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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 21, 2026 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/23/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims / Response to Amendment
This office action is in response to an amendment filed on January 21, 2026.
Claims 1 and 3-24 were previously pending. Applicant amended claim 1; claim 25 is newly added.
Claims 1 and 3-25 are currently pending, with claims 4-5, 7, 9-10, 14-24 withdrawn.
Claims 1, 3, 6, 8, 11-13 and 25 are under consideration.
All of the amendment and arguments have been thoroughly reviewed and considered. All of the previously presented rejections have been withdrawn as being obviated by the amendment of the claims.
Applicant's amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
This office action contains new grounds for rejection necessitated by amendment.
Priority -- Updated
Regarding claims 1, 3, 6, 8, 11-13 and 25, the earliest priority is 10/31/2019 because the priority document (PCT/EP2019/079845) filed that date is the first to disclose applying any pressure on reaction tube.
Claim Objections
Claim 1 is objected to because of the following informalities:
In claim 1, line 3, "providing a liquid sample contained within in a reaction tube" should read "providing a liquid sample contained within a reaction tube."
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
For the purpose of applying prior art, claim 1 recites "a parameter of the assay", which is not defined in the applicant's disclosure. Page 6 of specification provides the following description regarding "parameter":
"… the visual monitoring of a parameter of the assay, such as the colour change in a colorimetric LAMP assay, becomes possible during the run of the assay"
Thus, in light of the specification and under BRI, the term "parameter" is interpreted as any observable and/or measurable characteristic related to an assay.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1, 3, 6, 8, 11-13 and 25 are rejected under 35 U.S.C. 112(b), 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 1 has been amended to recite "a reaction tube having a volume of up to 200 μI," the tube including a sidewall and a bottom wall. The claim is indefinite because the metes and bounds of the terms "sidewall" and "bottom wall" are not sufficiently clear given the broad scope of "reaction tube."
A "reaction tube" encompasses a wide range of tube geometries and configurations, including cylindrical reaction vessels with round bottom or conical bottom (e.g., centrifuge tubes), V-shaped vessels with round or flat bottoms (e.g., microcentrifuge tubes, PCR tubes); round-reaction flasks, pear-shaped vessels, and U-shaped reaction tubes. The claim does not specify the shape or geometry of the tube.
Neither the claim nor the specification provides a definition or structural distinction between the "sidewall" and the "bottom wall" across all the possible configurations of the "reaction tube." In certain tube shapes, the transition between the side portion of the tube and the bottom portion of the tube may be continuous or curved, making it unclear where the bottom wall ends and the sidewall begins. This ambiguity creates uncertainty in claim interpretation, particularly because the claim requires the sidewall to be made of translucent or a transparent material, while no such requirement is imposed on the bottom wall.
Without clear objective boundaries or criteria for distinguishing these structural features, the scope of the claim reciting "sidewall" and the "bottom wall" cannot be determined with reasonable certainty.
Claims 3, 6, 8, 11-13 and 25 are rejected for depending from claim 1 and not remedying the indefiniteness.
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.
Claims 1, 6, 8, 11-13 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Velders ( Velders et al. ; Loop-mediated isothermal amplification (LAMP) shield for Arduino DNA detection. BMC Res Notes 11, 93 (2018). Feb ; doi.org/10.1186/s13104-018-3197-9), in view of Bio-Rad2 (MJ Mini Gradient Thermal Cycler Instruction Manual; Published by Bio-Rad, 2009), as evidenced by
BioRad 1(BioRad, “Hard-Shell PCR Plates”, web.archive.org/web/20160823150356/https://www.bio-rad.com/webroot/web/pdf/lsr/literature/Bulletin_5496.pdf ; Archived August 23, 2016 on WaybackMachine);
Bioplastics ("0.2 ml (q)PCR 8-tube-strips with single attached caps"; 2012);
Eppendorf (Eppendorf Forensic DNA Grade; published by Eppendorf AG; 2017).
A) Velders teaches performing a Loop‑mediated isothermal amplification (LAMP) with colorimetric detection using a battery-operated, low-cost device for DNA detection by visual inspection (Abstract; page 2, right-hand col, para 2, lines 15-16 to page 3, left-hand col, lines 1-3).
