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 .
Status of Claims
Applicant' s amendment filed 10/17/2025 is acknowledged. Claims 1 and 12-13 have been amended. Claims 1-20 are pending in the instant application and claims 1-13 are the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
Previous Rejection
Status of Prior Rejections/Objections:
The 112(b) rejections to claim(s) 1, 12, and 13 and dependent claims thereof is/are withdrawn in view of the amendments to the claims.
The prior art rejection(s) under 35 USC 103 directed to the following claims are maintained:
Claims 1-4 and 6-13 over Tanner
Claim 5 over Tanner in view of Naik
Claim 12 over Tanner in view of Tian
Claim 13 over Tanner in view of Byers
The double patenting rejections over copending applications 17576971, 17576972, 17576973, and 17576975 are withdrawn in view of the accepted terminal disclaimers approved 10/20/2025.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
Claim 12 is objected to because of the following informalities: There is a period after the “C”; this appears to be a typo. Appropriate correction is required.
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.
Regarding claim 1, it is noted that “pH sensitive” dyes lack a limiting definition and this can also be interpreted broadly as, for example, fluorescent dyes that perform better under certain pH conditions in addition to more conventional pH indicators like those in para [0025] and those that are intended to be used to indicate pH changes.
Regarding claim 5, the claim recites “further comprising: providing a solid phase reaction medium comprising cellulose or glass fiber”. The step of providing was interpreted broadly, lacking any information about timing, was broadly to occur at any point in the method such that the “a solid phase reaction medium” could encompass at least “the solid phase reaction medium” of the dispensing step of claim 1 and “a second solid phase reaction medium” provided, for example, after the dispensing.
Regarding claim 13, the claim recites “further comprising: providing a heating uniformity in the testing environment that has a variability of…”. Variability [i.e., the extent to which a set of data is spread/clustered] was interpreted broadly to encompass interpretations including variability between/among “runs” of the method, measurement points of a heating apparatus, etc. and across various measures of variability including standard deviation, range, etc.
Claim Rejections - 35 USC § 103
Claim(s) 1-4 and 6-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tanner (US 10,968,493 B1; filed 07/24/2020).
Regarding claims 1-2 and 10, Tanner teaches a method of testing for the presence of a target nucleic acid (entire document, e.g., col 25, para 4-5; Abstract; col 29, embodiment 21/18/17/12/2), comprising:
providing a biological sample (col 8, para 5; col 4, para 1: “blood, … saliva, mucous, … urine, feces”; instant claim 2) and dispensing into a test environment (col 25, para 5) comprising:
a matrix such as paper, plastic, or glass [i.e., solid phase] (col 22, lines 5-8; wherein the reagents of the master mix may be stored in a freeze dried/lyophilized form (col 22, lines 2) and immobilized on said matrix (col 3, line 19-22), wherein the lyophilized LAMP master mix may comprise a pH sensitive dye (col 21, lines 66-67 through col 22 line 2; col 39, line 1-29; col 29, embodiment 21/18/17/12/2).
Tanner teaches a lyophilized master mix free from hygroscopic agents in a tube embodiment (col 39, line 1-6; col 39, line 28), wherein the master mix also comprises RT enzyme and was capable of RT-LAMP (col 39, lines 1, 38, and 48; see also col 29, embodiment 21/18/17/12/2 and col 6, line 17; instant claim 10). Tanner teaches a reaction container [e.g., a tube] and a matrix as alternatives (col 22, lines 5-8; col 25, para 5 through col 26).
Tanner teaches rehydration of the master mix when combined with a sample (col 22, para 2; col 25, para 5 through col 26).
Tanner teaches that pH dependent colorimetric LAMP is quick, easy, reliable, and suitable for scale-up in molecular diagnosis and that a desirable format for measuring color change is a strip test such as those routinely used in pregnancy tests (col 22, para 2).
