DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant's election with traverse of Group II and the species of microbial nucleic acids in the reply filed on 04 September 2025 is acknowledged. The traversal is on the ground(s) that the claims are drawn to a single inventive concept and there would be no search burden to examine Group I with Group II. It is asserted that:
“independent claim 4 recites a method for enriching a target nucleic acid in a sample comprising, inter alia, "[4a] lysing the non-target cell by a cell lysis unit of a diagnostic system to release a non-target nucleic acid from the non- target cell; and [4b] depleting the non-target nucleic acid by a target nucleic acid enrichment unit of the diagnostic system, thereby [4c] enriching the target nucleic acid of the target microorganism in the sample," (emphasis added). Likewise, independent claim 1 recites a diagnostic system comprising, inter alia, "[la] a cell lysis unit configured to lyse a non-target cell in the sample, wherein the target microorganism and the non-target cell originate from different species; a target nucleic acid enrichment unit equipped with an immobilized adsorption device, connected to the cell lysis unit, and configured to [1b] deplete a nucleic acid of the lysed non-target cell, thereby [ic] enriching a nucleic acid of the target microorganism in the sample," (emphasis added). Accordingly, at least elements la, ib, and ic of claim 1 respectively correspond to elements 4a, 4b, and 4c of claim 4. “
This is not found persuasive because the particular diagnostic system of Group I is not required by the method of Group II and specifically independent claims 4 or 20 of Group II. The fact that the method of claim 4 of Group II includes a step of lysing non-target cells, depleting non-target nucleic acid and enriching for target nucleic acid does not mean that a search for the methods of Group II is co-extensive with a search of a diagnostic system comprising a cell lysis unit, a target enrichment unit, a sequencing unit and a sequence analysis unit. The methods of Group II do not require a sequencing unit or a sequence analysis unit, particularly wherein the sequencing unit is connected to the target nucleic acid enrichment unit and the sequence analysis unit is connected to the sequencing unit and configured to receive sequencing data. Further, the steps of lysing non-target cells and depleting non-target nucleic acids in the methods of Group II can be performed using alternative laboratory assays, such as manual lysis of cells in a tube and centrifugation of the resulting mixture to separate non-lysed cells from lysed cells/released target nucleic acids, respectively. Thus, the inventions require a different field of search including searching different classification symbols and employing different search strategies and queries. Accordingly, it is maintained that undue search burden would be required to search the invention of Group I together with the invention of Group II.
The requirement is still deemed proper and is therefore made FINAL.
Note however, that the species of bacterial nucleic acids (claim 10) is rejoined with the elected species of microbial target nucleic acids (claim 9).
Claim Status
3. Claims 1-20 are pending.
Claims 1-3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 4-20 read on the elected invention and have been examined herein.
Specification
4. The use of the terms TWEEN™ and TRITON™ which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
This is one example of a trademark that is used in the specification. The specification should be reviewed for any additional trademarks or trade names and the terms should be accompanied by their generic terminology and capitalized or where appropriate accompanied by a proper symbol.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
5. 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 17 and 20 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 17 is indefinite over the recitation of “an Illumina sequencing assay, a Nanopore sequencing assay, a PacBio sequencing assay.” The specification does not provide a limiting definition for what constitutes an Illumina sequencing assay, a Nanopore sequencing assay or a PacBio sequencing assay. Illumina and PacBio are names of companies that disclose and sell reagents for performing sequencing assays. However, there is no limiting definition for what constitutes an “Illumina sequencing assay” or a “PacBio sequencing assay” and the types of sequencing assays disclosed by Illumina and PacBio may change over time. Further, Oxford Nanopore Technologies has disclosed a sequencing assay but there is no limiting definition but the types of sequencing assays disclosed by this company may also change over time. It is not clear as to whether a “Nanopore sequencing assay” is intended to encompass any sequencing assay that utilizes a nanopore proteins or is intended to only encompass any currently known and later developed sequencing assay from Oxford Nanopore Technologies. Accordingly, the metes and bounds of the claimed subject matter is not clear.
Claim 20 contains the trademark/trade names TWEEN™ and TRITON™. MPEP 2173.05 states “If the trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982).”The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular type of oligonucleotide probe and, accordingly, the identification/description is indefinite.
