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 .
DETAILED ACTION
Claims 1-40 are cancelled in the amendment filed on 03/08/2024.
Claims 41-63 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 41-58 and 63, and species of bis-bromoxylene and dithiobismaleimideoethane and K35C, in the reply filed on 12/29/2025 is acknowledged. The traversal is on the ground that the groups share the special technical feature of cages that are programmable. This is not found persuasive because the prior art of Malay (cited in the Restriction Requirement mailed on 11/6/2025) teaches that the cages are also programmable: the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption). Thus, the cages are programmed to break apart (“open”) in response to millimolar levels of reducing agents.
The requirement is still deemed proper and is therefore made FINAL.
Claims 52-62 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species (note that claims 52-58 are not drawn to the elected species of cross-linker), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/29/2025.
The elected species of bis-bromoxylene and dithiobismaleimideoethane are free of prior art. Therefore, the provisional requirement for election of species has been modified and the species in claim 44 are also examined.
Claims 41-51 and 63 are examined herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See line 14 on page 32 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 disclosure is also objected to because of the following informalities: homobifunctional is misspelled as “homobisfunctional” throughout the specification. See, for example, lines 12, 14, and 16 on page 4.
Appropriate correction is required.
Claim Objections
Claims 41, 43, 45, and 47 are objected to because of the following informalities:
In claim 41, “An artificial TRAP-cage.” TRAP should be replaced with trp RNA-binding attenuation protein (TRAP) in its first appearance in the claim set.
In claim 43, “homobisfunctional” is a misspelling of “homobifunctional.”
In claim 45, “bismaleimideohexane” is a misspelling of “bismaleimidohexane.”
In claim 47, “is between 6 to 60” should be replaced with either “is 6 to 60” or “is between 6 and 60.”
Appropriate correction is required.
Drawings
The drawings are objected to because the resolution of Fig. 2(I), 2(II), and 3 is 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.
Claim Rejections - 35 USC § 112
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 41-51 and 63 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 41 is drawn to an artificial TRAP-cage comprising both a selected number of TRAP rings and cross-linkers selected for their specific cleavage characteristics, whereby the cages are programmable to be opened or remain closed on demand, under specific conditions. Claim 41 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. It is further unclear what the “specific cleavage characteristics” and “specific conditions” are.
Claim 42 recites “(i) a reduction resistant / insensitive molecular cross-linker, and (ii) a reduction responsive / sensitive molecular cross-linker.” The claim is indefinite because it is unclear whether the slash indicates alternatives. Furthermore, “insensitive” is narrower in scope than “resistant,” so it is unclear whether the claim scope is the broader (resistant) or narrower (insensitive).
Claim 43 is indefinite because the claim recites “selected from the group comprising…” which is not a closed group. Applicant may consider amending to “selecting from the group consisting of…”
Claim 48 recites “The cage according to claim 41, which comprises a mixture of different programmable cross-linkers.” It is unclear whether claim 48 is limiting the programmable cross-linkers that hold the TRAP rings in place or whether this claim encompasses, for example, a TRAP cage encapsulating a mixture of different programmable cross-linkers.
Claim 49 is indefinite because “desired” is a subjective term, Per MPEP 2173.05(b)(IV): A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. In addition, the claim limitation requiring the cage “can be programmed to deliver said cargo” conflicts with the requirement in claim 41 that the cages are programmable to be opened or remain closed on demand. Thus, it is unclear whether the cages are already programmable or whether an additional modification is required to render the cages programmable. Claim 49 is further indefinite because the claim has multiple interpretations due to the active verb and the conditional language “can be programmed.” In one interpretation, the claim is drawn to the artificial TRAP cage further comprising a cargo, wherein the cage is programmed to deliver the cargo in a specifically timed and desired location. In a second interpretation, the claim is drawn to a method of encapsulating a cargo, further comprising the optional step of programming the cage to deliver the cargo in a specifically timed and desired location.
Claim 50 is indefinite because the claim recites mutations without a reference sequence. In addition, “one or more mutations selected from the group consisting of K53C, R64S, and K35C/R64S” renders claim 50 indefinite because the combination of “one or more” with “K35C/R64S” leads to ambiguity in the claim scope. 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).
