DETAILED ACTION
Status of Application
Claims 1-13 and 16-17 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 of claim 9, and cancellation of claims 14-15 as submitted in a communication filed on 03/15/2026 is acknowledged.
Applicant’s election without traverse of Group I, claims 1-13 and 16, drawn to a process for detecting inhibitors of human tRNA modification enzyme as submitted in communication filed on 03/15/2026 is acknowledged.
Claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/15/2026.
Claims 1-13 and 16 are at issue and will be examined to the extent they encompass the elected invention.
Priority
Acknowledgment is made of a claim for foreign priority under 35 U.S.C. 119(a)-(d) to BE2021/5646 filed on 08/13/2021. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
This is the US national application which entered the national stage from PCT/EP2022/069969 filed on 08/13/2021.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show Figure 1B (paragraph 0098) as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). 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.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: Figure 2A (Paragraph 0106) and Figure 2B (Paragraph 0107). 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. 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
Claims 1-13 and 16 are objected due to the recitation of “HTS” and “TR-FRET”. Abbreviations unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation is used. Appropriate correction is required.
Claim 7 is objected due to the recitation of “EPL3”. Abbreviations unless otherwise obvious and/or commonly used in the art, should not be recited in the claims without at least once reciting the entire phrase for which the abbreviation is used. Appropriate correction is required.
Claim 11 is objected to because of the following informalities: There is a space needed “3’” and “end”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-13 and 16 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.
Claims 1-13 are indefinite due to the recitation of “A cell-free HTS assay” for the following reasons: An assay can be defined as a testing product like a biochemical kit or it can be defined as a procedure for measuring biochemical activity. As written, it is unclear if the term “assay” is a product (i.e. a biochemical kit) or a method (i.e. A procedure). For examination purposes, it will be assumed that claims 1-13 are methods. Correction is required.
Claim 6 is indefinite due to the recitation of “anticodon binding enzyme” for the following reasons: It is unclear because (a) it lacks objective boundaries and the term is not well-defined in the art, making it unclear which enzymes meets the limitation, (b) it is unclear if the recited term encompasses any type of enzyme that is able to bind to an RNA, and (c) it is unclear if the recited term encompass a protein with a particular enzymatic activity that alters an anticodon in some way. For examination purposes, this claim will be interpreted as a duplicate of claim 1. Correction is required.
Claim 13 recites the limitation " the fluorescence tagged protein". There is insufficient antecedent basis for this limitation in the claim. For examination purposes claim 13 will be interpreted as a duplicate of claim 1 as interpreted above. Appropriate correction is required.
Claim Rejections - 35 USC § 103 (AIA )
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.
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.
Claims 1, 6, 9, 10,12,13 16 are rejected under 35 U.S.C. 103 as being unpatentable over Mandecki (US 20150118678 A1 published 04/30/2015), in view of Trotta (US 20050053985 A1 published 03/10/2005).
Mandecki teaches a method for identifying test compounds with antimicrobial activity by mixing an elongation factor with GTP and an aminoacylated transfer RNA in the presence of said test compound (Page 1, paragraph 0006). Mandecki teaches that the elongation factor is operably linked to a first energy transfer pair member and the aminoacylated tRNA is operably linked to a second energy transfer pair member (Page 1, paragraph 0006). Mandecki teaches the first energy transfer pair member and the second energy transfer pair member form a fluorescence resonance energy transfer pair and the level of fluorescence in the presence of the test compound is compared to the level of fluorescence in the absence of the test compound or the level of fluorescence in the presence of a control compound (Page 1, paragraph 0006). Mandecki teaches that the difference in fluorescence indicates that the test compound possesses antimicrobial activity (Page 4, paragraph 0031). Mandecki teaches that the tRNA substrate is labeled with dye (Page 1, paragraph 0016). Mandecki does not teach the identification of inhibitors of human tRNA modification enzymes and does not teach a cell-free TR-FRET competition assay.
