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 .
Status of Application, Amendments and/or Claims
The amendment of 10 December 2025 has been entered in full. Claims 3, 6, 8, 10, 16, and 20 are amended. Claims 4, 7, 9, 11-13, 15, 17-19, 21-27, 29, 31-78 are cancelled. Claims 79-86 are added.
Claims 1-3, 5, 6, 8, 10, 14, 16, 20, 28, 30, and 79-86 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-3, 5, 6, 8, 10, 14, 16, 20, 28, and 30, drawn to a hierarchical protein, in the reply filed on 10 December 2025 is acknowledged.
Claims 1-3, 5, 6, 8, 10, 14, 16, 20, 28, 30, and 79-86 are under consideration in the instant application.
Information Disclosure Statement
The five information disclosure statements (IDS) submitted on 17 April 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
1. Claims 1-3, 5, 6, 8, 10, 14, 16, 20, 28, 30, and 79-86 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1, for example, is directed to a hierarchical protein structure comprising two or more proteins extending in one or more dimensions, the hierarchical protein structure comprising:
a first protein comprising: (i) a patch A comprising one or more polynucleotides conjugated to the surface of the first protein; and (ii) a patch B comprising one or more polynucleotides conjugated to the surface of the first protein; and
a second protein comprising: (i) a patch A' comprising one or more polynucleotides conjugated to the surface of the second protein; and (ii) a patch B' comprising one or more polynucleotides conjugated to the surface of the second protein;
wherein the one or more polynucleotides of the patch A hybridizes to the one or more polynucleotides of the patch A', and/or the one or more polynucleotides of the patch B hybridizes to the one or more polynucleotides of the patch B' to form the hierarchical protein structure.
The specification of the instant application teaches that by defining the chemical anisotropy of a protein’s surface via mutagenesis, DNA interactions can be defined spatially, that is, axially or equatorially with respect to the geometry of an anisotropic protein (page 6, [0025]). The specification continues to disclose that through careful DNA design, the relative interaction strengths of the axial and equatorial faces can be modulated to confine each assembly step to a single direction, thereby directing proteins to assemble hierarchically along specific, multi-step pathways (page 6, [0025]). The specification indicates that the invention harnesses the programmability of DNA and the chemical addressability of protein surfaces to control the hierarchical, multi-step assembly of protein building blocks mediated by multiple, distinct DNA hybridization events (page 6, [0026]).
The specification teaches that proteins of the disclosure refer to a polymer comprised of amino acids, including and without limitation, antibodies, enzymes, structural proteins, and hormones (including naturally occurring, non-naturally occurring, fusion proteins, and mimetics) (pages 7-8, [0029-0033]). The specification states that polynucleotides contemplated by the disclosure include DNA, RNA, modified forms, and combinations thereof (pages 8-9, [0034]). The specification states that a polynucleotide or a modified form thereof, is generally from about 3 nucleotides to about 50 nucleotides in length (page 10, [0037]). The specification continues to teach that polynucleotides of 2-50, or more nucleotides in length are contemplated (page 10, [0037]).
In the instant specification, stable protein 1 (SP1) (SEQ ID NO: 1) was selected as the protein for assembly (page 12, [0041]). In order to align the chemical anisotropy of the protein’s surface to the shape anisotropy of the protein, a mutant “Sp1m” (with mutations K18Q, K44Q, and addition of E20C) was recombinantly expressed with 24 surface accessible primary amines and 12 thiols located axially and equatorially (page 12, [0041]; Table 1). The specification discloses that the designed chemical anisotropy was then exploited to introduce orthogonal DNA ligands to the axial and equatorial faces utilizing two different crosslinkers (pages 12-13, [0042]; page 14, [0046]). The specification discloses that building blocks where the axial and equatorial DNA sequences have disparate melting temperatures were used, such that directionally specific interactions occur at different temperatures (page 14, [0047]; page 16, [0049], Table 2).
