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 .
Information Disclosure Statement
The IDS received on March 12, 2024 and March 17, 2025 are proper and are being considered by the Examiner.
Drawings
The drawings received on August 4, 2023 are acceptable.
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.
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 1, 2, 4, 5-6, 10, 11, 15-18, 20, 23, and 25-28 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 1 is indefinite because the claim recites the intent of “treatment” for B. spp infection, but does not actively recite any steps of treatment. Rather, claim 1 simply recites a diagnosis step for B. spp infection. For the purpose of prosecution, the claim has been construed as being directed to a diagnostic method where no active step of treatment is recited.
Claims 2, 4, 5-6, 10, 11, 15-18, 20, 23, and 25-28 are indefinite by way of their dependency on claim 1.
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 1, 2, 4-7, 10, 11, 15-18, 20, 23, and 25-28 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of natural correlation without significantly more. The claims recite a natural correlation of the presence of microbial cell-free nucleic acids of B. spp that which exists in an infected subject. This judicial exception is not integrated into a practical application because the claimed steps of the method do not actively integrate this judicial exception into a practical application. Specifically, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception based on the analysis under the current Patent Eligibility Guidelines (herein, “PEG”) as discussed below.
Step 1 Inquiry under PEG
Step 1 inquiry under Patent Eligibility Guidelines (herein, “PEG”) determines whether or not the claimed invention is drawn to one of the recognized statutory classes of invention. Claims 1, 2, 4-7, 10, 11, 15-18, 20, 23, and 25-28 satisfy the present inquiry as being drawn to a method.
Step 2A Inquiry under PEG
A recently revised PEG now performs step 2A inquiry under a 2-prong analysis, and the subject claims analyzed accordingly as follows:
Prong 1:
Prong-1 inquiry under step 2A determines whether the claims recite an abstract idea, a law of nature, or a natural phenomenon. As stated above, the claims are directed to a method of diagnosis1 based on the presence of cell-free DNA of B. spp. in a blood sample of an infected subject. Therefore, claims recite a judicial exception.
Prong 2:
Prong-2 inquiry under step 2A determines whether or not the claims recite additional elements that integrate the judicial exception into a practical application in a manner that imposes a meaningful limit on the judicial exception.
Claim 1 does not recite any additional elements other than the detection of cell-free DNA of B. spp. in blood samples of an individual that have been infected.
Claim 2, 5, 6, 10, 11, and 27 recite additional elements. Specifically, claim 2 recites the step of quantifying the cell-free DNA (claim 2), but recites in a highly generic means which simply tantamount to capturing the judicial exception itself without significantly more. Claims 5, 6, 10, 11, and 27 recite means of detecting the B. spp. by means of next generation sequencing that involve adapter attachment, alignment of the sequence read products against reference sequences, and spiking of controls for quantitation purposes, all of which is routinely done and provides no meaningful limitation to the judicial exception.
Claim 7 recites a step of “treatment” that recites, “administering a therapeutic treatment to the subject”. However, the Office has determined that this is not a specific treatment of condition so diagnosed because its dependent claim 8 further recites that the therapeutic treatment is Borrelia-directed therapy. If claim 8 is Borrelia-directed therapy, where the diagnosis of the subject is for Borrelia infection, then it becomes generic as to what claim 7 is treating. Therefore, claim 7 is not deemed to be a specific treatment to the condition so diagnosed.
Claims 15-18, 20, 23, 25, and 26 recite the condition of the subject, such as having arthritis of the joints, or the state of the subject (being after 6 month of tick bite), being serologically positive and amounts thereof). However, this is also judicial exception that correlates to an infection with the phenotype. Therefore, the claims do not add significantly more to the judicial exception discussed above.
As explained by the Supreme Court, in order to transform a judicial exception into a patent-eligible application, the additional element or combination of elements must do ‘more than simply stat[e] the [judicial exception] while adding the words ‘apply it’”. Alice Corp. v. CLS Bank, 573 U.S. __, 134 S. Ct. 2347, 2357, 110 USPQ2d 1976, 1982-83 (2014) (quoting Mayo Collaborative Servs. V. Prometheus Labs., Inc., 566 U.S. 66, 72, 101 USPQ2d 1961, 1965). Thus, for example, claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 134 S. Ct. at 2358, 110 USPQ2d at 1983. See also 134 S. Ct. at 2389, 110 USPQ2d at 1984 (warning against a § 101 analysis that turns on “the draftsman’s art”) (MPEP 2106.05(f))
Step 2B Inquiry under PEG
Step 2B inquiry of the PEG determines whether or not additional elements are provided and whether such elements amount to significantly more than the judicial exception in the claims.