Trotta teaches a process for detecting inhibitors of purified human tRNA splicing endonuclease using FRET. Trotta teach a process for screening for competitors or enhancers of the binding of one member of a complex with another member of the complex labeled by any means (Page 62, paragraph 0496). Trotta teaches a method for identifying a compound that modulates human tRNA splicing endonuclease activity that requires contacting a complex of the invention with tRNA splicing endonuclease activity with a substrate of a tRNA splicing endonuclease (Page 8, Paragraph 0049), which refers to any nucleotide sequence recognized and excised by a human tRNA splicing endonuclease, including tRNA (Page 17-18, paragraph 0108). Trotta teaches the protein in FRET can be tagged with HIS (Page 20, Paragraph 0127) or GST (Page 41, paragraph 0304).
Claims 1, 6, 12, 10, 12, 13, 16 are directed in part to a cell-free HTS method for detecting inhibitors of human tRNA modification enzymes using a TR-FRET screening assay to (a) select the candidate inhibitors that reduce the TR-FRET signal wherein a cell-free TR-FRET screening assay is conducted by contacting in a screening reaction mixture containing: a tRNA fragment as a substrate, a purified human tRNA modification enzyme, and a candidate inhibitor compound and (b) using the TR-FRET assay to screen out false positives of the TR-FRET-based screening.
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 method of Trotta by using a tRNA attached to a donor fluorophore and a tRNA splicing endonuclease attached to an acceptor fluorophore, and screen out false positives. A person of ordinary skill in the art is motivated to practice the method of Trotta such that the donor and acceptor fluorophores are in different molecules because FRET can be used such that the donor and acceptor fluorophores are in different molecules as disclosed by Mandecki et al. One of ordinary skill in the art has a reasonable expectation of success at arriving to using a TR-FRET screening reaction mixture comprising a tRNA fragment, a human tRNA modification enzyme, and a candidate inhibitor compound, wherein the substrate is labeled with a donor fluorophore and wherein the human tRNA modification enzyme is labeled with a acceptor fluorophore because all that is required is adding a donor fluorophore to the tRNA substrate and an acceptor fluorophore to the enzyme in the method of Trotta and follow up with a TR-FRET competition assay to screen out false positives. 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 2 and 5, are rejected under 35 U.S.C. 103 as being unpatentable over Mandecki and Trotta, in view further view of Guenther (US 20080199870 A1 Published 08/21/2008)
The teachings of Mandecki et al. and Trotta et al. have been described above. Mandecki and Trotta do not teach the tRNA fragment being a fragment of the anticodon loop of the tRNA and the human tRNA modification enzyme interacting with the t-stem loop, the D-loop or the T-loop (Page 30, claims 12-14). Guenther teach methods of identifying an inhibitor of tRNA-target molecule interaction by forming a mixture comprising least one nucleic acid molecule derived from or corresponding to a tRNA loop having at least one modified nucleotide, where the tRNA loop is selected from the group consisting of a ΤψΟ-Ιοορ, a D-loop, and an anticodon loop.
Claims 2 and 5 are directed in part to the method of claim 1 wherein the tRNA fragment is a fragment of the anticodon loop of the tRNA and the human tRNA modification enzyme is an enzyme interacting with the t-stem loop, the D-loop or the T-loop.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use have the anticodon loop of the tRNA as the substrate and have the human tRNA modification enzyme interacting with the t-stem loop, the D-loop or the T-loop in a TR-FRET screening mixture for detecting inhibitors of human tRNA modification enzyme. A person of ordinary skill in the art is motivated to modify the methods in Mandecki et al. and and Trotta et. al to have the anticodon loop of the tRNA as the substrate and have the human tRNA modification enzyme interacting with the t-stem loop, the D-loop or the T-loop as suggested by Guenther. One of ordinary skill in the art has a reasonable expectation of success at arriving to using a TR-FRET screening reaction mixture comprising a tRNA fragment, a human tRNA modification enzyme, a candidate inhibitor compound, wherein the anticodon loop of the tRNA is the substrate and the human tRNA modification enzyme interact with the t-stem loop, the D-loop or the T-loop because all that is required adding a fluorophore to the anticodon loop and adding a human tRNA modification enzyme that interacts with the t-stem loop, the D-loop or the T-loop . 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 3, 4, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Mandecki and Torotta, in view further view of Shen et al. (Journal of Molecular Medicine 96:1167–1176 Published 2018)
The teachings of Mandecki and Trotta have been described above. Torotta teaches labeling the substrate with biotin (Page 48, Paragraph 0360). Mandecki and Torotta do not teach the length of tRNA fragments.
