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 .
Election/Restrictions
Applicant’s election without traverse of group II, claims 2-5, in the reply filed on 1/13/2026 is acknowledged.
Claims 1, 6 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/13/2026.
Priority
The instant application was filed 08/14/2023 and is a national stage entry of PCT/EP2021/084559 with an international filing date: 12/07/2021 and claims foreign priority to DE10 2020 216 120.8, filed 12/17/2020. It is noted the prior document is not in English,
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/13/2023, 8/14/2023 are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 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.
Claims 2-5 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.
MPEP 2163 IB New or amended claims section II
With respect to newly added or amended claims, applicant should show support in the original disclosure for the new or amended claims. See, e.g., Hyatt v. Dudas, 492 F.3d 1365, 1370, n.4 (Fed. Cir. 2007) (citing MPEP § 2163.04 which provides that a "simple statement such as ‘applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the claim limitation ‘___’ in the application as filed’ may be sufficient where the claim is a new or amended claim, the support for the limitation is not apparent, and applicant has not pointed out where the limitation is supported."); see also MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure."); and MPEP § 2163.04
Claim 2 has been amended to recite, “A method for detecting adapter dimers in a DNA library during a qPCR, wherein the DNA library comprises DNA fragments which are flanked at both free ends by adapter molecules including a first adapter molecule having a first adapter nucleotide sequence and a second adapter molecule having a second adapter nucleotide sequence, and adapter dimers including the first and second adapter molecules, comprising: adding the an adapter dimer-specific probe to a qPCR batch comprising the DNA library, wherein the adapter dimer-specific probe comprises a fluorophore labelling the probe and designed to bind specifically to the first adapter nucleotide sequence of the first adapter molecule and to the second adapter nucleotide sequence of the second adapter molecule; determining a number of adapter dimers contained in the DNA library using a signal emitted by the adapter dimer-specific probe; andcalculating an actual number of DNA fragments in the DNA library using the determined number of adapter dimers.” The instant response asserts, “Claim 2 has been amended to place it in independent form by incorporating the limitations of claim 1 and providing antecedent basis for certain elements.” However claims 1 and 2 were amended on 8/14/2023. The response of 8/14/2023 asserts, “The abstract has also been amended. Each of the claims 1-6 has been amended. No new matter has been added. Applicants respectfully request entry of the above amendments and a prompt and favorable action on the merits.” Thus the response does not indicate where support for the amendment. Further the amendments now require, “designed to bind specifically to the first adapter nucleotide sequence of the first adapter molecule and to the second adapter nucleotide sequence of the second adapter molecule.” However the claims filed 8/14/2023 recited, “ a fluorophore labelling the probe designed
Claim 3 has been amended to recite, “wherein: adding the adapter dimer-specific probe includes adding at least one adapter-specific probe ; determining the number of adapter dimers includes determining using a signal emitted by the adapter-specific probe; calculating the actual number of DNA fragments includes calculating the actual number of DNA fragments using
Claim 4 has been amended to recite, “The method according to claimfurther comprising: determining the amount of DNA to be used in NGS sequencing based on the calculation of the actual number of DNA fragments
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-5 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, 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 2 recites,” dimer-specific probe.” The recitation of “dimer-specific” suggests there are dimer non-specific probe. The specification and claims provide no guidance on how to differentiate the relative terms of “dimer-specific” from dimer non-specific probe. Thus the metes and bounds are unclear.
Claim 2 further recites, “bind specifically to the first adapter nucleotide sequence of the first adapter molecule and to the second adapter nucleotide sequence of the second adapter molecule.” The recitation of bind specifically is a relative term which suggest there is also, bind non-specifically . The specification and claims provide no standard to differentiate bind specifically from bind non-specifically.
Further the claim recites, “determining a number of adapter dimers contained in the DNA library using a signal emitted by the adapter dimer-specific probe; and calculating an actual number of DNA fragments in the DNA library using the determined number of adapter dimers.” The recitation is vague unclear and incomplete how determining a number of adapter dimers is done and “calculating an actual number of DNA fragments in the DNA library using the determined number of adapter dimers.” Thus the metes and bounds are unclear.
The metes and bounds are unclear as the claim recites, “adding an adapter dimer-specific probe to a qPCR batch comprising the DNA library, wherein the adapter dimer-specific probe comprises a fluorophore labelling the probe and designed to bind specifically to the first adapter nucleotide sequence of the first adapter molecule and to the second adapter nucleotide sequence of the second adapter molecule; determining a number of adapter dimers contained in the DNA library using a signal emitted by the adapter dimer-specific probe; and calculating an actual number of DNA fragments in the DNA library using the determined number of adapter dimers.” The metes and bounds are unclear how adding to a qPCR batch allows for the determining and calculating step as the adding step does not explicitly require qPCR and/or anything which would require a signal to be emitted. Thus it is unclear how the determining and calculating is performed.