Therefore, the claims of the instant application are broadly interpreted by the Examiner as reading upon a hierarchical protein structure comprising two or more proteins extending in one or more directions, wherein the protein structure comprises any “first protein”, any “second protein”, and any polynucleotides (2 to over 50 nucleic acids in length) comprised on patches, A, B, A’, and B conjugated to the surfaces of the first and second proteins. However, the specification does not teach all possible first proteins, all possible second proteins, and all possible polynucleotides comprised on patches, A, B, A’, and B’, wherein one or more polynucleotides of patch A hybridizes to one or more polynucleotides of patch A’, and/or one or more polynucleotides of patch B hybridizes to one or more polynucleotides of patch B’.
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof.
In the instant case, one factor present in the hierarchical protein structure claims is a structural requirement of (i) a first protein comprising a patch A comprising one or more polynucleotides conjugated to the surface of the first protein and patch B comprising polynucleotides conjugated to the surface of the first protein, and (ii) a second protein comprising a patch A’ comprising one or more polynucleotides conjugated to the surface of the second protein and patch B’ comprising polynucleotides conjugated to the surface of the second protein. The other factor present in the claims is a functional requirement that one or more polynucleotides of patch A hybridizes to one or more polynucleotides of patch A’, and/or one or more polynucleotides of patch B hybridizes to one or more polynucleotides of patch B’. There is no identification of any particular sequence or structure of the first protein, second protein, or polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins) that must be conserved in the claimed hierarchical protein structure in order to provide the desired structure and function encompassed by the claims. Thus, the claims are drawn to a genus of hierarchical protein structures comprising all possible first proteins, all possible second proteins, and all possible polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins).
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of first proteins, second proteins, and polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins) and the function of wherein the polynucleotides of patch A hybridize to one or more polynucleotides of patch A’, and/or one or more polynucleotides of patch B hybridizes to one or more polynucleotides of patch B’ to form a hierarchical protein structure. In other words, the specification does not teach the structure of the first proteins, second proteins, and polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins) which results in a hierarchical protein structure with the claimed required characteristics. The description of the Sp1m-DNA conjugate as disclosed in Examples 1-4 and at pages 14-19 of the specification is not adequate written description of an entire genus of hierarchical protein structures comprising all possible first proteins, all possible second proteins, and all possible polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins).
The specification of the instant application teaches that the chemical complexity of protein surfaces makes it challenging to design protein building blocks that will transform into targeted materials by traversing an intended assembly pathway (page 5, [0024]). The specification continues to state that while powerful de novo design strategies have been utilized to create proteins with predetermined interfaces and assembly outcomes, this approach inherently deviates from the pool of naturally occurring protein building blocks that could be utilized for materials engineering. Other strategies have relied on introducing controlled molecular interactions to the surfaces of proteins ranging from metal coordination chemistries to hydrophobic and host-guest interactions. However, achieving specificity and orthogonality through these means can be challenging (page 6, [0024]). Relevant literature also teaches that proteins have a wide array of potentially accessible structures as a result of their larger number of component building blocks, as well as the broader range of interactions these can undergo to influence global structure (Watson et al. Biomol 12: 1523, 2022; page 1, 1st paragraph). Watson et al. discloses that this broader molecular space available to proteins makes them inherently more difficult to program for specific shapes and interactions (page 1, 1st paragraph). Watson et al. state that “[u]ndertaking precision chemistry on biological molecules is inherently challenging, given the ubiquity of many functional groups and thus only a specific range of chemical modifications are applicable in this setting” (page 2, 1st paragraph). Furthermore, Stephanopoulos et al. teach that direct covalent modification of a protein with an oligonucleotide poses distinct challenges in reactivity and site specificity of the target (Chem 6: 364-405, 2020; page 367, last paragraph). Stephanopoulos et al. also disclose that proteins and DNA are both large molecules with many potentially reactive sites, so achieving efficient coupling without compromising function can be difficult (page 367, last paragraph). This challenge is exacerbated when the protein of interest is highly cationic, which can lead to non-specific aggregation with the oligonucleotide (page 367, last paragraph).