Therefore, while Tanner does not explicitly teach the hydroscopic agent free LAMP master mix in combination with a solid phase reaction medium capable of being rehydrated, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed inventions to have utilized the hygroscopic free lyophilized master mix containing the pH sensitive dye of the tube environment on the matrix, motivated by the desirable physical format and the quick, easy, and reliable nature of the pH-based test, as taught by Tanner. Further, such a simple substitution of container/matrix would have been obvious as Tanner teaches that such were recognized alternatives for the sample purpose. See MPEP 2144.06. There would have been a strong expectation of success as Tanner teaches all the necessary components, and is directed toward such a diagnostic method using pH sensitive LAMP and lyophilized mixtures.
It is further noted that changes to order of steps regarding the order of steps regarding, for example, the combination of the lyophilized reagent mixture and the sample prior to rehydrating the medium are also held to be obvious variants. See MPEP 2144.04(IV)(C).
Regarding claim 3, in the method of Tanner, Tanner teaches collecting a sample from a human or other mammalian subject with a nasal, oral, or buccal swab (para 4, para 1; also, Fig. 29 and col 38, Example 3: “Nasal samples are collected by swab”).
Regarding claim 4, in the method of Tanner, Tanner teaches that the test environment is substantially free of at least pH-affecting reagents and optimizing (col 39, line 1-6; see also col 13, para 9, spanning col 14; Fig. 21; and col 19, para 2).
Tanner also teaches that the pH of the buffer of the rehydrated master mix in lyophilized form is slightly changed when the master mix is rehydrated so the pH is taken into account during formulation (col 22, para 1). It would therefore be a matter of routine optimization as to what degree of pH-affecting reagents are present in the test environment. See MPEP 2144.05(II).
Regarding claims 6-9 and 11, in the method of Tanner, Tanner teaches that the target nucleic acid may be from a viral pathogen, including SARS-CoV2 (col 4, para 2; col 44, para 1).
Regarding claim 12, in the method of Tanner, Tanner teaches heating the medium with a heating block or water bath to a temperature suitable for isothermal amplification (col 3, para 3; paper: col 25, para 5). Tanner teaches raising a temperature prior to incubation (col 24, para 3).
Tanner does not explicitly teach the amount by which the temperature is raised.
However, the courts have held that optimization through routine experimentation, and in particular, when related to differences in temperature, do not support patentability (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Thus, the claimed temperature range merely represents routine optimization of the teachings of the cited prior art.
It is further noted that the methods are directed to isothermal amplification and that the order of steps is not limited (i.e., the temperature may be prior or after to the rehydrating, or even after any detection), nor is the total amount of temperature raised and/or time over which it is raised limited (i.e., raising the temperature by approximately 0 C for about a second would meet the limitation). Accordingly, it is not identified that such is a critical temperature for such a method of testing.
Regarding claim 13, in the method of Tanner, Tanner teaches a heating step using a water bath or small heating block (col 25, para 5). Tanner teaches that the LAMP described requires a 65 C temperature step (col 26, line 8).
While Tanner does not explicitly teach a uniformity or variability, it is noted that the courts have held that optimization through routine experimentation, and in particular, when related to differences in temperature, do not support patentability (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Thus, the claimed temperature range merely represents routine optimization of the teachings of the cited prior art related to a particular temperature.
As noted in the interpretation above, variability may encompass at least reproducibility across results or variability across measurement points on/in the test environment. As Tanner teaches a 65 C target, it would have been obvious to optimize for said target to achieve at least a run-to-run or sample-to-sample variability of less than 1 C.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over by Tanner (US 10,968,493 B1; filed 07/24/2020), as applied to claim 1 above, and in view of Naik (Naik P., et al. Nucleic Acid Amplification on Paper Substrates. In: Advanced Functional Materials and Sensors. Singapore: Springer Nature Singapore Pte Ltd.; 2019. p. 115–46.).
Regarding claim 5, in the method utilizing a paper medium of Tanner, Tanner teaches a solid matrix such as paper (col 25, para 5, spanning col 26) but fails to explicitly teach the type of fiber used in said solid matrix.
