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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/29/2026 has been entered.
Claims Status
The amendment filed on 04/29/2026 has been entered.
Claims 1 and 12 were amended in the claim set filed on 04/29/2026.
Claims 1-15 are pending.
Applicant’s election without traverse of Group I (claims 1-7), drawn to a kit comprising spike-in internal standard (IS) reagents, in the reply filed on 05/15/25 is acknowledged. 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Claims 8-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, drawn to a method, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/15/2025.
Claims 1-7 are currently under examination.
Priority
This application is a 371 of PCT/US20/60333 filed on 11/13/2020 which claims benefit of 62/935,705 filed on 11/15/2019. Accordingly, the priority date of instant claims is determined to be 11/15/2019, the filing date of 62/935,705.
Specification
The reference in the specification is not a proper information disclosure statement. The specification filed on 05/11/2022 includes a reference on page 10. 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 § 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.
Claims 1-2 and 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Willey et al. (“Willey”; Patent App. Pub. No. WO 2014082032 A1, May 30, 2014) in view of Herbert Marble (“Marble”; Patent App. Pub. No. US 20140287946 A1, Sept. 25, 2014).
Willey discloses the controlling for non-systematic error in an amplification-based next generation sequencing (NGS) library preparation comprises including of an internal amplification control (IAC) sharing identical priming sites to a native nucleic acid target template of interest in a NGS library preparation; and mimicking the kinetics of the native nucleic acid target in the amplification reaction, and controlling for sample-, platform-, experiment-, operator-and/or target-specific variation in amplification efficiency. (Abstract)
Regarding claim 1, Willey teaches a product comprising “internal amplification control (IAC)/competitive internal standards (IS) described herein may be assembled and provided in the form of kits” and “The IAC may be provided in… several known working concentrations” (Para. 238). Willey teaches a product comprising “a mixture of a known number (i.e., abundance, concentration and/or amount) of internal standard nucleic acid molecules corresponding to unique nucleic acid targets (also defined as 'native target" or NT)” (Para. 73). Willey teaches a product comprising “Each nucleic acid target is similar to its respective internal standard, with the exception of one or more changes to the nucleic acid sequence. These differences between native target and internal standard are identifiable with sequencing, and can include … alteration to the ordering or composition of nucleotides used” (Para. 74). Willey teaches a product comprising “Each of the competitive IAC contained identical target-specific priming sites to their respective native nucleic acid template targets” (Para. 107) and “Internal standard… contains one or more base substitutions internal to the primer sites” (Para. 159).” Willey also teaches a product comprising “standardized mixtures comprising a competitive template for said first nucleic acid and a competitive template for a second nucleic acid … wherein said competitive templates are at known concentrations relative to each other … obtaining a first relationship…obtaining a second relationship … and comparing said first and said second relationships” (Para. 19) and “combined in a 1:1 stochiometric molar ratio” (Para. 154). “a mixture of a known number (i.e., abundance, concentration and/or amount) of internal standard nucleic acid molecules corresponding to unique nucleic acid targets (also defined as 'native target" or NT)” reads on contains multiple synthetic internal standard (IS) sequences at different concentrations for a single endogenous target gene and mixed at different known concentrations relative to each other. “comparing said first and said second relationships” reads on at a known ratio relationship. “so that each IS sequence is distinguishable from the IS sequence at each other concentration” is interpreted as intended use. It is noted that the courts have held that “while features of an apparatus may be recited either structurally or functionally, claims directed to an apparatus must be distinguished from the prior art in terms of structure rather than function.” In re Schreiber, 128 F.3d 1473, 1477-78, 44 USPQ2d 1429, 1431-32 (Fed. Cir. 1997). In addition, “[A]pparatus claims cover what a device is, not what a device does.” Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). See MPEP § 2114.
Thus, Willey suggests a kit for quantifying the amount of at least one nucleic acid of interest in a sample, comprising: spike-in internal standard (IS) reagents present as a complexity calibration ladder (CCL) that contains multiple synthetic internal standard (IS) sequences at different concentrations for a single endogenous target gene, wherein the IS sequence, at each concentration, contains a nucleotide change at a different position along the sequence so that each IS sequence is distinguishable from the IS sequence at each other concentration; and wherein the multiple internal standard (IS) sequences for the single endogenous target gene are mixed at different known concentrations relative to each other, and at a known ratio to IS for other targets.