Claims 42-51 and 63 are rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
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 41-44, 46-51 and 63 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to an artificial TRAP-cage comprising a selected number of TRAP rings which are 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 on demand, under specific conditions.
In the absence of any special definition provided in the specification for “molecular,” molecular is given its broadest reasonable interpretation as relating to molecules, which are chemical substances formed by two or more atoms bonded together. Thus, S-Au-S is a molecular cross-linker because Au forms a coordination bond with two sulfur atoms.
The person of ordinary skill in the art would not have recognized, at the time the application was filed, that the inventors had possession of the claimed genus of artificial TRAP-cages.
The specification discloses that TRAP is the trp RNA-binding attenuation protein rom Geobacillus stearothermophilus (specification lines 18-20 on page 1). The specification discloses in Example 1 the preparation of TRAP-cageDTME and TRAP-cageBMH (page 30, line 21). In these two species of TRAP-cage, the molecular cross-linkers DTME and BMH are used. The cages are prepared by mixing the cross-linkers with TRAP(K35C/R64S) and incubating at room temperature for 1 hour (lines 10-13 on page 34). Each of these molecular cross-linkers has specific cleavage characteristics: TRAP-cageDTME readily disassembles upon addition of reducing agents, whereas TRAP-cageBMH is unaffected by reducing agents (lines 16-19 on page 35). The specification also discloses species of TRAP-cage with cross-linkers Au(I), Ag(I), Cd(II), Co(II), or Zn((II) (lines 12, 18, and 29-30 on page 36). The specification discloses that the TRAP metal-binding site has been reengineered to target metal ions with preference for tetrahedral coordination (lines 1-2 on page 37). Thus, the mutations S33H/K35C and S33H/K35H are necessary for cage assembly upon addition of Zn(II) and Co(II) (lines 1-7 on page 37). In contrast, Au(I), Ag(I), and Cd(II) are made from TRAP with mutations K35C/R64S (lines 12 and 18 on page 36).
The specification exemplifies two additional species of TRAP-cages: TRAP-cages with the molecular cross-linker 1,3-dibromoxylene (DBX) or 1,3-bisbromomethyl-4-nitrobenzene (line 14 and 17 on page 37). The specification discloses that TRAP-cageDBX is resistant to reducing conditions (line 13 on page 38), whereas the TRAP-cage with 1,3-bisbromomethyl-4-nitrobenzene as the molecular cross-linker is photo-cleavable (lines 33-35 on page 38). Artificial TRAP-cages with DBX or 1,3-bisbromomethyl-4-nitrobenzene are prepared by first preparing an Au(I)-induced TRAP-cage, and then exchanging the Au(I) with DBX or 1,3-bisbromomethyl-4-nitrobenzene, which the specification calls a templating reaction (lines 3-6 on page 37). However, the specification discloses that the structure of the resulting cages is different than the Au(I)-induced TRAP cage: “In case of Au(I) induced cages there were 120
connections identified (-S-Au-S- bridges) but in the case of the DBX-cage the number of
connections drops down to half of that number” (lines 26-28 on page 38). 60 linker molecules and the same overall geometry forces a slightly different TRAP rings orientation (lines 28-29 on page 38).
Malay et al. (Nature 569.7756 (2019): 438-442) teaches a TRAP-cage comprising TRAP rings held in place by gold or mercury (Abstract, Figure 1(a)). The metal ions interact with thiol groups during cage assembly (page 438, right column, top paragraph and page 439, right column, top line), so they are molecular cross-linkers. The cage is artificial because the cage is chemically synthesized (page 443, Methods, left column, Cage assembly, paragraph 1). Malay teaches that the number of TRAP rings in the TRAP-cage is 24 (page 439, left column, top paragraph after Fig. 1 caption). Thus, Malay teaches two species of molecular cross-linker and both contain metal atoms.
To summarize, although the specification discloses several species of artificial TRAP-cages with molecular cross-linkers, they are not a representative number of species of the claimed genus of artificial TRAP-cages. Although there appears to be some predictability with the molecular cross-linkers that contain metal atoms, there is a lack of predictability with respect to other types of molecular cross-linkers. Although some molecular cross-linkers spontaneously form cages in the presence of TRAP protein (e.g. DTME and BMH), 1,3-dibromoxylene (DBX) and 1,3-bisbromomethyl-4-nitrobenzene both require the use of a templating reaction and result in structurally-distinct TRAP-cages from the Au(I)-induced TRAP cages. The person of ordinary skill in the art would have been unable to predict which molecular cross-linkers would have resulted in a TRAP-cage structure, either by spontaneous assembly or templating.
