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 Claims
The preliminary amendment filed 09/27/2026 is acknowledged. Claims 3, 5-8, 10, 12, 14, 16, 19, 21, 23, 27, 28, and 30 are amended. Claims 11, 15, 17, 18, 26, 29, and 31-33 are cancelled. Claims 1-10, 12-14, 16, 19-25, 27, 28, and 30 are pending and under examination.
Election/Restrictions
Applicant’s election without traverse of group I (claims 1-10, 12-14, 16, 19, and 20) in the reply filed on 02/04/2026 is acknowledged.
Upon further consideration, the restriction requirement is withdrawn as the claims of groups II, III, and IV are not patentably distinct from group I.
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 drawings [see Fig. 3A] are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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.
Specification
The use of the terms “Phos-tag” and “BODIPY”, which are trade names or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 7 recites “amino acids 6 to181 of,” which is missing a space between “to” and “181.” Appropriate correction is required.
Claim 12 is objected to because of the following informalities: the claim recites a “a KIX domain” without spelling out the acronym in its first use. Appropriate correction is required.
Claim Rejections - 35 USC § 112b
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 1-10, 12-14, 16, 19-25, 27-28, and 30 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.
The specification teaches that “apoferritin” refers to the complete cage unit, however, the term is also used throughout the claims seemingly to refer to both an individual apoferritin subunit and the assembled apoferritin cage. For example, claim 1b recites “the apoferritin” while claim 1a recites “a plurality of apoferritin proteins.” First, if this is understood in light of the specification’s definition of a fully formed cage unit, then it cannot comprise the cage unit as required by instant claim 1a. Second, it becomes unclear what the cargo protein is connected to. Similarly, claim 24 recites a fusion protein comprising “an apoferritin protein,” which suggests it is the complete apoferritin cage, but in light of the previous claims it could be interpreted as comprising at least one subunit. As such, this distinction is material to the scope of the claims. Accordingly, applicant is required to provide appropriate antecedent definitions to clarify the meaning of the term, identify when apoferritin is referred to in the plurality, and consistently distinguish between the apoferritin cage and its individual subunits.
To advance compact prosecution, the claims will be interpreted such that they refer to the apoferritin cage subunits and not the cage itself, and all claims reciting a limitation of “the apoferritin” such as claims 6, 8, and 9, will be understood as meaning “at least one apoferritin” as this appears consistent with the drawings.
Furthermore, claim 6 recites “a truncated apoferritin protein lacking up to the first 5…,” [emphasis added] which comprises embodiments in which none of the amino acids are deleted, but in such an embodiment there would be no truncation. Accordingly, it is unclear what is being described with reasonable certainty. To advance compact prosecution, the claim is interpreted such that each apoferritin protein is truncated at at least one position within the first 5 amino acid residues. Appropriate correction is required.
Therefore, claims 1-10, 12-14, 16, and 19-25, 27, 28, and 30 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite.
Claim Rejections - 35 USC § 112a
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 1-10, 12-14, 16, and 19-23 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 recites “such that the tag protein points outward from the inner shell and increases the rigidity of the cargo protein of interest.” The specification, however, does not reasonably convey that the applicant was in possession of a protein double shell nanostructure in which the tag protein increases the rigidity of the cargo protein. Conversely, the specification states that the maltose binding protein (MBP) “cannot be resolved,” that the “MBP density is noisy,” and that MBP was added “to facilitate protein purification and possibly reduce the air-water interface damage to the KIX domain and apoferritin cage during vitrification.” The specification subsequently discloses that the closer to the apoferritin shell, the more stable the KIX domain, and discloses the introduction of cysteine substitutions in the KIX domain and apoferritin to stabilize the KIX domain on the apoferritin shell through the formation of disulfide bonds. As such, while the specification states that the MBP pointing outward provides rigidification, the specification describes the attachment between the cargo and the apoferritin as the mechanism that is associated with increased rigidity of the cargo rather than the outward facing MBP tag. Claims 2-10, 12-14, 16, and 19-23 are included in this rejection for requiring the composition of claim 1.