Shen teaches that the length of tRNA fragments is between 14-30 bases (Page 1, Abstract).
Claims 3,4, and 11 are directed in part to the method of claim 1 wherein the tRNA fragment comprises between 15 and 21 bases.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the methods taught by Mandecki and Torotta and use tRNA fragments between 15 and 21 bases as the substrate. A person of ordinary skill in the art is motivated to modify the methods in Mandecki et al. and Torotta add biotinylated tRNA fragments between 15 and 21 bases, as taught by Shen, to the screening mixture. One of ordinary skill in the art has a reasonable expectation of success at arriving to using TR-FRET a screening reaction mixture comprising a tRNA fragment between 15 and 21 bases because all that is required is utilizing tRNA fragments with the standard length and biotinylating the fragment. 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.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Mandecki and Torotta, in view further view of Delaunay (Journal of Experimental Medicine 213.11 (2016): 2503-2523)
The teachings of Mandecki and Trotta have been described above. Torotta teaches methods for treating or managing a proliferative disorder, like metastatic breast cancer, by administering a compound identified in the FRET assay (Page 76-77 , paragraph 635-636). Mandecki and Torotta do not teach about ELP3.
Delaunay teaches that ELP3 tRNA modification is up-regulated in human breast cancers and sustain metastasis (Page 1, abstract). Delaunay teaches that Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer (Page 1, abstract).
Claim 7 is directed in part to the method of claim 1 wherein the human tRNA modification enzyme is ELP3.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the methods taught by Mandecki and Torotta and screen for inhibitors for tRNA modification enzyme, ELP3. A person of ordinary skill in the art is motivated to modify the methods in Mandecki et al. and Torotta to screen for ELP3 inhibitors to determine potential therapeutics for breast cancer as suggested by Shen. One of ordinary skill in the art has a reasonable expectation of success at arriving to using TR-FRET to identify inhibitors of ELP3 because all that is required is adding ELP3 to the screening mixture. 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.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Mandecki and Torotta, in view further view of Caron (PLoS one 7(8):e44159, page 1-7, 2012)
The teachings of Mandecki and Trotta have been described above. Mandecki and Torotta do not teach a method of FRET wherein the human tRNA modification enzyme is a non active recombinant form of the enzyme.
Caron teaches a method performing FRET on active and inactive enzymes (Page 5, figure 2).
Claim 8 is directed in part to the method of claim 1 wherein the human tRNA modification enzyme is a non active recombinant form of the enzyme.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the methods taught by Mandecki and Torotta and include a non active recombinant form of the enzyme. A person of ordinary skill in the art is motivated to modify the methods in Mandecki et al. and Torotta and (a) perform FRET on non active recombinant forms of the human tRNA modification enzyme in a screening mixture to detect inhibitors of non active human tRNA modification enzymes, and to (b) further characterize the inhibitor and determine if an inhibitor of an enzymatically active form can also bind to the non-active form, because the non-active form may have a different 3D conformation and the inhibitor can be specific for the active form and not to the non-active form. One of ordinary skill in the art has a reasonable expectation of success at arriving to using TR-FRET to identify inhibitors of non active recombinant forms of the human tRNA modification enzyme because all that is required is adding a non active recombinant forms of the human tRNA modification enzyme to the screening mixture. 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.
Conclusion
No claim is in condition for allowance
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/SYNPHANE L SHELTON/Examiner, Art Unit 1652
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
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