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 .
DETAILED ACTION
Priority
This application is a continuation of International Application No. PCT/US2021/064445, filed December 20, 2021, which claims the benefit of U.S. Provisional Patent Application No. 63/128,552, December 21, 2020, U.S. Provisional Patent Application No. 63/199,497, filed January 3, 2021, and U.S. Provisional Patent Application No. 63/139,245, filed January 19, 2021, that is hereby acknowledged by the Examiner.
Status of the Claims
The amendment dated 09/03/2024 is acknowledged. Claims 95-132 are pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/16/2024 and 12/05/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the Examiner.
Drawings
The drawing filed on 06/20/2023 are acknowledged and accepted by the Examiner.
Claim Rejections - 35 USC § 112
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.
Claims 129 and 132 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 129 and 132 are rejected for containing a reference to tables. MPEP 2173.05(s) states “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant's convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). Reference characters corresponding to elements recited in the detailed description and the drawings may be used in conjunction with the recitation of the same element or group of elements in the claims. Generally, the presence or absence of such reference characters does not affect the scope of a claim. See MPEP § 608.01(m) for information pertaining to the treatment of reference characters in a claim’.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 95-103 and 105-125 are rejected under 35 U.S.C. 103(a) as being unpatentable over Christians et al. “Christians” (US PGPUB 2017/0275691) in view of Chiu et al. “Chiu” (WO2019213624, IDS of record dated 07/16/2024) and further in view of Wang et al. “Wang” (US Patent 10,928,401, priority publication date March 12, 2020).
The claims are directed to a method of detecting a secondary infection in a human subject with a
first infection, the method comprising:
(a) providing a first plasma sample from blood obtained from the human subject with the first infection, wherein the first plasma sample comprises microbial cell-free nucleic acids (mcfNA) from at least two different microbes;
(b) producing a sequencing library comprising mcfNA attached to adapters;
(c) measuring an amount of total mcfNA in the first plasma sample by performing massively parallel next generation sequencing on the sequencing library to obtain sequence reads comprising the mcfNA attached to adapters, wherein the total mcfNA comprises mcfNA from at least two different microbes;
(d) providing a second plasma sample from blood obtained from the human subject with the first infection, wherein the second plasma sample comprises one or more inflammatory biomarkers;
(e) measuring an amount of the one or more inflammatory biomarkers in the second plasma sample;
(f) comparing the amount of total mcfNA comprising mcfNA from at least two different microbes to a threshold amount of total mcfNA;
(g) comparing the amount of the one or more inflammatory biomarkers to a threshold amount of inflammatory biomarkers; and
(h) detecting a secondary infection that is different from the first infection when the amount of total mcfNA comprising mcfNA from at least two different microbes exceeds the threshold amount of total mcfNA and wherein the amount of the one or more inflammatory biomarkers exceeds the threshold amount of inflammatory biomarkers.
Regarding claims 95-99, 101-102, 111-119, 121 and 124-125, Christians discloses methods for determining relative abundance of one or more non-host species in a sample from a host. Also provided are methods involving addition of known concentrations of synthetic nucleic acids to a sample and performing sequencing assays to identify non-host species such as pathogens. Also provided are methods of tracking samples, tracking reagents, and tracking diversity loss in sequencing assays (Abstract). Christians discloses “In some cases, the test sample is a biological sample. In some cases, the biological sample is whole blood, plasma, serum, or urine. In some cases, the target nucleic acids are cell-free nucleic acids. In some cases, the cell-free nucleic acids are cell-free DNA (para [0056], microbial cell-free) (instant claim 96). Christians discloses the first and second pathogen nucleic acids are derived from either the same or different pathogens (para [0036]). Christians discloses a method of preparing a nucleic acid library from an initial sample, comprising: (a) adding one or more process control molecules to the initial sample to provide a spiked initial sample (para [0007]; "method further comprises generating a sequencing library from the sample, wherein the at least 1,000 synthetic nucleic acids are added to the sample before the generating the sequencing library"; para [0092]; "the methods provided herein involve the use of spike-in synthetic nucleic acids that have special features such as specific sequences, lengths, GC content, degrees of degeneracy, degrees of diversity, and/or known starting concentrations"); and (b) generating a nucleic acid library from the spiked initial sample (para [0007)). Christians discloses that the spike-in synthetic nucleic acids are added to unprocessed samples such as whole blood (para [0095]; "The methods may involve adding the spike-in synthetic nucleic acids to a variety of different samples including, but not limited to ... unprocessed samples (e.g., whole blood)") (para [0095]); and bioinformatic analysis includes “Synthetic spike-in reads are identified by aligning to the database of the full spike-in sequences. The remaining reads are aligned to a curated database of over 8000 reference sequences of viruses, prokaryotes, and eukaryotes including fungi, protozoa, and parasites. Duplicate reads, assumed to be derived from PCR duplication or sequencing instrument error, are identified based on alignment
and removed. Relative abundance of organisms is expressed as estimated deduped reads (EDR), or reads per million (RPM, normalized to total reads for the sample), or reads per volume of sample (MPM, molecules per microliter). MPM is a normalized quantity that calculates the estimated number of nucleic acid fragments represented for each organism in 1 microliter of plasma. This calculation is derived from the number of sequences present for each organism normalized to the known quantity of synthetic
DNA spiked into plasma at the beginning of the extraction” (para [0410] and [0412]) (instant claims 111-119). Moreover, Christians discloses the nucleic acid library may be prepared by a single or double-stranded DNA or RNA, whereby, for example, “ligating a primer docking sequence onto one end of the ssDNA fragment, and hybridizing a primer to the primer docking sequence. The primer can comprise at least a portion of an adaptor sequence that couples to a next-generation sequencing platform” (para [0252] and [0291]) (instant claim 95 steps (a) thru (c) and (f)).