Furthermore claim 1 recites “a tag protein,” which encompasses a genus of proteins. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus MPEP 2163(II)(3)(a)(i)(C).
As discussed above, the specification provides a single embodiment comprising MBP, the demonstrated embodiment relies upon cysteine substitutions and disulfide bonds to achieve stability but does not describe any particular structural or functional characteristics necessary to demonstrate possession of the claimed genus of tag proteins that increase cargo rigidity. Claims 2-10, 12-14, 16, and 19-23 are included in this rejection for explicitly or implicitly requiring the composition of claim 1 without sufficiently limiting the genus.
Therefore, claims 1-10, 12-14, 16, and 19-23 are rejected under 35 U.S.C. 112(a) for lack of written description.
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.
Claims 1-5, 16, 21, 24, 25, 27, 28, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Coscia et al., in view of Kim et al., and in further view of Smyth et al.
Claims 1-5, and 16 are drawn to a double shell nanostructure, claim 21 is drawn to a method of use, claim 24 is drawn to a fusion protein, claims 25, 27, and 28 are drawn to a vector, and claim 30 is drawn to a method of making the vector.
Coscia et al. teaches a scaffold-based approach for enabling cryo-electron microscopy (cryo-EM) analysis of small monomeric proteins below 40kDa, said method comprising fusing a target protein to a homo-oligomeric scaffold protein to generate a chimeric particle suitable for cryo-EM analysis [see abstract] (instant claims 3, 4, and 21). Coscia et al. teaches optimizing the junction between the target and scaffold to obtain a sufficiently rigid chimeric particle [see abstract], and teaches that the target subunits can adopt the same orientation relative to the scaffold [see p. 8, par. 2].
Coscia et al. does not teach or suggest using an apoferritin scaffold, the inclusion of a tag protein, or the claimed structural orientation.
Kim et al. discloses a double chambered 24-subunit (instant claims 1 and 2) homo-oligomeric short human ferritin nanocage in which peptide and protein moieties (proteins of interest) are genetically fused with different terminal regions of ferritin subunits at their N- and C-termini (instant claim 1) [see abstract] via a linker [see fig. 1] (instant claim 16) that can be improved by altering said linkers length and flexibility [see p. 15, col. 2, par. 1]. In this cage, the ferritins are shortened by removal of the fifth helix (helix E) [see abstract]. Kim et al. teaches generating the fusion protein by transfecting E. coli cells (instant claim 30) with a pET28 vector, which comprises a T7 promotor and which one would understand to comprise an expression cassette encoding the fusion protein (instant claims 25 and 30), and growing/culturing said cells [see p. 13, col. 2].
Kim et al. does not teach or suggest an additional tag protein attached to the cargo protein.
Smyth et al. discloses the use of maltose-binding protein (MBP) as a large affinity fusion tag for a protein of interest (instant claims 1 and 5), teaching that MBP is advantageous for the protein of interest as it increases protein expression, enhances solubility, protects from proteolysis, improves folding, and aids in protein purification, but also teaches that conventional fusion of a large affinity tag to a protein of interest can result in conformational heterogeneity due to a flexible linker. Smyth et al. teaches rigidly fusing the protein of interest to MBP using a short amino acid linker (instant claim 16) and explains that this rigid fusion strategy can facilitate structural determination of experimentally challenging proteins by improving protein expression, purification, and folding while reducing the conformational heterogeneity that is introduced by the addition of the fusion tag [see abstract].