Presently, the additional elements discussed above are recited in a general way and the additional elements are that which is routinely and conventionally involved in disease diagnostics based on molecular biology, such as the use of NGS sequencing from cell-free DNA samples.
Therefore, these elements are not deemed significantly more than inclusion of that are commonly used, routine and conventional.
Therefore, the present claims lack patent eligibility.
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, 7-9, 15-17, 20, 23, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Liebling et al. (Arthritis and Rheumatism, May 1993, vol. 36, no. 5, pages 665-675) in view of Wright et al. (American Family Physician, 2012, vol. 85, no. 11, pages 1086-1093).
With regard to claim 1, Liebling et al. teach a method of detecting the presence of Borrelia spp. infection in a subject comprising the steps of:
collecting one of more blood samples from the subject at the time when the subject does not have erythema migrans (EM) rash and wherein the one of more blood samples comprise microbial cell-free nucleic acids (“[n]inety-nine specimens of blood, urine, cerebrospinal fluid (CSF), or synovial fluid from 44 patients and 47 controls were obtained”, page 666, 1st column; see Table 1, where of the 99 specimens from 91 subjects, among the Lyme Disease patients, only samples 55 and 60 were from patients with erythema migrans);
detecting mcfNA from Borrelia spp. in one or more blood samples (“patients 17, 20, and 21) had B. burgdorferi DNA detected in their urine at a time when CNS symptoms were present. Similarly, 13 patients (41, 42, 45-47, 49, 52, 54-57, 61, and 62), representing both the early and late stages of Lyme disease, had B. burgdorferi DNA detected in their serum.”, page 670, 2nd column).
With regard to claim 15, the subject had arthritis of a joint (see Table 2).
With regard to claims 20 and 26, the subject is bitten by a tick carrying Borrelia bacteria by at least 6 months prior to collecting of the one or more blood sample (“the detection of Borrelia DNA in the 13 CSF samples from patients with neurologic manifestations and in 4 of the 5 synovial fluid samples from patients with arthritis suggests that even in the late stages of disease2, intact organisms are still present in these sites”, page 673).
With regard to claim 23, the subject is serologically positive for Borrelia antibodies (see Table 1, with SF column (serologic findings) and Serum column where Borrelia is found).
With regard to claim 27, the sensitivity of the detection was approximately 76.7% (“the specificity of this technique was 96.4%, with a sensitivity of 76.7%”, Abstract).
With regard to claim 28, the mcfNA is derived from B. burgdorferi (“we have used … a nested PCR technique, to detect B burgdorferi DNA in the body fluids of patients suspected of having Lyme disease”, page 665, 2nd column).
While Liebling et al. teach that their method is used for detecting the presence of Borrelia burgdorferi responsible for causing Lyme disease, the artisans do not explicitly teach that the diagnosed patients should be treated (claim 1, in-part, claims 7 and 8), utilizing drugs (claim 9).
While Liebling et al. explicitly teach that patients suffering Lyme disease shows varying symptoms, including arthritis of joints (see list of arthritic patients in page 666, 1st column, such as rheumatoid arthritis, juvenile polyarthritis, gouty arthritis, osteoarthritis, gonococcal arthritis, meningococcal arthritis, etc.), the artisans do not explicitly teach that the arthritis is from joint of a knee, elbow, temporomandibular joint and hip (claims 15 and 16).
Liebling et al. explicitly teach that the “gold standard” of positive Lyme testing that involves culturing, this standard is rarely achieved:
“Lyme disease is an infectious disorder in which ‘gold standard’ of diagnosis, i.e., culture of the etiologic agent from clinical material, is rarely achieved.” (page 672, 1st column)
However, Liebling et al. do not explicitly teach that the samples being assayed were culture-negative (claim 17).
Wright et al. teach a well-known practice of treating Lyme disease with an oral medication, doxycycline (“experts recommend doxycycline as the preferred agent for oral treatment”, page 1090, 2nd column).
