DETAILED ACTION
Status of the Application
Claims 43-63 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A preliminary amendment filed on 03/112024 cancelling claims 1-42 and adding new claims 43-63 is acknowledged.
Applicant’s election with traverse of Group I, claims 43-53 and 61 drawn to an artificial TRAP-cage, comprising a selected number of TRAP rings and encapsulated therein at least one guest cargo, as recited in independent claims 43 and further limited in dependent claims 44-53 and species election of interleukin-2 (IL-2), 24 as the species of number of rings for the TRAP, K35C as the species of mutation for the TRAP-cage protein and reduction responsive/sensitive linker as the species of cross-linker, in reply filed on 07/08/2026 is acknowledged.
The traversal is on the grounds that the groups are all directed to a TRAP-cage with an encapsulated guest cargo and Malay does not disclose actual encapsulation of a guest cargo within the TRAP-cage. The TRAP ring observed in Malay’s Extended Data Figure 8d is a structural subunit of the cage itself, present as a consequence of assembly geometry, not as a purposively introduced guest cargo. The encapsulated-cargo feature is therefore not anticipated by Malay, and it remains a special technical feature capable of providing unity. However, Malay et al. teaches that protein cages play roles in cargo delivery (see abstract) and Michalak (TRAP-cage as a tool for protein encapsulation, Masters theses, 06/20/2017) teaches the ability of TRAP-cage encapsulation of a negatively supercharged GFP variant (see Abstract).
The requirement is still deemed proper and is therefore made FINAL.
Claims 45-46, 54-60 and 62-63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species (note claims 45-46 are not drawn to the elected species of guest cargo), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 07/08/2026.
Claims 43-44, 47-53 and 61 are examined herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119
(a)-(d). The certified copy has been filed in parent Applications No. PLP.437113, LU102571, LU102572, LU102569, PLP.437114 and PLP.437115, filed on 02/24/2021. The instant application is a 371 national stage application of PCT/PL2022/050011 filled on 02/24/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/21/2023 is acknowledged.
The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the
information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because the resolution of Fig. 1-3, 5, 7, and 10-12 are
too low for legibility, especially given the small size of each panel. 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or
other form of browser-executable code. See line 17 of pg. 44 and line 19 of pg. 50 for the embedded hyperlink. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level
domain name without any prefix such as http:// or other browser-executable code. See
MPEP § 608.01.
The use of the terms: SpyCatcher/SpyTag which are a trade name or a mark used in commerce, have been used in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever it appears or, where
appropriate, include a proper symbol indicating use in commerce such as ™, ℠, or ® following
the terms.
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
Claims 43, 48-49 and 50 are objected to because of the following informalities:
Claim 43 is objected to in the recitation of “artificial TRAP-cage”. TRAP should be replaced with trp RNA-binding attenuation protein (TRAP) in its first appearance in the claim set. Appropriate correction is required.
Claim 48 is objected to in the recitation of “cargos” and “cargoes”. It is
suggested that applicants maintain consistency throughout the claims. Appropriate correction is required.
Claim 49 is objected to in the recitation of “PTD4”. PTD4 should be replaced with protein transduction domain (PTD4) in its first appearance in the claim set. Appropriate correction is required.
Claim 50 is objected to in the recitation of “between 6 to 60” and should be replaced with either “is 6 to 60” or “is between 6 and 60”. Appropriate correction is required.
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 43-44, 47-53 and 61 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.
Claim 43 (claims 44, 47-53 and 61 dependent therefrom) is indefinite in the recitation of “selected number of TRAP rings”. Claim 43 is indefinite because “selected” requires the exercise of subjective judgment. See MPEP 2173.05(b)(IV) regarding subjective terms:
A claim term that requires the exercise of subjective judgment without restriction may
render the claim indefinite. Appropriate correction is required.
Claim 49 is indefinite in the recitation of “including at least one external decoration”. It is unclear what compound constitutes a “decoration”. Appropriate correction is required.
Claim 50 is indefinite in the recitation of both a broad range and value falling within the broad range. Appropriate correction is required.
Claim 51 is indefinite because the claim recites mutations without a reference sequence. For examination purposes, claim 51 will be interpreted as a protein having a Q residue or K residue at any amino acid position. Appropriate correction is required.
