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 .
Claim Objections
Claim 11 is objected to because of the following informalities: “within plurality” should be “within the plurality”. Appropriate correction is required.
Claim 17 is objected to because of the following informalities: “one sample reaction chambers” should be “one sample reaction chamber”. Appropriate correction is required.
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.
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, 4, 8-12, 14 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627).
Regarding claim 1, Toumazou disclosed a device (e.g. see Fig 2) for performing LAMP (e.g. see page 644, left column, last paragraph). The device comprised a plurality of reaction chambers (e.g. see Fig 2; see also page 644, right column under “Genotyping using a pH-sensing integrated circuit”: “We loaded the samples onto three-chamber flow cells…”). The device comprised integrated heaters (heating elements) in thermal communication with the reaction chambers (e.g. see Fig 2). Each chamber comprised an associated ISFET (ion-selective field effect transistor) comprising a source (S), drain (D), and gate (e.g. see Fig 2). These ISFETs constitute “probes” extending from the respective reaction chambers to a data processor, which in turn was coupled to a display (e.g. see page 642, right column, 2nd paragraph: “…analyzer board, which provides both power and a simple microcontroller interface to read digital data from the chip, sends control signals to the chip, performs genotyping and transfers results to an on-board display or personal computer…”).
Regarding claim 4, see e.g. page 644, right column under “Genotyping using a pH-sensing integrated circuit”: “We loaded the samples onto three-chamber flow cells mounted onto the chip, where one chamber contained primers targeting the wild-type allele CYP2C19*1 (81G or 806C) and another chamber contained primers targeting one of the SNP variants, CYP2C19*2 or CYP2C19*17. The middle chamber functioned as a reference control chamber containing primers to both wild type and mutants, but lacking dTTP.”
Regarding claim 8, Toumazou stated (page 644, left column, 2nd paragraph): “For the isothermal amplification, the integrated circuit was configured to heat and maintain the chip at a constant temperature while simultaneously monitoring the pH signal. We observed amplification of NAT2 1,200 s (20 min) after the start of the reaction but did not observe amplification in the control reaction (Fig. 3b).” However, turning to Fig. 3b, it shows that the LAMP reaction and data collection continued for at least 1,750 seconds, which is just over 29 minutes. Therefore, the heating elements of Toumazou’s device were configured to heat the reaction chambers to a consistent temperature for at least 29 minutes.
Regarding claims 9 and 10, the pH-LAMP was performed at 63 °C (first page of “Online Methods” following main article, right column, 2nd paragraph).
Regarding claim 11, as discussed in the article, a LAMP reaction was performed in each of the three chambers of Toumazou’s device (e.g. see page 644, section entitled “Genotyping using a pH-sensing integrated circuit”).
Regarding claim 12, see page 643, left column: “One of the three reaction chambers functioned as a reference control chamber, which we used to cancel common-mode noise or non-ideal sensor behavior (electrochemical disturbances, sensor drift, temperature dependence and/or fabrication variability) that was not amplification-specific. We eliminated these effects by taking a differential measurement between ISFET signals derived from an experimental reaction (such as reactions containing primers matching the target sequence) and a reference control reaction (such as reactions lacking polymerase or a dNTP, or containing mismatching primers).” This is a form of comparing to control data. Regarding a “visual representation of the test results”, Toumazou disclosed transferring results to an on-board display; see page 642, right column, 2nd paragraph.
Regarding claims 14 and 17, with the exception of the “sample chamber”, the teachings of Toumazou are applied to claim 14 as discussed for the claims above.
Toumazou did not disclose a “sample chamber” configured to receive the sample as recited in claims 1 and 14. Toumazou appears to have injected the sample directly into the flow cell forming the reaction chambers, rather than have a separate, discrete “sample chamber” into which the sample was first introduced.
