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 .
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 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.
Priority
The instant application, filed 10/10/2023 is a 371 filing of PCT/PL2022/050009, filed 02/24/2022, and claims foreign priority to PLP.437113, filed 02/24/2021, PLP.437115, filed 02/24/2021, LU102569, filed 02/24/2021, LU102572, filed 02/24/2021, LU102571, filed 02/24/2021, and PLP.437114, filed 02/24/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 03/11/2024 is acknowledged. Claims 1-47 are cancelled and claims 48-72 are new. Claims 48-72 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/21/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing from the specification. See item 1) a) or 1) b) below.
The instant specification recites the following sequences without an accompanying SEQ ID NO:
Page 33, first paragraph: YARAAARQARA and YARAAARQARAG;
Page 33, paragraph 4, LPXTG, LPXT(G)n; and LPSTG; and
Page 38, Example 2, paragraph 1: GTGGSLPSTG.
The drawings recite the following sequences without an appropriate SEQ ID NO in either the drawing or the description of the drawing in the specification:
Fig. 4b: GTGGS-LPSTGG; and
Fig. 4e: ENLYEQGGGGGS.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings 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 “Nanobody”, “SpyCatcher”, and “SpyTag” are trade names or marks used in commerce, have 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.
Drawings
The drawings are objected to because they are low resolution making them difficult to read. In particularly see the scale bars in Fig. 1; the text in Fig. 3; and the images in Fig. 5.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 55 is objected to for the following informality: the claim recites “chainor” in line 5. Correction to “chain or” is suggested.
Claim 64 is objected to for the following informality: the claim recites “wherein step (i) the expression system is from”. The claim is missing a word between “wherein” and “step”, for instance, the word “in”.
Claim 65 is objected to for the following informality: the claim recites “wherein purification of the said units from the expression system of step (i) by using FPLC-based purification”. The claim is missing a word between “step (i)” and “by”, for instance the word “is”.
Claim Rejections - 35 USC § 112(b)
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 48-72 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.
Regarding claims 48, 57, 63, and 71, claims 1 and 63 contain the trademark/trade name “Nanobodies” and claims 57 and 71 contain the trademark/trade name “SpyCatcher/SpyTag”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe particular material or product and, accordingly, the identification/description is indefinite.
Claims 49-62 and 64-72 are rejected by virtue of their dependency on a rejected claim as they do not resolve the ambiguity discussed above.
Claims 49, 50, 53-54, and 56-57 recite “the external decoration(s)” and limitations that limit the decoration and/or attachment of the decoration. Claim 48, on which the claims ultimately depend, recite “a plurality of external decorations”, indicating more than one external decoration. It is unclear if the recitation of “the external decoration(s)” in claims 49, 50, 53-54, and 56-57 includes all of the plurality of external decorations recited in claim 48 and if all must be the same decoration and attached in the claimed manner or if only some of the plurality of external decorations are limited by the instant claim limitations. See MPEP 2173.05(e) which states “ if two different levers are recited earlier in the claim, the recitation of "said lever" in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended.”
For instance, claim 50 recites that “the external decoration is a viral, microbial, or cancer antigen.” It is unclear based on the recitation whether all of the plurality of external decorations must be one of the three recited or if the plurality of external decorations can be anything as long as they comprise at least one of the recited antigens.
Appropriate correction is required.
Claim 54 recites the limitation “or the chemical modification is by cysteine, maleimide-based conjugation, or…”. Based on the position of the “or” recitations and the comma between “cysteine” and “maleimide”, it is unclear if “the chemical modification is by cysteine” and “maleimide-based conjugation” are intended to be two distinct means of attachment for the external decorations or if it is applicant’s intention to claim cysteine-maleimide based conjugation. Appropriate correction/clarification is required.
Additionally, the claim recites “an externally facing cysteine residue of the TRAP-cage”, “the cysteine residue”, and “cysteine, maleimide-based conjugation”. There is insufficient antecedent basis for cysteine residues in the TRAP-cage. Claim 48, on which the claim depends, recites an artificial TRAP cage comprising a selected number of TRAP rings. Native TRAP protein contains no native cysteines. As such, there would not be any cysteine amino acids that could be being referenced.
Appropriate correction is required.
In the instant office action, the claims are interpreted as encompassing TRAP ring units that have been modified to include cysteine residues.
Claim 55 depends on claim 53, and ultimately claim 48, and recites limitations regarding attachment including, “ii) bio-conjugation by maleimide labelled fluorescent dyes for attachment of surface thiols…”. It is unclear what “surface thiols” are being referenced in the claim as neither maleimide nor the native TRAP protein contains surface thiols rendering the metes and bounds of the claim indefinite. For instance, the claim could be interpreted as requiring that the maleimide labelled dyes have surface thiols or that the maleimide labelled dyes be attached to surface thiols that are introduced on the surface of the TRAP cage.
Appropriate correction/clarification is required.
In the instant office action, the claim is interpreted as encompassing TRAP ring units that have been modified to include surface thiols for bio-conjugation.
