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 .
Examiner’s Note
2. There is not an attorney of record on file due to a lack of an official power of attorney (POA) of record. While an attorney number has been provided on the application data sheet (ADS; submitted 04/17/2023), this is not the equivalent of a POA or an authorization to act in a representative capacity. In order to expedite prosecution in the instant application, It is suggested that a POA be filed as per MPEP § 402 or MPEP § 1807 or an Authorization to Act in a Representative Capacity be filed as per MPEP § 403 in order for the Office to freely and openly discuss the merits of the case with the applicant’s representative. Please refer to https://www.uspto.gov/about–us/contact–us if you have questions regarding the proper filing of a power of attorney.
DETAILED ACTION
Priority
3. The instant application is a continuation–in–part of International Patent Application No. PCT/US2021/010031 filed on 08/04/2021.
Information Disclosure Statement
4. No information disclosure statement (IDS) was present at the time of this office action. Applicant is reminded of the duty to disclose information to the Office which is material to patentability as defined in 37 CFR 1.56. This includes a list of all patents, publications, or other information that should be considered by the Office pursuant to 37 CFR 1.98(b). See MPEP § 609.
Drawings
5. The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5). Figures 4C and 4D do not include the data points for the T–cell receptor quantity and clonality as disclosed in the specification. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
6. The instant application contains at least one drawing executed in color. Figures 4A, 4B, and 4D have multiple parts that refer to and are differentiated by various colors. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the USPTO patent electronic filing system. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2). Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Specification
7. The disclosure is objected to because of the following informalities:
On page 10 in paragraph 0036, line 5, there are two periods after “cancer progression” when there should only be one period.
Appropriate correction is required.
8. The use of the terms QuantStudio™ in paragraph 0116 on page 32; KingFisher™ in paragraphs 0151 and 0152 on pages 45 and 46, respectively; MagMAX™ in paragraph 0151 on page 45; MicroAmp™ in paragraph 0153 on page 46; TaqPath™ in paragraphs 0006, 0083, 0153, and 0157 on pages 2, 22, 46, and 48, correspondingly; No ROX™ in paragraph 0153 on page 46; and possibly others in the specification, which are trade name(s) or a mark(s) used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, ℠, or ® following the terms. 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.
9. The disclosure contains an embedded hyperlink and/or other form of browser–executable code in paragraph 0172 on page 55. Applicant is required to delete the embedded hyperlink and/or other form of browser–executable code; references to websites should be limited to the top–level domain name without any prefix such as http:// or other browser–executable code. See MPEP § 608.01.
10. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors in the specification of which applicant becomes aware.
Claim Objections
11. Claims 1, 7, 8, 10, 11, 17, and 18 are objected to because of the following informalities:
In claim 1, line 1, the acronym “SARS–CoV–2” is recited, but not defined in the claim. An acronym should be defined the first time it appears in the claims. For the purposes of examination, “SARS–CoV–2” is interpreted to mean “severe acute respiratory syndrome coronavirus 2”, as defined in the specifications;
In claim 1, line 11, the phrase “to a quantification” is grammatically incorrect. More appropriate language would be “to the quantification”;
In claim 1, line 12, there should be a comma after subjects;
In claim 2, line 2; and claim 5, line 2, the phrase “to a same tissue” is grammatically incorrect. More appropriate language would be “to the same tissue”;
In claim 7, line 4, the acronym “COVID” is recited, but not defined in the claim. An acronym should be defined the first time it appears in the claims. For the purposes of examination, “COVID” is interpreted to mean “COVID–19”, which denotes “coronavirus disease 2019”, as defined in the specifications;
In claim 8, line 20, the phrase “sample is low” is grammatically incorrect. More appropriate language would be “sample are low”;
In claim 8, lines 23 and 24, “Differentially Methylated” is randomly capitalized and should be “differentially methylated”;
In claim 8, line 29, the phrase “wherein RNA” is grammatically incorrect. It is recommended that the phrase read “wherein the RNA”;
In claim 8, line 29, there is an extra comma after “can be” that should be removed;
In claim 8, line 31, “SRAS–CoV–2” is a typo and should be “SARS–CoV–2”;
In claim 8, line 39, “Specific” is randomly capitalized and should be “specific”;
In claim 8, line 39, there is an extra space in “and/or” that should be removed;
In claim 8, line 42, there are two periods after “having cancer” when there should only be one period;
In claim 10, line 3, the phrase “to quantifying” is grammatically incorrect. It is recommended that the phrase read “to quantify”;
In claim 11, line 3, the phrase “sample for presence” is grammatically in correct. More appropriate language would be “sample for the presence”;
In claim 17, line 1, there is an extra comma after cancer that should be removed;
In claim 18, line 1, the acronym for “Human Papilloma Virus” has already been defined as “HPV” in claim 1, line 1. A phrase does not need to be repeated once an acronym has been defined in the claims.
Appropriate correction is required.
Claim Rejections – 35 USC § 112
35 USC § 112(b)
12. 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.
13. Claims 1, 6, 8, 12, and 18 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.
14. The phrase “independently high or high” in claims 1 and 18 is a relative phrase which renders the claims indefinite. The threshold for what is a “high” amount of SARS–CoV–2 nucleic acids is ambiguous – i.e., how “high” is high? In other words, it is unclear the amount of SARS–CoV–2 nucleic acids that must be present over the HPV nucleic acids to be considered “high” and thus indicative of an increased risk for the subject to progress towards cancer or have cancer. Moreover, it is unclear the amount of SARS–CoV–2 nucleic acids that must be present on their own, i.e., “independently” of the amount of HPV nucleic acids, to indicate the increased risk of cancer. The phrase is not defined by the claims and the specification does not provide a standard for ascertaining the requisite degree. The claim.
