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 .
Applicants Amendment
Applicants’ amendment filed 8/3/2026 has been received and entered. Claim 11 has been added.
Claims 1-11 are pending.
Priority
This application filed 5/3/2021 is a divisional of 16/087724 filed 9/24/2018, now US Patent 11,268141 which is a 371 national stage filing of PCT/US17/23151 filed 3/20/2017 which claims benefit to US Provisional application 62/313032 filed 3/24/2016.
No comments on the summary of priority was made in the instant response.
Information Disclosure Statement
Applicants acknowledge the examiner’s comments regarding the signed IDS and listing in the specification at [0060].
37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, in review of the specification, the limitation and requirement of ‘exhibiting substantially the same’ does not appear to be supported in the specification. Review of the specification provides no guidance nor support for the metes and bounds of the properties that are ‘substantially’ the same, nor does it teach what elements of a nucleic acid, a control compared to a target, would be or how they would be defined or designed for the breadth of the claims of any target and all the possible properties of the various steps of lysis, extraction and amplification. The specification provides literal support for ‘substantial*’ four times but two are in the context of hybridization and the other are related to the control all being the same and nothing with regards to any target (see [00048] and [00094]). Claim 11 represents a new embodiment not recited nor specifically contemplated in the present specification. No other evidence of support is provided, and a general review of the art of record does not appear to provide that a nucleic acid that is a target and another nucleic acid used as a control has any different properties relative to the steps of the claim or as inherent properties based on intended use of a nucleic acid.
Applicants support (noted on page 6 in the arguments to the art rejection) is acknowledged, but this appears to support that the control is present during the processing and has no indication or teaching that the control has the same or substantially the same properties of a target nucleic acid. In particular, because both are nucleic acid targets for amplification and given the breadth of the possible samples, specific processing steps required of the claims, there appears to be a lack of necessary guidance on what is substantially the same beyond both being a nucleic acid.
Amending the claims to be consistent with the disclosure, for example with properties of the control and target specifically supported in the specification would address the basis of the rejection.
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 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 1-10 stand and newly added claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Swiger et al. (US 2005/0014176 A1), BIOFIRE Diagnotistics, (US 2015/0232916 A1), Guenin et al. (J Exp Bot v 60, n 2 2009) and Luu-The et al (Biotechniques 38:287-293 Feb 2005)(all of record in IDS filed).
Claims 1-10 have not been amended. Claim 11 has been added and provides a wherein clause describing the control nucleic acid exhibiting substantially the same properties as the target for lysis, extraction and amplification efficiency. Given the guidance of the specification, the limitations of claim 11 do not appear to provide any unique features to a control nucleic acid that would not be ‘substantially’ the same as a target in a ‘sample’; note that while the claim recites ‘lysing’ there is no specific cell, type of tissue,.. required to be present in the sample. For purposes of interpretation any control nucleic acid that is added to a sample and can be extracted as a control appears to be encompassed by the claim and substantially the same, and is provided by the cited references using control spiked DNA put into a sample.
Applicants provide an overview of each of the references and argue that BioFire’s ‘control nucleic acid’ corresponds to a ‘sample processing control, and that Swinger’s quantification standards may be incorporated into BioFire as a quantitative control. More specifically, it is argued that the claims require that control be added to the sample and participate in the isolation process as a final quantification standard.
In response, with respect to adding a control at the beginning of the isolation process, the basis of the rejection specifically points to BioFire for providing ‘wherein at least one sample processing control is added to said sample prior to step a) or during step a) in a known amount a multiplexed PCR reaction is provided, containing a control nucleic acid at a known initial concentration; paragraph [0085]’ which provides for adding a control to the starting material/sample. While BioFire clearly provides for providing ‘a known initial concentration’ it does not specifically state to use amplification as a means of quatification during or at the end of purification. Swiger et al. is simply provided as evidence of the level of skill in the art for designing and using quantitative nucleic acids, and Guenin et al. and Luu-The et al are provided for further evidence of the knowledge and context for the use of quatitative PCR as a means to detect such nucleic acids present in a sample. The portions of the specification are acknowledged, however it appears that the references to provide adding the control to the initial sample. The skilled artisan would readily recognize that a control added to the sample would serve as a control or more generally represent the possible loss of nucleic acids at each step of the purification process. Providing a known initial amount clearly provides that basis of comparison to the starting material and ending material as generally required of the claims.
It is noted that claim 1 provides broad generic steps of lysing, extracting and performing ‘amplification’, and no specific steps where quantification is actually required. Claim 3 provides for ‘quantifying’ and other dependent steps set forth equations used in qPCR that are used to provide the amount of a target in a sample. The motivation statement is not conclusionary but rather summarized the teaching of providing a control to a sample. The skilled artisan would readily appreciate that a control is added to evaluate possible loss during an isolation process. The statement regarding the location of the control is to address when the control is ‘during step a)’ and the logic of providing a larger master mix of the control with the lysis buffer so that each of the samples obtains the same amount.