With respect to the metal-induced TRAP cages, the specification discloses the structural features required for assembly: metal ions with tetrahedral coordination require the mutations S33H/K35C or S33H/K35H (lines 1-7 on page 37). Rulı́šek et al. (Journal of inorganic biochemistry 71.3-4 (1998): 115-127) teaches the preferred coordination geometries of several different metal ions: see Figure 1 on page 125. Notably, Ni2+, Co2+, and Cd2+ have the same preferred structure (coordination 6), Zn2+ and Cd2+ have tetrahedral coordination, whereas Hg2+ is planar (Fig. 1). Thus, the person of ordinary skill in the art would have been able to predict other metals to induce TRAP-cage formation. However, claim 41 is not limited to molecular cross-linkers comprising metals and instead encompasses a much larger genus.
Claim 42 limits the specific cleavage characteristics of the molecular cross-linker to reduction resistant, reduction responsive, or photoactivatable. However, Applicant has also not disclosed a representative number of species of the claimed genus. Although the person of ordinary skill in the art would have been able to visualize species of molecular cross-linkers with these characteristics, the person of ordinary skill in the art would not have been able to determine which of these cross-linkers are capable of assembling TRAP-cages given the unpredictability in the art with respect to TRAP-cage assembly from molecular cross-linkers.
Claim 43 recites a homobifunctional molecular moiety or its derivatives and claim 44 recites derivatives of bis-halomethyl benzene. However, the specification discloses only a handful of homobifunctional molecular moieties and does not disclose any TRAP-cages wherein the TRAP rings are held in place by derivatives of these moieties. There is no guidance provided within the specification for derivatization of the homobifunctional moieties such that the derivatives can still assemble TRAP-cages. In addition, although the specification provides a working example of the TRAP-cage wherein the TRAP rings are held in place by 1,3-bisbromo-4-nitrobenzene (see specification, page 37, Example 5, paragraph 2) and 1,2- bis-bromomethyl-3-nitrobenzene (Fig. 6g), the species of 1,3-bis-bromomethyl-4,6-dinitro-benzene is not tested, nor are any other bis-halomethyl benzenes.
Claim 48 recites an artificial TRAP-cage comprising a mixture of different programmable cross-linkers. However, the specification provides no working examples with mixtures of different programmable cross-linkers and the prior art does not teach any species of TRAP-cage wherein the TRAP rings are cross-linked with mixtures of different cross-linkers. There is an exceptionally high degree of unpredictability in the art with respect to artificial TRAP-cages with mixtures of cross-linkers.
Claim 49 recites the TRAP-cage encapsulates a cargo and can be programmed to deliver said cargo in a specifically timed and desired location. Thus, claim 49 introduces an additional genus of TRAP-cages in which the TRAP-cage encapsulates a cargo. None of the working examples provided in the specification include a cargo within the TRAP cage and no guidance is provided within the specification. The prior art of Michalak (2017. TRAP-cage as a tool for protein encapsulation. Online. 20 June 2017) teaches the encapsulation of a negatively supercharged GFP variant by assembling TRAP-cages in the presence of magnesium ions (English Abstract). However, this single species is not representative of the claimed genus of TRAP-cages encapsulating any cargo.
Therefore, the person of ordinary skill in the art would not have recognized that the inventors had possession of claimed invention at the time the application was filed.
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 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.
Claims 41-44, 47, 50-51, and 63 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Malay et al. (Nature 569.7756 (2019): 438-442; cited in the Restriction Requirement mailed on 11/6/2025).
In the absence of any special definition provided in the specification for “molecular,” molecular is given its broadest reasonable interpretation as relating to molecules, which are chemical substances formed by two or more atoms bonded together. Thus, S-Au-S is a molecular cross-linker because Au forms a coordination bond with two sulfur atoms.
