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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/16/2025, 09/19/2025, 12/17/2025, 02/12/2026, 04/24/2026 are 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 April 29, 2026.
Claims 26-37 and 40-57 were previously pending. Applicant amended claims 26 and 37; cancelled claims 34 and 56.
Claims 26-33, 35-37, 40-55 and 57 are currently pending, with claims 51-52 and 54 withdrawn.
Claims 26-33, 35-37, 40-50, 53, 55 and 57 are under examination.
All of the previously presented rejections have been withdrawn as being obviated by the amendment of the claims.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.
Election/Restrictions
The requirement for election of the "Species of analyte forms" ; "Species of analyte capture" and Species of amplification reagent," set forth in the office action mailed on March 30, 2026 have been withdrawn in view Applicant's claim amendment filed on April 29, 2026, which have amended the claims to exclude the non-elected species.
Applicant’s election without traverse of the following species in the reply filed on April 29, 2026 is acknowledged:
Species of first solvent: F) the first solvent contains a first detection probe for determining the presence of the second form of the analyte, and wherein the first solvent does not contain an amplification oligonucleotide (claim 53) 1;
Species of first and second probes: H) the first and second probes are indistinguishable from each other in step (f) (claim 55) 2.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 51-52 and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 26-33, 35-37, 40-50, 53, 55 and 57.
Priority
Regarding claim 26 and its dependent claims 27-33, 35-37, 40-50, 53, 55 and 57, the earliest priority is 07/10/2018 because the priority document (PCT/US2018/041472) filed that date is the first to disclose limitations such as "dissolving an amplification reagent with a first solvent" and "wherein the first solvent does not contain a polymerase or nucleoside triphosphates, wherein the first solvent is an analyte specific reagent (ASR) that contains one or more oligonucleotides which, in combination with the oligonucleotides of the amplification reagent, are sufficient to amplify and detect a second region of a second form of the analyte," which together represent the step of supplementing an IVD assay with additional analyte specific reagent (ASR) in a single reaction, as noted in the Applicant's remarks 3.
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 26 recites the term "analyzer" in "providing a sample to an analyzer." The application's disclosure does not expressly define "analyzer" with any structural features.
Thus, the term "analyzer" is interpreted under BRI as any entity capable of performing any analyzing function in a process, encompassing analytical devices such as a spectrophotometer that analyzes absorbance of a sample, or a lab technician who performs analytical tests.
For the purpose of applying prior art, claim 26 recites "analyte specific reagent (ASR)," which is defined in the specification as follows:
“Analyte-specific reagents” or “ASRs” refer to reagents that interact specifically with a single analyte or substance generated in the presence of an analyte. For example, in a PCR assay, primers and probes for a single analyte would be considered ASRs. In an ELISA assay, a primary antibody that recognizes a single analyte would be considered an ASR. " ([00126])
For the purpose of applying prior art, claim 26 recites "in vitro diagnostic (IVD)," which is defined in the specification as follows:
"An “in vitro diagnostic” or “IVD” is a product used to perform an assay on a biological sample in isolation from the source of the sample. Where the source is a multicellular organism, a sample is generally obtained from the organism and then subjected to analytical procedures (e.g., amplification and/or binding reactions) in an artificial environment, e.g., a reaction vessel." ([00127])
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 26-33, 35-37, 40-50 and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Buse (US20160060680A1 - Method for analyzing plurality of samples; published 2016-03-03), in view of
Takara (High Fidelity PCR EcoDry™ Premix Protocol-At-A-Glance (PT5152-2); 2013);
Cobb (Cobb et al. The cobas® 6800/8800 System: a new era of automation in molecular diagnostics. Expert Rev Mol Diagn. 2017 Feb;17(2):167-180. doi: 10.1080/14737159.2017.1275962. PMID: 28043179);
Poomipak (Poomipak et al. "Molecular detection and subtyping of human influenza A viruses based on multiplex RT-PCR assay." International Research Journal of Biotechnology 2.4 (2011): 85-9).