Applicants argue that Guenin and Luu-The fail to provide that the controls remedy the deficiencies of above.
In response, Guenin et al and Luu-The et al were provided to show the level of skill in the art for qPCR and Ct/Cp measurements that were well known. Arguments that they use housekeeping genes fails to appreciate the breadth that the claims encompass any target and encompass any of the nucleic acids analyzed in the cited references.
Therefore, for the reasons above and of record, the rejection is maintained.
The rejection of record is provided below for completeness and clarity of the record.
Swiger discloses a method of performing quantitative amplification on a sample (a novel method for quantitative analysis of the initial amount of target nucleic acids in a sample; paragraph [0011]), comprising amplifying the sample in an amplification mixture (PCR reaction mixtures; paragraph [0051]), the amplification mixture comprising a pair of target primers (the forward and reverse primers; paragraph [0051]) configured to amplify a target that may be present in the sample (PCR primers for the target nucleic acid sequence of the simulant pathogen; paragraph [0049]), the amplification mixture further comprising a plurality of quantification standard nucleic acids (multiplex standards; paragraph [0030]) each provided at a different known concentration (containing known starting amounts of each of the different nucleic acids are used; paragraph [0030]) and at least one pair of quantification standard primers (primers are selected to produce PCR amplification products of each of the different target nucleic acids; paragraph [0030]), the quantification standard primers configured to amplify quantification standard nucleic acids (primers are selected to produce PCR amplification products of each of the different target nucleic acids; paragraph [0030]), generating a standard curve from the quantification standard amplicons, and quantifying the target nucleic acid using the standard curve (the full range of standard from 10 femtograms to 10,000 femtograms and the unknown starting quantity of a target nucleic acid sample is derived by locating its elution peak area on the plot line and extrapolating the starting target quantity from the x-axis of the plot; paragraph [0058]). Swiger further discloses wherein the amplification mixture further comprises a plurality of additional pairs of target primers configured to amplify a plurality of additional targets that may be present in the sample (primers are selected to produce PCR amplification products of each of the different target nucleic acids; paragraph [0030]). Swiger discloses further comprising, subsequent to the amplifying step, dividing the amplification mixture into a plurality of individual reactions (quantitative plot of target nucleic acid standard dilution series for target; paragraph [0025]), a first group of the plurality of individual reactions each comprising a pair of primers configured to further amplify one of the different targets that may be present in the sample (primers are selected to produce PCR amplification products of each of the different target nucleic acids; paragraph [0030]), and a second group of the plurality of individual reactions each comprising a pair of primers configured to further amplify one of the quantification standard nucleic acids (the internal standard is different, it will require its own primers; paragraph [0040]), and subjecting the plurality of individual reactions to amplification conditions to generate one or more target amplicons and a plurality of quantification standard amplicons (a PCR amplification products resulting from said target nucleic acid and a standard; paragraph [0011]), wherein the generating and quantifying steps take place subsequent to the subjecting step. Swiger further discloses further comprising detecting amplification of each of the quantification standard nucleic acids using a label (fluorescent labeling of the primers may be used to allow PCR elution peak detection; paragraph [0035]) specific for that quantification standard nucleic acid (the internal standard is different, it will require its own primers; paragraph [0040]). Swiger further discloses wherein each of the plurality of internal quantification standard nucleic acids is provided to the amplification mixture (multiplex standards; paragraph [0030]) in known amounts to also serve as process controls (an internal standard may also be used; paragraph [0040]). Swiger discloses use of at least one sample processing control as a quantification standard in a method for quantifying a nucleic acid in a sample (multiplex standards; paragraph [0030]).