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (See page 1117). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (See Vas-Cath at page 1116). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of the hierarchical protein structure comprising all possible first proteins, all possible second proteins, and all possible polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins) recited in the claims, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The specific first protein, second protein, and polynucleotides comprised on the patches are required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
2. Claims 1-3, 5, 6, 8, 10, 14, 16, 20, 28, 30, and 79-86 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 1, for example, is directed to a hierarchical protein structure comprising two or more proteins extending in one or more dimensions, the hierarchical protein structure comprising:
a first protein comprising: (i) a patch A comprising one or more polynucleotides conjugated to the surface of the first protein; and (ii) a patch B comprising one or more polynucleotides conjugated to the surface of the first protein; and
a second protein comprising: (i) a patch A' comprising one or more polynucleotides conjugated to the surface of the second protein; and (ii) a patch B' comprising one or more polynucleotides conjugated to the surface of the second protein;
wherein the one or more polynucleotides of the patch A hybridizes to the one or more polynucleotides of the patch A', and/or the one or more polynucleotides of the patch B hybridizes to the one or more polynucleotides of the patch B' to form the hierarchical protein structure.
The specification of the instant application teaches that by defining the chemical anisotropy of a protein’s surface via mutagenesis, DNA interactions can be defined spatially, that is, axially or equatorially with respect to the geometry of an anisotropic protein (page 6, [0025]). The specification continues to disclose that through careful DNA design, the relative interaction strengths of the axial and equatorial faces can be modulated to confine each assembly step to a single direction, thereby directing proteins to assemble hierarchically along specific, multi-step pathways (page 6, [0025]). The specification indicates that the invention harnesses the programmability of DNA and the chemical addressability of protein surfaces to control the hierarchical, multi-step assembly of protein building blocks mediated by multiple, distinct DNA hybridization events (page 6, [0026]).
The specification teaches that proteins of the disclosure refer to a polymer comprised of amino acids, including and without limitation, antibodies, enzymes, structural proteins, and hormones (including naturally occurring, non-naturally occurring, fusion proteins, and mimetics) (pages 7-8, [0029-0033]). The specification states that polynucleotides contemplated by the disclosure include DNA, RNA, modified forms, and combinations thereof (pages 8-9, [0034]). The specification states that a polynucleotide or a modified form thereof, is generally from about 3 nucleotides to about 50 nucleotides in length (page 10, [0037]). The specification continues to teach that polynucleotides of 2-50, or more nucleotides in length are contemplated (page 10, [0037]).
In the instant specification, stable protein 1 (SP1) (SEQ ID NO: 1) was selected as the protein for assembly (page 12, [0041]). In order to align the chemical anisotropy of the protein’s surface to the shape anisotropy of the protein, a mutant “Sp1m” (with mutations K18Q, K44Q, and addition of E20C) was recombinantly expressed with 24 surface accessible primary amines and 12 thiols located axially and equatorially (page 12, [0041]; Table 1). The specification discloses that the designed chemical anisotropy was then exploited to introduce orthogonal DNA ligands to the axial and equatorial faces utilizing two different crosslinkers (pages 12-13, [0042]; page 14, [0046]). The specification discloses that building blocks where the axial and equatorial DNA sequences have disparate melting temperatures were used, such that directionally specific interactions occur at different temperatures (page 14, [0047]; page 16, [0049], Table 2).
Therefore, the claims of the instant application are broadly interpreted by the Examiner as reading upon a hierarchical protein structure comprising two or more proteins extending in one or more directions, wherein the protein structure comprises any “first protein”, any “second protein”, and any polynucleotides (2 to over 50 nucleic acids in length) comprised on patches, A, B, A’, and B conjugated to the surfaces of the first and second proteins. However, the specification does not teach all possible first proteins, all possible second proteins, and all possible polynucleotides comprised on patches, A, B, A’, and B’, wherein one or more polynucleotides of patch A hybridizes to one or more polynucleotides of patch A’, and/or one or more polynucleotides of patch B hybridizes to one or more polynucleotides of patch B’.