Malay teaches a TRAP-cage comprising TRAP rings held in place by gold or mercury (Abstract, Figure 1(a)). The metal ions interact with thiol groups during cage assembly (page 438, right column, top paragraph and page 439, right column, top line), so they are molecular cross-linkers. The cage is artificial because the cage is chemically synthesized (page 443, Methods, left column, Cage assembly, paragraph 1).
Regarding claims 41-42 and 44, Malay teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption), so the TRAP cage is reduction responsive (opens under reducing conditions).
Regarding claim 43, the molecular cross linker S-Au-S (Malay page, 444 right column, Structural refinement, bottom of paragraph) is homobifunctional (chemical cross-linker featuring two identical reactive groups at opposite ends of a spacer arm) because the Au acts as the spacer arm and the sulfur groups are both reactive (connected with the other amino acids in the TRAP cage).
Regarding claim 47, the number of TRAP rings in the TRAP-cage is 24 (page 439, left column, top paragraph after Fig. 1 caption).
Regarding claim 50, Malay teaches a TRAP cage comprising the amino acid substitutions K35C and R64S with similar structure and stability (page 440, right column, paragraph 1 after figure caption).
Regarding claim 51, Malay teaches that the TRAP cage is stable upon exposure to high temperatures, chaotropic agents, and a wide range of pH conditions that include non-neutral pH conditions (page 440, left column, paragraph 2 after figure caption and Fig. 3c).
Claim 63 is a product-by-process claim (product produced by the method of instant claim 61). As such, the method steps are only given weight insofar as they limit the structure of the claimed product. The method of claim 61 requires that the produced TRAP-cage is cross-linked by a reduction responsive molecular cross-linker. Thus, claim 63 is also anticipated by Malay because Malay teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption) so the TRAP cage is reduction responsive (opens under reducing conditions).
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 49 is rejected under 35 U.S.C. 103 as being unpatentable over Malay et al. (Nature 569.7756 (2019): 438-442; cited in the Restriction Requirement mailed on 11/6/2025) in view of Michalak (2017. TRAP-cage as a tool for protein encapsulation. Online. 20 June 2017).
See discussion of Malay above, which is incorporated into this rejection as well.
Malay does not teach that the TRAP-cage encapsulates a cargo.
Michalak teaches that one of the key aspects of drug delivery is the protection of active molecules until they reach the place of action and suggests that protein cages may help to protect such cargo while reducing unwanted interactions with the environment (English Abstract). Michalak teaches the encapsulation of a negatively supercharged GFP variant by assembling a TRAP-cage in the presence of magnesium ions (English Abstract). Michalak hypothesizes that magnesium ions bridge negative charges on the inner surface of TRAP and the negatively charged GFP (English Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the TRAP-cage of Malay by assembling the TRAP cage in the presence of magnesium ions and negatively charged GFP in order to encapsulate the GFP per the teaching of Michalak. The person of ordinary skill in the art would have been motivated to develop a model for drug delivery using the cages of Malay. The person of ordinary skill in the art would have had a reasonable expectation of success in the encapsulation of negatively charged GFP within the TRAP-cage.
Since Malay’s molecular cross-linkers are responsive to reducing conditions (Malay page 440, right column, paragraph 1 after figure caption), the TRAP-cage encapsulating the GFP cargo would have been capable of delivering the cargo in a specifically timed and desired location because whenever the cage is exposed to the reducing conditions, the GFP would have been released.
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 41-44, 47, 50-51, and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23 and 40-44 of copending Application No. 17/268,596 (hereafter ‘596) as evidenced by Malay et al. (Nature 569.7756 (2019): 438-442; cited in the Restriction Requirement mailed on 11/6/2025). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 41-44, 47, 50-51, and 63 are anticipated by claims, 23 and 40-44 of ‘596.
Claim 23 of ‘596 is drawn to a method of generating a protein cage biomolecule complex comprising contacting a TRAP protein comprising a cysteine residue with a gold-donor agent to form a -S-Au-S- bond. Claim 41 of 596 recites a modified protein cage obtainable by the method of claim 23.
Claim 40 of ‘596 recites that the protein complex consists of 24 TRAP protein units, Claim 42 of ‘596 is drawn to the modified protein cage of claim 41 comprising 24 TRAP rings.