While Willey does broadly suggest the IS sequence, at each concentration for the single endogenous target gene, contains a nucleotide change at a different position along the sequence (Para. 73-74, etc.), Willey does not explicitly teach wherein the IS sequence, at each concentration, contains a nucleotide change at a different position along the sequence. Willey teaches that “many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof.” (Para. 243).
Marble discloses technology relating to detecting nucleic acids in a sample and particularly, but not exclusively, to systems and methods related to panels that are used to evaluate sequencing efficacy. (Abstract)
Marble teaches a product comprising "kits for carrying out any of the methods, the kits having one or more or all of the components necessary, useful, or sufficient to conducts the methods… kits for determining the specificity and/or sensitivity of a nucleic acid sequencing reaction comprising one or more or all of: a) a plurality of synthetic nucleic acids in predetermined concentrations that differ in sequence and concentration from each other and that differ in sequence from a target nucleic acid" (Para. 16; Para. 26). Marble also teaches a product comprising "predetermined concentrations of a plurality of synthetic nucleic acids to a sample containing a target nucleic acid, wherein two or more different members of said plurality of synthetic nucleic acids differ from one another in concentration and sequence" (Para. 11; Para. 26) and “the synthetic nucleic acids and the target nucleic acid differ by one or more single nucleotide polymorphisms. For example, in some embodiments, the synthetic nucleic acids differ from each other by the location of the single nucleotide polymorphism” (Para. 11; Para. 26). Thus, Willey and Marble suggest a kit for quantifying the amount of at least one nucleic acid of interest in a sample, comprising: spike-in internal standard (IS) reagents present as a complexity calibration ladder (CCL) that contains multiple synthetic internal standard (IS) sequences at different concentrations for a single endogenous target gene, wherein the IS sequence, at each concentration, contains a nucleotide change at a different position along the sequence so that each IS sequence is distinguishable from the IS sequence at each other concentration; and wherein the multiple internal standard (IS) sequences for the single endogenous target gene are mixed at different known concentrations relative to each other, and at a known ratio to IS for other targets.
Willey and Marble are both considered to be analogous to the claimed invention because they are in the same field of nucleic acid standard controls. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the kit for quantifying the amount of at least one nucleic acid of interest in a sample comprising spike-in internal standard reagents as taught by Willey to incorporate wherein the IS reagent, at each concentration for the single endogenous target gene, contains a nucleotide change at a different position along the sequence as taught by Marble and provide a product according to the limitations of claim 1. One of ordinary skill in the art would have been motivated to do so in order to have a kit that is used for the standardization of nucleic acid detection of a sample as well as evaluation of efficacy of the controls used in nucleic acid assays. One of ordinary skill in the art would have had a reasonable expectation of success given that internal standards such as ACCL controls are known standards that have been developed as a standard amongst researchers to help measure reproducible lower limit sensitivity of quantified data and are commercially available and these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1. Doing so would improve assessment parameters for sensitivity and specificity of nucleic acid detection in nucleic acid assays such as PCR, Multiplex-PCR and next-generation sequencing (NGS).
The teachings of Willey and Marble are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claims 2 and 6-7, depend on claim 1. Claims 4-5 depend on claim 2, which depends on claim 1.
Regarding claim 2, Willey teaches a product wherein “competitive IS corresponding to the endogenous targets” (Para. 153). Willey also teaches a product wherein “External RNA Control Consortium (ERCC)” (Para. 149) and “For the 28 competitive IS templates corresponding to ERCC targets, no such reference material exists for normalization” (Para. 155). Thus, Willey teaches a product wherein the spike-in IS reagents comprise one or more of: i) an endogenous complexity calibration ladder (ECCL) that includes synthetic internal standard competitors for at least one endogenous target gene; and ii) an alien complexity calibration ladder (ACCL) that includes synthetic internal standard competitors for at least one alien target gene.
Regarding claim 4, Willey teaches a product wherein “The kits may include … ERCC targets” (Para. 239). Thus, Willey teaches a product wherein the alien complexity calibration ladder (ACCL) comprises at least one of the External RNA Controls Consortium (ERCC) sequences.
Regarding claim 5, Willey teaches a product wherein “ERCC targets were synthesized” (Para. 151) and “Each ERCC target is at a different concentration” (Para. 160). Thus, Willey teaches a product wherein the endogenous complexity calibration ladder (ECCL) and/or the alien complexity calibration ladder (ACCL) comprises synthetic IS for the endogenous and/or alien target and includes IS sequences at different concentrations.