A) Buse teaches diagnostic systems and methods for performing molecular assays that comprise target nucleic acid amplification reactions ([0003]).
Regarding claim 26, Buse teaches a method of determining whether any of multiple forms of a nucleic acid analyte are present in a sample ([0003]; [0006]), the method comprising the steps of:
providing a sample to an analyzer (page 26, claim 29, “(a) loading the diagnostic system with the plurality of samples; (b) after step (a), performing a first assay on a first sample subset of the plurality of samples”) ;
producing a purified form of the sample by exposing the sample to reagents and conditions adapted to isolate and purify multiple forms of a nucleic acid analyte (page 27, claim 31/29, “wherein preparing the first sample subset comprises isolating and purifying a first target nucleic acid of the first assay; [0006] lines 4-6, molecular assays that detect mutations analyses multiple forms of analytes in a sample (i.e., nucleic acid comprising different point mutations));
dissolving an amplification reagent with a first solvent ([0285] “the fluid within the mixing well 762 is mixed to dissolve the lyophilized reagent” ),
wherein the amplification reagent is a component of an in vitro diagnostic (IVD) assay ([0137] diagnostic system that performs target nucleic acid amplification reaction in vitro) and contains
a polymerase ([0167] “the unit-dose reagent 768 comprises a component for performing a nucleic acid amplification reaction. For example, the nucleic acid amplification reaction component can be a polymerase, nucleoside triphosphates, or any other suitable component”) ,
nucleoside triphosphates ([0167]) and
oligonucleotides sufficient to amplify and detect a first region of a first form of the analyte ([0008] “amplification primer that is designed or selected to exhibit specificity under the particular conditions of use for a nucleic acid sequence belonging to an organism or virus of interest”; see also [0012]; [0128] ; [0167] assay specific reagents sufficient to conduct a PCR reaction targeting multiple forms such as Flu A, Flu B, RSV, parainfluenza 1, 2, and 3, Human Metapneumovirus, Adenoviris, H1, H3, 2009 H1N1, and/or Tamiflu resistance.),
wherein the first solvent does not contain a polymerase or nucleoside triphosphates (Buse does not teach the fluid used to dissolve the lyophilized reagent contains polymerase or nucleoside triphosphates. As would be understood by a skilled artisan, the dissolving fluid does not need to contain any polymerase or dNTP, as these are already present in the dried reagent),
contacting the purified form of the sample with the dissolved amplification reagent, thereby forming an amplification reaction mixture ([0124]; [0286]; [0289]);
exposing the amplification reaction mixture to temperature conditions sufficient for amplifying the analyte ([0292]-[0296]); and
determining whether at least one of the first and second forms of the analyte is present in the sample ([0008] detection probe or amplification primer can be labeled for detection with reporter moiety; [0014]; [0015]; [0121]-[0123]).
In summary, Buse teaches a method for performing an IVD molecular assay that involves the use of an analyzer, purifying nucleic acids, and detecting nucleic acid analytes through amplification reactions.
Buse teaches that a variety of known molecular assays can be used to detect various diagnostic indicators, including analytes of interest in a sample, such as microbes, viruses, or mutations in an organism ([0006]). A skilled artisan would readily understand that Buse teaches the detection of multiple forms of nucleic acid analysis, as mutations in an organism are represented by differences in sequences.
Furthermore, Buse teaches the use of reagents for performing a single amplification reaction specific to different target nucleic acids of various pathogens and their subtypes ([0167]):
"Exemplary assay specific reagents 768 held in the reagent pack 760 include unitized reagents for performing a single amplification reaction, for example, PCR and/or a detection reaction utilizing a sample. Such reagents may be specific for one target nucleic acid or a plurality of different target nucleic acids. For example, the plurality of different target nucleic acids may be part of a respiratory panel, and the unitized reagents are sufficient to conduct a PCR reaction targeting Flu A, Flu B, RSV, parainfluenza 1, 2, and 3, Human Metapneumovirus, Adenoviris, H1, H3, 2009 H1N1, and/or Tamiflu resistance. "
Thus, a skilled artisan would understand that Buse clearly teaches and suggests analyzing a detecting multiple forms of analytes in a single reaction, using its diagnostic system, such as subtypes or variants of a virus.
