DETAILED ACTION
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 .
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) of Chinese patent application No. 202210592343.6, filed on May 27, 2022 and Japanese patent application No. 2023-087169, filed on May 26, 2023.
All content in this instant application is supported in the Chinese patent application No. 202210592343.6, filed on May 27, 2022, thus the effective filing date of examined instant claims 1-5 have an effective filing date of May 17, 2022.
Election/Restrictions
Applicant's election, with traverse, of the invention of Group I, claims 1-5, drawn to a method for preparing an electrochemiluminescent (ECL) probe, in the reply filed on 03/26/2026 is acknowledged.
Group II, claims 7-18, drawn to a method for detecting a modified nucleic acid using an electrochemiluminescent (ECL) nanoprobe, and Group III, claims 6 and 19-21, drawn to an ECL nanoprobe and kit, are withdrawn, by Applicant, with traverse, from further consideration as being drawn to a nonelected invention, in the reply filed 03/26/2026 is acknowledged.
The traversal is on the ground(s) that the Office simply states a conclusion of distinctness between Group I and Group II without adequately demonstrating mutual exclusivity or substantially distinct design, mode of operation, function, or effect.
This is not persuasive. The distinctness test for related processes that are independent or distinct, has the following requirements (See MPEP § 806.05(j)):
(1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect
(2) the inventions do not overlap in scope, i.e., are mutually exclusive; and
(3) the inventions as claimed are not obvious variants.
Under requirement 1 above, the inventions of Group I (claims 1-5) and Group II (claims 7-18) have materially different designs since the method of Group I (claims 1-5) comprises doping a metal complex ion to an inorganic oxide nanoparticle and modifying the metal-doped inorganic oxide nanoparticle with capture secondary antibody. However, these method steps are absent in the method steps claimed in Group II (claims 7-18), and instead the method claimed in Group II comprises mixing, capturing, labeling and immobilizing a target analyte (modified nucleic acid site) on an electrode surface followed by detecting and quantifying the modification. Further, Group I and Group II have distinctly different effects since the effect of Group I is the production of an ECL nanoprobe but the effect of Group II is the detection of a target analyte.
Under requirement 2 above, because the inventions of Group I and Group II have different results, specifically the invention of Group I results in the production of an ECL nanoprobe but the result of Group II is the detection of a target analyte (modification site on nucleic acid), the scope of the two inventions do not overlap. Further demonstrating the inventions of Group I and Group II do not overlap in scope is how the claims for the method steps for Group I (eg., adding metal complex, biding secondary antibody) do not read on the method steps for Group II (eg., mixing sample with capture molecule, capturing and labeling target modified site, and performing the detection).
Under requirement 3 above, there is no indication on the record that inventions recited in Group I and Group II are obvious over each other under the requirements of 35 U.S.C. 103.
Further, the traversal is also on the ground(s) that the Office has failed to provide evidence to support the assertion that the claimed product, recited in Group III, can be made by the alternative process (i.e. reverse microemulsion method) provided as an example by the Examiner, which is distinct from the method recited in Group I.
This is not persuasive because “[t]he burden is on the examiner to provide an example to support the determination that the inventions are distinct, but the example need not be documented. If applicant either proves or provides convincing evidence that the example suggested by the examiner is not workable” then the burden shifts back the Examiner “to suggest another viable example or withdraw the restriction requirement.” See MPEP § 806.05(j). However, in the traversal on these grounds that the restriction between Group II and Group III was improper, the Applicant failed to provide convincing evidence that the example suggested by the examiner is not workable. Thus, demonstration of distinctness between Group I and Group III remains proper.
Further, the traversal is also on the ground(s) that since the Office provided no comment regarding the relationship between Group II and Group III then the Office has failed to meet the burden for the restriction requirement of these groups.
This is not persuasive because the inventions claimed in Group II ( and Group III ( are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown (See MPEP § 806.05(h)):
(1) the process for using the product as claimed can be practiced with another materially different product or
(2) the product as claimed can be used in a materially different process of using that product.
In the instant case, the process of using the product as claimed in Group II (eg., mixing sample with capture molecule, capturing and labeling target modified site, and performing the detection) can be practiced using the same primary capture antibody specific for the modified nucleic acid site but with a fluorescently labeled secondary antibody (detection) probe that has specificity for the primary capture antibody, which is a materially different product from the ECL nanoprobe and kit (product) recited in Group III.