It would have been obvious to combine these teachings to generate the claimed structure because the references address complementary aspects of the same structural-biology problem. Coscia et al. identifies the difficulty of determining structures of small proteins by Cryo-EM and teaches that using an oligomeric protein scaffold to increase particle size, establish a defined orientation, and obtain a sufficiently rigid chimeric particle, Kim et al. provides an acceptable ferritin scaffold capable of presenting a protein of interest, and Smyth et al. teaches that MBP with a short linker is a suitable protein tag for increasing protein yield while reducing the conformational variability introduced by attaching tag proteins. The combination of these teachings merely takes the known scaffolding concept taught by Coscia et al. and incorporates the known components of Smyth et al. and Kim et al., and would therefore have provided a reasonable expectation that the resulting construct would produce a more rigid cargo protein (instant claims 1 and 24). Furthermore, although the art does not explicitly teach that the tag protein points outward, it would have been an obvious and preferable orientation because it provides necessary presentation and accessibility of the protein of interest such that it can be resolved clearly under cryo-EM (instant claim 1).
It would have been obvious to use the protein double shell nanostructure in EM to determine the structure of the cargo protein as Coscia et al. explicitly teaches that the scaffolding framework is useful for obtaining high resolution structural information of small proteins (instant claim 21).
It would have been obvious and expected that one interested in creating the claimed protein would be required to generate it using standard molecular biology techniques as discussed above. That is, it would have been obvious to generate a vector comprising an expression cassette for expressing the fusion protein in the claimed sequence, transfect E. coli cells as is known in the art, and culture the cells under suitable conditions to express the protein (instant claims 25, 27, 28, and 30).
Regarding the limitation of wherein the tag protein “increases the rigidity of the cargo protein of interest,” this is interpreted as an inherent property of the claimed configuration (instant claim 1).
Therefore, claims 1-5, 16, 21, 24, 25, 27, 28, and 30 are rejected under 35 U.S.C. 103.
Claims 1, 6, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Coscia et al., in view of Kim et al., and in further view of Smyth et al., Zhang et al. and Rucker et al.
Claims 1, 6, and 7 are drawn to a double shell nanostructure.
The disclosure of Coscia et al., Kim et al., and Smyth et al. are discussed above.
The combination of references does not teach or suggest deletion of amino acids in the apoferritin N-terminal.
Of note, SEQ ID NO: 1 of the instant application corresponds to the sequence for mouse apoferritin and is 182 amino acids in length.
Zhang et al. teaches that deletion of either the first 13 residues at the N-terminus or last 22 residues at the C-terminus of human ferritin still allows the cage to assemble [see p. 5413, par. 4-5]. Rucker et al. teaches that the amino acids responsible for the formation of the cage are conserved between mice and humans Rucker et al. teaches that the first 5 amino acids between mice and humans are shared and that the E helices largely overlap [see Fig. 7].
It would have been obvious to combine these teachings and remove N-terminal residues of the apoferritin cage as Coscia et al. teaches that the junction between a target protein and the scaffold protein is an important determinant of rigidity of the particle, and expressly teaches deletion of residues as an improvement, Zhang et al. teaches that deletion of up to 13 amino acids of ferritin N-terminus still produces a cage. One would have had a reasonable expectation of success given that Rucker et al. teaches that the amino acids responsible for mouse and human ferritin cage formation are conserved. Furthermore, identification of the specific claimed deletions of the N-terminal would have constituted routine optimization of a known result-effective variable with a finite number of possible deletions in view of the art (instant claims 6 and 7). Regarding claim 7, positions 155-176 are located within helix V of the apoferritin cage and, as taught by Kim et al. and Zhang et al., is not required for the formation of the cage in humans. Further, as discussed above, Rucker et al. teaches that human and rodent apoferritin have conserved residues in terms of cage formation. As such, a person having ordinary skill in the art would have understood truncation of this domain to be optional up to an including position 155. Therefore, inclusion or removal of position 182 would have constituted a routine design choice (instant claim 7).
Therefore, claims 1, 6, and 7 are rejected under 35 U.S.C. 103.
Claims 1, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Coscia et al., in view of Kim et al., and in further view of Smyth et al., Pu et al. and Douglas et al.
Claims 1, 8, and 10 are drawn to a double shell nanostructure.
The disclosure of Coscia et al., Kim et al., and Smyth et al. are discussed above.
The combination of references does not teach or the substitution to the claimed cysteine residues.