Claim 56 recites the limitation “the N-terminus sequence of the external decoration”. There is insufficient antecedent basis for this limitation in the claim rendering the metes and bounds of the claim indefinite. The claim depends on claim 48 and neither claim 48 nor claim 56 recite a N-terminus sequence of the external decoration. Additionally, claim 48 does not limit the external decorations and, as such, the claim encompasses any type of decoration including those that do not contain a sequence and would not necessarily have a N-terminus sequence. For instance, see claim 49 which encompasses external decorations including lipids, oligosaccharides, dye molecules, small molecules, etc. all of which do not contain sequences and would not have an N-terminal sequence, but are encompassed by claim 48.
Appropriate correction is required.
Claim 61 depends on claim 48 and recites the limitation that the artificial TRAP-cage protein is modified to comprise any one or more mutations selected from the recited group of mutations. The mutations recited include, in order, the original amino acid – the location – the amino acid that is substituted in place of the original amino acid. The positions recited in the claim are relative and depend on the parent sequence to which the modification is being made. Additionally, there is insufficient antecedent basis for the position and the original amino acid recited in the substitutions as there is no parent sequence recited that could be being referenced. Neither of claim 61, nor claim 48 on which it depends, recite a sequence in which the recited positions could be referencing rendering the metes and bounds of the claim indefinite.
Claim 63 recites a method of making a TRAP cage and includes the steps of (i) obtaining TRAP ring units by expression of the TRAP ring units in a suitable expression system and purification of said units. Part (ii) of the claim recites conjugation of the TRAP ring units by “at least one free thiol linkage” with a crosslinker. There is insufficient antecedent basis for the limitation of “at least one free thiol linkage” in the claim. The native TRAP protein contains no native cysteines and; therefore, would not be reasonably expected to comprise any free thiol groups. As such, the TRAP rings expressed in part (i) would not be reasonably expected to comprise a free thiol group.
Appropriate correction is required.
In the instant office action, the claims are interpreted as encompassing TRAP ring units that have been modified to include cysteine residues comprising free thiol groups.
Additionally, part (iii) of the claim recites “what is appropriate for the external decoration that is to be attached to the cage exterior surface”. There is insufficient antecedent basis for “the external decoration” in the claim. The method and steps prior to (iii) do not recite an external decoration that could be being referenced rendering the metes and bounds of the claim indefinite.
Claim 65 recites the limitation “columns such as a mixture of affinity based and size exclusion columns”. The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). This is particularly the case as the limitations following the phrase “such as” are narrower embodiments of the preceding limitations.
Claim 67 recites the limitation “or the chemical modification is by cysteine, maleimide-based conjugation.” Based on the position of the “or” recitations and the comma between “cysteine” and “maleimide”, it is unclear if “the chemical modification is by cysteine” and “maleimide-based conjugation” are intended to be two distinct means of attachment for the external decorations or if it is applicant’s intention to claim cysteine-maleimide based conjugation. Appropriate correction/clarification is required.
Additionally, the claim recites the limitations “an externally facing cysteine residue of the TRAP-cage” and “the cysteine residue” and “cysteine, maleimide-based conjugation” There is insufficient antecedent basis for cysteine residues in the TRAP-cage. Claim 48, on which the claim depends, recites an artificial TRAP cage comprising a selected number of TRAP rings. The native TRAP protein contains no native cysteines. As such, there would not be any cysteine amino acids that could be being referenced.
Appropriate correction is required.
In the instant office action, the claims are interpreted as encompassing TRAP ring units that have been modified to include cysteine residues.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 48-51, 53-56, 58-70, and 72 are rejected under 35 U.S.C. 103 as being unpatentable over Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data in view of US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007.
Malay teaches that symmetrical protein cages have evolved to fulfil diverse roles in nature, including compartmentalization and cargo delivery, and have inspired synthetic biologists to create novel protein assemblies via the precise manipulation of protein-protein interfaces (abstract).
Malay generated protein cages for which assembly and disassembly can be triggered via metal ion coordination. Malay teaches that it was previously demonstrated that a cysteine substituted variant of TRAP (trp RNA-binding attenuation protein)- a bacterial ring-shaped protein amendable to genetic modification- could form non-native shell architectures when reacted with triphenylphosphine-derivatized gold nanoparticles. Malay proposes that metal-ion thiol interactions could be responsible for the formation of precise higher-order assemblies. To explore this hypothesis, Malay engineered a double-mutant TRAP bearing both a lysine-to-cysteine mutation at residue 35 (K35C), which generates 11 equally spaced thiol groups along the outer rim of the oligomeric ring, and an arginine-to-serine mutation at residue 64 (R64S), which neutralizes positive charges around the central cavity of the ring to prevent non-specific interactions with anionic groups (TRAP(K35C/R64S); Fig. 1a). Malay teaches that a minimal reaction containing purified TRAP(K35C/R64S) and monosulfonated chloro(triphenylphosphine)gold(I) as a source of Au ions, resulted in the efficient self-assembly of monodisperse spheres, or “TRAP-cage”, which were around 22 nm in diameter and were visible within minutes (page 438, paragraph bridging columns; Fig. 1a-1d; Extended data Fig. 1). Malay teaches that TRAP is an 11-mer protein ring (abstract).
