DETAILED ACTION
Response to Amendment
Applicant’s response to the office action filed on January 20, 2026 has been entered. The claims pending in this application are claims 1, 3-6, and 8-19 wherein claims 8, 9, and 13-19 have been withdrawn in the restriction requirement mailed on May 22, 2025. The objections and rejections not reiterated from the previous office action is hereby withdrawn in view of applicant’s amendment filed on January 20, 2026. Claims 1, 3-6, and 10-12 will be examined.
Claim Objections
Claim 1 is objected to because of the following informalities: (1) “detecting and/or quantitating” in the preamble should be “detecting” since there is no quantitating step in the content of the claim; (2) “part of said double-stranded terminal stem-loop structure” should be “a part of said double-stranded terminal stem-loop structure”; and (3) “any kind of solid support” in last line should be “a solid support”.
Claim 10 is objected to because of the following informalities: (1) “a lanthanide ion carrier ligand and a lanthanide ion” in item (a) should be “a lanthanide ion carrier ligand carrying a lanthanide ion”; and (2) “before hybridisation of said single-stranded terminal sequence of said first oligonucleotide probe to said first region of the single-stranded nucleic acid analyte, and hybridization of said single-stranded terminal sequence of said second oligonucleotide probe to said second region of the single-stranded nucleic acid analyte” should be “before the hybridization of said single-stranded terminal sequence of said first oligonucleotide probe to said first region of the single-stranded nucleic acid analyte, and the hybridization of said single-stranded terminal sequence of said second oligonucleotide probe to said second region of the single-stranded nucleic acid analyte”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Scope of Enablement
This rejection is different from the rejection under 35 U.S.C. 112(a) mailed on September 26, 2025.
Claims 10 and 11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for detecting a single-stranded nucleic acid analyte recited in claims 10 and 11 when 5’ or 3’ end of a single-stranded terminal sequence of the first oligonucleotide probe recited in claim 1 is labeled with a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand and 3’ or 5’ end of a single-stranded terminal sequence of the second oligonucleotide probe recited in claim 1 is labeled with an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion, does not reasonably provide enablement for detecting a single-stranded nucleic acid analyte using the methods recited in claims 10 and 11 when a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand is labeled on any kind of location of the first oligonucleotide probe recited in claim 1 and an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion is labeled on any location of the second oligonucleotide probe recited in claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court considered the issue of enablement in molecular biology. The Court summarized eight factors to
be considered in a determination of “undue experimentation”. These factors include: (a) the quantity of experimentation necessary; (b) the amount of direction or guidance presented; (c) the presence or absence of working examples; (d) the nature of the invention; (e) the state of the prior art; (f) the relative skill of those in the art; (g) the predictability of the art; and (h) the breadth of the claims. The Court also stated that although the level of skill in molecular biology is high, results of experiments in molecular biology are unpredictable.
To begin, there is no direction or guidance to show that a single-stranded nucleic acid analyte can be detected using the methods recited in claims 10 and 11 when a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand is labeled on any kind of location of the first oligonucleotide probe recited in claim 1 and an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion is labeled on any location of the second oligonucleotide probe recited in claim 1. While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether a single-stranded nucleic acid analyte can be detected using the methods recited in claims 10 and 11 when a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand is labeled on any kind of location of the first oligonucleotide probe recited in claim 1 and an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion is labeled on any location of the second oligonucleotide probe recited in claim 1.