Claim 3 recites, “adding the adapter dimer-specific probe includes adding at least one adapter-specific probe for a first adapter molecule.” The claim is confusing and unclear as claim 2 requires, “wherein the adapter dimer-specific probe comprises a fluorophore labelling the probe and designed to bind specifically to the first adapter nucleotide sequence of the first adapter molecule and to the second adapter nucleotide sequence of the second adapter molecule;” Thus the claim appears to unclear as it attempts to define the “adapter dimer-specific probe” in different ways or alternatively claim 3 fails to further limit claim 2 as it defines adapter dimer-specific probe in a way different than the independent claim. Claim 4 recites, “further comprising: determining the amount of DNA to be used in NGS sequencing based on the calculation of the actual number of DNA fragments in the DNA library.” The claims appear to be vague, unclear and incomplete as it does not provide how to determine the amount of DNA to be used in NGS sequencing. Further the recitation, “the amount of DNA” lacks antecedent basis in the claim as neither claim 4 nor claim 2 provide antecedent basis for this limitation. Further it is unclear if or how “the amount of DNA” encompasses adapter dimer, or some other DNA.
Claim 5 recites, “wherein it is a targeted sequencing in which a length of the DNA fragments is known.” The recitation of “it” is vague unclear and incomplete as to what it is referencing.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 2-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to mental step or abstract idea without significantly more. The claim(s) recite(s) the abstract idea or mental step of determining and calculating . This judicial exception is not integrated into a practical application because no additional steps depend from or specifically integrate the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims provide no specific reagent or steps which provide for significantly more .
Claim analysis
The instant claim 2 is directed A method for detecting adapter dimers in a DNA library during a qPCR, wherein the DNA library comprises DNA fragments which are flanked at both free ends by adapter molecules including a first adapter molecule having a first adapter nucleotide sequence and a second adapter molecule having a second adapter nucleotide sequence, and adapter dimers including the first and second adapter molecules, comprising: adding an adapter dimer-specific probe to a qPCR batch comprising the DNA library, wherein the adapter dimer-specific probe comprises a fluorophore labelling the probe and designed to bind specifically to the first adapter nucleotide sequence of the first adapter molecule and to the second adapter nucleotide sequence of the second adapter molecule; determining a number of adapter dimers contained in the DNA library using a signal emitted by the adapter dimer-specific probe; and calculating an actual number of DNA fragments in the DNA library using the determined number of adapter dimers. The determining a number of adapter dimers contained in the DNA library using a signal emitted by the adapter dimer-specific probe is a calculation to determine number using the emitted signal and thus is a judicial exception of mental step, abstract idea. Further the “calculating an actual number of DNA fragments in the DNA library using the determined number of adapter dimers” is a judicial exception of mental step, abstract idea, calculation.
The adding an adapter dimer-specific probe to a qPCR batch comprising the DNA library is considered to be an active step requiring a sample.
Dependent 3 provides determining and calculating step similar to the independent claims. Claim 4 provides another determining step which is also a calculation, mental step, abstract idea or judicial exception. Claim 5 provides a wherein clause which appears to limit the type of sequencing.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea, calculation or mental step.
With regards to claim 2, the claim recites, “determining a number of adapter dimers contained in the DNA library using a signal emitted by the adapter dimer-specific probe; and calculating an actual number of DNA fragments in the DNA library using the determined number of adapter dimers. ” These are abstract idea or mental step or calculation.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as in the claims provide no step which depend from or otherwise integrate the judicial exception.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No
With regards to claim 2 the claim requires a single active step adding a dimer-specific probe to qPCR batch The art of Heredia (Digital PCR (method and protocols: method in molecular biology 1768, pages 477-488) and Taylor (Scientific Reports | 7: 2409 | DOI:10.1038/s41598-017-02217) demonstrates this is routine and conventional.
Thus the claim does not provide additional steps which are significantly more.
Dependent claims fail to provide any limitations which integrate the judicial exception or provide for significantly more.
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.
Claim(s) 2-5 are is/are rejected under 35 U.S.C. 103 as being unpatentable over Heredia (Digital PCR (method and protocols: method in molecular biology 1768, pages 477-488) and Taylor (Scientific Reports | 7: 2409 | DOI:10.1038/s41598-017-02217
As detailed above the claims and confusing and unclear. This rejection is set forth in what can be interpreted from the claims. Claim 3 either fails to further limit the independent claim or demonstrates the adapter dimer specific probe can comprise two probes.