Malay teaches that the structure of the TRAP-cage was elucidated using cryo-electron microscopy single-particle analysis which revealed a spherical architecture featuring 24 uniform rings and side square apertures along three orthogonal axes (page 438, right column, paragraph 3). Malay further teaches that all 24 rings preserved the 11-fold rotational symmetry of the native TRAP protein (page 439, left column, paragraph 1).
Malay teaches that the addition of a gold (I)-triphenylphosphine compound to a cysteine-substituted, 11-mer protein ring (TRAP) triggers supramolecular self-assembly, which generates monodisperse cage structures with masses greater than 2 MDa. Cryo-electron microscopy confirms that the assemblies are held together by 120 S-AuI-S staples between the protein oligomers, and exist in two chiral forms. The cage shows extreme chemical and thermal stability, yet readily disassembles upon exposure to reducing agents. In addition to gold, mercury (II) is also found to enable formation of the protein cage (abstract).
Malay concludes that the general stability of TRAP-cage and its controllable disassembly hints at potential applications as an intracellular delivery agent (page 441, right column, paragraph 1).
The linkages taught by Malay meet the limitations of a programmable cross-linker as the Au or Hg acts to link the TRAP rings together and Malay teaches that the cross-linking readily disassembles and has controllable disassembly. This is further supported by the instant disclosure, page 20, paragraph 3, which states that programmable is intended to convey that the TRAP-cages have properties conferred on, or engineered into them, that make them prone or susceptible or predisposed to behave in a particular way based on exposure to specific environmental conditions or stimuli.
Malay teaches that, to make the TRAP cages, E. coli cells were transformed with a plasmid harboring the TRAP(K35C/R64S) gene. The cells were grown at 37C with shaking in 3L of LB media. The supernatant was purified by ion exchange chromatography on an AKTA purifier (GE healthcare life sciences) using 4 x 5ml HiTrap QFF columns with binding in 50 mM Tris-HCl, pH 7.9 or 8.5, 0.05 M NaCl, ±2 nM DTT buffer and eluting with a 0.05-1 M NaCl gradient. Fractions containing TRAP were pooled and concentrated using Amicon Ultra MWCO centrifugal filters and subjected to SEC on a HiLoad 26/600 Superdex 200pg column in cage buffer at RT (page 443, supplemental materials, Methods, protein expression and purification). The AKTA purifier used by Malay to purify the TRAP protein is a known fast protein liquid chromatography (FPLC) system as evidenced by US’889 page 60, [0535], which teaches ion exchange and SEC performed on an Akta purifier FPLC.
The formation of the TRAP cage was carried out by mixing TRAP(K35C/R64S) and Au-TPPMs in aqueous solution. Reactions were incubated for at least 3 days at RT; reaction times of up to three months were found to give similar results. Formation of the TRAP cage was confirmed using TEM and native PAGE. Any precipitated material was removed by centrifugation and the TRAP cage was purified by SEC on either Superose 6 Increase 10/300 GL or HiPrep 16/60 Sephacryl S-500 HR columns or HiLoad 16/600 Superdex 200pg columns (page 443, Supplemental materials, Methods, Cage assembly).
The teachings of Malay differ from the instantly claimed invention in that Malay does not teach that the TRAP-cage further comprises a plurality of external decorations attached thereto or that the method of making the TRAP cage comprises modification of an external surface for external decoration attachment.
US’889 teaches compositions and methods utilizing nanoparticles comprising protein cages having various features including externally and/or internally located targeting moieties, disassembly mechanisms, therapeutic agents, medical imaging agents, and combinations thereof (page 1, page 1, [0002]). US’889 teaches that the protein cages are self-assembling and include a plurality of subunits with at least one of the subunits being a modified subunit (page 2, [0012]). The protein cages can be thought of as molecular “lego” sets. That is, they can be assembled with precision and from a predetermined number of protein subunits. The protein cage assemblies are typically spherically symmetrical structures that provide precisely defined exterior in interior surfaces (page 4, [0069]). US’889 teaches viral and non-viral protein cages, including those derived from bacteria (pages 5-6). US’889 also teaches that the monomers of the protein cages can be naturally occurring ring or variant forms, including amino acid substitutions, insertions, or deletions. For example, the amino acid residues on the outer surface of one or more of the monomers can be altered to facilitate functionalization for attachment of additional moieties, for example, targeting moieties such as antibodies, polymers for delivery or formation of non-covalent chimeras; or to allow for crosslinking, e.g., the incorporation of cysteine residues to form disulfides (page 22, [0245]).
US’889 teaches that the protein cage may have a modified subunit that is chemically or genetically modified, or both. A chemically modified subunit may also include a linker and one or more proteins, such as antibodies and/or peptides including a targeting moiety (page 2, [0013]). US’889 teaches the attachment of materials and/or agents to the surfaces of the protein cages (page 8, [0101]). In some embodiments, the protein cage includes a targeting moiety on the exterior of the cage and a therapeutic on the interior of the cage. For example, the protein cage may include an antibody as the targeting moiety and a drug on the interior as a therapeutic agent (page 13, [0146]). US’889 further teaches the attachment of nucleic acids, lipids, carbohydrates, and small molecule materials (pages 10-11, [0127]).
