EPO Machine Translation), hereinafter Kim.
Kim teaches spheromers (referred to as nanoparticles) comprising 24 self-assembling ferritin monomers each conjugated to a peptide-MHC complex (MHC receptor protein + antigenic peptide) (Abstract, Para. 0008, Para. 0015-0018, Para. 0025, Para. 0027, Para. 0046, Para. 0070). The type of the ferritin monomer used to form a spheromer is not particularly limited but refers to a protein in which 24 monomers can self-assemble into a nanostructure (Para. 0025). The MHC receptor protein and ferritin monomer may be conjugated via chemical means or enzymatic action (Para. 0018) or via a linker, including but not limited to peptide and non-peptide linkers (Para. 0034-035). Peptide linkers can include those that increase flexibility of the fusion protein or the activity of each fusion partner, including flexible linkers such as the GGGGS (G4S) linker (Para. 0038-0039).
Thus, Kim meets the limitations of instant claims 1-3.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 4 rejected under 35 U.S.C. 103 as being unpatentable over Kim, as applied to claims 1- 3 above, and further in view of Tatur et al (Tatur, Jana et al. “A highly thermostable ferritin from the hyperthermophilic archaeal anaerobe Pyrococcus furiosus.” Extremophiles : life under extreme conditions vol. 10,2 (2006): 139-48. doi:10.1007/s00792-005-0484-x), hereinafter Tatur.
The teachings of Kim have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the ferritin used to form a spheromer is the maxi-ferritin Pyrococcus furiosus.
However, Tatur teaches that while ferritins in general are relatively resistant to thermal denaturation, the ferritin from Pyrococcus furiosus (PfFtn) is the most thermostable ferritin known so far; PfFtn is a 24-mer whose activity has a half-life of 48 h at 100°C and 85 min at 120°C. Further, no apparent melting temperature was found up to 120°C. The extreme thermostability of PfFtn has value for biotechnological applications, including construction of nano-sized structures for nanotechnological purposes (see Abstract and “Hyperthermostability” section under Discussion).
It would have been obvious to one of ordinary skill in the art to the spheromer/nanoparticles of Kim such that self-assembling 24-mer ferritin used is Pyrococcus furiosus, which is a maxi-ferritin as defined by the instant claims. One of ordinary skill in the art would have been motivated to do so since Pyrococcus furiosus is extremely thermostable and thus has value for biotechnological applications, including construction of nano-sized structures for nanotechnological purposes as taught by Tatur. Therefore, one of ordinary skill in the art would reasonably expect a spheromer comprising a peptide-MHC conjugated to Pyrococcus furiosus ferritin monomers can effectively treat a disease or disorder in a subject.
Claims 9 and13 are rejected under 35 U.S.C. 103 as being unpatentable over Kim, as applied to claims 1-3 above, and further in view of Bhatia et al (WO2008073856A2), hereinafter Bhatia.
The teachings of Kim have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the self-assembling ferritin monomers of the spheromer are conjugated to the peptide MHC complexes by a biotin-streptavidin interaction.
However, Bhatia teaches that for nanoparticle conjugates, either the nanoparticle or the biomolecule (its fusion partner) can be functionalized with biotin with the other being functionalized with streptavidin. These two moieties specifically bind to each other non-covalently and with high affinity, thereby linking the nanoparticle and the biomolecule (Para. 0269 on Page 74). Further it is taught that an optically detectable moiety such as a fluorescent or luminescent dye, etc., can be entrapped, embedded, or encapsulated by a nanoparticle core and/or coating layer or is otherwise conjugated to the particle (Para. 00108 of Appendix A on Page 151) and thus are useful in in vivo imaging techniques (Para. 00331 on Page 91). The term ‘nanoparticle’ encompasses polymeric particles (Abstract). As such, ferritin spheromers would be considered nanoparticles and can thus be functionalized with biotin while its fusion partner is functionalized with streptavidin.
It would have been obvious to one of ordinary skill in the art to modify the ferritin nanoparticle conjugates taught by Kim such that the pMHC complexes and ferritin monomers are conjugated through a biotin-streptavidin interaction. In particular, it would have been obvious to functionalize the ferritin monomers with biotin and to functionalize the MHC receptor proteins with streptavidin. One of ordinary skill in the art would have been motivated to do so since biotin and streptavidin non-covalently bind with specificity and high affinity, thereby providing a means for linking nanoparticles, such as ferritin, with biomolecules, such as pMHC complexes as taught by Bhatia. Further, it would have been obvious to modify the ferritin nanoparticle to include a fluorescent or luminescent dye so as to render the nanoparticle detectable, for example, in imaging assays. Therefore, one of ordinary skill in the art would reasonably expect that the ferritin monomers and pMHC complexes of the spheromer disclosed by Kim can be effectively conjugated via a biotin-streptavidin interaction and that incorporation of a fluorescent or luminescent dye would permit detection of the resulting particle in imaging applications.
Claims 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kim in view of Bhatia, as applied to claims 1- 3, 9, and 13 above, and further in view of Fairhead et al (Fairhead, Michael, and Mark Howarth. “Site-specific biotinylation of purified proteins using BirA.” Methods in molecular biology (Clifton, N.J.) vol. 1266 (2015): 171-84. doi:10.1007/978-1-4939-2272-7_12), hereinafter Fairhead.
The teachings of Kim in view of Bhatia have been discussed above and differ from the instantly claimed invention in that it is not specifically taught that the ferritin monomers are genetically modified to comprise a biotinylation signal sequence, such as AviTag.
However, Fairhead teaches that chemical biotinylation often generates heterogeneous products, which may have impaired function, but enzymatic biotinylation with E. coli biotin ligase (BirA) is highly specific in covalently attaching biotin to the 15 amino acid AviTag peptide, giving a homogeneous product with high yield. AviTag can conveniently be added genetically at the N-terminus, C-terminus or in exposed loops of a target protein (see Summary). To add flexibility between the AviTag and the target protein, it is further suggested to include a flexible two residue GS linker between the AviTag and the target protein or any other surrounding peptide tag or domain and to optimize the spacer length to enable biotinylation or increase yield of protein (see Footnote 2).
It would have been obvious to one of ordinary skill in the art to the ferritin nanoparticle conjugates taught by Kim in view of Bhatia such that biotin-streptavidin interaction involves genetic modification of ferritin monomers to comprise a biotinylation signal sequence, such as AviTag. One of ordinary skill in the art would have been motivated to do so since the AviTag can be conveniently be added genetically to a target protein, such as a ferritin monomer, and permit site-specific enzymatic biotinylation using E. Coli biotin ligase (BirA) as taught by Fairhead. Fairhead further teaches that enzymatic biotinylation provides more specific covalent attachment of bitoin compared to chemical biotinylation. Moreover, it would have been obvious to include a flexible glycine-serine (GS) linker of at least two residues between the AviTag and ferritin monomers in view of Fairhead’s teaching that such linkers can increase flexibility and facilitate biotinylation by BirA or improve protein yield. Therefore, one of ordinary skill in the art would reasonably expect that pMHC complexes can be effectively conjugated to ferritin through a biotin-streptavidin interaction wherein the ferritin monomers are genetically modified to comprise an AviTag biotinylation signal sequence, and further separated from the ferritn monomer by a GS linker to improve flexibility and biotinylation efficiency.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