While Buse does not explicitly disclose the aspect of supplementing additional analyte-specific oligonucleotides (contained in a solvent) to an amplification reagent mixture, this feature is obvious in view of the knowledge in the art.
Dissolving a dried amplification reaction master mix with a solvent containing additional reaction components, such as target-specific primers, is a known practice in the field, as supported by Takara. Takara discloses a lyophilized PCR master mix with instructions to dissolve the dried reagent using water containing primers (page 1, see protocol steps 1-2).
Poomipak teaches the development of updated multiplex RT-PCR assay for the detection of influenza viruses and their subtypes (Abstract, Table 1). Poomipak emphasizes the need for updated primers that specifically target new strains, as assays developed one or two years ago prior to a new pandemic can become insufficient for detecting new strains due to the high mutation rate of the virus. This can result in misdiagnosis and the continued spread of the virus:
“Previous studies described multiplex RT-PCR methods for influenza virus detection in several objectives including subtyping of H5N1 avian influenza A virus (Payungporn et al., 2004), subtyping of H7 and H9 avian influenza A virus (Thontiravong et al., 2007) and typing of A/B or subtyping of H1/H3/H5 (Boonsuk et al., 2008). However, the human pandemic influenza A virus was emerged in 2009 and continue to infect in human population at the present times. Moreover, naturally influenza virus has high rate of mutation within its genomic RNA that may cause mismatches between primers from previous studies and the target gene of current outbreak influenza viral strain resulting in misdiagnosis. Therefore, the aim of this study was to develop an update method based on multiplex RT-PCR for typing (influenza A and influenza B) and subtyping of influenza A virus that potentially infect to human at the present time (pH1N1, seasonal H1N1, seasonal H3N2 and avian H5N1 subtypes).” (page 086, left-hand col, para 2)
Thus, there is a clear and recognized need for the continuous updating of pathogen detection molecular assays to account for constant viral mutations and to prevent future outbreaks. This includes updating existing assays to incorporate target-specific detection reagents (e.g., PCR primers) capable of detecting new strains.
A skilled artisan would understand that the IVD diagnostic system comprising lyophilized PCR reagents disclosed in Buse could be applied to the detection of influenza viruses as taught by Poomipak. Given the high mutation rate of viral stains, which produces new subtypes requiring updated detection assays, a skilled artisan would have found it prima facie obvious and motivated to supplement additional primers that target new variants, to the dissolving fluid (e.g., solvent) used to reconstitute the dried amplification master mix in the system of Buse. This approach offers an flexible and cost-effective way to improve assay performance while still utilizing the existing IVD reagents. This is particularly important as assays may need to be updated annually in response to emerging subtypes and strains.
The person of ordinary skill would have had a reasonable expectation of success in doing so, as dissolving dried PCR master mix with solvents containing primers is well-established practice in the art, as disclosed in Takara.
Therefore, such a combination meets the claimed limitations below:
wherein the first solvent is an analyte specific reagent (ASR) that contains one or more oligonucleotides (Takara teaches using water comprising primers to reconstitute lyophilized PCR master mix ) which, in combination with the oligonucleotides of the amplification reagent, are sufficient to amplify and detect a second region of a second form of the analyte (as discussed above, the dissolving fluid only contains additional primers, thus it need to be combined with the PCR master mix to carry out amplification),
wherein the oligonucleotides of the amplification reagent are insufficient to amplify and detect the second region of the second form of the analyte (as discussed above, the oligonucleotides in the master mix are not sufficient to detect new stains or subtypes due to viral mutation, see Poomipak, Table 1, additional primer pairs are needed to detect subtypes),
wherein the one or more oligonucleotides of the first solvent are insufficient to amplify and detect the first or second form of the analyte (the primers in the dissolving fluid alone are insufficient because they still needs the enzymes, buffer, dNTP for the amplification), and
wherein the first and second regions each comprise a different nucleotide base sequence (Poomipak, Table 1, the primers detecting different variants and subtypes comprise different sequences hybridizing to different complementary sequence).