Christians discloses the measuring the microbial cell-free nucleic acids (mcfNA) from at least two different microbes to a threshold amount of total mcfNA, Christians does not explicitly disclose a secondary infection.
Chiu, however, discloses methods, compositions and kits for detecting taxons of pathogenic microorganisms present in low titers in a sample. Compositions, methods and kits for detection of pathogenic co-infections are also provided (Abstract). Chiu also discloses a method of detecting a secondary infection in a subject with a first infection. Chiu states “In this manner, if the sample (environmental, plant, animal, and/or from a human subject) is possibly infected with, or has been exposed to one or more pathogenic microorganisms (including the first taxon of pathogens), embodiments allow for the screening of multiple pathogenic microorganisms using the same assay, while still allowing certain pathogenic microorganisms to be targeted so as to enable detection when present at low amounts” and “The Bayesian birth-death skyline model was used to estimate temporal changes in Re, the effective reproductive number of the CAM clade of ZIKV, directly from sequence data (FIG. 4C). For each point in time, Re represented the average number of secondary infections caused by a case (hence Re >1 and Re <1 represented epidemic growth and decline, respectively) (para [0006] and [0200]; Fig. 4C). It would have been obvious to one of ordinary skill in the art to generate a method of detecting infections in a human subject comprising mcfNA from plasma samples as disclosed by Christians whereby the method can detect secondary infections as disclosed by Chiu. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the fact that Chiu discloses “the sample may be an unprocessed sample (e.g., whole blood) or a processed sample (e.g, serum, plasma) that contains cell-free or cell-associated nucleic acids. In some embodiments, the sample is enriched for certain types of nucleic acids, e.g., DNA, RNA, cell-free DNA, cell-free RNA, cell-free circulating DNA, cell-free circulating RNA, etc” (para [0096]); and demonstrates the detection of secondary infections (Fig 4C).
Although Christians discloses the measuring the microbial cell-free nucleic acids (mcfNA) from at least two different microbes to a threshold amount of total mcfNA, Christians does not explicitly disclose providing a plasma sample from the subject comprising inflammatory biomarkers for measuring, comparing and detecting a secondary infection based on the one or more inflammatory biomarkers.
Wang, however, discloses methods and systems for diagnosing diseases and monitoring their progression and therapeutic responses by detecting a presence or absence, or an increase or decrease, of one or more substances in a sample (Abstract), using methods based on liquid chromatography, immunoassay, electrochemistry etc. (column 41 lines43-46) (instant claim 99). Wang discloses methods and systems for diagnosing a disease, determining the risk of developing a disease, monitoring the progression of a disease, and/or monitoring the therapeutic responses of a disease in a subject by measuring the concentration, quantity and/or amount of one or more substances in a substantially small amount (e.g., less than 5 microliters) of biological sample from the subject. The measured concentration, quantity and/or amount of one or more substances in the sample may or may not be compared with that in a control sample to make the diagnosis. For example, in some cases, an elevated or lowered amount of one or more substances in the sample of the subject may be indicative of a disease. In some cases, when compared with the control, the same level of one or more substances in the sample of the subject may signal the absence of a disease (column 14 lines 16-21). Wang discloses substances may comprise one or more markers whose presence or absence is indicative of a disease, disorder, infection or environmental exposure; whereby the marker can be a nucleic acid, a cell-free nucleic acid, a protein, a cellular component, or combinations thereof (column 29 lines 31-39) (instant claim 98); whereby “In some embodiments of aspects provided herein, the one or more nucleic acid molecules include cell free deoxyribonucleic acid (DNA) and/or cell free ribonucleic acid (RNA) (column 4 lines 13-16) (instant claim 97). Wang discloses embodiments of inflammatory biomarkers such as interleukin (IL)-1, IL-6, IL-8, Il-10, IL-1B, IL-1Ra, TNF-a monocyte chemoattractant protein-I (MCP-1) etc.), soluble CD40 ligand and serum amyloid A (SAA) (column 29 line 40 to column 30 line 23) (instant claims 95 steps (d), (e), (g) and (h); and 121 and 124-125).