Regarding claim 6, Willey teaches a product wherein “The kits may also provide primers designed specifically to amplify the IS of 150 endogenous targets, the IS of 28 ERCC targets, and their corresponding native targets” (Para.240). The IS of 150 endogenous targets is interpreted as synthetic internal standards. Willey teaches a product wherein “internal amplification control (IAC)/competitive internal standards (IS) … provided in the form of kits” (Para.238). Willey teaches a product wherein “the kit provides the IAC and reagents necessary to perform a PCR, including Multiplex-PCR and next-generation sequencing (NGS).” (Para.238). Thus, Willey teaches a product further comprising reagents for measurement of expression and/or somatic mutations in multiple genes in a sample of cells, the kit including: a) PCR primers for each target gene; b) synthetic internal standard for each target gene; and c) reagents to prepare PCR products as a library for next generation sequencing, and/or oligonucleotides baits to capture IS and/or NT sequence fragments.
Regarding claim 7, Willey teaches a product wherein “a nucleic acid can comprise naturally occurring DNA, e.g., genomic DNA; RNA, e.g., mRNA, and/or can comprise a synthetic molecule, including but not limited to cDNA” and “can be, e.g., DNA, RNA, or hybrid DNA/RNA molecules” (Para. 62). Wiley teaches a product wherein “nucleic acid of interest" may be referred to as a "target" nucleic acid, and/or a "gene of interest," e.g., a gene being evaluated, may be referred to as a target gene” (Para. 61). Thus, Willey teaches a product wherein the nucleic acid of interest comprises one or more of: RNA to be measured, mRNA, DNA, cDNA, genomic DNA and variant alleles.
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have developed a kit with spike-in internal standard reagents (endogenous and/or alien complexity ladder(s) at different concentrations) to be used in at least one of PCR, Multiplex-PCR and next-generation sequencing (NGS) as taught by Willey. One of ordinary skill in the art would have been motivated to do so in order to have a kit that is used for the standardization of nucleic acid sequencing. One of ordinary skill in the art would have had a reasonable expectation of success given that internal standards such as ACCL controls are known standards that have been developed as a standard amongst researchers to help measure reproducible lower limit sensitivity of quantified data and are commercially available.
Response to Arguments
Applicant' s arguments filed 04/29/2026 (Pg.5) with respect to claim 1-2 and 4-7 have been considered but do not apply to the new grounds of rejection. To clarify some instances argued in the response filed 04/29/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Willey describes that these changes are used for each gene-specific IS to distinguish the IS from the native gene target, not to differentiate ISs among different concentrations for the same target gene... Willey does not teach or suggest the IS sequence, at each concentration for the single endogenous target gene, contains a nucleotide change at a different position along the sequence so that each IS sequence is distinguishable from the IS sequence at each other concentration for the single endogenous target gene.” (Pg. 5)
Response: Applicant's arguments filed 04/29/2026 have been fully considered but do not apply to the new grounds of rejection in view of Willey and Marble. As stated above in the non-final rejection towards claim 1 under 35 U.S.C. 103, Willey teaches a product comprising “internal amplification control (IAC)/competitive internal standards (IS) described herein may be assembled and provided in the form of kits” and “The IAC may be provided in… several known working concentrations” (Para. 238). Willey teaches a product comprising “a mixture of a known number (i.e., abundance, concentration and/or amount) of internal standard nucleic acid molecules corresponding to unique nucleic acid targets (also defined as 'native target" or NT)” (Para. 73). Willey teaches a product comprising “Each nucleic acid target is similar to its respective internal standard, with the exception of one or more changes to the nucleic acid sequence. These differences between native target and internal standard are identifiable with sequencing, and can include … alteration to the ordering or composition of nucleotides used” (Para. 74). Willey teaches a product comprising “Each of the competitive IAC contained identical target-specific priming sites to their respective native nucleic acid template targets” (Para. 107). “a mixture of a known number (i.e., abundance, concentration and/or amount) of internal standard nucleic acid molecules corresponding to unique nucleic acid targets (also defined as 'native target" or NT)” reads on contains multiple synthetic internal standard (IS) sequences at different concentrations for a single endogenous target gene and mixed at different known concentrations relative to each other. Furthermore, “so that each IS sequence is distinguishable from the IS sequence at each other concentration” is interpreted as intended use. It is noted that the courts have held that “while features of an apparatus may be recited either structurally or functionally, claims directed to an apparatus must be distinguished from the prior art in terms of structure rather than function.” In re Schreiber, 128 F.3d 1473, 1477-78, 44 USPQ2d 1429, 1431-32 (Fed. Cir. 1997). In addition, “[A]pparatus claims cover what a device is, not what a device does.” Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). See MPEP § 2114. Thus, Willey does suggest the IS sequence, at each concentration for the single endogenous target gene, contains a nucleotide change at a different position along the sequence .
