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 .
Amendments Received
Amendments to the claims were received and entered on January 12, 2026.
Status of Claims
Claims 1-3, 6, 8, 10, 12, 26-32, 37-38, 40, 54-64 are currently pending and under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/US19/65078 filed on December 6, 2019. Acknowledgment is made of applicant’s claim for benefit under 35 U.S.C. 119(e) of Provisional application No. 62/776,399, filed on December 6, 2018. The present application and all claims are being examined with an effective filing date of December 6, 2018. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Withdrawn Rejections
In view of Applicant’s amendments, rejections of claims 1-3, 6, 8, 10, 12, 26-32, 37-38, 40, and 54-62 under 35 USC § 102 by Mirkin, are hereby withdrawn.
Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
Claims 1-3, 6, 8, 10, 12, 26-32, 37-38, 40, and 54-64 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mirkin and Brodin (WO2016028940, herein “Mirkin”, cited in the IDS), as evidenced by Niemeyer et al. (“Oligonucleotide-directed self-assembly of proteins: semisynthetic DNA–streptavidin hybrid molecules as connectors for the generation of macroscopic arrays and the construction of supramolecular bioconjugates,” Nucleic Acids Research 22:5530–5539 (1994), cited it PTO-892).
Regarding claims 1, 30, 37, and 59-60, Mirkin discloses methods of forming ordered crystalline/superlattice structures comprising protein-containing core-shell nanoparticles functionalized with oligonucleotides, wherein complementary oligonucleotides associated with different nanoparticles hybridize to direct assembly of the crystalline structure (Abstract; para 0007–0009; Fig. 14b; Table 2). Mirkin further discloses that oligonucleotides are attached to the protein-containing particles (para 0073–0075), expressly exemplifies short complementary “sticky end” sequences including 5′-TTCCTT-3′, which is 6 nucleotides in length and falls within the claimed 2–10 nucleotide range (para 0231; Table 1), and discloses polynucleotide lengths generally ranging from about 5 to about 100 nucleotides (para 0094). Mirkin therefore teaches contacting protein-containing conjugates bearing attached oligonucleotides under conditions sufficient for complementary oligonucleotide hybridization-directed assembly of ordered protein-containing crystalline/superlattice structures. Mirkin does not expressly exemplify both attached oligonucleotides as being 2–10 nucleotides in length as recited in claim 1. Nonetheless, Mirkin teaches programmable DNA-directed assembly using complementary oligonucleotide interactions and expressly exemplifies short complementary sticky-end sequences and a polynucleotide length range encompassing such short sequences (para 0009; para 0231; Table 1; para 0094), such that selection of oligonucleotide length within Mirkin’s disclosed range represents routine optimization of a result-effective variable known to affect hybridization specificity and lattice ordering.
Regarding the claimed limitation that the first protein and second protein associate via protein-protein interactions (PPI) to form the protein crystal, Mirkin acknowledges prior protein crystallization approaches relying on PPIs (para 0005) and describes non-covalent associations, including protein binding and hydrophobic interactions, among agents associated with the protein core (para 0078/para 0125), indicating that native protein surface interactions can occur in protein-containing assemblies. Although Mirkin emphasizes complementary oligonucleotide interactions to provide programmable control over assembly (para 0009), Mirkin does not teach that native protein surface interactions are excluded from contributing to the assembled structure. Rather, Mirkin’s teachings that oligonucleotide hybridization directs assembly while protein cores retain surface interaction capabilities support a person of ordinary skill in the art understanding that native protein-protein surface interactions can contribute to packing, stabilization, and ordering of protein cores within a DNA-directed lattice.
As evidenced by Niemeyer et al., oligonucleotide-directed self-assembly of proteins using semisynthetic DNA–streptavidin hybrid molecules as connectors generate macroscopic protein arrays and supramolecular bioconjugates. Specifically, Niemeyer et al. teaches that such hybrid molecules may serve as “connectors in the oligonucleotide-directed self-assembly of proteins” and further teaches use of nucleic acid sequences “as a template for the formation of an array of proteins.” Niemeyer et al. additionally describes “a non-covalent assembly of biomolecules, previously connected to single-stranded DNA” for construction of supramolecular bioconjugates. Niemeyer et al. therefore further evidences that complementary nucleic acid hybridization was conventionally used to template assembly of ordered protein-containing structures formed through non-covalent interactions.