US’889 teaches that the protein cages include a plurality of proteins as targeting moieties. In one embodiment, the cages include a plurality of peptides, such as 2-20 peptides. The plurality of peptides may also be more than 30 peptides (page 30, [0328]). US’889 also teaches embodiments where cages are labeled with different peptides, for instance, in Fig. 12, where the cage comprises a cell targeting peptide as well as an aggregation ligand (page 2, [0028]; Fig. 12).
US’889 teaches that targeting moieties is meant to include functional groups that serve to target or direct the delivery vehicle, i.e., the cage comprising at least one medical imaging agent, to a particular location or association. Thus, for example, a targeting moiety may be used to target a molecule to a specific target protein or enzyme or to a particular cellular location, cell type, or diseased tissue (page 30, [0331]).
US’889 teaches that suitable targeting moieties include, but are not limited to, proteins, nucleic acids, carbohydrates, lipids, hormones, including proteinaceous and steroid hormones, growth factors, receptor ligands, antigens, and antibodies. Proteins in this context means proteins including antibodies, oligopeptides, peptides, and derivatives and analogs thereof (page 30, [0332]). US’889 also teaches enzymes and peptides associated with viruses, bacteria, and cancer (page 9, [0114]; page 31, [0336]) as well as fluorescent dyes (page 36, [0376]).
Targeting moieties may be added to the surface of the protein cages either by engineering the protein cages to express the targeting moiety or by the addition of functional groups to the surface of the protein cage (page 34, [0358]). Multiple chemical approaches may be used for ligand attachment. Activation of carboxylic acid groups and reaction with nucleophiles such as primary amines affords the coupling of ligands through formation of amide linkers. Engineered thiol functional groups (cys) on the protein may be modified by reaction with commercially available maleimide or iodoacetamide bifunctional linkers. In addition, synthetic methodologies developed for attachment through azide groups and photochemical reactions of nucleophiles with tyrosine residues can be utilized. The range of established synthetic procedures is summarized in table 1, listing all reactions previously demonstrated as effective for attachment of molecules to protein cage architectures (page 29, [0323]; page 9, table 1). In some embodiments, targeting peptides are incorporated genetically as either N- or C- terminal fusions or by incorporation into surface exposed loops in the subunits of the protein cage. N- and C- terminal fusions as well as fusions into surface exposed loops to protein cage subunits will be used to present peptides on the cage surfaces. For instance, the DNA oligonucleotides encoding for the GRD, NGR, F3, and LyP-1 may be introduced into surface exposed loops or N- and C-termini of the protein cage architecture by site-direct mutagenesis (page 32, [0338]).
US’889 also teaches enzymatic coupling (page 24, [0265]) and the use of “click chemistry” (page 29, [0324]). US’889 teaches that click chemistry is a modular protocol for organic synthesis that utilizes powerful, highly reliable and selective reactions for the rapid synthesis of compounds. One application involves the use of azides or alkynes as building blocks due to their ability to react with each other in a highly efficient and irreversible spring-loaded reaction. In one embodiment, the attachment to a protein cage of proteins as targeting moieties and/or therapeutic agents and/or drugs as therapeutic agents, is achieved through the use of an azide linkage (pages 29-30, [0324]).
US’889 further teaches that the protein cages can include a disassembly mechanism in which the disassembly of the protein cage is controlled. Control of cage disassembly may be control of the opening and/or closing of pores present in the protein cage or may be control of the integrity of the protein cage architecture itself. In one embodiment, the integrity of the protein cage architecture may be formulated such that the cage is sensitive to modification by various in vivo endogenous enzymes or digestion of the protein cage, particularly the individual subunits forming the cage. The disassembly mechanism may include, without limitation, a pH sensitive mechanism; a redox sensitive mechanism; a reversible or irreversible chemical switch mechanism; and an enzymatic release mechanism (page 26, [0291]).
US’889 teaches compositions and pharmaceutical compositions using the disclosed peptide cages for use in delivering therapeutic agents to patients and teaches that the compositions may be administered. Generally, sterile aqueous solutions of the nanoparticles can be administered to a patient in a variety of ways including orally, intrathecally, and especially intravenously (page 38; [0403]-[0408]). A “patient” is taught to include humans and animals and organisms and the method are applicable to both human therapy and veterinary applications (page 37, [0398]). US’889 teaches methods to treat conditions including cancer (page 10, [0121]) and also teaches the inclusion of therapeutics that are antiviral or antibacterial as well as anti-inflammatory (page 10, [0122]-[0125]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the TRAP cage and the method of making the TRAP cage disclosed by Malay to further modify the surface of the TRAP-cage for external decoration with a plurality of external decorations, including antibodies, epitopes, antigens, proteins, peptides, nucleic acids, lipids, dye molecules, or small molecule therapeutics, as taught by US’889 using the methods disclosed by US’889 for adding external decorations to protein cages. An ordinarily skilled artisan would have been motivated to add external decorations in order to tune the application of the protein cages (US’889, [0068]), for instance by adding targeting moieties which serve to target or direct the delivery of the cage to a particular location (US’889, [0331]). An ordinarily skilled artisan would have had a reasonable expectation of success because both Malay and US’889 are teaching protein cages and both teach cages self-assembled by protein rings.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data in view of US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007 as applied to claim 48 above, and in further view of Regberg, J., et al (2012) Applications of Cell-penetrating peptides for tumor targeting and future cancer therapies Pharmaceuticals 5; 991-1007.