Kindwall disclosed a device for preparing nucleic acid from a sample and performing nucleic acid amplification. In one embodiment, shown in Fig. 12, a sample 2205 was introduced into a sample chamber 22201, lysis solution added, and the lysed sample passed into isolation chamber 2230 through valve 2216. Following nucleic acid purification, the nucleic acid was apportioned to reaction chambers 2240a-c via valves 2222a-c for amplification. See column 31, line 44 through column 32, line 7.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the device of Toumazou by incorporating a sample receiving, preparation and allocating architecture similar to that of Kindwall. One would have been motivated to do this because Toumazou stated (page 645, right column, 2nd paragraph): “The slight variability observed between different chambers may be due to pipetting errors as we loaded only 2 μl per chamber…Such technical variability can be minimized by integrating seamless sample preparation and delivery to the chip…”. Thus, one would have been motivated to integrate an automated sample preparation and allocating system similar to the arrangement of Kindwall’s Figure 12 device to minimize chamber-to-chamber variability. To be clear, the rejection does not suggest a complete incorporation of Kindwall’s device into Toumazou’s device, as Kindwall’s device was configured to perform different analyses than Toumazou’s. The rejection merely proposes reconfiguring Toumazou’s device to allow for loading sample into a sample receiving chamber, such as in Kindwall’s device, extraction of nucleic acid, as in Kindwall’s device, and apportioning the resulting sample to a plurality of reaction chambers, as in Kindwall’s device.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627) as applied to claims 1, 4, 8-12, 14 and 17 above, and further in view of Mooney (US 2022/0254458).
The teachings of Toumazou and Kindwall have been discussed. While Toumazou indicated the transfer of results from the analyzer board to a display, Toumazou did not specifically state what “form” the results would take (e.g., text, graphical, etc.).
However, displaying test results as positive or negative in a text form was known in the prior art, as exemplified by Mooney (see Fig. 3C and page 13, roughly midway down the table, referencing Fig. 3C).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to configure the device suggested by the combined teachings of Toumazou and Kindwall to display the results in a text format, indicating positive or negative, since this was known in the art, and would have allowed a user to immediately ascertain the result.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627) as applied to claims 1, 4, 8-12, 14 and 17 above, and further in view of Trivett (US 2020/0355715).
The teachings of Toumazou and Kindwall have been discussed. While Toumazou indicated the transfer of results from the analyzer board to a display, Toumazou did not specifically state what “form” the results would take (e.g., text, graphical, etc.).
Trivett disclosed the use of different colored lights (LEDs) to indicate positive or negative results (paragraph [0178]).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to configure the device suggested by the combined teachings of Toumazou and Kindwall to display the results in a colored light format, indicating positive or negative, since this was known in the art, and would have allowed a user to immediately ascertain the result.
Claim(s) 5 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627) as applied to claims 1, 4, 8-12, 14 and 17 above, and further in view of Lipshutz (US 5,856,174).
The teachings of Toumazou and Kindwall have been discussed. These references did not disclose or suggest a one-way sealing mechanism to lock the sample within the sample chamber.
Lipshutz disclosed systems for preparing and analyzing samples (abstract). Regarding introducing the sample, Lipshutz taught (column 4, lines 48-60):
“The sample collection portion of the device of the present invention generally provides for the identification of the sample, while preventing contamination of the sample by external elements, or contamination of the environment by the sample. Generally, this is carried out by introducing a sample for analysis, e.g., preamplified sample, tissue, blood, saliva, etc., directly into a sample collection chamber within the device. Typically, the prevention of cross-contamination of the sample may be accomplished by directly injecting the sample into the sample collection chamber through a sealable opening, e.g., an injection valve, or a septum. Generally, sealable valves are preferred to reduce any potential threat of leakage during or after sample injection.”
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the device suggested by the combined teachings of Toumazou and Kindwall by incorporating a sealable opening over the sample chamber as disclosed by Lipshutz in order to avoid leakage during or after introducing the sample.
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627) as applied to claims 1, 4, 8-12, 14 and 17 above, and further in view of Latham (US 2023/0279380).
The teachings of Toumazou and Kindwall have been discussed. Kindwall disclosed valves between the sample receiving chamber and each of the respective reaction chambers as discussed for claim 1 above. However, Kindwall did not disclose these as “one-way valves”.
Latham disclosed a microfluidic device for introducing a sample, isolating nucleic acid from the sample, and apportioning the nucleic acid to a plurality of reaction chambers 32 (Fig. 7A, paragraph [0026]). As in Kindwall’s device, valves were used to control the flow of fluid. In Latham’s case, one-way valves 38 were employed (Fig. 7A, paragraph [0026]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the device suggested by the combined teachings of Toumazou and Kindwall by using one-way valves as taught by Latham, since these types of valves were known in the art in the same context as the valves of Kindwall’s device for the same purpose. See MPEP 2144.06 and 2144.07.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627) as applied to claims 1, 4, 8-12, 14 and 17 above, and further in view of Southgate (US 5,863,801).