Since the specification teaches that “[T]he terms ‘lanthanide ion carrier chelate’, ‘ion carrier chelate’ and ‘carrier chelate’ shall be understood to include as such essentially non-luminescent lanthanide chelate complexes and their derivatives, which comprise a chelating ligand, i.e. ion carrier ligand, and a luminescent lanthanide ion, but which do not comprise an efficient light-harvesting antenna chromophore that is essential to efficiently excite the luminescence of the lanthanide ion in the carrier chelate. Examples of lanthanide ion
carrier are cyclic or non-cyclic aminopolycarboxylic acid chelates of europium(III) or other luminescent lanthanide ions, where coordination number of the lanthanide ion is preferably equal to or more than 6 dentates, optimally 7 or 8, but which do not contain efficient light-harvesting antenna structure to sensitize and excite the luminescence of the lanthanide ion [PCT Int. Appl. WO 2010/109065]. Additional structures of ion carrier chelates for labelling of an oligonucleotide are illustrated e.g. in US Pat. No. 6,949,639”, “[T]he terms ‘complementing ligand’, ‘light harvesting antenna’ or ‘antenna ligand’ shall be understood to include as such essentially non-luminescent chelating ligands and their derivatives, which comprise a light-harvesting chromophore or other excitable structure and which are capable of complementing a lanthanide ion carrier chelate to form a luminescent lanthanide complex, where the luminescence of the lanthanide ion in the carrier chelate is excited through non-radiative energy transfer from a light-harvesting chromophore or other excitable structure in the antenna ligand upon either its photoexcitation or electroexcitation. Typically the antenna ligand is a monodentate, bidentate, tridentate or tetradentate ligand, most preferably bidentate or tridentate ligand, the organic light harvesting structure contains aromatic rings or heterocycles, and the light-harvesting structures has a triplet state energy level appropriate for the trivalent lanthanide ion present in the ion carrier chelate. Examples of suitable triplet state energies and light-harvesting structures for lanthanide ions are presented in PCT Int. Appl. WO 2010/109065 and J. Luminescence (1997) 75: 149-169”, “[I]n typical embodiments of the invention the ion carrier chelate is pentadentate, hexadentate, heptadentate or octadentate, preferably hexadentate, heptadentate or octadentate. e.g. the lanthanide ion carrier ligand is derived from linear or cyclic chelators, such as EDTA and DTPA or NOTA and DOTA, respectively. Examples of preferred ion carrier ligands such as (2,2’,2’’-(10-(3-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid and N1-(4-isothiocyanatobenzyl)diethylenetriamine-N1,N2,N3,N3-tetraacetate) are described in PCT Int. Appl. WO 2010/109065, and “[F]IG. 5 illustrates an example of a luminescence binary probe hybridization assay system, comprising two chelate-complementation oligonucleotide probes, wherein a first oligonucleotide probe (21), labeled with a lanthanide ion carrier chelate (19) via a linker (20), comprises a double-stranded 5’ terminal stem-loop sequence and a single-stranded 3’ overhang, that is complementary to the 3’ terminal region of the nucleic acid analyte (28); and wherein a second oligonucleotide probe (27), labeled with a light-harvesting antenna (24) via a linker (23), comprises a linear single-stranded oligonucleotide complementary to the nucleic acid analyte (25) non-overlapping with the 3’ terminal region, that is complementary to the first oligonucleotide probe. The regions of the nucleic acid analyte that are complementary to the probe sequences are located adjacently in the sequence of the nucleic acid analyte. Upon excitation at lambda-1 the lanthanide ion carrier chelate (21) and the light-harvesting antenna (24) are practically non-luminescent when the probes are not bound to the same nucleic acid analyte molecule. (B) Both first (21) and second (27) oligonucleotide probe hybridize to their complementary regions of the nucleic acid analyte molecule (28). The adjacent hybridization of the probes results in directed self-assembly and formation of the fluorescent chelate complex (26), which produces luminescence emission at lambda-2 wavelength upon excitation at lambda-1 wavelength” (see paragraphs [0090], [0091], [0132]), and [0150], and Figure 5 of US 2023/0212652 A1), the specification clearly indicates that in a switchable lanthanide luminescence label system, 5’ or 3’ end of a single-stranded terminal sequence of a first oligonucleotide probe is labeled with a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand and 3’ or 5’ end of a single-stranded terminal sequence of a second oligonucleotide probe is labeled with an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion, both the first oligonucleotide probe and the second oligonucleotide probe are non-luminescent before they bind to an identical single-stranded target nucleic acid, after the first oligonucleotide probe and the second oligonucleotide probe hybridize to the identical single-stranded target nucleic acid, the lanthanide ion carrier ligand carrying the lanthanide ion or the antenna ligand of the first oligonucleotide probe and the antenna ligand or the lanthanide ion carrier ligand carrying the lanthanide ion of the second oligonucleotide bind to each other and form a highly luminescent mixed chelate complex. Since claim 10 does not require that, in a switchable lanthanide luminescence label system, 5’ or 3’ end of a single-stranded terminal sequence of the first oligonucleotide probe recited in claim 1 is labeled with a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand and 3’ or 5’ end of a single-stranded terminal sequence of the second oligonucleotide probe recited in claim 1 is labeled with an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion, if a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand is labeled on any kind of location of the first oligonucleotide probe recited in claim 1 such as a middle region of the first oligonucleotide probe and an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion is labeled on any location of the second oligonucleotide probe recited in claim 1 such as a middle region of the second oligonucleotide probe, after the first oligonucleotide and the second oligonucleotide probe hybridize to an identical single-stranded nucleic acid analyte, the lanthanide ion carrier ligand carrying the lanthanide ion or the antenna ligand of the first oligonucleotide probe and the antenna ligand or the lanthanide ion carrier ligand carrying the lanthanide ion of the second oligonucleotide cannot bind to each other to form a highly luminescent mixed chelate complex such that it is unpredictable how a single-stranded nucleic acid analyte can be detected when a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand is labeled on any kind of location of the first oligonucleotide probe recited in claim 1 and an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion is labeled on any location of the second oligonucleotide probe recited in claim 1.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art”. The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement”.