The combination of Malay and US’889 teach the artificial TRAP cage of claim 48 as discussed in detail above.
As discussed above, Malay teaches that the general stability of TRAP cage and its controllable disassembly hints at potential applications as an intracellular delivery agent (page 441, right column, paragraph 1).
US’889 further teaches that the targeting moiety may be used to either allow the internalization of the nanoparticle composition to the cell cytoplasm or localize it to a particular cellular compartment (page 34, [0353]). US’889 teaches that the targeting moiety can be all or a portion of the HIV-1 Tat protein, and analogs and related proteins, which allows very high uptake into target cells (page 34, [0355]).
The combination of Malay and US’889, however, do not explicitly teach cell penetrating agents.
Regberg teaches that cell-penetrating peptides provide a highly promising strategy for intracellular drug delivery. Cell-penetrating peptides are short peptides capable of translocation through the cellular plasma membrane on their own or together with cargoes. The first CPPs were derived from naturally occurring proteins such as TAT from HIV-TAT and penetratin from the Antennapedia homeodomain. Following this, large numbers of new CPPs, protein-derived as well as designed, have been produced (abstract; paragraph bridging pages 991-992). Regberg provides examples of CPPs in Table 1, pages 992-993, which include PTD4.
Regberg teaches that cell penetrating peptides could also be used to increase the uptake of other drug delivery systems including liposomes and different types of nanoparticles (page 993, paragraph 1). Regberg teaches that numerous CPPs have been described so far and that they have been successfully applied in vitro and in vivo for delivery of therapeutic molecules varying from small molecules, nucleic acids, proteins, proteins and peptides, to liposomes, and nanoparticles (page 999, 4. Drug loading). Regberg teaches that nanoparticles modified with CPPs could potentially have increased cellular uptake, enable crossing of the blood-brain barrier or, in the case of combined penetrating/targeting peptides, display increased specificity of delivery (page 1003, 5. Future aspects, paragraph 2).
Regberg teaches CPP loading and targeting strategies including covalent conjugation of CPP to cargo; CPP coupled to targeting ligand and cargo; activatable CPP construct consisting of a peptide, cargo, and protectin polyanion with a target specific MMP cleavable linker, where after cleavage of the linker, the peptide disassociates and becomes an active CPP; non-covalent complexes of CPPs and cargo where the complex is formed by electrostatic and hydrophilic interactions (Fig. 1, page 993).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the artificial TRAP-cage taught by the combination of Malay and US’889 to include a cell penetrating peptide, including PTD4, as taught by Regberg as at least one of the plurality of external decorations. An ordinarily skilled artisan would have been motivated to include a cell penetrating peptide as one of the external decorations as a strategy to increase intracellular drug delivery of the TRAP-cage. An ordinarily skilled artisan would have had a reasonable expectation of success because US’889 teaches that the external decoration on peptide cages can include those that allow for the internalization of the nanoparticle composition to the cell cytoplasm and Regberg teaches the application of the disclosed cell penetrating peptides for the intracellular delivery of nanoparticles.
Claims 50, 57 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data in view of US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007 as applied to claims 48 and 63 above, and in further view of Wang, W., et al (2019), Ferritin nanoparticle-based SpyTag/SpyCatcher enabled click vaccine for tumor immunotherapy Nanomedicine: Nanotechnology, biology, and medicine 16; 69-78.
The combination of Malay and US’889 teach the artificial TRAP cage of claim 48 and the method of claim 63 as discussed in detail above.
US’889 further teaches that the protein cages can be used as vaccines and that vaccine agents can be attached to the protein cages as described (pages 17 and 18, [0188]-[0199]).
The combination of Malay and US’889; however, do not disclose that the external decoration is conjugated using SpyCatcher/SpyTag.
Wang teaches that, recently, tumor neoantigens have been attractive for development of personal therapeutic vaccines. However, to instantly deliver multiple neoantigens for efficient anti-tumor immunity is still challenging. Wang discloses a SpyCatcher-modified ferritin nanoparticle platform, which permits convenient and stable covalent conjugation with tumor specific antigens containing SpyTag in a click-link manner. Wang teaches that the study disclosed demonstrates a ferritin nanoparticle based, SpyTag/SpyCatcher-enabled click vaccine platform for use in personalized tumor immunotherapy (abstract). Wang teaches that ferritin nanoparticles are a protein nanoplatform for in vivo antigen delivery, presentation, and immune stimulation and is self-assembled from 24 copies of identical ferritin subunits (page 69, right column, paragraph 2).