Wright et al. teach the development of arthritis occur in Lyme patients who had been exposed to the infection prior to 6 months (“Arthritis is usually manifestation of late disease, and occurs in up to 60 percent of untreated patients … typically present approximately 6 months after infection with joint pain and swelling, and synovial fluid findings that suggests an inflammatory process. Chronic arthritis primarily involves the knees and hips”, page 1088, 1st column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Liebling et al. with the teachings of Wright et al., thereby arriving at the invention as claimed for the following reasons.
With regard to treating a patient diagnosed and/or suspected of having Lyme disease based on the method disclosed by Liebling et al. with a conventionally prescribed oral medicine, such as doxycycline, doing so would have been obvious as evidenced by Wright et al. who explicitly teach that the use of doxycycline for treating patients suspected/diagnosed with Lyme disease is a conventional practice, requiring no more than a common sense.
With regard to assaying for the presence of Borrelia spp. from patients with arthritis of joints of knee and hips, Liebling et al. explicitly teach that their subjects had arthritis, and while the artisans did not explicitly point to their location, based on Wright et al. who confirm that arthritic joints involve knees and hips in late-stage Lyme patients (which Liebling et al. also state late-stage), one of ordinary skill in the art would have been motivated to assay from patients with arthritic joints from locations associated with late-stage Lyme progression, such as knees and hips.
Lastly, because Liebling et al. explicitly teach that the “gold standard” of positive Lyme testing that involves culturing, is rarely achieved, one of ordinary skill I the art would have also been motivated to apply the teachings of Liebling et al. for subjects who exhibit symptoms of Lyme disease who have been serologically tested negative:
“Lyme disease is an infectious disorder in which ‘gold standard’ of diagnosis, i.e., culture of the etiologic agent from clinical material, is rarely achieved.” (page 672, 1st column)
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Claims 1, 4-9, 15-18, 20, 23, and 25-28 are rejected under 35 U.S.C. 103 as being unpatentable over Handel et al. (Poster Abstracts, 2019, suppl 2. Page S133; IDS ref) in view of Blauwkamp et al. (US 2017/0016048 A1, published January 19, 2017), Liebling et al. (Arthritis and Rheumatism, May 1993, vol. 36, no. 5, pages 665-675) and Wright et al. (American Family Physician, 2012, vol. 85, no. 11, pages 1086-1093).
With regard to claim 1, Handel et al. teach a method of assaying for B. spp. (B. burgdorferi) infection in a cell-free DNA of a subject (“[w]e sought to determine whether an emerging technology, next-generation sequencing (NGS) of microbial cell-free DNA (mcfDNA) can detect B. burgdorferi DNA”, page S133, 1st column), comprising the steps of:
collecting one or more samples from the subject, wherein the one or more blood samples comprise microbial cell-free nucleic acids (mcfNA) (“[p]atients aged 1-17 years with a clinically-identified single or multiple EM were enrolled … Three blood samples were taken during the study period”, page S133); and
detecting mcfNA from Borrelia spp. in one of more blood samples (“mcfDNA was extracted from plasma and NGS performed. Human reads were removed and remaining sequences were aligned to a curated microbial database. Only mcfDNA testing was performed …”, page S133).
With regard to claim 4, the sample is plasma (“mcfDNA was extracted from plasma and NGS performed”, page S133).
With regard to claim 6, Handel et al. teach that the sequence reads were aligned against a database of known sequences so as to identify the specific read fragments specific to Borrelia (“[h]uman reads were removed and remaining sequences were aligned to a curated microbial database”, page S133).
With regard to claim 28 the assay was directed for mcfNA from B. burgdorferi (see above).
The method taught by Handel et al. do not involve patient samples where EM rash were present and therefore, do not teach obtaining blood samples from subjects who does not have an EM rash at the time said sample was collected.
Handel et al. also teach that their method did not result in the detection of Borrelia spp. DNA sequences from the cell-free microbial nucleic acid and therefore, do not conclude in a diagnosis of its presence.
While Handel et al. explicitly teach that NGS (next generation sequencing) was performed on the plasma extracted cell-free DNAs from the samples, the artisans do not explicitly teach the process involved in NGS sequencing. Consequently, Handel et al. do not teach the ligation of adapters to the cell-free nucleic acids from plasma (claim 5), or administer treatment upon diagnosis for Borrelia spp. infection (claim 7), a therapy thereto (claim 8), using drugs (claim 9).
Handel et al. do not explicitly teach that the subjects had arthritis of a joint (claim 15), such as of knee, elbow, temporomandibular, and hip (claim 16).