Regarding claim 1, Velders teaches a method comprising:
providing a liquid sample contained within in a reaction tube having a volume of up to
200 μI, said tube including a sidewall made of a translucent or a transparent material
and a bottom wall, the volume of the liquid sample being sufficient to be viewed through
said sidewall (Fig. 2, the reaction tube being a PCR tube; page 2, methods);
positioning the reaction tube to provide an unobstructed view of the liquid sample through the sidewall during heating (Fig. 2; page 2. Right-hand col, lines 11-12; page 3, left-hand col, lines 1-3 “In fact, it should be noted that being the PDMS transparent, the real-time LAMP can be performed by naked-eye as well.”);
heating the liquid sample by bringing the bottom of the reaction tube in direct thermal
contact with a heating element (Fig. 2; page 2, right-hand col, para 1), and
visually monitoring a parameter of the liquid sample of the assay through the sidewall of the reaction tube while simultaneously heating the bottom of the reaction tube (Fig. 2; page 2, right-hand col, para 2, lines 15-16 to page 3, left-hand col, lines 1-3).
Velders teaches its assay uses Eppendorf PCR tubes (Fig. 2; page 2, lines 11-12), which share a standard size of 200μI being the maximum volume, as evidenced by Bioplastics (entire document, 0.2ml PCR tubes is compatible with most PCR cyclers, including Eppendorf's) and Eppendorf (page 6, PCR Tubes 0.2 mL).
Velders teaches colorimetric detection (Fig. 1; page 2, results, "We also tested an end point detection with SYBR green, and this latter gave an eye detectable signal"). While Velders does not explicitly demonstrate real-time monitoring of the assay, it clearly suggests it by stating: “In fact, it should be noted that being the PDMS transparent, the real-time LAMP can be performed by naked-eye as well.” (page 3, left-hand col, lines 1-3 )
Thus, a person of ordinary skill in the art would understand that Velders suggests real-time monitoring of the colorimetric signal using its disclosed LAMP assay and device.
Accordingly, it would have been obvious to a skilled artisan to perform real-time colorimetric detection by visually monitoring color changes through the transparent PDMS material holding the PCR tube during amplification, while the tube remains on the heating device for continuous incubation.
Regarding "applying pressure on the reaction tube towards the heating element," although Velders does not explicitly teach this limitation, it would have been an obvious step when performing temperature incubation using a heating block. It is common knowledge in the art that firm contact between reaction tubes and the heating block is necessary to achieve uniform heating. This is supported by Bio-Rad2, an instruction manual for a thermal cycler used for heating and cooling reaction tubes (entire document). Bio-Rad2 teaches that sample vessels must be in complete contact with the heating block to ensure unfirm heating, and explicitly instructs users to press the tubes into the block to ensure proper contact (page 22, lines 15-18).
Therefore, a person of ordinary skill in the art would have found it obvious before the effective filing date of the claimed invention to apply pressure to the reaction tube toward the heating element, to ensure adequate thermal contact and uniform heating during the LAMP assay. This combination would have been obvious as it represents the KSR principle of predictable use of prior art knowledge (i.e., press reaction tube toward heating block to ensure uniform heating) according to a known method (i.e., using heat block to incubate reaction tubes) to yield predictable results. (See MPEP §2143).
The person of ordinary skill would have had a reasonable expectation of success in making the modification because the references disclose complementary teachings that are technically compatible. Both Velders and Bio-Rad2 teach heating samples in PCR reaction tubes, and Bio-Rad2 provides clear motivation and technical justification for ensuring uniform heating via applying pressure, which is directly relevant to Velders 's assay.
B) Regarding claim 6, Velders teaches wherein a longitudinal axis of the reaction tube forms an angle of from 60 to 120 degrees with the heating element (Fig.2, the tube is placed vertically on the heating block, thus the tube's axis is 90 degrees with the heating element).
Regarding claim 8, Velders teaches an area of the reaction tube which is in thermal contact with the heating element is up to 12 mm2, as evidenced by BioRad.
Velders teaches the bottom of a PCR tube is in thermal contact with the heating block (Fig. 2). BioRad teaches a typical PCR reaction tube in PCR plate has a bottom diameter of 3.16mm (page 4) for surface area estimation. A skilled artisan would recognize that individual, separate PCR reaction tubes are standardized to have the same dimensions as those in a plate to ensure compatibility with the thermocycler models commonly available on the market.