Claim 20 is indefinite over the recitation of “contacting the sample with a solid phase” because it is not clear as to whether “the sample” refers to a) the sample that includes a target microorganism and a non-target cell or b) to the sample that has been contacted with a non-ionic surfactant or to the sample in both a) and b).
Claim Rejections - 35 USC § 102
6. 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.
Claim(s) 4-15 and 20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Singer et al (U.S. 20200331938).
Singer et al teaches a method for enriching a target microbial / bacterial nucleic acid in a sample (e.g., para [0009] and [0011]), comprising: providing a sample comprising a target microorganism and a non-target cell, wherein the target microorganism and the non-target cell originate from different species (e.g., a sample comprising eukaryotic cells and microbial cells (para [0011]); selectively lysing the non-target eukaryotic cells using one of the eukaryotic cell lysis agents listed at para [0153] (which step is considered to be a step of lysing non-target cells by a cell lysis unit of a diagnostic system) to release non-target eukaryotic nucleic acids from the non-target eukaryotic cells (see also para [0014], [0021] and [0151-0152]; and depleting the non-target eukaryotic nucleic acid from the sample treated with the eukaryotic lysis agent by contacting the sample with an anionic-exchange resin / microparticle (which is considered to be a target nucleic acid enrichment unit of a diagnostic system; see, e.g., para [0021], [0057] and [0142]), thereby enriching the target nucleic acid of the target microorganism in the sample.
Note that neither the specification nor the claims define what constitutes a “unit of a diagnostic system” as it applies to a “cell lysis unit of a diagnostic system” or a “target nucleic acid enrichment unit of the diagnostic system.” Nor do the claims require any connection or interaction between the units. The claims as broadly recited encompass methods wherein cell lysis is performed using a cell lysis agent and separately a target enrichment step is performed using an anion-exchange microparticle or other resin. Further, Singer teaches that the methods can be performed using an automated integrated device (e.g., para [0166], [0433] and thereby teaches that the lysing step and enrichment step are part of an integrated detection device.
Regarding claims 5 and 20, Singer teaches lysis of the non-target eukaryotic cells using a solution that comprises, for instance, the non-ionic surfactants of saponin, TWEEN™ or TRITON™ (e.g., para [0153]).
Regarding claims 6 and 20, Singer teaches depleting the sample of non-target nucleic acids using an anionic-exchange microparticle or resin, which is considered to be a “solid phase adsorbent,” and removing the anionic exchange microparticle or resin to thereby enrich the target nucleic acid in the sample (e.g., para [0021], [0057], [0148] and [0235]).
Regarding claim 7, Singer does not specify the length of the enriched target microbial DNA. However, in the absence of evidence to the contrary, the resulting enriched microbial DNA is considered to be at least 2,000 nucleotides in length since Singer teaches that amplicons produced from this microbial DNA may be between about 400 to 4000 bp in length (para [0323]). Note also that Singer teaches that the selective lysis of eukaryotic cells/ leukocytes in a sample did not affect the integrity of bacterial DNA from Borrelia burgdorferi (para [0459]).
Regarding claim 8, Singer exemplifies methods wherein “[t]he calculated removal rate was 99.95%±0.04% of the human DNA from 20 ml whole-blood” (para [0460]). Thereby, the method of Singer is one which results in at least a 10-fold enrichment of the target nucleic acid originally present within the sample. See also para [0463]
Regarding claims 9 and 10, Singer teaches that the target nucleic acid to be enriched is microbial nucleic acid and particularly is bacterial nucleic acid (e.g., para [0122]).
Regarding claims 11 and 12, as discussed above, Singer teaches that the non-target cell in the sample is a eukaryotic cell and particularly a mammalian cell (e.g., para [0010-0011], and [0013-0014]).
Regarding claims 13 and 14, Singer teaches that the sample is a biological sample from a subject suffering from an infection disease such as sepsis or pneumonia (para [0127]).
Regarding claim 15, Singer (para [0129]) states “the sample comprises a bodily fluid, bodily excretion, or bodily secretion, e.g., blood, urine, saliva, stool, or sputum. In some embodiments, samples are comprised of human blood.”
Claim Rejections - 35 USC § 103
7. 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) 16-18 is/are rejected under 35 U.S.C. 103 as being unpatentable Singer et al (U.S. 20200331938) in view of Nelson et al (Cell Reports. Feb 2019. 26: 2227-2240, e1-e5, and Supplementary Information p. 1-20, 40 pages total).