Handel et al. do not teach that the blood culture is negative at the time of collecting of one or more blood samples (claim 17), or that the subject is negative for Borrelia by PCR test of a blood sample (claim 18).
Handel et al. do not teach that the subject had been bitten by a tick by at least 6 months prior to collection of the blood (claim 20).
Handel et al. do not teach that the subject is serologically negative for Borrelia antibodies (claim 23), or that the concentration of Borrelia mcfDNA is 1-1,000 molecules per microliter of plasma (claim 25).
Handel et al. do not teach that their tested subject has disseminated late-stage Lyme disease (claim 26), or that the sensitivity of the detection is at least 60% (claim 27).
Blauwkamp et al. teach a method of sequencing a particular population of cell-free nucleic acids of interest (such as infectious organisms or pathogens) from a sample comprising a complex mixture of cell-free nucleic acids, wherein the desired population of nucleic acids make up a minor portion of the complex mixture, wherein the artisans teach employing NGS (Next-Generation Sequencing) technology:
“present disclosure generally provides methods of identifying non-host nucleic acids in samples taken from a host and in which host nucleic acids are present … methods have a variety of applications, including, for example, identification of infectious or pathogenic organisms within a host through the analysis of cell-free samples taken from a host … enriched nucleic acids may then be analyzed in order to identify the presence of the non-host nucleic acids and the presence of a pathogen or infectious organisms within the host” (section [0004])
Blauwkamp et al. explicitly teach that the sample containing such cell-free nucleic acids of infectious agents or pathogens include plasma (“method begins by providing cell-free blood or plasma form the host”, section [0005]).
The process by which Blauwkamp et al. prepare the sample involves the cell-free nucleic acids from the sample being attached to adapters, and an eventual sequencing reaction by NGS:
“providing a sample of nucleic acids from the host, wherein the sample of nucleic acids from the host comprises host nucleic acids and non-host nucleic acids … mixing the sample of nucleic acids from the host with a collection of oligonucleotides, thereby obtaining a mixture, wherein the collection of nucleotides comprises at least 1,000 oligonucleotides with different nucleotide sequences, wherein the different nucleotide sequences are specifically selected to contain non-host nucleic acid sequences at least 10 nucleotides in length” (section [0006])
“collection of oligonucleotides comprising at least 1,000 oligonucleotides linked to a sequencing adapter sequence” (section [0025])
“method further comprises sequencing the primed or captured non-host nucleic acids by conducting a sequencing assay such as a Next Generation sequencing assay” (section [0007])
Liebling et al. teach a method of detecting the presence of Borrelia spp. infection in a subject by collecting one of more blood samples from the subject at the time when the subject does not have erythema migrans (EM) rash and wherein the one of more blood samples comprise microbial cell-free nucleic acids (“[n]inety-nine specimens of blood, urine, cerebrospinal fluid (CSF), or synovial fluid from 44 patients and 47 controls were obtained”, page 666, 1st column; see Table 1, where of the 99 specimens from 91 subjects, among the Lyme Disease patients, only samples 55 and 60 were from patients with erythema migrans) and detecting mcfNA from Borrelia spp. in one or more blood samples (“patients 17, 20, and 21) had B. burgdorferi DNA detected in their urine at a time when CNS symptoms were present. Similarly, 13 patients (41, 42, 45-47, 49, 52, 54-57, 61, and 62), representing both the early and late stages of Lyme disease, had B. burgdorferi DNA detected in their serum.”, page 670, 2nd column).
Liebling et al. teach that the subject had arthritis of a joint (see Table 2).
The subject is bitten by a tick carrying Borrelia bacteria by at least 6 months prior to collecting of the one or more blood sample (“the detection of Borrelia DNA in the 13 CSF samples from patients with neurologic manifestations and in 4 of the 5 synovial fluid samples from patients with arthritis suggests that even in the late stages of disease3, intact organisms are still present in these sites”, page 673).
The subject is serologically positive for Borrelia antibodies (see Table 1, with SF column (serologic findings) and Serum column where Borrelia is found).
The sensitivity of the detection was approximately 76.7% (“the specificity of this technique was 96.4%, with a sensitivity of 76.7%”, Abstract).
Liebling et al. explicitly teach that patients suffering Lyme disease shows varying symptoms, including arthritis of joints (see list of arthritic patients in page 666, 1st column, such as rheumatoid arthritis, juvenile polyarthritis, gouty arthritis, osteoarthritis, gonococcal arthritis, meningococcal arthritis, etc.).