Claims 23 and 41 of ‘596 anticipate instant claims 41-42 and 44 because TRAP cages comprising the -S-Au-S bond are fully reversible and break apart in response to millimolar levels of reducing agents as evidenced by Malay (page 440, right column, paragraph 1 after figure caption; page, right column, page 444, bottom of Structural refinement paragraph) so the TRAP cages are reduction responsive (open under reducing conditions).
Regarding instant claim 43, the -S-Au-S- is a hombifunctional molecular cross-linker, so claim 23 of ‘596 also anticipates instant claim 43.
Instant claim 47 is anticipated by claims 40 and 42 of ‘596.
Instant claim 50 is anticipated by claims 43-44 of ‘596 because claim 43 of ‘596 recites that the TRAP protein contains a K35C mutation, and claim 44 of ‘596 recites the TRAP protein additionally contains a R64S mutation. Instant claim 50 is also anticipated by claim 23 of ‘596 because the mutation K35C is also required in claim 23 of ‘596.
Instant claim 51 is also anticipated by claims 23 and 41 of ‘596 because the TRAP cage with -S-Au-S cross-linkers is stable upon exposure to high temperatures, chaotropic agents, and a wide range of pH conditions that include non-neutral pH conditions as evidenced by Malay (page 440, left column, paragraph 2 after figure caption and Fig. 3c).
Claim 63 is a product-by-process claim (product produced by the method of instant claim 61). As such, the method steps are only given weight insofar as they limit the structure of the claimed product. The method of claim 61 requires that the produced TRAP-cage is cross-linked by a reduction responsive molecular cross-linker. Thus, claim 63 is also anticipated by claims 23 and 41 of ‘596 because the -S-Au-S- cross-linker is reduction responsive as evidenced by Malay (page 440, right column, paragraph 1 after figure caption).
This is a provisional nonstatutory double patenting rejection.
Claim 49 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23 and 40-44 of copending Application No. 17/268,596 (‘596) in view of Michalak as evidenced by Malay.
See discussion of claims 23 and 40-44 of ‘596 above, which is incorporated into this rejection as well.
Claims 23 and 40-44 of ‘596 do not recite that the cage further encapsulates a cargo that can be programmed to deliver said cargo in a specifically timed and desired location.
Michalak teaches that one of the key aspects of drug delivery is the protection of active molecules until they reach the place of action and suggests that protein cages may help to protect such cargo while reducing unwanted interactions with the environment (English Abstract). Michalak teaches the encapsulation of a negatively supercharged GFP variant by assembling a TRAP-cage in the presence of magnesium ions (English Abstract). Michalak hypothesizes that magnesium ions bridge negative charges on the inner surface of TRAP and the negatively charged GFP (English Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the TRAP-cage of claims 23 and 40-44 of ‘596 by assembling the TRAP cage in the presence of magnesium ions and negatively charged GFP in order to encapsulate the GFP per the teaching of Michalak. The person of ordinary skill in the art would have been motivated to develop a model for drug delivery using the cages of claims 23 and 40-44 of ‘596. The person of ordinary skill in the art would have had a reasonable expectation of success in the encapsulation of negatively charged GFP within the TRAP-cage.
Since the S-Au-S molecular cross-linkers are responsive to reducing conditions as evidenced by Malay (Malay page 440, right column, paragraph 1 after figure caption), the TRAP-cage encapsulating the GFP cargo would have been capable of delivering the cargo in a specifically timed and desired location because whenever the cage is exposed to the reducing conditions, the GFP would have been released.
This is a provisional nonstatutory double patenting rejection.
Claims 41-44, 47, 49-51, and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 48-49, 52, 58-61, 63, and 72 of copending Application No. 18/547,274 (reference application; hereafter ‘274) in view of Malay.
Claim 48 of ‘274 recites an artificial TRAP-cage comprising a selected number of TRAP rings and a plurality of external decorations attached thereto.
Claim 49 of ‘274 recites that the external decorations are selected from epitopes antigens, and cell penetrating peptides.
Claim 52 of ‘274 recites that at least one of the external decorations comprises a cell penetrating agent to promote intracellular delivery of the cage.
Claim 58 of ‘274 of recites that the cage further includes an internal cargo encapsulated therein.