Heredia teaches, “Next-generation sequencing (NGS) has unlocked vast genetic information and accelerated discoveries in the life sciences and medicine which were unobtainable before. In order to utilize NGS technology, sequencing libraries are constructed typically with adapter sequences which bind to sequencing surfaces and are clonally amplified to boost signal. An important feature of such libraries is to ensure that the adapted library fragments are at a concentration which allows for efficient clonal amplification to occur without mixing with another adapted library fragment. This is achieved in various forms such as creating an emulsion where droplets of the emulsion contain a sequencing surface such as a bead particle and a single adapted library fragment which can bind to oligonucleotides complementary to the adapter sequence and thus be clonally PCR amplified in the droplets from the single starting template. Examples of the emulsion methodology include Ion Torrent™ and Roche 454® sequencing technologies [1, 2]. If the emulsions contain two or more adapted library molecules, then the resulting bead sequencing surfaces will generate mixed reads which cannot be differentiated. Thus, quantification of the input of adapted library molecules in to the emulsion is a critical component of the sequencing workflow. (477)
Heredia teaches,” The Droplet Digital PCR Next-Generation Sequencing Library QC Assay enables the user get highly accurate library quantification , and also provides information on the relative library size and amount of adapter dimers generated in the library construction process. “
Heredia teaches
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Heredia teaches,” The TruSeq library quantification kit contains a 5′-nuclease assays designed to detect and quantify both the P5 and P7 adaptor arms (Fig. 1a, b). The combined signal from each assay is thus used to confirm the formation of bona fide library fragments, which display themselves as double-positive clusters within the 2-channel plot (Fig. 2). Additionally, by exploiting the ability of the QX-100 platform to detect subpopulations of templates with differing amplification efficiencies and with different combinations of P5 and P7 moieties a qualitative measure of library purity can be obtained.” (483) Heredia teaches, “ These intentional assignments for the library clusters enable the user to quantify the total number of library molecules which could occupy space on sequencing flow cell, specifically those library molecules which contain either insert or empty adapter-dimers and these are quantified in the FAM channel data in QuantaSoft. By assigning the adapter dimers cluster as double positive, it is possible to simultaneously quantify what percent of the total library molecules are empty adapter dimers, which can be quantified in the HEX channel on QuantaSoft. Figure 5b plots the concentration values across the dilutions series in the FAM and HEX channels according to the assignments in Fig. 5a. The data obtained in Fig. 5c allows the user to compute the percent of adapter-dimers (HEX) compared to the total library molecules (FAM) values. Figure 6 demonstrates the power of ddPCR library QC by quantitating 12 different sequencing libraries, pooling them together based on the results at equimolar concentrations, and sequencing them to show excellent concordance between ddPCR balancing and the number of reads obtained from each library on the illumina sequencer.” (483-486).
Heredia teaches digital droplet PCR. Heredia does not teach qPCR.
However, Taylor teaches ddPCR vs qPCR. (title, abstract) Taylor teaches, “The data generated from standard curves of 1/2 serially diluted DNA in water gave the expected results with excellent precision, reaction efficiency and similar dynamic range for both ddPCR and qPCR platforms (Fig. 1). Thus, for samples that contain very low or no levels of background contaminants, ddPCR and qPCR technologies give similar performance for absolute and relative quantification. However, in the case of miRNA and mRNA, the components of the reverse transcription (RT) reaction can also act as inhibitors of Taq polymerase, altering reaction efficiency and the associated Cq values to give artifactual qPCR data if not adequately diluted (Fig. 2)1” (page 4, bottom)Taylor teaches, “qPCR is an excellent tool for the detection of 2 fold or greater expression differences with good statistical significance above about 100 copies (<30 Cqs) in applications such as gene expression and/or miRNA analysis and absolute DNA quantitation. Although reference gene normalization serves the important purpose of correcting for differential loading of cDNA between samples, it may not reduce contaminant dependent data variability observed with qPCR (Figs 3 and 4) which can only be addressed through sample dilution7. Thus quantification of low expressing/abundant targets using qPCR is challenging because sample dilution is not possible to adequately minimize the effect of contaminants while maintaining quantifiable levels of cDNA. ddPCR technology permits quantification of these samples with excellent precision.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to do both qPCR for ddPCR. The artisan would be motivated to determine if qPCR provided similar results as ddPCR taught by Heredia provide the same quantitation of adapter dimers and target sequences in the DNA library.. The artisan would have a reasonable expectation of success as the artisan is merely substituting one PCR technique for another.
With regards to claim 3, Heredia teaches a probe to adapter specific probe to a first adapter and determining the amount of adapter dimers and target nucleic acid.
With regards to claim 4, Heredia teaches a probe to adapter specific probe to a first adapter and determining the amount of adapter dimers and target nucleic acid.
With regards to claim 5, Heredia teaches,” 12. Access NGS library quality by quantitating adapter dimers. It is possible to assess adapter dimer concentrations if there are two or more distinct clusters and the user is confident, based on expected sizes of the library that there is an additional unaccounted for cluster which should be assigned to adapter dimers. “
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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