Liebling et al. explicitly teach that the “gold standard” of positive Lyme testing that involves culturing, this standard is rarely achieved:
“Lyme disease is an infectious disorder in which ‘gold standard’ of diagnosis, i.e., culture of the etiologic agent from clinical material, is rarely achieved.” (page 672, 1st column)
Wright et al. teach a well-known practice of treating Lyme disease with an oral medication, doxycycline (“experts recommend doxycycline as the preferred agent for oral treatment”, page 1090, 2nd column).
Wright et al. teach the development of arthritis occur in Lyme patients who had been exposed to the infection prior to 6 months (“Arthritis is usually manifestation of late disease, and occurs in up to 60 percent of untreated patients … typically present approximately 6 months after infection with joint pain and swelling, and synovial fluid findings that suggests an inflammatory process. Chronic arthritis primarily involves the knees and hips”, page 1088, 1st column).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Handel et al. and their explicit suggestion, with the teachings of Blauwkamp et al., Liebling et al. and Wright et al., thereby arriving at the invention a claimed for the following reasons.
Handel et al. teach the motivation to employ NGS sequencing to detect the infectious agent known to be responsible for causing Lyme disease, that is, Borrelia burgdorferi, by detecting its microbial cell-free nucleic acid present in cell-free sample such as plasma:
“Diagnosing Lyme disease often involves laboratory evaluation, yet available tests have limitations. Serology remains negative for weeks after infection occurs, and may then remain positive for years. Borrelia burgdorferi blood PCR testing has low sensitivity, rendering it unhelpful. We sought to determine whether an emerging technology, next-generation sequencing (NGS) of microbial cell-free DNA (mcfDNA), can detect B. burgdorferi DNA in the plasma of pediatric patients with erythema migrans (EM)” (page S133).
Handel et al. employs a conventionally established means of generating sequence reads for the next-generation sequencing, which involves the attachment of sequencing adapters, generating sequence reads (as evidenced by Blauwkamp et al.), and identifying the microbial sequence reads by comparison against a reference database:
“mcfDNA was extracted from plasma and NGS performed. Human reads were removed and remaining sequences were aligned to a curated microbial database. Only mcfDNA testing was performed …” (page S133, Handel et al.)
Handel et al., however, concludes that no Borrelia sequence was found from their plasma samples via NGS:
“[a]ll 14 plasma samples … were negative for B. burgdorferi DNA by mcfDNA sequencing.” (page S133)
Handel et al., however, provides a rationale for such a finding in that the potential cause for finding was due to the fact that the B. burgdorferi infections were in its early stage infection and were still localized on the site of infection as presented in the erythema migrans rash:
“This approach is unlikely to be helpful in diagnosing early localized Lyme disease. This may be because spirochetes are localized to the periphery of the rash in EM and spirochetemia likely occurs at later stages of infection” (page S133)
Handel et al. also specifically provide a suggestion that this method should be applied for detections in, “late disseminated Lyme disease”, that is late-stage Lyme disease:
“[f]ollow-up studies are planned to investigate how NGS of mcfDNA performs during early and late disseminated Lyme disease” (page S133)
Indeed, Liebling et al. demonstrate that cell-free Borrelia burgdorferi nucleic acid sequences are found in patients having late-stage Lyme diseases where some do not present an EM rash (see above discussion of Liebling et al.) and Wright et al. teach that only 80 % of the patients actually develop EM and even lesser developing the classic EM rash associated with tick bites:
“As many as 80 percent of patients develop the characteristic erythema migrans rash, which may be confused with other similar conditions … Approximately 19 percent of erythema migrans rashes are a ‘bull’s-eye’ rash” (page 1087, Wright et al.)
Therefore, one of ordinary skill in the art would have been motivated to apply the teachings of Handel et al. to assay for the presence of Borrelia burgdorferi in cell-free samples of subjects suspected of having symptoms related to Lyme disease without the presentation of EM (which typically occurs during early onset of exposure.4).
And upon diagnosis, treating a patient diagnosed and/or suspected of having Lyme disease with a conventionally prescribed oral medicine, such as doxycycline would have been obvious as evidenced by Wright et al. who explicitly teach that the use of doxycycline for treating patients suspected/diagnosed with Lyme disease is a conventional practice, requiring no more than a common sense.