Claim 59 recites that the number of TRAP rings in the TRAP-cage is between 6 to 60 or is 12, 20, or 24.
Claim 60 of ‘274 recites that the TRAP rings are held in place by cross-linkers which comprise one or more programmable cross-linkers.
Claim 61 of ‘274 recites that the TRAP-cage protein is modified to comprise any one or more mutations selected from the group consisting of K35C, R64S, or K35C/R64S.
Claim 63 of ‘274 is drawn to a method of making an artificial TRAP-cage comprising conjugation of the TRAP ring units by at least one free thiol linkage with a cross-linker. Claim 72 of ‘274 recites a TRAP-cage produced by the method of claim 63.
Regarding instant claim 41, claims 48-49, 52, 58-61, 63, and 72 of ‘274 do not recite that the TRAP rings in the TRAP-cage are held in place by molecular cross-linkers selected for their specific cleavage characteristics, whereby the cages are programmable to be opened or remained closed on demand under specific conditions.
Malay teaches a TRAP-cage comprising TRAP rings held in place by gold or mercury (Abstract, Figure 1(a)). The metal ions interact with thiol groups during cage assembly (page 438, right column, top paragraph and page 439, right column, top line), so they are molecular cross-linkers. The cage is artificial because the cage is chemically synthesized (page 443, Methods, left column, Cage assembly, paragraph 1). Malay teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption) so the TRAP cage is reduction responsive (opens under reducing conditions). Malay’s molecular cross linker S-Au-S (Malay page, 444 right column, Structural refinement, bottom of paragraph) is homobifunctional (chemical cross-linker featuring two identical reactive groups at opposite ends of a spacer arm) because the Au acts as the spacer arm and the sulfur groups are both reactive (connected with the other amino acids in the TRAP cage).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to assemble the TRAP-cage of claims 48-49, 52, 58-61, 63, and 72 of ‘274 by using the molecular cross-linker S-Au-S, per the teaching of Malay. The person of ordinary skill in the art would have been motivated to do so because claims 48-49, 52, 58-61, 63, and 72 of ‘274 are drawn to a TRAP-cage. Assembly of the TRAP-cage requires cross-linkers (see claims 60 and 63 of ‘274), so the person of ordinary skill in the art would have turned to Malay for the specific cross-linker. The person of ordinary skill in the art would have had a reasonable expectation of success in assembling the TRAP-cage of claims 48-49, 52, 58-61, 63, and 72 of ‘274 with Malay’s cross-linkers.
Regarding claims 42 and 44, Malay teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption) so the TRAP cage is reduction responsive (opens under reducing conditions).
Regarding claim 43, the molecular cross linker S-Au-S (Malay page, 444 right column, Structural refinement, bottom of paragraph) is homobifunctional (chemical cross-linker featuring two identical reactive groups at opposite ends of a spacer arm) because the Au acts as the spacer arm and the sulfur groups are both reactive (connected with the other amino acids in the TRAP cage).
Instant claim 47 is obvious over claim 59 of ‘274 in view of Malay.
Instant claim 49 is obvious over claim 58 of ‘274 in view of Malay.
Instant claim 50 is obvious over claim 61 of ‘274 in view of Malay.
Regarding instant claim 51, Malay teaches that the TRAP cage is stable upon exposure to high temperatures, chaotropic agents, and a wide range of pH conditions that include non-neutral pH conditions (page 440, left column, paragraph 2 after figure caption and Fig. 3c).
Instant claim 63 is a product-by-process claim (product produced by the method of instant claim 61). As such, the method steps are only given weight insofar as they limit the structure of the claimed product. The method of claim 61 requires that the produced TRAP-cage is cross-linked by a reduction responsive molecular cross-linker. Thus, claim 63 is also obvious over claims 48-49, 52, 58-61, 63, and 72 of ‘274 in view of Malay because Malay teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption) so the TRAP cage is reduction responsive (opens under reducing conditions).
This is a provisional nonstatutory double patenting rejection.
Claims 41-42 and 49 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 53 of copending Application No. 18/547,242 (hereafter ‘242). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 41-42 and 49 are anticipated by claim 53 of ‘242.