The teachings of Toumazou and Kindwall have been discussed. In Toumazou’s device, the “reference” reaction chamber (Fig. 2) received sample, but one of the four nucleotides required for amplification was omitted (see discussion of claim 4 in the main rejection). Thus, in modifying Toumazou’s device to incorporate a sample chamber, sample preparation and allocating architecture as in Kindwall’s Fig. 12, one would simply have omitted such dNTP from one of the reaction chambers, as in Toumazou’s original device.
However, Southgate taught an alternative, wherein a sample preparation device was configured to keep a “negative control” isolated from the sample. See Fig. 1 and column 8, lines 28-51, and column 9, lines 10-35, where positive control 310 and negative control 320 remain isolated from the sample 300.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the device suggested by the combined teachings of Toumazou and Kindwall by employing an isolated flow path for positive and negative controls (the negative control serving the same function as Kindwall’s “reference” reaction), since this was a known alternative to providing a negative or “reference” sample, as disclosed by Southgate.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627) as applied to claims 1, 4, 8-12, 14 and 17 above, and further in view of Punyani (US 2023/0074766).
The teachings of Toumazou and Kindwall have been discussed. In Toumazou’s device, pH change was used to detect amplification in the LAMP amplification reaction.
Punyani, however, disclosed that alternatively, a change in conductivity could be used as an indication of amplification.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the device suggested by the combined teachings of Toumazou and Kindwall by measuring conductivity change as an indication of amplification, since Punyani taught this as an alternative to the use of pH change as an indicator of amplification.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627) as applied to claims 1, 4, 8-12, 14 and 17 above, and further in view of O’Horo (Critical Care Nephrology. Elsevier, 2019. 560-567).
The teachings of Toumazou and Kindwall have been discussed. Toumazou disclosed the concept of detecting multiple different targets; see page 645, last paragraph before “Discussion”. Toumazou did not suggest testing for the five specific pathogens recited in claim 18.
However, all of these were known pathogens causing hypoxic respiratory failure in ICUs; see Table 96.1, first group in table, page 561.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the device suggested by the combined teachings of Toumazou and Kindwall to test for the pathogens recited in claim 18, as these were all known pathogens and testing for them would have provided a benefit to patients and doctors.
Claim(s) 16, 19 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Toumazou (Nature Methods 10(7):641-645 (2013)) in view of Kindwall (US 10,690,627) and Lipshutz (US 5,856,174) as applied to claims 5 and 15 above, and further in view of Ramanathan (US 2025/0312787, priority date May 3, 2022).
The teachings of Toumazou, Kindwall and Lipshutz have been discussed. Specifically, Lipshutz provides a reason to modify the sample chamber to provide a seal to prevent introduced sample from leaking out. Lipshutz did not disclose that closing the seal would push sample from the sample chamber to the reaction chambers.
Ramanathan disclosed (paragraph [0111]): “The sample fluid 641 is dispensed into the cartridge 650 by screwing the dispensing cap 610 onto the sample reservoir 618. As described above, as the dispensing cap 610 is screwed on, the dispensing mechanism of the dispensing cap 610 breaks the seal at the base of the sample reservoir 618, and the gasket of the dispensing cap 610 creates a seal between the sample reservoir 618 and the dispensing cap 610. Further rotation of the dispensing cap 610 compresses the gasket further and pressurises the air above the sample fluid 641, which forces the liquid 641 to move further into the cartridge 650: specifically, into the reaction chamber 617. The reaction chamber 617 is preloaded with soluble, dried or lyophilised reagents, which then react with the fluidic sample.”
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the device suggested by the combined teachings of Toumazou, Kindwall and Lipshutz by configuring the sample chamber to be closed with a cap, which cap would then pressurize the sample chamber forcing sample to pass into the reaction chambers in a manner similar to that disclosed by Ramanathan. This would have allowed for a simple solution to fluid movement in the device, reducing the need for more expensive components such as pumps or mechanical pressure-generating means.
Conclusion
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/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
1 “2220” is not shown in the figure but is mentioned in the description of the figure at column 31, line 46.