With regard to assaying for the presence of Borrelia spp. from patients with arthritis of joints of knee and hips, Liebling et al. explicitly teach that their subjects had arthritis, and while the artisans did not explicitly point to their location, based on Wright et al. who confirm that arthritic joints involve knees and hips in late-stage Lyme patients (which Liebling et al. also state late-stage), one of ordinary skill in the art would have been motivated to assay from patients with arthritic joints from locations associated with late-stage Lyme progression, such as knees and hips.
With regard to the application of Handel et al.’s method for samples which have been determined PCR-negative for the presence of Borrelia burgdorferi, one of ordinary skill in the art would have recognized that the sensitivity of the NGS assay as being far greater than that of a PCR reaction and thus would have been motivated to apply the teachings of Handel et al. for samples which may have been determined to be PCR-negative for Borrelia burgdorferi.
As to the concentration of Borrelia mcfDNA is 1-1,000 molecules per microliter of plasma, the Office contends that because the means employed for the detection is an identical process, that is, NGS, the sensitivity requirement would necessarily be met.
Lastly, because Liebling et al. explicitly teach that the “gold standard” of positive Lyme testing that involves culturing, is rarely achieved, one of ordinary skill I the art would have also been motivated to apply the teachings of Liebling et al. for subjects who exhibit symptoms of Lyme disease who have been serologically tested negative:
“Lyme disease is an infectious disorder in which ‘gold standard’ of diagnosis, i.e., culture of the etiologic agent from clinical material, is rarely achieved.” (page 672, 1st column)
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Claims 2, 10, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Handel et al. (Poster Abstracts, 2019, suppl 2. Page S133; IDS ref) in view of Blauwkamp et al. (US 2017/0016048 A1, published January 19, 2017), Liebling et al. (Arthritis and Rheumatism, May 1993, vol. 36, no. 5, pages 665-675) and Wright et al. (American Family Physician, 2012, vol. 85, no. 11, pages 1086-1093), as applied to claims 1, 4-9, 15-18, 20, 23, and 25-28 above, and further in view of Hardwick et al. (Nature reviews Genetics, June 2017, vol. 18, pages 473-484).
The teachings of Handel et al., Blauwkamp et al., Liebling et al. and Wright et al. have already been discussed above.
Handel et al., Blauwkamp et al., Liebling et al. and Wright et al. do not explicitly teach quantification of the Borrelia spp. cell-free nucleic acids from the sample (claim 2), nor spiking in of synthetic control DNAs (claims 10 and 11).
Hardwick et al. teach a method of quantifying during NGS reactions, wherein the method includes known concentrations of spike-in DNA standards (see Figure 1, also below):
“the abundance of a DNA sequence in a patient sample can be determined by comparison to a reference sequence of known abundance, along with the uncertainty associated with this measurement. This calibration allows standardization of measurements across multiple samples, and allows diagnostic thresholds to be anchored to reference standards” (page 474, 2nd column)
“Spike-ins are typically prepared individually and can be combined at different concentrations to formulate complex mixtures in which many features are represented and internal ‘ladders’ are built to measure the quantitative features of the accompanying sample” (page 478)
“Synthetic DNA spike-in controls have been used to represent instances of human genetic variations … The ability to represent genetic variation, particularly with clinical relevance, enables spike-ins to evaluate the detection of these variants with NGS technologies … By manipulating the abundance of specific DNA spike-ins, it is also possible to simulate quantitative features of genome biology … These internal DNA spike-in ladders can derive quantitative statistics that are specific to an individual library” (page 478)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Handel et al., Blauwkamp et al., Liebling et al. and Wright et al. with the teachings of Hardwick et al., thereby arriving at the invention as claimed for the following reasons.
The rationale to do so is supported by the Supreme Court in KSR, wherein the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Analogously, the use of a spiked-in synthetic DNA control in the method of Handel et al. would have allowed the quantitation of the Borrelia burgdorferi nucleic acid sequences from the sample, a routine determination of a diagnostics assay.
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 December 15, 2025
/YJK/
1 Claim interpretation made under 112(b) rejection.
2 Late-stage of Lyme disease is known to include months to years subsequent to the exposure.
3 Late-stage of Lyme disease is known to include months to years subsequent to the exposure.
4 Wright et al., see Tables 1 and 4, where EM rash is shown in early stage of infection.