For the reasons discussed herein above, the requirement is still deemed proper and is
therefore made FINAL.
Claim Status
Claims 1-21 are pending. Claims 6-21 are withdrawn. Claims 1-5 are examined herein below.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 1-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Santra et al., (Santra et al., Conjugation of Biomolecules with Luminophore-Doped Silica Nanoparticles for Photostable Biomarkers, 2001, Analytical Chemistry, 73, 20, 4988-4993), in view of Zluvova et al., (Zluvova et al., Immunohistochemical study of DNA methylation dynamics during plant development, 2001, Journal of Experimental Botany, 52, 365, 2265-2273), and as evidenced by Sakamoto et al, (Sakamoto et al., Enzyme‑linked immunosorbent assay for the quantitative/qualitative analysis of plant secondary metabolites, 2018, Journal of Natural Medicines, 72, 32–42).
Throughout the article, Santra teaches a conjugation method for labeling biomolecules with optically stable metal organic luminophores, such as tris(2,2¢-bipyridyl)dichlororuthenium(II) hexahydrate [Ru(bpy)3]2+], which can be applied to other biomolecules. Santra teaches the conjugation method comprises uniform luminophore [Ru(bpy)3]2+]-doped silica (LDS) nanoparticles, which have been prepared using a water-in-oil (W/O) microemulsion method. Santra teaches the luminophores [Ru(bpy)3]2+] are doped inside the silica nanoparticles, and the silica surfaces can be used to covalently bind biomolecules. Santra teaches an example of this with an antibody for leukemia cell recognition that is immobilized onto the luminophore[Ru(bpy)3]2+] -doped nanoparticle for leukemia cell identification. Santra teaches the leukemia cells were identified easily, clearly, and with high efficiency using these antibody-coated luminophore[Ru(bpy)3]2+] -doped silica nanoparticles. Santra also teaches advantages of using small, uniform luminophore-doped nanoparticles include easy preparation, good photostability, high sensitivity, hydrophilicity (prevents agglomeration), and resistance to aqueous (high pH) and nonaqueous solvents.
Regarding claims 1, Santra teaches a method for preparing an electrochemiluminescent nanoprobe, the method comprising: adding a metal complex ion to an inorganic oxide nanoparticle to provide a metal-doped inorganic oxide nanoparticle; and binding a secondary antibody to the metal-doped inorganic oxide nanoparticle to provide a metal-doped inorganic oxide nanoparticle modified with the secondary antibody (Santra et al., 2001, Analytical Chemistry, 73, 20, pgs. 4988-4989, Abstract and all paras; and pg. 4989, Fig. 1). Santra does not teach the secondary antibody binds an antibody against nucleic acid-specific site modification.
Throughout the review article, Zluvova teaches performing an immunohistochemical technique using an indirect detection method to study global changes in DNA methylation, specifically 5-methylcytosine (5-mC), of seed germination and shoot apical meristem development in Silene latifolia. Zluvova teaches an immunohistochemical assay for detection of 5-mC modifications comprises an anti-5-mC as the primary antibody (Ab) against the 5-mC modification in DNA and the secondary antibody FTC-labeled anti-mouse antibody that identifies the anti-5-mC Ab (pg. 2269, footnote for Fig. 2).
Zluvova teaches the limitation(s) of claim 1 reciting wherein the secondary antibody (goat anti-mouse) is configured to identify a specific antibody (anti-5mC) against nucleic acid-specific site modification (5mC = 5 methylcytidine site on DNA) [Zluvova et al., 2001, Journal of Experimental Botany, 52, 365, pg. 2266, last para -pg. 2267, first cont sentence; and pg. 2269, caption/footnote for Fig. 2].
It would have been prima facie obvious, at the time of filing, to combine the teachings of Santra and Zluvova to substitute the secondary antibody coated on the metal-doped ECL nanoprobe in the method taught by Santra with the anti-species secondary antibody with affinity for a same-species primary antibody against a specific site modification on a nucleic acid, as taught by Zluvova. The prior art teaches that an anti-species secondary antibody can be a universal secondary antibody against any primary antibody raised in the same species [i.e. original animal species of primary and secondary are unified] (see Sakamoto et al., 2018, Journal of Natural Medicines, 72, pg. 36, full para 1). Thus, a skilled artisan would have been motivated to combine these teaches in order to substitute the secondary antibody taught by Santra with the universal secondary antibody taught by Zluvova because it would make the detection system more versatile since a commercially available universal secondary antibody can be used with different indirect detection assays for different target analytes. At the time of filing, the method of preparing a metal complex-doped inorganic oxide ECL nanoprobe modified with a secondary antibody was successfully taught by Santra and a readily available and universal anti-species secondary antibody specific for a primary against a specific modification site on a nucleic acid was taught by Zluvova. Thus, at the time of filing, a person having ordinary skill in the art would have a reasonable expectation of success because combining these known teachings to substitute the secondary antibody to yield a readily available and more versatile detection system amounts to a simple substitution of known components, with known functions in the art, to yield expected and predictable results.