An invention would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention if some teaching in the prior art would have led that person to modify the prior art teachings to arrive at the claimed invention with a reasonable expectation of success. Given that Mirkin teaches DNA-directed assembly of protein-containing crystalline/superlattice structures using attached complementary oligonucleotides, expressly exemplifies short sticky-end sequences falling within the claimed 2–10 nucleotide range, and recognizes protein-protein and non-covalent surface interactions in protein-containing assemblies, and further in view of Niemeyer’s evidentiary teachings that protein–oligonucleotide conjugates were conventionally used in oligonucleotide-directed self-assembly of ordered protein-containing structures, it would have been obvious to a person of ordinary skill in the art to select short complementary oligonucleotides attached to protein-containing cores in order to direct hybridization-driven assembly while reasonably expecting native protein-protein surface interactions to contribute to stabilization and ordering within the assembled lattice. Further, there would have been a reasonable expectation of success that such modification would successfully result in a method of producing an ordered protein-containing crystal structure because Mirkin expressly teaches programmable hybridization-directed assembly of crystalline/superlattice structures using attached complementary oligonucleotides, while Niemeyer further evidences that protein–oligonucleotide conjugates were conventionally used in DNA-guided assembly of ordered protein structures. Selection of oligonucleotide length within Mirkin’s disclosed range therefore represents routine optimization of a result-effective variable to achieve more predictable hybridization specificity and lattice ordering, and the claimed method would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 2-3 and 31-32, Mirkin discloses a plurality of core-shell nanoparticles, as described above, wherein each core-shell nanoparticle comprises the same protein (claim 22), and wherein at least 2 core-shell nanoparticles comprise different proteins (claim 23).
Regarding claims 6 and 8, Mirkin teaches that “using linkers that are complementary to each other, but not to themselves, allows the assembly of binary lattices containing either two different enzymes” (para 0203). Additionally, Mirkin discloses “wherein the plurality of polynucleotides of a first core-shell nanoparticle have a polynucleotide sequence that is sufficiently complementary to a polynucleotide sequence of the plurality of polynucleotides of a second core-shell nanoparticle to hybridize and form a superlattice structure” (claim 26). Accordingly, Mirkin teaches complementary attached polynucleotides configured to hybridize with one or more complementary polynucleotides associated with a second protein-containing conjugate as recited in claims 6 and 8.
Regarding claims 10 and 38, as discussed above, Mirkin acknowledges prior protein crystallization approaches relying upon protein-protein interactions (para 0005) and further describes non-covalent associations including protein binding and hydrophobic interactions among protein-containing assemblies (para 0078 and 0125). A person of ordinary skill in the art would have understood that native protein surface interactions, including hydrophobic interactions, van der Waals interactions, electrostatic interactions, hydrogen bonding, salt bridges, disulfide interactions, and related non-covalent interactions, are inherent and expected contributors to stabilization and packing within assembled protein lattices. Accordingly, the claimed protein-protein interaction types would have been obvious in view of Mirkin and the ordinary knowledge in the art regarding protein surface interactions.
Regarding claims 12 and 40, Mirkin discloses SAXS data and X-ray diffraction patterns for protein-protein superlattices (Fig. 21; para 0223–0227; Table 2). The disclosed figures present SAXS-derived structure factor data with q-values extending to approximately 0.08 Å^-1, corresponding to structural features on the order of approximately 78 Å. Although SAXS is a low-angle scattering technique and does not directly provide atomic-resolution structural determination, the presence of multiple sharp, well-defined higher-order Bragg peaks and narrow peak widths indicates a highly ordered long-range crystalline lattice.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to arrive at the claimed invention with a reasonable expectation of success. Before the effective filing date of the claimed invention, a person of ordinary skill in the art, having knowledge of protein crystallography and diffraction principles, would have recognized that the degree of periodicity and long-range crystalline order disclosed by Mirkin reflects a lattice structure capable of supporting diffraction to angstrom-level resolution when subjected to appropriate crystallographic techniques and conditions, as evidenced by Brodin. Accordingly, it would have been obvious to a person of ordinary skill in the art that the disclosed protein crystal assemblies would be capable of diffracting to angstrom-level resolution as recited in claims 12 and 40. Therefore, the invention as a whole would have been prima facie obvious before the effective filing date of the claimed invention to a person of ordinary skill in the art.
Regarding claims 26 and 54, Mirkin discloses the core-shell nanoparticle compositions described above, “wherein the protein exhibits catalytic, signaling, therapeutic, or transport activity” (claim 2). Accordingly, Mirkin teaches protein-containing crystalline assemblies comprising proteins having the recited functional activities.