Claim 52 is indefinite because the claim recites mutations without a reference sequence. In addition, “one or more mutations selected from the group consisting of K35C, K35H, R64S, E48Q, E48K, K35C/R64S, K35H/R64S, S33C, S33H, S33C/R64S, S33H/R64S, S33C/K35H S33H/K35H, S33C/K35C, S33H/K35C, K35C/E48Q, K35C/E48K, K35H/E48Q, K35H/E48K, S33C/E48Q, S33C/E48K, S33C/E48Q and S33C/E48K” renders claim 52 indefinite because the combination of “one or more” with “K35C/R64S, K35H/R64S, S33C/R64S, S33H/R64S, S33C/K35H S33H/K35H, S33C/K35C, S33H/K35C, K35C/E48Q, K35C/E48K, K35H/E48Q, K35H/E48K, S33C/E48Q, S33C/E48K, S33C/E48Q and S33C/E48K” leads to ambiguity in the claim scope. For example, K35C/R64S can be interpreted as alternatives, so it is unclear whether the mutations are (i) K53C or R64S, or (ii) one or more mutations selected from K53C and R64S (includes the combination of K35C and R64S). For examination purposes, claim 52 will be interpreted as a duplicate of claim 43. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 43-44, 47 and 52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Michalak (TRAP-cage as a tool for protein encapsulation, Masters theses, 06/20/2017).
Claim 43 is directed to an artificial TRAP-cage comprising a selected number of TRAP rings and encapsulated therein at least one guest cargo. Claim 44 is directed to the cage according to claim 43, wherein the guest cargo is selected from the group consisting of a protein, an enzyme, an antigen, an antibody. a protein macromolecule, a lipid, a peptide, a nucleic acid, a small molecular cargo, a peptide nucleic acid, a carbon-based structure, a metal, a toxin or a nanoparticle. Claim 47 is directed to the cage according to claim 43, wherein the guest cargo is a protein, a fluorescent protein, interleukin-2 (IL-2), or Neoleukin-2/15 (NL-2). Claim 52 is directed to the cage according to claim 43, wherein the artificial TRAP-cage protein is modified to comprise any one or more mutations selected from the group consisting of K35C, K35H, R64S, E48Q, E48K, K35C/R64S, K35H/R64S, S33C, S33H, S33C/R64S, S33H/R64S, S33C/K35H S33H/K35H, S33C/K35C, S33H/K35C, K35C/E48Q, K35C/E48K, K35H/E48Q, K35H/E48K, S33C/E48Q, S33C/E48K, S33C/E48Q and S33C/E48K. Please see claim interpretation under 112(b).
Michalak teaches artificial protein cages made from mutated trp-RNA binding attenuation protein (TRAP) with a double mutation (TRAP K35C R66S) to form the cage. Michalak suggests that TRAP-cage assembled in the presence of magnesium ions was able to encapsulate a negatively supercharged GFP variant (see abstract). Therefore, the teachings of Michalak anticipate instant claims 43, 44, 47 and 51-52 as written/interpreted.
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.
Claims 43, 48 and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Michalak (TRAP-cage as a tool for protein encapsulation, Masters theses, 06/20/2017), in view of Douglas et al. (US20070258889A1, published 11/08/2007, IDS citation #1 08/21/2023).
The teachings of Michalak regarding claim 43 have been discussed above.
Douglas et al. teaches protein cages for selective entrapment and release of materials (see paragraph [0298]). Douglas et al. teaches that they investigated the ability of the cages to simultaneously encapsulate cargo molecules on the Hsp cage interior (see paragraph [0452]). Douglas et al. teaches both peptides and antibodies were incorporated on the exterior surface of Hsp cages (see paragraph [0452]). Douglas et al. teaches attaching a reactive dye to the exterior of the Hsp cage (see paragraph [0517]).
Douglas et al. does not teach an artificial TRAP-cage.
Claim 48 is directed to the cage according to claim 43, wherein the cage comprises multiple guest cargos and wherein the guest cargoes are the same or different from one another. Claim 49 is directed to the cage according to claim 43, 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.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the TRAP cage disclosed in Michalak to incorporate multiple guest cargos simultaneously and add external decorations as taught by Douglas et al.
A person of ordinary skill in the art is motivated to add multiple guest cargo and add external decoration to the TRAP cage because the external decoration can allow the cage to have a targeting moiety and tailor the amount of cargo released from the cage for therapeutic use.
One of ordinary skill in the art has a reasonable expectation of success because the proposed modifications are well-known in the art as evidenced by Douglas et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 43, 50-51, 53 and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Michalak (TRAP-cage as a tool for protein encapsulation, Masters theses, 06/20/2017), in view of Malay (Nature, published 05/08/2019).
The teachings of Michalak regarding claim 43 have been discussed above.
