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 .
Status of the Application
Claim(s) 1-18 are pending and under examination
Claim(s) 19 and 20 are canceled.
Applicant’s election without traverse of Group I, which includes Claims 1-18 in the reply filed on 08/11/2026 is acknowledged.
Claim Objections
Claim 13 objected to because of the following informalities: claim 13 recites “standards comprises 1x1010 or greater, 10x1010 or greater, or 100x1010 or greater standards”, which appear to be a typographical or grammatical error. The applicant likely intended to write 1x1010 or greater, 10x1010 or greater, or 100x1010 or greater standards per ¶0033, 0065 0198 of Applicant’s specification. Appropriate correction is required.
Claim Interpretation
For purposes of examination, the “5' universal oligonucleotide” and “3' universal oligonucleotide” are interpreted as sequence portions incorporated into the same nucleic acid construct containing the UMI and the intervening region (not two separate pieces of nucleic acids). This interpretation follows from claim 1’s limitation of “at least one region between” the UMI and either universal oligonucleotide, wherein region determines the length of the standard, and interpretation is consistent with applicant’s Fig. 2B.
Claim Rejections - 35 USC § 112(b)
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.
Claim(s) 14 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 14 recites “the number of standards in the pool is greater than the number of amplicons generated by an amplification reaction.” However, neither claims 1 nor claim 14 defined the recited “amplification reaction”. The claims do not specify the template subjected to amplification, the amount of starting material, the number of amplification cycles, reaction conditions, primers, polymerase, or any other parameter from which the number of amplicons generated by amplification can be determined. Hence it is unclear what amplification reaction provides the required comparison, what number of amplicons can be used as reference value, and consequently what number of standards required in the claim scope. Since one of ordinary skill in the art cannot determine with reasonable certainty the scope of protection, the metes and bounds of the claim are unascertainable. Accordingly, claim 14 is not examined any further, as the claim language does not to define amplification reaction with sufficient clarity to permit meaningful patentability analysis.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-2, 4-15 and 17-18 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Christians et al. (US20170275691A1, EFD: March 24th 2017).
Regarding claim 1, Christians discloses a pool of nucleic acid standards of different lengths, wherein the nucleic acid standards comprise a unique molecular identifier (UMI) and: a) a 5′ universal oligonucleotide, wherein the 5′ universal oligonucleotide is the same for all standards; b) a 3′ universal oligonucleotide, wherein the 3′ universal oligonucleotide is the same for all standards; and c) at least one region between the UMI and the 5′ universal oligonucleotide and/or between the UMI and the 3′ universal oligonucleotide; wherein the length of the at least one region determines the length of the standard. [figure 4 below and ¶0193-0195]
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Regarding claim 2, Christians discloses the pool further comprises a further nucleic acid standard that comprises a UMI and: a) a 5′ universal oligonucleotide, wherein the 5′ universal oligonucleotide is the same for all standards; and b) a 3′ universal oligonucleotide, wherein the 3′ universal oligonucleotide is the same for all standards; wherein the further nucleic acid standard does not comprise at least one region between the UMI and the 5′ universal oligonucleotide or between the UMI and the 3′ universal oligonucleotide. (e.g. synthetic spiked-in nucleic acids, such as Spark nucleic acids, may comprise fixed forward sequence and/or a fixed reverse sequence and a unique barcode sequence. The fixed forward sequence and/or fixed reverse sequence can be common to all nucleic acids in the Spark size set. [¶0193-0194])
Claims 4 and 5 recited “an amplicon amplified from a sequence of interest” , which constitutes a product-by-process limitation. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) See MPEP § 2113. Accordingly, claims 4 and 5 do not recite any structural characteristics that distinguishes the recited amplicon from the corresponding nucleic acid recited in claim 1, but merely specify the nucleic acid is produced by amplification. Thus, rejection of claim 1 applies to claims 4 and 5. Moreover, Christians discloses spike-in synthetic nucleic acids may contain genomic DNA, PCR products, or any combination thereof [¶0144].
Regarding claim 6, Christians discloses one region between the UMI and the 5′ universal oligonucleotide and/or between the UMI and the 3′ universal oligonucleotide each comprise an arbitrary sequence. (“arbitrary sequence” is interpreted as a simply a nucleic acid sequence comprising nucleotides, without requiring any particular nucleotide sequence or sequence identity. The specification further explains the sequence maybe random or known/not random [¶0222]. Christians teaches the variable length region comprises filler sequence, which a nucleic acid sequence made of nucleotides [¶0195], this disclosure meets the recited “arbitrary sequence” limitation. If applicant meant to claim “arbitrary sequence” as a sequence “ not related to the sequence of interest” per ¶0195 in specification, Christians also teaches spike-in synthetic nucleic acids contain no human nucleic acids, no nucleic acids that can be found in nature, no sample nucleic acids [¶0147].)
Regarding claims 8 and 9, Christians discloses the standards comprise double-stranded DNA (e.g. spike-in synthetic nucleic acids may contain double-stranded DNA [¶0144])
Regarding claims 10-12, Christians discloses each standard comprises a different UMI, wherein the UMIs are a random set of sequences comprising 18 base pairs. (e.g. Spark size set contain a unique forward sequence and/or a unique reverse sequence. The unique sequence can distinguish Sparks in the size set from each other. The unique sequence can be 18 bp [0194]. The unique sequence can be degenerate/randomized [¶0225 and ¶0049])
Regarding claim 13, Christians discloses the pool of standards comprises 1×1010 or greater standards, wherein each standard comprises a different UMI. (e.g. Spank nucleic acids can have a diversity of about or at least about 1×1011 unique sequences. [¶0228]).