Claim 53 of ‘242 recites the TRAP rings are held in place by a molecular cross-linker that is reduction responsive or photo-activatable. Claim 53 of ‘242 depends from claim 43 of ‘242, which is drawn to an artificial TRAP-cage comprising a selected number of TRAP rings and encapsulated therein at least one guest cargo.
Instant claims 41 and 49 are anticipated by claim 53 of ‘242.
Instant claim 42 is also anticipated by claim 53 of ‘242 for the embodiments in which the molecular cross-linker is reduction responsive or photoactivatable.
This is a provisional nonstatutory double patenting rejection.
Claims 41-44, 47, 50-51, and 63 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-52 and 54-63 of copending Application No. 18/547,242 (hereafter ‘242) in view of Malay.
Claims 43-52 and 54-63 of ‘242 each require an artificial TRAP cage.
Claim 50 of ‘242 recites the number of TRAP rings in the TRAP-cage is between 6 and 60 or 12, 20 or 24.
Claim 52 of ‘242 recites that the TRAP cage comprises any one or more mutations selected from K35C, R64S, and K35C/R64S.
Regarding instant claim 41, claims 43-52 and 54-63 of ‘242 do not recite that the TRAP rings in the TRAP-cage are held in place by molecular cross-linkers selected for their specific cleavage characteristics, whereby the cages are programmable to be opened or remained closed on demand under specific conditions.
Malay teaches a TRAP-cage comprising TRAP rings held in place by gold or mercury (Abstract, Figure 1(a)). The metal ions interact with thiol groups during cage assembly (page 438, right column, top paragraph and page 439, right column, top line), so they are molecular cross-linkers. The cage is artificial because the cage is chemically synthesized (page 443, Methods, left column, Cage assembly, paragraph 1). Malay teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption) so the TRAP cage is reduction responsive (opens under reducing conditions). Malay’s molecular cross linker S-Au-S (Malay page, 444 right column, Structural refinement, bottom of paragraph) is homobifunctional (chemical cross-linker featuring two identical reactive groups at opposite ends of a spacer arm) because the Au acts as the spacer arm and the sulfur groups are both reactive (connected with the other amino acids in the TRAP cage).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to assemble the TRAP-cage of claims 43-52 and 54-63 of ‘242 by using the molecular cross-linker S-Au-S, per the teaching of Malay. The person of ordinary skill in the art would have been motivated to do so because claims 43-52 and 54-63 of ‘242 each require a TRAP-cage. Assembly of the TRAP-cage requires cross-linkers (see claim 54 of ‘242, step (ii)), so the person of ordinary skill in the art would have turned to Malay for the specific cross-linker. The person of ordinary skill in the art would have had a reasonable expectation of success in assembling the TRAP-cage of claims 43-52 and 54-63 of ‘242 with Malay’s cross-linkers.
Regarding claims 42 and 44, Malay teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption), so the TRAP cage is reduction responsive (opens under reducing conditions).
Regarding claim 43, the molecular cross linker S-Au-S (Malay page, 444 right column, Structural refinement, bottom of paragraph) is homobifunctional (chemical cross-linker featuring two identical reactive groups at opposite ends of a spacer arm) because the Au acts as the spacer arm and the sulfur groups are both reactive (connected with the other amino acids in the TRAP cage).
Instant claim 47 is obvious over claim 50 of ‘242 in view of Malay.
Instant claim 50 is obvious over claim 52 of ‘242 in view of Malay.
Regarding instant claim 51, Malay teaches that the TRAP cage is stable upon exposure to high temperatures, chaotropic agents, and a wide range of pH conditions that include non-neutral pH conditions (page 440, left column, paragraph 2 after figure caption and Fig. 3c).
Instant claim 63 is a product-by-process claim (product produced by the method of instant claim 61). As such, the method steps are only given weight insofar as they limit the structure of the claimed product. The method of claim 61 requires that the produced TRAP-cage is cross-linked by a reduction responsive molecular cross-linker. Thus, claim 63 is also obvious over claims 43-52 and 54-63 of ‘242 in view of Malay because Malay teaches that the cages are fully reversible and break apart in response to millimolar levels of reducing agents (page 440, right column, paragraph 1 after figure caption) so the TRAP cage is reduction responsive (opens under reducing conditions).
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657