To set up a more flexible and efficient ferritin NP vaccine platform, the SpyTag/SpyCatcher conjugation technique was introduced into the NP construction. The SpyTag/SpyCatcher system was recently developed based on the split protein CnaB2 from Streptococcus pyogenes. Once mixed under nearly any common conditions, SpyTag and SpyCatcher can rapidly and efficiently covalently conjugate to each other through an isopeptide bond. In the study provided, Wang developed a ferritin NP vaccine platform displaying SpyCatcher on the surface. The NP platform was tested to conjugate single or multiple tumor-specific antigens, which were fused with SpyTag for vaccine construct (page 70, left column, paragraphs 1 and 2).
Wang concludes that the SpyTag/SpyCatcher technique offers a flexible and convenient way to construct NP-based vaccines (page 77, right column, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the artificial TRAP-cage and method taught by the combination of Malay and US’889 to conjugate the external decoration, such as a cancer/tumor specific antigen, to the artificial TRAP cage using SpyTag/SpyCatcher conjugation as disclosed by Wang. An ordinarily skilled artisan would have been motivated to use the SpyTag/SpyCatcher conjugation system as Wang teaches that the technique offers a flexible and convenient way to construct nanoparticle based vaccines. Additional Wang teaches the use of such conjugation system for the development of personalized tumor immunotherapy. An ordinarily skilled artisan would have had a reasonable expectation of success as all of Malay, US’889, and Wang are teaching nanoparticles derived from protein self-assembled subunits.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
17/268,596
Claims 48-51, 53-56, 58-70, and 72 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23, 25-26, 30-34, 36-37, 40-45, and 48 of copending Application No. 17/268,596 in view of Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data and US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007.
App’596 claims a method of conjugating a free thiol group to a moiety of a trp RNA-binding attenuation (TRAP) protein, comprising providing a Geobacillus stearothermophilus TRAP protein with a cysteine residue at amino acid position 35, contacting the TRAP protein with a gold-donor agent to form a -S-Au-S- bond, characterized in that the gold donor agent is halogen(triarylphosphine)gold(I), wherein the moiety with the free thiol group is the cysteine moiety at position 35, and generating a protein cage biomolecule complex.
App’596 further claims that the conjugated complex is composed of multiple units of the same TRAP protein, and that the complex is symmetric. App’569 further claims that the method encompasses purifying the conjugation product. App’569 claims that the TRAP protein is expressed in a suitable expression system and purification of the TRAP protein prior to conjugation. App’596 claims that the protein complex consists of 24 TRAP protein units.
App’596 further claims a modified protein cage obtained by the method and that the TRAP protein contains a K35C mutation and, additionally, can contain a R64S mutation.
The claims of App’596 differ from the instantly claimed invention in that App’596 does not claim that the TRAP-cage comprises a plurality of external decorations attached thereto.
The teachings of Malay and US’889 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the TRAP cage and the method of making the TRAP cage claimed in App’596 with the teachings of Malay and US’889 to arrive at the instantly claimed invention by further modify the surface of the TRAP-cage for external decoration with a plurality of external decorations, including antibodies, epitopes, antigens, proteins, peptides, nucleic acids, lipids, dye molecules, or small molecule therapeutics, as taught by US’889 using the methods disclosed by US’889 for adding external decorations to protein cages. An ordinarily skilled artisan would have been motivated to add external decorations in order to tune the application of the protein cages (US’889, [0068]), for instance by adding targeting moieties which serve to target or direct the delivery of the cage to a particular location (US’889, [0331]). An ordinarily skilled artisan would have had a reasonable expectation of success because App’596, Malay and US’889 all teach protein cages and Malay demonstrates that TRAP cages had been considered for intracellular delivery of therapeutics.
Claim 52 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23, 25-26, 30-34, 36-37, 40-45, and 48 of copending Application No. 17/268,596 in view of Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data and US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007 as discussed above, and in further view of Regberg, J., et al (2012) Applications of Cell-penetrating peptides for tumor targeting and future cancer therapies Pharmaceuticals 5; 991-1007.
The claims of App’596 modified by Malay and US’889 teach the TRAP-cage of instant claim 48 as discussed above.
The combination, however, does not explicitly teach cell penetrating agents.
The teachings of Regberg are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the artificial TRAP-cage taught by the combination of App’596, Malay and US’889 to include a cell penetrating peptide, including PTD4, as taught by Regberg as at least one of the plurality of external decorations. An ordinarily skilled artisan would have been motivated to include a cell penetrating peptide as one of the external decorations as a strategy to increase intracellular drug delivery of the TRAP-cage. An ordinarily skilled artisan would have had a reasonable expectation of success because US’889 teaches that the external decoration on peptide cages can include those that allow for the internalization of the nanoparticle composition to the cell cytoplasm and Regberg teaches the application of the disclosed cell penetrating peptides for the intracellular delivery of nanoparticles.