Naik rectifies this by teaching that chromatography paper and glass fiber are the most preferred substrates across amplification protocols using paper substrates and that the choice of the substrate is determined by the nature of task to be performed (pg. 140, 8.5.2 Choice of the Paper Substrate, para 1). Naik teaches that most of the studies on LAMP have used glass fibers as their substrate of choice; that glass fibers have better resistance to chemicals and are inert, which makes them ideal substrates for reactions; and that glass fibers enable efficient reagent storage and are biocompatible (pg. 121, para 3).
Therefore, it would have been obvious before the effective filing date of the claimed invention to combine the method of Tanner in utilizing a solid matrix such as paper in a LAMP reaction with the choice of a glass fiber solid matrix as taught by Naik, motivated by the desire to take advantage of the chemical resistance, biocompatibility, and efficient reagent storage, as taught by Naik. There would be a strong expectation of success as this is applying a known technique/device to a known method and both are directed to LAMP.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over by Tanner (US 10,968,493 B1; filed 07/24/2020), as applied to claim 1 above, and in view of Tian (Tian CJ, et al. Development of a fluorescent-intercalating-dye-based reverse transcription loop-mediated isothermal amplification assay for rapid detection of seasonal Japanese B encephalitis outbreaks in pigs. Arch Virol. 2012 Aug;157(8):1481-8. Epub 2012 May 10).
Regarding claim 12, in the method of Tanner, Tanner also teaches performing RT-LAMP and LAMP reactions with a master mix supplemented with a fluorescent double-stranded DNA binding dye and incubated on a real-time qPCR machine to confirm that amplification corresponded to color change and provide correlations between input and color (col 35, para 2). Tanner teaches that the colorimetric embodiments are pH dependent and that the dye is in the master mix (col 23, para 1) and that fluorometric dyes may pH sensitive (col 21, line 67; col 2, para 1).
Tanner teaches increasing the temperature of the mix (col 24, para 3); however, Tanner fails to explicitly teach raising a temperature of the test environment by a particular rate.
Tian rectifies this by teaching a real-time monitoring of RT-LAMP comprising a melting curve analysis comprising increasing a temperature by 0.1 °C/s (pg. 1483, Analysis of RT-LAMP products, Approach 1, para 1).
Tian further teaches that real-time RT-LAMP is more economical because the amplification of a specific LAMP product can be measured by high-throughput techniques in a normal real-time PCR thermocycler without the need to purchase an expensive Loopamp real-time turbidimeter (pg. 1486, para 1). Tian teaches analysis of the melting curves to determine that the specific reaction products were due to amplification and that close agreement has been shown between fluorescent intercalating-dye-based and turbidimetry-based real-time LAMP (pg. 1486, Discussion, para 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Tanner that also comprises pH sensitive fluorescent dye with the method of melting curve analysis comprising raising the temperature of the test environment by 0.1 °C/s of Tian. The artisan would be so motivated because Tian teaches such melting curve analysis can utilize equipment that the artisan already (i.e., avoiding the need to purchase additional equipment) and for use as a confirmatory analysis as taught by Tian and Tanner. There would have been a strong expectation of success as melt curves and RT-LAMP/LAMP were well known within the art, as shown by Tanner and Tian. Further, it is noted that a test environment, broadly claimed, may encompass a solid phase medium in a tube or similar obvious modifications to combine for such confirmatory testing of the method, motivated by the teaching of Tian to utilize equipment owned by the artisan.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over by Tanner (US 10,968,493 B1; filed 07/24/2020), as applied to claim 1 above, and in view of Byers (Byers KM, et al. Versatile printed microheaters to enable low-power thermal control in paper diagnostics. The Analyst. 2020;145(1):184–96. Epub 2019 Nov. 2.)
Regarding claim 13, in the method of Tanner, Tanner teaches a heating step of a solid matrix such as paper on a surface heated by a homemade water bath or small heating block that can be transported in a backpack for environmental use that results in a color change to indicate a result (col 25, para 5, spanning col 26). However, Tanner fails to teach a specific heating uniformity for heating for such a solid matrix.