There are no methods or working examples in the specification that indicate (I) all possible first proteins comprising: (i) a patch A comprising any one or more polynucleotides conjugated to the surface of the first protein; and (ii) a patch B comprising any one or more polynucleotides conjugated to the surface of the first protein; and (II) all possible second proteins comprising: (i) a patch A' comprising any one or more polynucleotides conjugated to the surface of the second protein; and (ii) a patch B' comprising any one or more polynucleotides conjugated to the surface of the second protein (wherein the one or more polynucleotides of the patch A hybridizes to the one or more polynucleotides of the patch A', and/or the one or more polynucleotides of the patch B hybridizes to the one or more polynucleotides of the patch B') results in the generation of a hierarchical protein structure that extends in one or more directions.
In other words, there are no methods or working examples that indicate all possible combinations of first and second proteins and all possible polynucleotide combinations comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins) favorably interact with one another to generate a hierarchical protein structure. A large quantity of experimentation would be required of the skilled artisan to generate a hierarchical protein structure comprising two or more proteins extending in one or more directions, wherein the protein structure comprises all possible first proteins, all possible second proteins, and all possible polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins), wherein the polynucleotides of patch A hybridize to one or more polynucleotides of patch A’, and/or one or more polynucleotides of patch B hybridizes to one or more polynucleotides of patch B’ to form a hierarchical protein structure. Such experimentation is considered undue. For example, there is no identification in the specification of any particular sequence or structure of the first protein, second protein, or polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins) that must be conserved in the claimed hierarchical protein structure in order to provide the desired structure and function encompassed by the claims. Additionally, how many polynucleotides are necessary on each protein to assemble the protein structure? Where should patches A, B, A’, and B’ be located on each respective protein (i.e., proper spatial distribution)? How are these patches introduced into the proteins? Does the sequence and/or structural conformation of the two or more proteins affect assembly of the hierarchical protein structure?
Furthermore, one skilled in the art would not be able to predict that the hierarchical protein structure comprising two or more proteins extending in one or more directions, wherein the protein structure comprises all possible first proteins, all possible second proteins, and all possible polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins), wherein the polynucleotides of patch A hybridize to one or more polynucleotides of patch A’, and/or one or more polynucleotides of patch B hybridizes to one or more polynucleotides of patch B’ to form a hierarchical protein structure would have the desired structural and functional activity. The specification of the instant application even teaches that the chemical complexity of protein surfaces makes it challenging to design protein building blocks that will transform into targeted materials by traversing an intended assembly pathway (page 5, [0024]). The specification continues to state that while powerful de novo design strategies have been utilized to create proteins with predetermined interfaces and assembly outcomes, this approach inherently deviates from the pool of naturally occurring protein building blocks that could be utilized for materials engineering. Other strategies have relied on introducing controlled molecular interactions to the surfaces of proteins ranging from metal coordination chemistries to hydrophobic and host-guest interactions. However, achieving specificity and orthogonality through these means can be challenging (page 6, [0024]).