Similar to Swiger, Biofire discloses a method for performing quantitative nucleic acid amplification on nucleic acid molecules in a sample (method for quantifying a target nucleic acid with a secondary PCR; paragraphs [0048], [0083]), comprising a) lysing said sample (a cell lysate; paragraph [0040]); b) extracting the nucleic acid molecules from said sample (DNA extraction; paragraph [0050]); c) performing nucleic acid amplification of the nucleic acid molecules (nucleic acid amplification; paragraph [0043]); wherein at least one sample processing control is added to said sample prior to step a) or during step a) in a known amount (a multiplexed PCR reaction is provided, containing a control nucleic acid at a known initial concentration; paragraph [0085]); characterized in that a nucleic acid sequence from the sample processing control serves as a quantification standard (the amplification of the control nucleic acid and the target nucleic acid produce an amplification curve; paragraph [0086]). Biofire discloses an instrument (the Film Array instrument; paragraph [0049]) for performing quantitative two-step PCR on a sample (method for quantifying a target nucleic acid with a secondary PCR; paragraphs [0048], [0083]), comprising an opening for receiving the sample vessel, a first heater for subjecting the amplification container to amplification conditions (a thermocycling element; paragraph [0092]), a second heater for subjecting the plurality of second-stage individual reaction wells to amplification conditions (thermocyclers; paragraph [0097]), a computer programmed to generate a standard curve using the amplification of the quantification standard nucleic acids and output a quantitative or semi-quantitative result for each amplified target (CPU may then generate an amplification curve, a melt curve, or any combination, which may or may not be printed, displayed on a screen, or otherwise outputted; paragraph [0096]). Biofire further discloses wherein the computer is further programmed to apply a correction factor to the standard curve for at least one of the targets (adjusted real-time PCR curves for the control and sample nucleic acids; paragraph [0036]). In all Biofire discloses a method of performing quantitative two-step amplification on a sample (method for quantifying a target nucleic acid with a secondary PCR; paragraphs [0048], [0083]), comprising amplifying the sample in a first-stage multiplex amplification mixture (the reagents are for nucleic acid extraction, first-stage multiplex PCR, dilution of the multiplex reaction; paragraph [0050]), the amplification mixture comprising a plurality of target primers (primers for amplifying a locus from a different one of the plurality of target nucleic acid sequence; paragraph [0008]), each target primer configured to amplify a different target that may be present in the sample (primers for amplifying a locus from a different one of the plurality of target nucleic acid sequence; paragraph [0008]), dividing the first-stage amplification mixture into a plurality of second-stage individual reactions (after first-stage PCR was complete, the mixture was diluted and was transferred to each of the second-stage wells; paragraph [0061]), a first group of the plurality of second-stage individual reactions each comprising at least one primer configured to further amplify one of the different targets that may be present in the sample (and each of the 102 second-stage wells is pre-loaded with a specific PCR primer pair; paragraph [0055]), subjecting the plurality of second-stage individual reactions to amplification conditions to generate one or more target amplicons (second-stage PCR; paragraph [0054), and each quantification standard amplicon having an associated quantification standard Cp (the true positive amplified much earlier with a Cp between 7.9 and 8.0; paragraph [0062]).
Biofire does not disclose the amplification mixture comprising a plurality of internal quantification standard nucleic acids each provided at a different known concentration and at least one quantification standard primer, the quantification standard primer configured to amplify quantification standard nucleic acids, and a second group of the plurality of second-stage individual reactions each comprising at least one primer configured to further amplify one of the quantification standard nucleic acids, and a plurality of quantification standard amplicons. However, Swiger does disclose the amplification mixture comprising a plurality of internal quantification standard nucleic acids (multiplex standards; paragraph [0030]) each provided at a different known concentration (containing known starting amounts of each of the different nucleic acids are used; paragraph [0030]) and at least one quantification standard primer (primers are selected to produce PCR amplification products of each of the different target nucleic acids; paragraph [0030]), the quantification standard primer configured to amplify quantification standard nucleic acids (primers are selected to produce PCR amplification products of each of the different target nucleic acids; paragraph [0030]), and a second group of the plurality of second-stage individual reactions each comprising at least one primer configured to further amplify one of the quantification standard nucleic acids (primers are selected to produce PCR amplification products of each of the different target nucleic acids; paragraph [0030]), and a plurality of quantification standard amplicons (multiplex standards; paragraph [0030]).
Guenin et al. and Luu-The et al are provided for further evidence of the knowledge and context for the use of quatitative PCR and the use of standards in calculations to derive a standard curve (Ct) to establish the concentration of a target of interest in the sample.
In view of the art as whole as evidenced by Swiger et al., BIOFIRE Diagnotistics, Guenin et al. and Luu-The et al, it would have been obvious to one of ordinary skill in the art at the time of the invention to modify the Biofire invention to provide the amplification mixture comprising a plurality of internal quantification standard nucleic acids each provided at a different known concentration and at least one quantification standard primer, the quantification standard primer configured to amplify quantification standard nucleic acids, and a second group of the plurality of second-stage individual reactions each comprising at least one primer configured to further amplify one of the quantification standard nucleic acids, and a plurality of quantification standard amplicons, as taught by Swiger, in order to provide a more convenient reaction mix.
Conclusion
No claim is 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 Joseph T Woitach whose telephone number is (571)272-0739. The examiner can normally be reached Mon-Fri; 8:00-4:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz R Skowronek can be reached at 571 272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Joseph Woitach/ Primary Examiner, Art Unit 1687