Claims 50, 57 and 71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23, 25-26, 30-34, 36-37, 40-45, and 48 of copending Application No. 17/268,596 in view of Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data and US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007 as discussed above, and in further view of Wang, W., et al (2019), Ferritin nanoparticle-based SpyTag/SpyCatcher enabled click vaccine for tumor immunotherapy Nanomedicine: Nanotechnology, biology, and medicine 16; 69-78.
The claims of App’596 modified by Malay and US’889 teach the TRAP-cage of instant claim 48 and the method of instant claim 63 as discussed above.
The combination, however, does not disclose that the external decoration is conjugated using SpyCatcher/SpyTag.
The teachings of Wang are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the artificial TRAP-cage and method taught by the combination of App’596, Malay and US’889 to conjugate the external decoration, such as a cancer/tumor specific antigen, to the artificial TRAP cage using SpyTag/SpyCatcher conjugation as disclosed by Wang. An ordinarily skilled artisan would have been motivated to use the SpyTag/SpyCatcher conjugation system as Wang teaches that the technique offers a flexible and convenient way to construct nanoparticle based vaccines. Additional Wang teaches the use of such conjugation system for the development of personalized tumor immunotherapy. An ordinarily skilled artisan would have had a reasonable expectation of success as all of App’596, Malay, US’889, and Wang are teaching nanoparticles derived from protein subunits.
This is a provisional nonstatutory double patenting rejection.
18/547,242
Claims 48, 52, and 58-62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-63 of copending Application No. 18/547,242. Although the claims at issue are not identical, they are not patentably distinct from each other.
App’242 claims an artificial TRAP-cage comprising a selected number of TRAP rings and encapsulated therein at least one cargo. App’242 further claims that the cage includes at least one external decoration, or a cell penetrating agent to promote intracellular delivery of the cage containing an internal guest cargo, or PTD4. App’242 claims that the number of TRAP rings in the cage is between 6 and 60, or is 12, 20, or 24. App’242 further claims that the TRAP cage comprises mutations that overlap with those of the instant claims. App’242 claims that the opening of the TRAP cage is programmable or is dependent on selection of a molecular or atomic cross-linker or wherein the cross-linker is reduction responsive or photo-activatable.
App’242 further claims a method of making the artificial TRAP cage. App’242 also claims a method of treating a patient comprising administering a TRAP cage to a subject.
App’242 claim 49 encompasses an artificial TRAP-cage comprising a selected number of TRAP rings and encapsulated therein at least one guest cargo further including at least one external decoration or a cell penetrating agent to promote intracellular delivery of the cage containing an internal guest cargo, or PTD4. As the claim encompasses a TRAP cage with a selected number of TRAP rings and a plurality of external decorations (at least one), the claim anticipates instant claim 48 as well as instant claim 58.
Additionally, The claims of App’242 include the features of instant claims 48, 52, and 58-62 and; therefore, renders the claims obvious as it would have been obvious to combine the features to arrive at the instantly claimed invention.
Claims 48-51, 53-56, 58-70, and 72 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-63 of copending Application No. 18/547,242 as discussed above, and in further view of Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data in view of US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007.
The claims of App’242 are as discussed in detail above.
The instant claims differ from those of App’242 in that the instant claims are drawn to the plurality of decorations and methods of conjugating the decorations to the TRAP cage. These additions, however, would have been obvious in view of the prior art.
The teachings of Malay and US’889 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the TRAP cage and the method of making the TRAP cage claimed in App’242 with the teachings of Malay and US’889 to arrive at the instantly claimed invention by further modify the surface of the TRAP-cage for external decoration with a plurality of external decorations, including antibodies, epitopes, antigens, proteins, peptides, nucleic acids, lipids, dye molecules, or small molecule therapeutics, as taught by US’889 using the methods disclosed by US’889 for adding external decorations to protein cages. An ordinarily skilled artisan would have been motivated to add external decorations in order to tune the application of the protein cages (US’889, [0068]), for instance by adding targeting moieties which serve to target or direct the delivery of the cage to a particular location (US’889, [0331]). An ordinarily skilled artisan would have had a reasonable expectation of success because App’242, Malay and US’889 all teach protein cages and Malay demonstrates that TRAP cages had been considered for intracellular delivery of therapeutics.
Claims 50, 57 and 71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-63 of copending Application No. 18/547,242 as discussed above, and in further view of Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data, US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007, and Wang, W., et al (2019), Ferritin nanoparticle-based SpyTag/SpyCatcher enabled click vaccine for tumor immunotherapy Nanomedicine: Nanotechnology, biology, and medicine 16; 69-78.
The claims of App’242 modified by Malay and US’889 teach the TRAP-cage of instant claim 48 and the method of instant claim 63 as discussed above.
The combination, however, does not disclose that the external decoration is conjugated using SpyCatcher/SpyTag.