Regarding claims 27 and 55, Mirkin teaches the core-shell nanoparticle compositions described above, wherein non-naturally occurring proteins, including fragments of proteins, are contemplated for use in the disclosed assemblies (para 0078, 0080–0081, 0084, 0131, and 0158). Accordingly, Mirkin teaches or suggests protein-containing assemblies comprising protein fragments as recited in claims 27 and 55.
Regarding claims 28 and 56, Mirkin expressly teaches assemblies wherein polynucleotides of a first core-shell nanoparticle have a sequence sufficiently complementary to polynucleotides of a second core-shell nanoparticle to hybridize and form a superlattice structure (claim 26). Mirkin further teaches compositions comprising a plurality of core-shell nanoparticles, wherein “plurality” is defined as “more than one” (para 0067), and additionally teaches embodiments comprising one or more additional core-shell particles containing additional enzymes that may be the same as or different from enzymes present in other particles (para 0180). Accordingly, Mirkin teaches or suggests protein-containing crystalline assemblies comprising first, second, and third protein-containing conjugates as recited in claims 28 and 56.
Regarding claims 29 and 57, Mirkin teaches various embodiments of nanoparticle and lattice dimensions, including crystalline lattices having lattice parameters ranging from approximately 28.3 nm to 31.7 nm (Table 2) and nanoparticle dimensions ranging from about 1 nm to about 250 nm (para 0170). A person of ordinary skill in the art would have reasonably understood that pore dimensions within such ordered crystalline lattices would be expected to fall within the claimed range of about 1 nm to about 100 nm in diameter. Accordingly, the claimed pore size range would have been obvious in view of Mirkin.
Regarding claim 58, Mirkin teaches a method of catalyzing a reaction “comprising contacting reagents for the reaction with a composition of the disclosure, wherein contact between the reagents and the composition results in the reaction being catalyzed” (para 0023). Specifically, Mirkin discloses “methods of using the disclosed core-shell particles or complexes of the same as catalysts for a chemical reaction to transform one or more reagents to a product. The methods can comprise contacting the one or more reagents of the reaction with a composition of a plurality of core-shell particles as disclosed herein such that contact of the reagent or reagents with the composition results in the reaction being catalyzed to form a product of the reaction, wherein the protein of the core- shell particle is an enzyme for the chemical reaction” (para 0193).
Regarding claims 59 and 60, Mirkin expressly exemplifies complementary sticky-end oligonucleotide sequences including the sequence 5′-TTCCTT-3′ (6 nucleotides in length) (para 0231; Table 1), and further teaches oligonucleotide lengths generally ranging from about 5 to about 100 nucleotides (para 0094). Accordingly, Mirkin teaches or suggests attached complementary oligonucleotides each having lengths within the claimed range of 5 to 10 nucleotides.
Regarding claims 61 and 62, Mirkin discloses protein-containing core-shell nanoparticle assemblies “wherein the protein exhibits catalytic, signaling, therapeutic, or transport activity.” Mirkin further teaches that “the DNA-functionalized proteins retain their native catalytic functionalities both in the solution and crystalline states” (para 0057). Additionally, Mirkin discloses exemplary protein crystal assemblies that were tested and confirmed for catalytic activity (para 0220; Figs. 14 and 19). Accordingly, Mirkin teaches protein crystal assemblies exhibiting catalytic activity as recited in claims 61 and 62.
Regarding claims 63 and 64, Mirkin teaches complementary oligonucleotide “sticky end” sequences used for hybridization-directed assembly (para 0231; Table 1). A person of ordinary skill in the art would understand that such complementary sticky-end hybridization requires single-stranded oligonucleotide regions capable of base pairing. Accordingly, the claimed single-stranded first and second polynucleotides would have been obvious in view of Mirkin.
Response to Arguments for Prior Art Rejections
Applicant’s amendment to independent claims 1 and 30 adding the limitation that the first polynucleotide is attached to the first protein and the second polynucleotide is attached to the second protein has been fully considered. In view of the amended claim language, the rejection under 35 U.S.C. §102 has been withdrawn because Mirkin does not expressly disclose the claimed arrangement identically as recited in the amended claims. However, the amendment does not render the claims patentable because the cited prior art, as set forth in the rejection under 35 U.S.C. §103, would have rendered the amended subject matter obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention. Specifically, Mirkin teaches protein-containing conjugates bearing attached oligonucleotides that assemble into ordered crystalline structures through complementary oligonucleotide hybridization, and the presently claimed arrangement and oligonucleotide lengths represent routine optimization and predictable implementation of Mirkin’s disclosed assembly system, as further evidenced by Niemeyer.