Applicants’ argument: “For at least this reason, dependent claims 2 and 4-7 are also patentable over Willey.” (Pg. 6)
Response: Applicant's arguments filed 04/29/2026 have been fully considered but they are not persuasive. See response above towards claim 1.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Willey et al. (“Willey”; Patent App. Pub. No. WO 2014/082032 A1, May 30, 2014) in view of Herbert Marble (“Marble”; Patent App. Pub. No. US 20140287946 A1, Sept. 25, 2014) as applied to claims 1-2 and 4-7 above, and further in view of Jiang et al. (“Jiang”; (2011). Synthetic spike-in standards for RNA-seq experiments. Genome research, 21(9), 1543–1551.
The teachings of Willey and Marble are documented above in the rejection of claims 1-2 and 4-7 under 35 U.S.C. 103. Claim 3 depends on claim 2, which depends on claim 1.
Regarding claim 3, Willey teaches a product wherein “samples … were then combined with Ambion External RNA Controls Consortium (ERCC) Spike-In Control RNA Mixes” (Para. 144) and “Both the endogenous and ERCC target mixtures of competitive IS” (Para. 155). Of note, ERCC is specifically indicated as an example in the specification of the instant application (Para. 120, instant application). Thus, Willey suggests a product wherein the endogenous complexity calibration ladder (ECCL) is combined with an alien complexity calibration ladder (ACCL).
Although intrinsic to the design of ERRC Spike in controls, Willey and Marble do not explicitly teach the limitations of claim 3 that alien complexity calibration ladder is not competitive with the at least one endogenous target gene and is not affected by a sample's biological properties.
Regarding claim 3, Jiang teaches a product wherein “Importantly, ERCC RNAs show minimal sequence homology with endogenous transcripts from sequenced eukaryotes. In RNA-seq experiments, this minimizes confounding alignment of ERCC reads to the target genome” (Pg. 1544, Col. 1, Results, Para. 2). Thus, Willey, Marble and Jiang suggest a product wherein the endogenous complexity calibration ladder (ECCL) is combined with the alien complexity calibration ladder (ACCL), and wherein the synthetic internal standard competitors of the alien complexity calibration ladder (ACCL) are not competitive with the single endogenous target gene and is not affected by a sample's biological properties.
Willey, Marble and Jiang are considered to be analogous to the claimed invention because they are in the same field of nucleic acid standard controls. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the kit for quantifying the amount of at least one nucleic acid of interest in a sample as taught by Willey and Marble to incorporate wherein the synthetic internal standard competitors of the alien complexity calibration ladder (ACCL) are not competitive with the single endogenous target gene and is not affected by a sample's biological properties as taught by Jiang and provide a method according to the limitations of claim 3. One of ordinary skill in the art would have been motivated to do so in order to further evaluate the efficacy of the controls in nucleic acid assays. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 3. A person of ordinary skill in the art would have had a reasonable expectation of success in providing a spike in control reagent that comprises an ERCC that is non-competitive since both claim elements were known before the effective filling date of the claimed invention. Doing so would eliminate interference with transcript discovery and quantification when using alien complexity calibration ladder such as ERRC spike-in controls in eukaryotic genomes.
Applicants’ argument: “Jiang cannot supply the deficiencies of Willey because Jiang also fails to teach or suggest an IS sequence, at each concentration for a single endogenous target gene, containing a nucleotide change at a different position along the sequence so that each IS sequence is distinguishable from the IS sequence at each other concentration for the single endogenous target gene.” (Pg. 6)
Response: Applicant's arguments filed 04/29/2026 have been fully considered but they are not persuasive. See response above towards claim 1.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Amiss et al. (Patent Pub. No. WO 2016160823 A1, Oct. 6, 2016) (Para. 11, 22, 27) Claim 1; and Willey et al. (Patent No. US 9944973 B2, April 17, 2018). (Para. 51-52, 60-62 and 68) Claim 1. Willey et al. (Patent Pub. No. US 20150292001 A1, Oct. 15, 2015). (Claims 4-5) Claim 1.
No claims are in condition for allowance.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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