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 1-63 are cancelled. Newly added claims 64-78 are pending.
Election/Restrictions
Newly submitted claims 75-77 are directed to an invention that lacks unity with the invention originally claimed for the following reasons:
Claim 75 is drawn to a method of treating a patient and claims 76-77 are drawn to a method of preparing an artificial TRAP-cage, which belong in Groups II and III, respectively, of the Requirement for Restriction mailed 11/6/2025. Applicant elected Group I, drawn to an artificial TRAP cage.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 75-77 are withdrawn from consideration as being directed to a nonelected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Response to Arguments
Applicant's arguments filed 7/21/2026 have been fully considered but they are not persuasive.
Applicant argues against the written description rejection of claims 64-74 and 78 under 35 U.S.C. 112(a) on the grounds that, based on Applicant’s working examples, a person of ordinary skill in the art would have been able to extrapolate the results to other similar molecules. Applicant argues that a skilled person would not need undue experimentation to prepare and use any derivative because the genus is not large: reactive groups (e.g. -CH2X, where X = Br, Cl, I) are structurally defined and the benzene ring substitution pattern would not fundamentally alter the crosslinking mechanism (Arguments, paragraph 1 on page 4).
In response, this argument is unpersuasive because Applicant has not given “derivative” its broadest reasonable interpretation in light of the specification. There is no special definition provided within the specification for derivative, thus derivative is given its plain and ordinary meaning as something that is based on, comes from, or takes its meaning from another source. Thus, a derivative of bis-halomethyl benzene includes bis-halomethyl benzene chemically converted into other compounds by an unlimited number of chemical reactions. The person of ordinary skill in the art would have been unable to reasonably predict and visualize species of the claimed genus.
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.
(New Rejection Necessitated by Amendment) Claims 64-74 and 78 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 64 recites an amino acid position 35 without a reference sequence, thus the claim is indefinite.
Claim 64 is further indefinite for because the claim does not present a closed group of alternatives: the claim recites selected from the group consisting of i), ii) or iii) rather than i, ii), and iii). Furthermore, it is unclear why the claim recites a subgroup i) bismaleimidohexane (BMH), bisbromobimane or a bis-bromoxylene.
Claim 78 depends from withdrawn claim 76, which recites the same problematic limitations as claim 64. Thus, claim 78 is also indefinite.
Claim 65 is likewise indefinite for reciting “selected from the group consisting of o-BBN, m-BBN, or BDNB” rather than “selected from the group consisting of o-BBN, m-BBN, and BDNB.”
Claim 72 recites the TRAP-cage according to claim 64, that encapsulates a cargo. It is unclear whether the TRAP-cage further comprises a cargo (i.e. the claim is drawn to a composition of matter comprising both the TRAP-cage and the cargo) or whether the claim is drawn to a TRAP-cage capable of encapsulating a cargo.
Claim 73 recites an amino acid position 64 without a reference sequence, thus the claim is indefinite.
Claims 65-74 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.
(New Rejection Necessitated by the Amendment) Claims 64, 68-74 and 78 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 64 is drawn to an artificial TRAP-cage comprising TRAP rings which are held in place by cross-linkers, wherein the cross-linkers are selected from the group consisting of BHM, bisbromobimane, bis-bromoxylene, DTME and a derivative of bis-halomethyl benzene, wherein the artificial TRAP-cage protein comprises a cysteine at amino acid position 35.
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 comprising TRAP-rings held in place by a derivative of bis-halomethyl benzene.
The specification discloses that TRAP is the trp RNA-binding attenuation protein from 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 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 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 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 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 orientation of the TRAP rings (lines 28-29 on page 38).
The specification does not disclose any TRAP-cages wherein the TRAP rings are held in place by derivatives of bis-halomethyl benzene. There is no guidance provided within the specification for derivatization of bis-halomethyl benzene 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.
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). 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 cross-linker and both contain metal atoms.
To summarize, although the specification discloses several species of artificial TRAP-cages with cross-linkers, they are not a representative number of species of the claimed genus of artificial TRAP-cages comprising TRAP rings held in place by derivatives of bis-halomethyl benzene. Although there appears to be some predictability with the cross-linkers that contain metal atoms, there is a lack of predictability with respect to other types of cross-linkers. Although some 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 derivatives of bis-halomethyl benzene would have resulted in a TRAP-cage structure, either by spontaneous assembly or templating.
Claim 68 recites the cross-linker is a derivative of bis-halomethyl benzene and the TRAp-cage is photocleavable. Claim 69 requires the cross-linker is photocleavable by exposure to UV light. Claim 74 requires that the artificial TRAP-cage is stable in elevated temperatures, stable in a non-neutral pH, and/or stable in chaotropic agents. However, Applicant has also not disclosed a representative number of species of the claimed genus. Although the person of ordinary skill in the art might have been able to visualize species of derivatives of bis-halomethyl benzene with these characteristics, the person of ordinary skill in the art would not have been able to determine which of these derivatives of bis-halomethyl benzene are capable of assembling TRAP-cages given the unpredictability in the art with respect to TRAP-cage assembly from cross-linkers.
Claim 72 recites the TRAP-cage encapsulates a cargo. Thus, claim 72 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, at the time the application was filed, that the inventors had possession of the claimed genus of artificial TRAP-cages comprising TRAP-rings held in place by a derivative of bis-halomethyl benzene.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CANDICE LEE SWIFT whose telephone number is (571)272-0177. The examiner can normally be reached M-F 8:00 AM-4:30 PM (Eastern).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise Humphrey can be reached at (571)272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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