In the response filed on 01/12/2026, Applicant argues that Mirkin does not expressly disclose first and second polynucleotides attached to first and second proteins, respectively, wherein each polynucleotide is 2–10 nucleotides in length, and further argues that Mirkin replaces protein-protein interactions with DNA-DNA interactions rather than utilizing both interactions cooperatively. Applicant additionally argues that the claimed 2–10 nucleotide range is critical because longer duplexes allegedly failed to crystallize in Applicant’s examples. The arguments are not persuasive because the rejection under 35 U.S.C. §103 does not rely on Mirkin as expressly disclosing the claimed invention identically as arranged in the claims. Rather, the rejection relies on the combined teachings of Mirkin and the knowledge of a person of ordinary skill in the art, as evidenced by Niemeyer, demonstrating that it would have been obvious to utilize short complementary oligonucleotides attached to proteins for programmable hybridization-directed assembly of ordered protein structures while reasonably expecting native protein surface interactions to contribute to packing and stabilization within the resulting lattice.
Applicant argues that paragraph [0231] of Mirkin allegedly discloses hybridization of an oligonucleotide to a protein-DNA conjugate rather than first and second proteins each bearing attached oligonucleotides. However, Mirkin expressly discloses protein-containing core-shell particles functionalized with attached oligonucleotides (paras 0073–0075), wherein complementary oligonucleotides associated with different particles hybridize to direct assembly of crystalline superlattice structures (paras 0007–0009; Fig. 14b; Table 2). Mirkin additionally exemplifies short complementary sticky-end sequences including the 6-nucleotide sequence 5′-TTCCTT-3′ (para 0231; Table 1) and teaches oligonucleotide lengths generally ranging from about 5 to about 100 nucleotides (para 0094). Selection of short complementary oligonucleotide lengths within Mirkin’s disclosed range for improved hybridization specificity and lattice control would have constituted routine optimization of a result-effective variable.
Applicant further argues that Mirkin allegedly teaches away from utilizing protein-protein interactions because Mirkin describes “trading protein-protein interactions for complementary oligonucleotide-oligonucleotide interactions.” However, Mirkin does not state that native protein surface interactions are absent or incapable of contributing to assembled structures. Rather, Mirkin explains that complementary oligonucleotide interactions provide programmable control over assembly relative to conventional crystallization approaches dependent solely upon native protein-protein interactions. Mirkin additionally acknowledges prior crystallization approaches based upon protein-protein interactions (para 0005) and further describes non-covalent associations including protein binding and hydrophobic interactions associated with protein-containing assemblies (para 0078; para 0125). Thus, Mirkin teaches that oligonucleotide hybridization directs assembly while protein cores retain native surface interaction capabilities. A person of ordinary skill in the art would have reasonably understood that such native protein surface interactions would predictably contribute to packing, ordering, and stabilization within the assembled lattice even where complementary oligonucleotide hybridization provides the primary programmable assembly mechanism. Niemeyer further evidences that oligonucleotide-directed self-assembly of protein conjugates into ordered protein arrays was known in the art. Niemeyer teaches semisynthetic DNA-streptavidin hybrid molecules used to generate macroscopic protein arrays through oligonucleotide hybridization, thereby evidencing that protein-oligonucleotide conjugates were conventionally used in ordered protein assembly systems and supporting the reasonable expectation that protein surface interactions and DNA hybridization can cooperatively exist within assembled protein structures.
Applicant additionally argues that the claimed 2–10 nucleotide range is critical because Applicant allegedly observed lack of crystallization using longer duplexes. However, evidence that certain embodiments may exhibit differing crystallization efficiencies or structural outcomes does not establish criticality of the entire claimed range absent evidence demonstrating that the claimed range achieves unexpected results relative to the closest prior art. Mirkin expressly teaches short complementary sticky-end sequences including 6-nucleotide sequences falling within the claimed range and further teaches oligonucleotide lengths overlapping the claimed subject matter. Optimization of oligonucleotide length for desired hybridization specificity, assembly behavior, and lattice organization would have been within the ordinary level of skill in the art.
Applicant’s arguments have been fully considered but are not persuasive. Accordingly, Applicant’s arguments have not overcome the rejection under 35 U.S.C. §103 because the cited prior art, taken as a whole, would have led a person of ordinary skill in the art to arrive at the claimed invention with a reasonable expectation of success before the effective filing date of the claimed invention.
Conclusion
No claim is in condition for allowance.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NAGHMEH NINA MOAZZAMI whose telephone number is (703)756-4770. The examiner can normally be reached Monday-Friday, 9:00-5:00.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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