Accordingly, it would have been obvious to one of ordinary skill in the art to generate a method of detecting a secondary infection in a human subject with a first infection as disclosed by Christians in view of Chiu, whereby inflammatory biomarkers are measured and compared for detection of an infection as disclosed by Wang. One of ordinary skill in the art would have been motivated with a reasonable expectation of success given the fact that Wang demonstrates utilizing cell-free nucleic acids for detecting inflammatory biomarkers for the accurate detection of infectious organisms (Example 8). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claim 100, Christian discloses embodiments of sequencing-by-synthesis in the methods (para [0262]).
Regarding claim 103, Christian discloses administering a therapeutic drug to the subject based on detecting an infection wherein the drug is an antimicrobial, and/or an antibiotic drug (paras [0302] and [0303]).
Regarding claims 105 and 106, Christians discloses the infection is a bacterial of fungal infection derived from different microbes or organism associated with an infectious disease or disorder (para [0178] and [0283]).
Regarding claims 107 and 110, Christians discloses S. aureus, P. aeruginosa (para [0421]) and Candida (para [0284]).
Regarding claims 108-109 and 122, With respect to the first infection being positive or negative pneumonia, it is not inventive and considered routine and obvious to one of ordinary skill in the art as routine experimentation/optimization. Christians states “The detection of pathogen or organ nucleic acids may involve comparing a level of pathogen or organ nucleic acids with a control or reference value in order to determine the presence or absence of the pathogen or organ nucleic acids and/or the quantity of pathogen or organ nucleic acids. The level may be a qualitative or a quantitative level. In some cases, the control or reference value is a predetermined absolute value indicating the presence or absence of the cell-free pathogen nucleic acids or cell-free organ-derived nucleic acids (para [0288]). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to detect any other types of diseases or conditions of the subject and/or detecting variations or nucleic acid sequences that make up a small portion of the total nucleic acid population in the sample.
Regarding claim 120, Christians discloses the subject has received an empiric antibiotic (para [0094]).
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 104 and 126-132 are rejected under 35 U.S.C. 103(a) as being unpatentable over Christians et al. “Christians” (US PGPUB 2017/0275691) in view of Chiu et al. “Chiu” (WO2019213624, IDS of record dated 07/16/2024) and Wang et al. “Wang” (US Patent 10,28,401, priority publication date March 12, 2020) as applied to claim 95 above, and further in view of Langford et al. “Langford” (Clinical Microbiology and Infection, epub July 2020, 26(2):1622-1629, IDS of record dated 07/16/2024). The teaching of Christians, Chiu and Wang are outlined above and incorporated herein.
Regarding claims 104 and 126-132, Christians discloses detecting, diagnosing and prognosing infections or diseases in patient samples, such as human blood samples. The methods may be used to detect rare microbial nucleic acid fragments in samples that are predominately made up of human nucleic acids. For example, cell-free DNA (cfDNA) in blood consists mostly of DNA fragments derived from the host but also contains a small amount of fragments from microbes in the body (para [0283]); exemplary diseases being SARS (para [0284]).
Christians does not explicitly disclose wherein the infection is COVID-19.
Langford, however, discloses bacterial coinfection with COVID-19 and treatment of the bacterial infection to determine the prevalence of bacterial co-infection and secondary infection in patients with COVID-19…The main outcome was the proportion of COVID-19 patients with an acute bacterial infection. Any bacteria detected from non-respiratory-tract or non-bloodstream sources were excluded…Bacterial co-infection is relatively infrequent in hospitalized patients with COVID-19. The majority of these patients may not require empirical antibacterial treatment” (Abstract); “Bacterial co-pathogens are commonly identified in viral respiratory tract infections such as influenza and are an important cause of morbidity and mortality, necessitating timely diagnosis and antibacterial therapy” (page 1622 column 2 para 1).
It would have been obvious to one of ordinary skill in the art to generate the method of detecting infections from a mcfNA as disclosed by Christians to detect a secondary infection as disclosed by Chiu utilizing inflammatory biomarkers as disclosed by Wang to include pathogens such as COVID-19 as disclosed by Langford. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the knowledge that Christians discloses their method may be used for SARS stating “For example, cell-free DNA (cfDNA) in blood consists mostly of DNA fragments derived from the host but also contains a small amount of fragments from microbes in the body (para [0283]); exemplary diseases being SARS” (para [0284]) and Langford teaches determining the prevalence of bacterial co-infection and secondary infections with COVID-19; and treatment of the bacterial infection, thus increasing the applicability and efficacy of the methods from Christians.
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Barry Chestnut whose telephone number is (571)270-3546. The examiner can normally be reached on M-Th 8:00 to 4:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BARRY A CHESTNUT/Primary Examiner, Art Unit 1672