This "hybrid" approach of developing an improved assay based on a previously established IVD system is known in the art, as supported by Cobb.
Cobb teaches an IVD system (The cobas® 6800/8800 System) with a ‘utility channel’ included in the design to allow laboratories to develop and perform LDTs using IVD-grade reagents (Figure 2 and legends), in order to meet the need to “effectively identifying and screening large populations for new emerging pathogens, as well as controlling the spread of new and existing pathogens by testing at-risk populations in endemic areas (e.g. Ebola virus, Influenza H5N1, and Zika virus).” (page 176, left-hand col, para 2).
Thus, at the time of filling the instant application, the concept of supplementing detection reagents to an established IVD system and reagents to identify emerging pathogens and control the spread of both new and existing pathogens is neither novel nor surprising, as the benefits of doing so are well-recognized and expected in the field of infectious disease diagnostics.
B) Regarding claim 27, Buse teaches sample is provided to the analyzer in a receptacle supported by a receptacle-holding rack during step (a) (Fig. 2; [0268])
Regarding claim 28, Buse and Poomipak teaches the purified form of the sample contains at least one of the first and second forms of the analyte (obvious in view of Poomipak and Buse, a positive sample for variant detection would comprise at least one subtype).
Regarding claims 29-32, Buse teaches step (b) comprises immobilizing at least one of the first and second forms of the analyte on a solid support ([0274]);
wherein the solid support is magnetically- responsive ([0274]);
wherein step (b) comprises removing non-immobilized components of the sample while exposing the sample to a magnetic field ([0274]);
wherein step (b) comprises resuspending the solid support in a buffered solution after removing the non-immobilized components of the sample([0274]).
Regarding claim 33, Buse teaches step (b) comprises exposing the sample to a capture probe capable of specifically immobilizing the target analyte on the solid support ([0009]).
Regarding claims 35-36, Buse teaches the amplification reagent is a lyophilizate ([0285]).
Regarding claim 37, Buse teaches the amplification reagent is a unit-dose reagent ([0167]).
Regarding claims 40-41, they recite:
"wherein the first solvent is contained in a vial supported by a first holder" and
"wherein the first holder supports a plurality of vials, wherein at least a portion of the vials contain a solvent that includes a set of amplification oligonucleotides not contained in the first solvent."
These limitations are obvious in view of the combined teachings of Buse, Takara, Poomipak and Cobb because they do not further limit the claimed method.
Per MPEP 2111.04, a wherein clause can limit a method claim if it contributes meaning and purpose to the manipulative steps.
In this instant case, the "wherein" clauses do not introduce any additional steps or modify any existing step. They merely describe how the first solvent is contained, which constitutes extra-solution activity and does not make a manipulative difference to the claim scope. For instance, whether a vial is supported by a holder or unsupported does not affect the amplification assay itself. The presence of other parts not required by the claimed steps, such as other vials containing additional solvent also do not limit the claimed method.
Therefore, this claim language is interpreted as descriptive statement without any associated active steps and do not distinguish the claims from the prior art.
Regarding claim 42, Buse teaches its diagnostic system contains a second solvent that does not contain any oligonucleotides ([0144] bulk reagent including water). The recitation "for dissolving the amplification reagent" is interpreted as intended use that does not limit the claimed method, as the claim does not require using the analyzer nor "a second solvent" in its dissolving step.
Regarding claim 43, it recites:
"wherein the second solvent is contained in a second holder having a sealed fluid reservoir and an access chamber that are fluidly connected, the access chamber being accessible by a fluid transfer device for removing the second solvent from the second holder."