Claims 7 recites “partially overlapping oligonucleotide” limitation, which is interpreted consistent with definition as “ identical over at least a portion of its sequence for all the standards”. Thus, the term encompasses oligonucleotides that overlap partially or entirely in the sequence.
Christians discloses pool of nucleic acid standards of different lengths, wherein the nucleic acid standards comprise a UMI and: a) a 5′ partially overlapping oligonucleotide, wherein the 5′ partially overlapping oligonucleotide is identical over at least a portion of its sequence for all the standards; and/or b) a 3′ partially overlapping oligonucleotide, wherein the 3′ partially overlapping oligonucleotide is identical over at least a portion of its sequence for all the standards; wherein the lengths of the 5′ partially overlapping oligonucleotide and/or the 3′ partially overlapping oligonucleotide determines the length of the standard. [Fig. 4 shown below]
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Regarding claim 15, Christians discloses a pool comprising plurality of Spark standards of different lengths. As discussed above with respect to claims 1 and 7, the Spark standards satisfy the limitations of both claims. Thus, the respective portions of the disclosed Spark standards meet the recited first and second portions of claim 15. Accordingly, Christians anticipated claims 15 for reasons discussed in claims 1 and 7.
Regarding claims 17, Christians discloses generating a pool of nucleic acid standards comprising: a) providing multiple copies of at least one sequence of interest comprising nucleic acids; b) providing a collection of oligonucleotides each comprising a UMI; and c) ligating at least one sequence of interest of (a) and at least one oligonucleotide comprising a UMI of (b). (e.g. (a) obtaining a sample comprising: (i) target nucleic acids; (ii) sequencing adapters; (b) conducting a ligation reaction on the sample such that the sequencing adapters preferentially ligate to the target nucleic acids over the at least one synthetic nucleic acid [0021]. Adapter may comprise a unique identifier sequence [¶0112])
Regarding claims 18, Christians discloses method of normalizing amplicon size bias comprising: a) combining a sample comprising a target nucleic acid with a pool of nucleic acid standards of different lengths, wherein each standard comprises a UMI; b) amplifying the standards and amplicons of a sequence of interest comprised in the target nucleic acid; c) sequencing the standards and the amplicons of the sequence of interest to generate sequencing data; d) determining a bias profile based on amplicon size using sequencing data from the standards; and e) normalizing amplicon size bias using the bias profile. (e.g. a method of determining a relative abundance or an initial abundance of a pathogen nucleic acids in a sample, the method comprising: (a) obtaining the sample comprises a plurality of pathogen nucleic acids; (b) adding a plurality of synthetic nucleic acids of different lengths; (c) performing a sequencing assay on the sample comprising the plurality of synthetic nucleic acids, thereby determining a final abundance of the synthetic nucleic acids and a final abundance of the plurality of pathogen nucleic acids; (d) comparing the final abundance and the known initial abundance of synthetic nucleic acids in order to produce a recovery profile for the synthetic nucleic acids; and (e) using the recovery profile for the synthetic nucleic acids to normalize the final abundance of the plurality of pathogen nucleic acids [¶0013]. spiked-in synthetic nucleic acids comprise unique coding sequence [¶0138]. Steps for preparing a sequencing library may include one or more of: extracting target nucleic acids from a sample, fragmenting the target nucleic acids, attaching adapters to the target nucleic acids, amplifying the target nucleic acid-adapter complexes and sequencing the amplified target nucleic acid-adapter complexes [¶0114].)
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Christians et al. (US20170275691A1, EFD: March 24th 2017).
Regarding claim 3, Christians discloses filler sequence can be 0.2-0.5 kb [¶0195], which overlap with the claimed range of 0.2 kb-10 kb. It would have been prima facie obvious to a person of ordinary skill in the art to select filler sequence lengths within the overlapping range to produce standards of different lengths, as Christian teaches that changing the filler sequence length changes the lengths of standards [[¶0191-0196]. This modification represents optimization of a result effective variable. The discovery of an optimum or workable range would have been within the ordinary skill in the art through routine experimentations. See MPEP § 2144.05 "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); and In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003); "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness."
Regarding claims 16, Christians discloses spike-in nucleic acid may comprises sequence of interest (e.g. spiked-in synthetic nucleic acids may contain one or more domains or regions of interest [¶0136]), oligonucleotides each comprising a UMI (e.g. spiked-in synthetic nucleic acids comprise unique coding sequence [¶0138]), and oligonucleotides of varying lengths (e.g. spiked-in synthetic nucleic acids comprise load sequence of various lengths [¶0137]). Although Christians does not disclose ligation of the domains as a way to generating spike-in nucleic acids, it would have been prima facie obvious to a person of ordinary skill in the art to ligate the disclosed domains to assemble the synthetic spike in nucleic acid synthesis with reasonable expectation of success because Christians explicitly teaches ligation joins two nucleic acids via phosphodiester bond formation [¶0113, 0144, 0338]. Applying this method to oligonucleotide with compatible ligatable ends would predictably connect domains into a single construct while preserving their disclosed functions. This modification represents combining prior art elements according to known methods to yield predictable results as set forth in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143, A).
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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