The teachings of Singer are presented above. Singer teaches sequencing the enriched nucleic acid using a sequencing assay to identify microorganisms present in the sample (e.g., para [0329] . Singer does not teach comparing sequencing data with a microbial genome database or resistance gene database and identifying a microorganism based on the result of the comparing.
However, Nelson teaches methods for identifying microorganisms present in samples obtained from human subjects (see abstract and p. 2228, col. 2). It is disclosed that following removal of human DNA, as well as extracellular DNA, from the sample obtained from a human subject, the enriched microbial DNA is analyzed by sequencing (see, e.g., abstract, p. 2228, col. 2 and p. e4-e5). The resulting sequencing data is then compared to sequencing information in databases, including an antibiotic resistance gene database and the SILVA database to identify particular microorganisms present in the sample (e.g., p. 2234, col. 1; p. e5 first full para; and p. 11 and 13-19 of Supplementary Information). Nelson teaches that this comparison of sequencing data aids in identifying the species of bacteria present in a sample (e.g., p. e5, first full para) and particularly aids in identifying antibiotic resistant microorganisms present in a sample (p. 2234, col. 2 to p. 2235, first para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Singer so as to have compared sequencing data generated by sequencing the enriched microbial nucleic acids with sequencing data in microbial genome database or resistance gene database so as to have accomplished the objective set forth by Nelson of accurately identifying the species of microorganism(s) present in a sample from a subject and determining their resistance to antibiotics.
Regarding claim 17, Singer does not specify the type of sequencing that is used to analyze the enriched microbial nucleic acids.
However, Nelson teaches that the enriched microbial nucleic acids are sequenced by next generation sequencing to generate sequencing data for metagenomic analysis (p. e4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Singer so as to have specifically performed the sequencing using a next generation sequencing assay since Nelson teaches that this is an effective means for sequencing enriched microbial nucleic acids to determine the identity of microorganisms present in a sample obtained from a subject.
Regarding claim 18, Singer teaches extracting the microbial nucleic acids from microbial cells present in the sample depleted of eukaryotic cells prior to performing the sequencing step (e.g., para [0014], [0021] and [0329]). Nelson also teaches extracting the microbial nucleic acids from microbial cells present in the sample depleted of eukaryotic cells prior to performing the sequencing step (p. e4 “Phylogenetic composition from metagenomic shotgun sequencing”).8. Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable Singer et al (U.S. 20200331938) in view of Nelson et al (Cell Reports. Feb 2019. 26: 2227-2240, e1-e5, and Supplementary Information p. 1-20, 40 pages total) and further in view of Lee et al (bioRxiv. 2016. Available via URL: <biorxiv.org/content/10.1101/048603v1.full.pdf>, p. 1-20).
The teachings of Singer and Nelson are presented above. The combined references do not teach that the sequencing of the enriched nucleic acid comprises generating sequencing data with at least 20 times the genome size of the target microorganism.
However, Nelson does exemplify sequencing methods in which “the mean coverage for detected resistance genes was 11.03, 17.83, 6.53, and 35.43 in samples 186, 205, 309, and 312, respectively” (p. 2234, col. 2). Nelson concludes that “(i)ncreased microbial sequencing coverage improves detection of important genes” (see “Highlights” on the coversheet).
Lee teaches that the error rate inherent in sequencing methods can be reduced by sufficient coverage (p. 3, first para). Lee compared the read lengths and coverage required to sequence genomes using different sequencing methods with high levels of accuracy (e.g., p. 8-9). Lee (p. 11) concludes:
“while our analysis suggests that 20x coverage of a genome should be enough to well assemble a genome, we recommend researchers sample >75x when using the new long read sequencing technologies to make the error correction steps most effective and to ensure high coverage is available of the longest reads. Ideally, if the budget and sample materials allows, we recommend assembling 20x coverage of error corrected reads exclusively over 20kbp long, using haploid or inbred samples if possible.”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Singer so as to have performed the sequencing assay at a high coverage, including at least 20x coverage of the genome, particularly when assembling a genome from the enriched microbial nucleic acids or performing long read sequencing assays in order to accomplish the objective set forth by Lee of ensuring the accuracy of the sequencing results.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682