Pu et al. teaches that engineered disulfide bonds may be introduced to stabilize flexible regions of proteins by reducing conformational entropy and locking a protein into a desired conformation, thereby facilitating structural determination [see p. 1, col. 1, par. 1]. Pu et al. further teaches that sites for engineered disulfide bonds may be identified using computational tools to assess structural and chemical considerations, including candidate residues, protein stability, conformational entropy, and the geometry of the candidate sites [see p. 1, col. 1, par. 3]. Pu et al. discloses introducing disulfide bonds into a fusion protein, which stabilized the fusion partner and improved the structural resolution of the fusion protein [see p. 1, col. 1, par. 2]. Douglas et al. similarly teaches that self-assembling protein cages, including ferritin cages, may be genetically modified, and also teaches that amino acid residues of cage subunits may be altered to facilitate crosslinking, including by incorporating cysteine residues to form disulfide bonds [see specification, p. 22, par. 245].
It would have been obvious to modify the appropriate residues of the apoferritin cage and/or cargo to cysteine residues to form the claimed disulfide bonds and increase rigidity of the cargo protein as Pu et al. teaches stabilization via disulfide bonds and Douglas et al. teaches that apoferritin is amenable to such modifications. Identification of the claimed mutations would have been a matter of routine optimization with an expectation of success as the art teaches that computational methods are a known and predictable tool for the identification of target residues (instant claims 8 and 10).
Therefore, claims 1, 8, and 10 are rejected under 35 U.S.C. 103.
Claims 1 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Coscia et al., in view of Kim et al., and in further view of Smyth et al., Pu et al., Douglas et al., and Berkmen et al.
Claims 1 and 9 are drawn to a double shell nanostructure.
The disclosure of Coscia et al., Kim et al., and Smyth et al., Pu et al. and Douglas et al. are discussed above.
The combination of references does not teach or suggest a serine substitution.
Berkman et al. teaches that when expressing a protein of unknown folding requirements, as is the case with novel fusion proteins, it is important to understand disulfide bonds in its structure [see p. 242, col. 2, par. 4]. Berkmen et al. teaches that disulfide bonds can be detrimental to protein chemistry as the mispairing of cysteines can cause misfolding and protein aggregation [see abstract]. Berkmen et al. teaches that recombinant expression of proteins in E. coli can result in the formation of aberrant disulfide bonds, and teaches that a possible solution to aberrant disulfide bonds is to mutate the non-essential cysteines that form the bonds [see p. 242, col. 1, par. 3]. Berkmen et al. teaches several methods to identify disulfide bonds including web-based servers and algorithms [see p. 242, col. 2, par. 4].
It would have been obvious to combine these teachings and substitute serine for problematic cysteine residues to eliminate the unwanted disulfide bonds. One seeking to form the desired disulfide bonds discussed above would have understood that additional free cysteine residues within the region of the introduced cysteines could compete in disulfide formation and/or promote protein aggregation and misfolding in general. Identification of particular cysteine residues would have been a matter of routine optimization, using the known prediction software as discussed above. Furthermore, the state of the art was such that serine was a known conservative substitute for surface cysteine residues, having similar size and polarity, and one would have reasonably assumed that substitution of particular cysteine residues for serine residues would reduce unwanted reactions while preserving protein structure (instant claim 9).
Therefore, claims 1 and 9 are rejected under 35 U.S.C. 103.
Claims 1, 12, 19, 20, 22, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Coscia et al., in view of Kim et al., and in further view of Smyth et al. and Wang et al.
Claims 1 and 12 are drawn to a double shell nanostructure, claims 19 and 20 are drawn to a complex of the nanostructure and a binding agent, and claims 22 and 23 are drawn to methods of use of the complex.
The disclosure of Coscia et al., Kim et al., and Smyth et al. are discussed above.
The combination of references does not teach or suggest that the cargo protein of interest is a KIX domain.