Malay et al. teaches the number of TRAP rings in the TRAP cage is 24 (see pg. 439, left column, top paragraph after Fig. 1 caption). Malay et al. teaches the TRAP protein is based on PDB ID: 4V4F, which has the following sequence: MYTNSDFVVIKALEDGVNVIGLTRGADTRFHHSEKLDKGEVLIAQFTEHTSAIKVRGKAYIQTRHGVIESEGKK, which has Q residues at positions 45 and 62 and K residues at positions 11, 35, 38, 54, 58, 73 and 74.
Malay et al. teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (see pg. 440, right column, paragraph 1 after figure caption), so the TRAP cage is reduction responsive (opening under reducing conditions). Malay et al teaches purification of the TRAP cages by size-exclusion chromatography and expression in E. coli BL21(DE3) cells (see Methods: Protein expression and purification). Malay et al. teaches 11 equally spaced thiol groups along the outer rim of the oligomeric ring (see pg. 438, right column, first paragraph).
Claim 50 is directed to the cage according to claim 43, wherein the number of TRAP rings in the TRAP-cage is between 6 to 60, or wherein the number of TRAP rings in the TRAP-cage is 12, 20 or 24. Claim 51 is directed to the cage according to claim 43, wherein the interior surface of the TRAP-cage lumen is supercharged and the TRAP-cage protein comprises an E48Q or a E48K mutation. Please see claim interpretation under 112(b). Claim 53 is directed to the TRAP-cage according to claim 43, wherein opening of the cage is programmable, or wherein the programmable opening of the cage is dependent on selection of a molecular or atomic cross-linker which hold the TRAP-rings in place in the TRAP-cage, or wherein the cross-linker is either (i) a reduction responsive/sensitive linker, whereby the cage opens under reduction conditions; or (ii) a photo-activatable linker whereby the cage opens upon exposure to light. Claim 61 is directed to a TRAP cage produced by the method of claim 54, which is a product-by-process claim. As such, the method steps are only given weight insofar as they limit the structure of the claimed product. The method of claim 54 requires making an artificial TRAP-cage with an encapsulated guest cargo, the method comprising: (i) obtaining TRAP ring units by expression of the TRAP ring units in a suitable expression system and purification of the said units from the expression system; (ii) conjugation of the TRAP ring units via at least one free thiol linkage with a cross-linker; (iii) modification of the TRAP ring units to provide a suitable interior surface environment for capturing a guest cargo; (iv) formation of the TRAP-cage by self-assembly to provide a cage lumen wherein the guest cargo is encapsulated; and (v) purification and isolation of the TRAP-cages encapsulating the guest cargo.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the TRAP cage disclosed in Michalak to be made up of 24 TRAP rings as taught by Malay et al. and have the cage open up under reducing conditions as taught by Malay et al.
A person of ordinary skill in the art is motivated to make a TRAP cage with 24 TRAP rings and make it open under reducing conditions because Malay et al. teaches that has potential applications as an intercellular delivery agent.
One of ordinary skill in the art has a reasonable expectation of success because the proposed modifications are well-known in the art as evidenced by Malay et al. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
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.
Claims 43, 49-50 and 52 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 73, 76, 81-82, and 84 of copending Application No. 18/547,274. Although the claims at issue are not identical, they are not patently distinct from each other
Application 18/547,274 claims A trp RNA-binding attenuation protein (TRAP)-cage comprising TRAP rings formed from TRAP proteins, wherein the TRAP-cage has a surface modification moiety attached thereto, wherein the surface modification moiety is selected from the group comprising: a protein, a peptide, a dye molecule and wherein the TRAP-cage encapsulates a cargo. The TRAP-cage according to claim 73, wherein the surface modification moiety is a cell penetrating agent to promote intracellular delivery of the cage, or wherein the surface modification moiety is cell penetrating peptide Protein Transduction Domain 4 (PTD4). The TRAP-cage according to claim 73, wherein the number of TRAP rings in the TRAP-cage is between 6 and 60 or wherein the number of TRAP rings in the TRAP-cage is 12, 20 or 24.The TRAP-cage according to claim 73, wherein the TRAP-cage protein is modified to comprise any one or more mutations selected from the group consisting of K35C, K35H, R64S, K35C/R64S, K35H/R64S, S33C, S33H, S33C/R64S, S33H/R64S, S33C/K35H, S33H/K35H, S33C/K35C and S33H/K35C, wherein the amino acid position numbering is based on the amino acid sequence of SEQ ID NO: 1 therein which anticipates claims 43, 49-50 and 52 of the instant application.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALTON KIEFER, PhD whose telephone number is (571)272-1235. The examiner can normally be reached M-F 7:30-5 EST.
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/DALTON EDWARD KIEFER/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