The teachings of Wang are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the artificial TRAP-cage and method taught by the combination of App’242, Malay, and US’889 to conjugate the external decoration, such as a cancer/tumor specific antigen, to the artificial TRAP cage using SpyTag/SpyCatcher conjugation as disclosed by Wang. An ordinarily skilled artisan would have been motivated to use the SpyTag/SpyCatcher conjugation system as Wang teaches that the technique offers a flexible and convenient way to construct nanoparticle based vaccines. Additional Wang teaches the use of such conjugation system for the development of personalized tumor immunotherapy. An ordinarily skilled artisan would have had a reasonable expectation of success as all of App’242, Malay, US’889, and Wang are teaching nanoparticles derived from protein subunits.
This is a provisional nonstatutory double patenting rejection.
18/547,256
Claims 48-51, 53-56, 58-70, and 72 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-63 of copending Application No. 18/547,256 in view of Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data in view of US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007.
App’256 claims an artificial TRAP-cage comprising a selected number of TRAP rings held in place by molecular cross-linkers, wherein the cross-linkers are selected for their specific cleavage characteristics, whereby the cages are programmable to be opened or remain closed under specific conditions. App’253 further claims that the TRAP rings in the TRAP cage is between 6 to 60, or is 12, 20, or 24. App’256 claims that the cage encapsulates a cargo and can be programmed to deliver the cargo to a timed and desired location. App’256 further claims that the TRAP-cage protein is modified with one or more mutations selected from a group which overlaps with the instant claims. App’256 further claims a method of treating a patient comprising administering the cage and a method of preparing the artificial TRAP cage.
The claims of App’256 differ from the instantly claimed invention in that App’256 does not claim that the TRAP-cage comprises a plurality of external decorations attached thereto.
The teachings of Malay and US’889 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the TRAP cage and the method of making the TRAP cage claimed in App’256 with the teachings of Malay and US’889 to arrive at the instantly claimed invention by further modify the surface of the TRAP-cage for external decoration with a plurality of external decorations, including antibodies, epitopes, antigens, proteins, peptides, nucleic acids, lipids, dye molecules, or small molecule therapeutics, as taught by US’889 using the methods disclosed by US’889 for adding external decorations to protein cages. An ordinarily skilled artisan would have been motivated to add external decorations in order to tune the application of the protein cages (US’889, [0068]), for instance by adding targeting moieties which serve to target or direct the delivery of the cage to a particular location (US’889, [0331]). An ordinarily skilled artisan would have had a reasonable expectation of success because App’256, Malay and US’889 all teach protein cages and Malay demonstrates that TRAP cages had been considered for intracellular delivery of therapeutics.
Claim 52 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-63 of copending Application No. 18/547,256 in view of Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data in view of US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007 as discussed above, and in further view of Regberg, J., et al (2012) Applications of Cell-penetrating peptides for tumor targeting and future cancer therapies Pharmaceuticals 5; 991-1007.
The claims of App’256 modified by Malay and US’889 teach the TRAP-cage of instant claim 48 as discussed above.
The combination, however, does not explicitly teach cell penetrating agents.
The teachings of Regberg are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the artificial TRAP-cage taught by the combination of App’256, Malay and US’889 to include a cell penetrating peptide, including PTD4, as taught by Regberg as at least one of the plurality of external decorations. An ordinarily skilled artisan would have been motivated to include a cell penetrating peptide as one of the external decorations as a strategy to increase intracellular drug delivery of the TRAP-cage. An ordinarily skilled artisan would have had a reasonable expectation of success because US’889 teaches that the external decoration on peptide cages can include those that allow for the internalization of the nanoparticle composition to the cell cytoplasm and Regberg teaches the application of the disclosed cell penetrating peptides for the intracellular delivery of nanoparticles.
Claims 50, 57 and 71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-63 of copending Application No. 18/547,256 in view of Malay, A.D., et al (2019) An ultra-stable gold-coordinated protein cage displaying reversible assembly Nature 569; 438-462 with Extended Data in view of US 2007/0258889 A1 (Douglas, T., et al) 8 Nov. 2007 as discussed above, and in further view of Wang, W., et al (2019), Ferritin nanoparticle-based SpyTag/SpyCatcher enabled click vaccine for tumor immunotherapy Nanomedicine: Nanotechnology, biology, and medicine 16; 69-78.
The claims of App’256 modified by Malay and US’889 teach the TRAP-cage of instant claim 48 and the method of instant claim 63 as discussed above.
The combination, however, does not disclose that the external decoration is conjugated using SpyCatcher/SpyTag.
The teachings of Wang are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the artificial TRAP-cage and method taught by the combination of App’256, Malay and US’889 to conjugate the external decoration, such as a cancer/tumor specific antigen, to the artificial TRAP cage using SpyTag/SpyCatcher conjugation as disclosed by Wang. An ordinarily skilled artisan would have been motivated to use the SpyTag/SpyCatcher conjugation system as Wang teaches that the technique offers a flexible and convenient way to construct nanoparticle based vaccines. Additional Wang teaches the use of such conjugation system for the development of personalized tumor immunotherapy. An ordinarily skilled artisan would have had a reasonable expectation of success as all of App’256, Malay, US’889, and Wang are teaching nanoparticles derived from protein subunits.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
Prosecution Insights