In view of above discussions, the skilled artisan will have no way to predict the experimental results. Accordingly, it is concluded that undue experimentation is required to make the invention as it is claimed. These undue experimentation at least includes to test whether a nucleic acid analyte can be detected using the methods recited in claims 10 and 11 when a lanthanide ion carrier ligand carrying a lanthanide ion or an antenna ligand is labeled on any kind of location of the first oligonucleotide probe recited in claim 1 and an antenna ligand or a lanthanide ion carrier ligand carrying a lanthanide ion is labeled on any location of the second oligonucleotide probe recited in claim 1.
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.
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 1, 3-6 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al., (Talanta, 85, 1760-1765, 2011) in view of Ueno et al., (US 2018/0080076 A1, published on March 22, 2018).
Regarding claims 1, 3-6 and 12, Yu et al., teach a bioassay method for detecting a single-stranded nucleic acid analyte employing a binary probe system, comprising: (I) contacting two oligonucleotide probes (ie., Probe 1 and Probe 2 in Figure 2) with a sample suspected of containing the single-stranded nucleic acid analyte (ie., the synthetic miRNA or the isolated total RNA), wherein (a) a first oligonucleotide probe comprises a double-stranded terminal stem-loop structure and a single-stranded terminal sequence overhang that is complementary to and is capable of selectively hybridizing with a first region of the single-stranded nucleic acid analyte (ie., the synthetic miRNA or the isolated total RNA), and b) a second oligonucleotide probe comprises a double-stranded terminal stem-loop structure and a single-stranded terminal sequence that is complementary to and is capable of selectively hybridizing with a second region of the single-stranded nucleic acid analyte (ie., the synthetic miRNA or the isolated total RNA),
wherein said first region of the single-stranded nucleic acid analyte is a first terminal region and said single-stranded terminal sequence overhang of said first oligonucleotide probe hybridizes to said first region of the single-stranded nucleic acid analyte, said hybridization results in formation of a first nick structure (ie., a first nick in a complex formed by Probe 1, a MicroRNA target, and Probe 2 before the ligation step wherein the first nick is in the complex formed by Probe 1, a MicroRNA target, and Probe 2 after the ligation step, see Figure 2) between a terminus of said single-stranded nucleic acid analyte and a first terminus of said first oligonucleotide probe, and said first terminus of said first oligonucleotide probe is a part of said double-stranded terminal stem-loop structure of said first oligonucleotide probe, and wherein said first region and said second region of the single-stranded nucleic acid analyte are adjacent regions of said single-stranded nucleic acid analyte, and said single-stranded terminal sequences of said first oligonucleotide probe and said second oligonucleotide probe hybridize to said single-stranded nucleic acid analyte forming a second nick structure (ie., a second nick in a complex formed by Probe 1, a MicroRNA target, and Probe 2 before the ligation step wherein the second nick cannot be seen in a complex formed by Probe 1, a MicroRNA target, and Probe 2 after the ligation step) between a second terminus of said first oligonucleotide probe and a first terminus of said second oligonucleotide probe; and (ii) detecting the presence or absence of said single-stranded nucleic acid analyte bound to said first oligonucleotide probe and said second oligonucleotide probe, wherein the presence of said single-stranded nucleic acid analyte bound to said first oligonucleotide probe and said second oligonucleotide probe (ie., by a real-time PCR assay) confirms the presence of the single-stranded nucleic acid analyte in the sample, wherein said second region of the single-stranded nucleic acid analyte is a second terminal region and said single-stranded terminal sequence of the second oligonucleotide probe hybridizes to said second region of said single-stranded nucleic acid analyte, and said hybridization results in formation of a third nick structure (ie., a third nick in a complex formed by Probe 1, a MicroRNA target, and Probe 2 before the ligation step wherein the third nick is in a complex formed by Probe 1, a MicroRNA target, and Probe 2 after the ligation step, see Figure 2) between a terminus of said single-stranded nucleic acid analyte and a second terminus of said second oligonucleotide probe comprising said double-stranded terminal stem-loop structure, and said second terminus of said second oligonucleotide probe is a part of said double-stranded terminal stem-loop structure of said second oligonucleotide probe, and wherein said second oligonucleotide probe is labelled (ie., by phosphorylation) as recited in claim 1 wherein