Wang et al. teaches that the GACKIX domain of CBP, also known as the KIX domain [as evidenced by Thakur et al., FIG. 2, “human/rat/mouse”], is a small protein whose conformational flexibility renders it difficult to characterize. The GACKIX domain comprises SEQ ID NO: 2 [see Wang et al., Supplementary, p. S1, par. 1]. Wang et al. teaches that stabilization of GACKIX by tethering it to an additional molecule can be used to facilitate its structural characterization [see abstract] (instant claim 12). Wang et al. teaches that the method of tethering comprises screening to identify candidate for molecules that can form a disulfide bond with the GACKIX domain at a residue substituted to a cysteine [see p. 2, par. 2] then experimentally evaluating the molecules using the appropriate assays [see p. 2, par. 3] (instant claim 23). Wang et al. further teaches that tethered GACKIX retains binding abilities, and further demonstrates that the ligands MLL and pKID bind to their corresponding binding sites (instant claims 19 and 20).
Wang et al. does not teach or suggest using a computational method comprising the three-dimensional structure of the cargo.
It would have been obvious to combine these teachings and utilize the GACKIX domain as a cargo of interest in the double shell nanostructure because the art identifies the GACKIX domain as a small dynamic protein with suitable properties to be incorporated into a scaffold for structural characterization. This selection would have merely been a predictable combination of a known scaffold to a known structural target, with a reasonable expectation of success given that the target has been shown to be suitable to tethering and imaging (instant claim 12). Further, it would have been obvious to provide the GACKIX cargo protein with a binding agent such as MLL or pKID prior to data collection using cryo-EM as discussed above (instant claim 22) as the art demonstrates that the ligands bind and could therefore provide structural information on the GACKIX-MLL/pKID binding complex (instant claims 19, 20, and 22).
Finally, it would have been obvious to use the atomic coordinates of the cryo-EM structure of the cargo to computationally screen a library for candidate molecules likely to bind and to subsequently test the candidates using proper assays as Wang et al. explicitly teaches that structural information obtained for a ligand binding protein can facilitate rational ligand screening and design. There would have been a reasonable expectation of success because structure based screening and subsequent experimental validation assays were established techniques for identifying molecules capable of interacting with a structurally characterized protein target and would have been a predictable application of a known structure-based screening workflow (instant claim 23).
Therefore, claims 12, 19, 20, 22, and 23 is rejected under 35 U.S.C. 103 are rejected under 35 U.S.C. 103.
Claims 1 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Coscia et al., in view of Kim et al., and in further view of Smyth et al., Pu et al., Douglas et al., Berkmen et al., and Wang et al.
Claims 1 and 14 are drawn to a double shell nanostructure.
The disclosure of Coscia et al., Kim et al., and Smyth et al., Pu et al. and Douglas et al., are discussed above.
The combination of references does not teach or suggest the substituting for cysteine residues specifically in a KIX domain.
The disclosure of Wang et al. is discussed above.
It would have been obvious to combine these teachings and introduce disulfide bonds into the KIX domain to stabilize it with the scaffold as the art above teaches that introducing cysteine mutations into apoferritin cages to increase rigidity is a known technique, Wang et al. teaches this method to provide rigidity to the GACKIX domain, and methods of identifying which residues within the apoferritin and/or KIX domains were known in the art as discussed above. As such, it would have been obvious to introduce mutations with a reasonable expectation of success, and identification of the claimed mutations would have been a matter of routine optimization with an expectation of success as the art teaches that computational methods are a known and predictable tool for the identification of target residues (instant claim 14).
Therefore, claims 1 and 14 are rejected under 35 U.S.C. 103.
Subject Matter Free of the Art
Claim 13 recites a specific sequence of the KIX domain relative to SEQ ID NO:2. Although Wang et al. teaches a composition comprising this sequence, the sequence of the KIX domain specifically is known in the art [see Genbank, Acc: AAC08447.1], and the truncation only requires deletion of a few residues at the ends of the sequence, the art nevertheless does not teach or suggest the particular truncation recited.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tirone D Johnson whose telephone number is (571)272-1256. The examiner can normally be reached M-F, 9-5 ET.
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/TIRONE D. JOHNSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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