This limitation is obvious in view of the combined teachings of Buse, Takara, Poomipak and Cobb because it does not further limit the claimed method.
In this instant case, the "wherein" clause merely describes a second solvent, it does not introduce any additional steps or modify any existing step because the claimed method does not require a second solvent in any of its steps. Therefore, this claim language is interpreted as descriptive statement without any associated active steps and do not distinguish the claims from the prior art.
Regarding claim 44, Buse teaches the amplification reagent is stored and dissolved in a mixing well of a reagent pack, the reagent pack including multiple mixing wells ([0167]).
Regarding claim 45, Buse teaches the amplification reaction mixture is formed in a reaction receptacle distinct from the reagent pack ([0056]; [0062]).
Regarding claim 46, Buse teaches closing the reaction receptacle with a cap prior to step (e), the cap engaging the reaction receptacle in a frictional or interference fit ([0042]; [0182]; [0060]).
Regarding claim 47, Buse teaches centrifuging the closed reaction receptacle prior to step (e), wherein the centrifuging step is performed in a centrifuge having at least one access port for receiving the reaction receptacle ([0056]; [[0058]]).
Regarding claim 48, Buse teaches reaction receptacle is a distinct, individual receptacle that is not physically connected to any other reaction receptacle as part of an integral unit ([0267] describes moving a reaction receptacle to a location, thus the reaction receptacle is separate from other receptacles).
Regarding claim 49, Buse teaches the temperature conditions include thermal cycling associated with a polymerase chain reaction (PCR) ([0296]).
Regarding claim 50, Buse teaches the determining step is performed in real-time ([0013]; [0015]).
Regarding claim 57, Poomipak teaches the second form of the analyte is a mutated form of the first form of the analyte (Poomipak, Table 1 discloses subtypes, which are mutated forms).
Claims 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over Buse in view of Takara, Poomipak and Cobb, as applied to claim 26 above and further in view of Hur (Hur et al. Detection of genetic variation using dual-labeled peptide nucleic acid (PNA) probe-based melting point analysis. Biol Proced Online. 2015 Nov 4;17:14. doi: 10.1186/s12575-015-0027-5. PMID: 26539063; PMCID: PMC4632671.)
The teachings of Buse, Takara, Poomipak and Cobbare are recited above and applied as for base claim 26.
Regarding claim 53, Buse already teaches target-specific probes ([0014]) and further notes that:
"Most molecular assays include a detection step in which the sample is exposed to a detection probe or amplification primer that is designed or selected to exhibit specificity under the particular conditions of use for a nucleic acid sequence belonging to an organism or virus of interest." ([0008]).
Thus, a person of ordinary skill in the art, in view of the teachings of Buse and the knowledge in the art, would have understood that detection using target-specific detection probes is a well-known alternative to target-specific amplification primers.
Accordingly, a skilled artisan would have found it obvious, as an alternative assay design approach for providing an updatable IVD assay capable of accommodating emerging strains, to use target-specific probes directed to sequences within a larger amplified region, such as a gene region, where the probes are designed such that different sequence variants within the amplicon can be distinguished by detection methods such as melting curve analysis, as taught in Hur (see Figs. 1, 4 and 7)
This combination would have been obvious as it represents the KSR principle of predictable use of a known technique (i.e., target-specific detection probes) applied to a known method (i.e., method of performing molecular assay) to yield predictable results (i.e., distinguishing sequence variants within a target region using target specific probes). (See MPEP §2143).
Regarding claim 54, Hur teaches melt curve analysis wherein the first and second probes are indistinguishable from each other in the detection step (Fig. 7).
Conclusion
No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Claims 51-52 are withdrawn as being drawn to non-elected species E.
2Claim 54 is withdrawn as being drawn to non-elected species G.
3 "the method comprising supplementing a particular IVD assay with a particular ASR in a single reaction as recited in step ( c) of claim 26" (Remarks - 01/22/2026, page 17)
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