Byers rectifies this by teaching a microheater that can be easily integrated into reactions that require low-power battery heating, wherein the microheaters are reusable and versatile (Abstract). Byers teaches that the variability (standard deviation) of one microheater design over 10 trials is about 0.5 °C (Fig. 4E). Byers teaches that the heater is compatible with LAMP assays (e.g. Conclusion, para 1; pg. 185, col 1, para 2).
Byers further teaches that because of their power lower requirements, such micro heaters can easily be integrated into emerging sample-to-answer nucleic acid amplification platforms (Conclusions, para 2).
Therefore, it would have been obvious to one of ordinary art at the time of filing to combine the method of Tanner with the microheater that provides a heating uniformity variability of less than 1 °C of Byers, motivated by the ability to allow the method to be easily integrated with sample-to-answer NAA platforms in a reusable manner, as taught by Byers (Conclusions, para 2). There would have been a strong expectation of success as the combination is of a known technique/device to a known method and both are directed to LAMP.
Response to Arguments
Applicant's arguments filed 10/17/2025 have been fully considered but they are not persuasive.
Applicant argues that Tanner fails to teach “dehydrated pH sensitive dye” or “hygroscopic agent free”. Applicant further alleges that because Tanner teaches that its master mix is reconstituted prior to use in an embodiment, the reconstitution step is separate and discrete from the usage of a biological sample [to hydrate the medium].
These arguments are not persuasive. Tanner teaches multiple embodiments, including multiple that use lyophilized (i.e., “dehydrated”) pH sensitive dyes (e.g., col 21, lines 66-67 through col 22 line 2; col 39, line 1-29; col 29, embodiment 21/18/17/12/2) and a hygroscopic agent free lyophilized master mix comprising such a dye (col 39, line 1-6; col 39, line 28).
While it is acknowledged that Tanner teaches embodiments in which lyophilized master mixes are reconstituted first with water and/or buffer, Tanner teaches immobilization of the master mix on solid medium and a broad embodiment whereby the master mix is merely reconstituted “prior to use in an amplification reaction” (col 3, para 2). Tanner then teaches an embodiment in which an aliquot of a sample is added to paper with the master mix dried and immobilized on to a medium, followed by a heating step, resulting in amplification in the sample (col 5, para 5). Therefore, while the master mix is not explicitly hygroscopic agent free in the embodiment in which the sample reconstitutes the solid medium hydrated by the sample, such would have been an obvious combination of the two embodiments of Tanner. Tanner teaches a solid medium form [in which a sample rehydrates the strip], like the routinely used pregnancy tests, is a desirable format. Therefore, there is strong motivation to choose this format for use with the hygroscopic agent free lyophilized master mix of Tanner, and as all elements are taught by Tanner, a high degree of predictability.
It is noted that Tanner also teaches a dried lysis reagent (e.g., col 26, para 2) to enable release of polynucleotides and/or normalization of pH (col 19, para 2) and/or addition of lysis buffer before the addition to the test environment to inactivate virus (col 19, para 3, spanning col 20) before providing the sample to the test environment.
Further, the breadth of the claims is noted. The claims merely require that the solid phase medium is “in combination with” the LAMP reagent mixture and dye and that the sample rehydrates the sample medium. An embodiment whereby the “test environment” is broadly interpreted to be, for example, a tube with the lyophilized mix and the solid phase medium together on a hot plate, also would be encompassed by the claim if a sample is dispensed on to the solid phase medium. Tanner also teaches such an embodiment of adding lyophilized master mix comprising dye to a solid phase medium with a sample added (col 21, para 6, spanning col 22).
Similarly, it is noted that changes to the sequence of adding ingredients are not generally patentable, absent evidence of criticality. See MPEP 2144.04(IV)(C). As only dispensing the sample onto the medium is claimed in claim 1, it is unclear what critical feature is necessitated by a prior combination based on the claim. It is noted that the structures of the preamble are not required by any other part of the claim.
For these reasons, the arguments are not found to be persuasive.
Conclusion
No claims are allowed.
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 Emma R Hoppe whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636