Regarding claim 2, Santra teaches the preparation method according to claim 1, wherein the inorganic oxide nanoparticle is a silicon dioxide nanoparticle, a titanium dioxide nanoparticle, a zinc oxide nanoparticle or an iron oxide nanoparticle, or a nanoparticle coated with silicon dioxide, titanium dioxide, zinc oxide or iron oxide (Santra et al., 2001, Analytical Chemistry, 73, 20, pgs. 4988-4989, Abstract and all paras; and pg. 4989, Fig. 1).
Regarding claim 3 Santra teaches the limitation(s) of claim 3 reciting the preparation method according to claim 1, wherein the inorganic oxide nanoparticle is a silicon dioxide nanoparticle (pgs. 4988-4989, Abstract and all paras; and pg. 4989, Fig. 1, note: silica nanoparticle is another name for silicon dioxide nanoparticle).
Regarding claim 4, the Specification of this instant application defines the generic portion of the specific (primary) antibody to be a region that “not for the specific portion of binding to the primary antibody and the nucleic acid-specific site modification… The generic portion is also referred to as a stationary region (instant Spec, pg. 12, last para and pg. 13 cont. sentence),” which the Examiner interprets to define the generic portion as the structural region of the primary antibody that does not include the antigen binding site, paratope, for the target nucleic acid modification site and that is a constant (stationary) region. Further, the prior art teaches that an anti-species antibody can be used as a universal secondary antibody because it binds to any antibody that originates from the same animal species (see Sakamoto et al, 2018, Journal of Natural Medicines, pg. 36, full para 1). This is possible due to recognition by an anti-species antibody of a constant region that is shared by all antibodies raised in the same animal species. Further, Zluvova teaches using a universal anti-mouse antibody to recognize and bind a specific (primary) antibody against a 5-mC DNA modification site. Thus, using the broadest reasonable interpretation and in light of the Specification, Zluvova teaches the limitation(s) of claim 4 reciting the preparation method according to claim 1, wherein the secondary antibody is a protein that identifies a generic portion of the specific antibody (Zluvova et al., 2001, Journal of Experimental Botany, 52, 365, pg. 2266, last para -pg. 2267, first cont sentence; and pg. 2269, caption/footnote for Fig. 2).
It would have been prima facie obvious, at the time of filing, to combine the teachings of Santra and Zluvova to substitute the secondary antibody coated on the metal complex- method ECL nanoprobe claimed in the method taught by Santra with the anti-species secondary antibody with affinity for a generic portion of a same-species primary antibody, as taught by Zluvova. As discussed above, recognition and binding by an anti-species antibody of a generic portion of all same-species primary antibodies occurs because binding is at a constant region that is shared by all primary antibodies raised in the same animal species as the secondary. This indicates that the anti-species antibody is a universal secondary antibody, thus a skilled artisan would have been motivated to combine these teaching to substitute the secondary antibody because it would make the detection system more versatile since it is commercially available and a universal secondary antibody can be used with different indirect detection assays for detecting different target analytes. Thus, at the time of filing, a person having ordinary skill in the art would have a reasonable expectation of success because combining these known teachings to substitute the secondary antibody to yield a more versatile detection system amounts to a simple substitution of known components, with known functions in the art, to yield expected and predictable results.
Regarding claim 5 Santra teaches the preparation method according to claim 1, wherein the metal complex ion is tris(bipyridine)ruthenium(II) complex ion [Ru(bpy)3]2+) [Santra et al., 2001, Analytical Chemistry, 73, 20, pgs. 4988-4989, Abstract and all paras; and pg. 4989, Fig. 1].
Conclusion
All examined claims (1-5) are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA L LIRIANO whose telephone number is (571)272-0085. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at (571)272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MELISSA LIZETTE LIRIANO/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/ Supervisory Patent Examiner, Art Unit 1677 May 6, 2026
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