The estimated area of the reaction tube bottom which is in thermal contact with the heating element is 7.84 mm2 (A=πr2=π·1.582≈7.84267), which falls within the claimed range of up to 12 mm2.
Regarding claim 11, Velders teaches the reaction tube is made of a transparent material (Fig.1 ).
Regarding claim 12, Velders teaches monitoring is carried out by a digital camera (page 1, right-hand col, lines 9-11; Fig 1).
Regarding claim 13, Velders teaches an isothermal nucleic acid amplification assay (abstract, LAMP).
Regarding claim 25, Velders teaches the volume of the liquid sample is at least 10 μI (page 2, line 8, 25 μI reaction vol ).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Velders, in view of Bio-Rad2, as applied to claim 1 above and further in view of MIAO2 (CN101696443B - Method and device for reducing evaporation and nonspecific reaction in PCR amplification; published on 2013-05-08; references are made to the attached copy with English translation), and as evidenced by BioRad (BioRad, “Hard-Shell PCR Plates”, web.archive.org/web/20160823150356/https://www.bio-rad.com/webroot/web/pdf/lsr/literature/Bulletin_5496.pdf ; Archived August 23, 2016 on WaybackMachine).
The teaching of Velders and Bio-Rad2 is recited above and applied as for base claim 1.
Regarding claim 3, while Velders in view of Bio-Rad2 teaches applying pressure on the reaction tube towards the heating element, as discussed in section above, it does not specifically teach the amount of pressure required.
MIAO teaches a device comprising a pressure cover with a liquid pressure pad, for improved temperature uniformity and greatly reduced evaporation ([0026]; [0013]).
Regarding claim 3, MIAO teaches the pressure applied to a tube is adjustable between 1-10 kg ([0033];[0040]), suggesting the vertical pressure applied to push down the tube onto the heating block can be routinely optimized by user.
BioRad contributes dimension information of PCR tubes typically used with thermocyclers, which is needed in converting the pressures specified in MIAO, in kgs to the pressure in Mpa as claimed. BioRad teach a typical dimension of a PCR tube appropriate for thermocycler is 5.5mm in diameter (page 4) and a depth of 12.2mm for the bottom half that come in contact with the heating block (19.85mm-7.64mm (total well depth – plate skirt height), page 4). Therefore, the surface area of the tube bottom half in contact with heating block is estimated to be A= πr(r + √(r2 + h2) =π·2.75·(2.75+√(12.22+2.752))≈131.8mm2.
MIAO teaches the pressure applied to a tube is adjustable between 1-10 kg ([0033]; [0040]), 1-10kg per surface area of the tube bottom in contact with the heating block (131.8mm2), converting to MPA is 0.075-0.75MPA, as 1 megapascal [MPa] = 0.1 kilogram-force/millimeter² [kgf/mm²]. This range overlaps with the claimed range of 0.4 MPa to 15 MPa.
MIAO also suggests potential benefits of its pressure cover, such as improved temperature uniformity and reduction of evaporation by more than 80% ([0013]; [0026]).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the device taught in Velders by incorporating a pressure cover comprising a liquid pressure pad, as taught by MIAO , to improve heating uniformity and reduce evaporation, as suggested by MIAO.
The person of ordinary skill would have had a reasonable expectation of success in making this modification, as all three references are in the same or over-lapping field of molecular biology, specifically nucleic acid amplification using heating elements. The references are technically compatible and provide complementary teachings. Velders teaches that its device for performing amplification reaction can be easily modified or upgraded (page 1, right-hand col, line 22), and MIAO teaches a specific enhancement for performing amplification reactions involving heating elements ꟷ namely, a pressure cover that improves thermal contact and reduces evaporation. This is directly relevant to Velders's teaching of performing a LAMP assay in a heated condition, and consistent with Bio-Rad2's teaching that applying pressure ensures uniform heating of samples.
Accordingly, a skilled artisan would have reasonably expected that incorporating the pressure cover of MIAO into the system and method of Velders in view of Bio-Rad2 would yield predictable result of more uniform heating and reduced evaporation, thereby improving the control and performance of the nucleic acid amplification process.
Conclusion
Claim 1 objected to; claims 1, 3, 6, 8, 11-13 and 25 are rejected. No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Cited in previous office action.
2 Cited in previous office action.