said first terminus is a 5’ end and said second terminus is a 3’ end as recited in claim 3, said single-stranded nucleic acid analyte is a length of 10-50 nucleotides (ie., mir-122 or mir-21 which has 22 nucleotides) as recited in claim 4, said single-stranded nucleic acid analyte is a microRNA (miRNA) with length of 17-25 nucleotides (ie., mir-122 or mir-21 which has 22 nucleotides) as recited in claim 5, said first oligonucleotide probe and said second oligonucleotide probe comprise deoxyribonucleic acid (DNA) or ribonucleic acids (RNA) or any combination of them as recited in claim 6, and a ligase enzyme is used to form a covalent bond in a place of any one or any combination of said first nick structure, said second nick structure, and said third nick structure formed upon occurrence of any of said hybridization events between said first oligonucleotide probe, said second oligonucleotide probe and the single-stranded nucleic acid analyte as recited in claim 12 (see pages 1761 and 1762, and Figure 2).
Yu et al., do not disclose that said first oligonucleotide probe is labelled as recited in claim 1.
Ueno et al., teach a method for detecting a target nucleic acid, comprising: (a) contacting a nucleic acid sample comprising a target nucleic acid, comprising a first portion and a second portion, with: (i) a detection probe, wherein the detection probe is labeled with a labeling substance and comprises a nucleic acid sequence that forms a stem-loop structure and having a 5’ protruding end or a 3’ protruding end that is capable of hybridizing to the second portion, and (ii) a capture probe comprising a nucleic acid sequence capable of hybridizing to the first portion, wherein the capture probe is immobilized to a substrate, under conditions to form a target nucleic acid-detection probe-capture probe complex by hybridizing the second portion to the detection probe and hybridizing the first portion to the capture probe; (b) ligating a first end of the detection probe with an end of the target nucleic acid and ligating a second end of the detection probe with an end of the capture probe; and (c) detecting the labeling substance of the nucleic acid-detection probe-capture probe complex formed on the substrate (see abstract and Figure 1).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have performed the method recited in claim 1 wherein said first oligonucleotide probe is labelled in view of the prior arts of Yu et al., and Ueno et al.. One having ordinary skill in the art would have been motivated to do so because Ueno et al., teach a method for detecting a target nucleic acid, comprising: (a) contacting a nucleic acid sample comprising a target nucleic acid, comprising a first portion and a second portion, with: (i) a detection probe, wherein the detection probe is labeled with a labeling substance and comprises a nucleic acid sequence that forms a stem-loop structure and having a 5’ protruding end or a 3’ protruding end that is capable of hybridizing to the second portion, and (ii) a capture probe comprising a nucleic acid sequence capable of hybridizing to the first portion, wherein the capture probe is immobilized to a substrate, under conditions to form a target nucleic acid-detection probe-capture probe complex by hybridizing the second portion to the detection probe and hybridizing the first portion to the capture probe; (b) ligating a first end of the detection probe with an end of the target nucleic acid and ligating a second end of the detection probe with an end of the capture probe; and (c) detecting the labeling substance of the nucleic acid-detection probe-capture probe complex formed on the substrate (see abstract and Figure 1). One having ordinary skill in the art at the time the invention was made would have a reasonable expectation of success to label the first oligonucleotide probe (ie., Probe 1 in Figure 2) taught by Yu et al., with a labeling substance and perform the method recited in claim 1 using the labeled first oligonucleotide probe in view of the prior arts of Yu et al., and Ueno et al., in order to detect the ligation complex formed by probe 1, probe 2, and the synthetic miRNA taught by Yu et al., based on detecting the labeling substance on probe 1 of the ligation complex.
Response to Arguments
Applicant’s arguments with respect to claims 1-7 and 10-12 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Frank Lu, Ph. D., whose telephone number is (571)272-0746. The examiner can normally be reached Monday to Friday, 9 AM to 5 PM.
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/FRANK W LU/
Primary Examiner, Art Unit 1683
March 30, 2026
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