Relevant literature also teaches that proteins have a wide array of potentially accessible structures as a result of their larger number of component building blocks, as well as the broader range of interactions these can undergo to influence global structure (Watson et al. Biomol 12: 1523, 2022; page 1, 1st paragraph). Watson et al. disclose that this broader molecular space available to proteins makes them inherently more difficult to program for specific shapes and interactions (page 1, 1st paragraph). Watson et al. state that “[u]ndertaking precision chemistry on biological molecules is inherently challenging, given the ubiquity of many functional groups and thus only a specific range of chemical modifications are applicable in this setting” (page 2, 1st paragraph). Furthermore, Stephanopoulos et al. teach that direct covalent modification of a protein with an oligonucleotide poses distinct challenges in reactivity and site specificity of the target (Chem 6: 364-405, 2020; page 367, last paragraph). Stephanopoulos et al. also disclose that proteins and DNA are both large molecules with many potentially reactive sites, so achieving efficient coupling without compromising function can be difficult (page 367, last paragraph). This challenge is exacerbated when the protein of interest is highly cationic, which can lead to non-specific aggregation with the oligonucleotide (page 367, last paragraph). McMillan et al. (Acc Chem Res 52: 1939-1948, 2019; cited on the IDS of 17 April 2024) also teach that a major challenge in designing other classes of materials, such as 2D crystals or 3D crystalline architectures with rotationally ordered proteins, remains the inherent flexibility of the linking unit between DNA and the protein surface, which may lead to many possible binding outcomes in the absence of sufficient preference for directional assembly (page 1944, column 2, 1st full paragraph). McMillan et al. state that a better thermodynamic understanding of how to design direction interactions on protein surfaces mediated by multivalent DNA binding needs to be developed to enable the rationale design of these interactions (page 1944, column 2, 1st full paragraph).
Due to the large quantity of experimentation necessary to generate a hierarchical protein structure comprising two or more proteins extending in one or more directions, wherein the protein structure comprises all possible first proteins, all possible second proteins, and all possible polynucleotides comprised on patches, A, B, A’, and B’ (that are conjugated to the first and second proteins), wherein the polynucleotides of patch A hybridize to one or more polynucleotides of patch A’, and/or one or more polynucleotides of patch B hybridizes to one or more polynucleotides of patch B’ to form a hierarchical protein structure, and screen such for desired functional activity; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the state of the art which establishes the unpredictability of modifying proteins with oligonucleotides to generate a functional structure (Watson et al., Stephanopoulos et al., McMillan et al.); and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Conclusion
No claims are allowable.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Cissell et al. Bioconjugate Chem 20(1): 15-19, 2009 (teach that two different fragments of Rluc are conjugated to complementary oligonucleotide probes; hybridization of the two probes fused with Rluc fragments results in reassembly of the fragments, generating active Rluc (abstract; Figure 1))
Ghosh et al. J Am Chem Soc 134: 13208-13211, 2012 (teach oligoG-peptide-oligoG strands; upon the addition of metal ions, formation of parallel G-quaduplexes occurs via H-bonding, metal-ligand and aromatic stacking interactions (page 13209; scheme 1; Figure 2; Figure 3c))
Lou et al. Nature Comm 7: 12294, 2016 (teach peptide-oligonucleotide conjugates and assembly into three-helix protein mimic)
MacCulloch et al. Org Biomol Chem 17: 1668-1682, 2019 (review of peptide-oligonucleotide conjugates)
Middel et al. ChemBioChem 18: 2328-2332, 2017 (teach two peptide nucleic acid (PNA)/peptide hybrids with complementary PNA strands recognize each other through PNA base pairing (Scheme 1))
Pan et al. Adv Sci 7: 1900973, 2020 (teach scFvs targeting different antigens are chemically conjugated at their C-termini to a 30-base DNA that was designed to pair with DNAs linked to other scFvs (page 1, bottom of column 2 through page 2, column 1; Figure 1); do not teach the scFvs each comprise two sets/patches of polynucleotides)
Sancho Oltra et al. ChemBioChem 11: 2255-2258, 2010 (teach a split enzyme engineered with oligonucleotides conjugated to each protein fragment; page 2255, bottom of column 1; Figure 1))
Thurley et al. J Am Chem Soc 129: 12693-12695, 2007 (hairpin peptide beacon that comprises a central protein peptide sequence flanked by two DNA-analogous self-complementary peptide nucleic acid arm segments (Figure 1a))
Van Buggenum et al. Sci Reports 6: 22675, 2016 (teach conjugation of antibodies to double stranded DNA utilizing tetrazine and TCO-dsDNA)
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BEB
Art Unit 1647
19 March 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647