15. Claims 6 and 8 recite “(positively or negatively)”. Due to the presence of parentheses, it cannot be determined whether or not the phrase is a recited limitation. Thus, the claim is rendered indefinite. Removal of the parentheses is suggested.
16. Claim 8 recites “(predetermined level)”. Due to the presence of parentheses, it cannot be determined whether or not the phrase is a recited limitation. Thus, the claim is rendered indefinite. Removal of the parentheses is suggested.
17. Claim 8 recites the phrase “can be”, which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. The phrase suggests that the limitation is optional or a preferred embodiment, but it is unclear from the claim language itself whether that limitation is essential for infringement or an optional feature. See MPEP § 2173.05(d). It is suggested that the phrase “can be” be replaced with “is” to remove the possibility of misconstruing the limitation of the claim.
18. The term “low” in claims 8 and 12 is a relative term which renders the claims indefinite. The threshold for what is a “low” amount of DNA methylation is ambiguous – i.e., how low is “low”? In other words, it is unclear the amount of DNA methylation that must be present in the sample to be considered “low” and thus indicative of an increased risk of having cancer. The term “low” is not defined by the claim and the specification does not provide a standard for ascertaining the requisite degree. This includes the phrases “sample is low in SARS–CoV–2” in claim 8 and “predetermined low” in claim 12. The claims are thus rendered indefinite.
Claim Rejections – 35 USC § 103
19. 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.
20. Claims 1 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Maher, M. C., et. al. (US 2021/0115520 A1; Published 04/22/2021), hereby Maher, in further view of Millar, D. S., et. al. (WO 2007/030882 A1; Published 03/22/2007), hereby Millar, and Liang, W., et. al., (2020). Cancer patients in SARS–CoV–2 infection: a nationwide analysis in China. The Lancet. Oncology, 21(3), 335–337 (Published 02/14/2020), hereby Liang. Claims 2 – 7, 9, 12, and 14 – 17, by virtue of their dependency on claim 1, are also rejected under 35 U.S.C. 103 as being unpatentable over Maher, Millar, and Liang.
Claims 8, 10, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Maher, Millar, and Liang, as applied to claim 1, which claims 8, 10, and 13 depend upon, and in further view of Mehdi, A., and Rabbani, S. A., (2021). Role of Methylation in Pro– and Anti–Cancer Immunity. Cancers, 13(3), 545, (Published 02/01/2021), hereby Mehdi.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Maher, Millar, and Liang, as applied to claim 1, which claim 11 depends upon, and in further view of Bhatt, A. P., et. al. (2017). The role of the microbiome in cancer development and therapy. CA: a cancer journal for clinicians, 67(4), 326–344, (Published 07/08/2017), hereby Bhatt.
Maher teaches a method for detecting cancer in a subject based on the presence or absence of genetic material, i.e., nucleic acids, that are derived from one or more pathogens found in a sample, wherein the pathogen is a virus (page 1, paragraph 0010; page 9, paragraph 0088; claim 1), as recited in instant claims 1 and 18. It is taught that the biological sample is obtained from the subject’s saliva, urine, stool, vaginal fluids, vaginal flushing fluids, tumor, or other tissue (page 10, paragraph 0091; page 13, paragraph 0118; claims 39 and 40), as required in instant claim 16. Page 4, paragraph 0027 and claim 13 go on to teach that pathogens, from at least two to at least twenty (page 7, paragraph 0056), can be analyzed in comparison to each other to determine the likelihood of cancer, as required in instant claims 1 and 18. Maher discloses that this is accomplished by splitting the biological sample into different aliquots, such that the number of aliquots correlates with the number of pathogens to be tested (page 25, paragraph 0229; claim 105); in other words, if the risk of cancer development in the presence of two pathogens is to be analyzed, then the first and second biological sample are two different aliquots from the same biological sample (page 3, paragraph 0021; claim 37; see also figure 2B as reproduced above), as stated in instant claims 1, 2, 14, and 18. It is further taught that the virus in the first biological sample is selected from a list that includes Human Papilloma Virus
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(HPV; page 25, paragraph 0230; claims 41, 43, and 44; see also figure 2B as reproduced above) and the virus in the second biological sample is different from HPV (page 7, paragraph 0056; page 19, paragraph 0167; see also figure 2E as reproduced below), as defined in instant claims 1, 2 – 8, and 18. Maher goes on to disclose that the nucleic acids in the isolated sample are sequenced (page 2, paragraph 0010), wherein an amount of sequences is generated to reflect an abundance level of particular nucleic acid fragments and targeted gene panel from the first virus followed by
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the second virus (page 2, paragraph 0016; page 3, paragraph 0021; page 26, paragraph 0232 – 0234), as defined in instant claims 1, 8, 15, and 18. It is further taught that the targeted gene panel includes genetic markers that are indicative of cancer, i.e., the methylation status, of corresponding target sequences (page 5, paragraph 0032; page 5, paragraph 0040; page 28, paragraph 0254; claim 132), as defined in instant claims 1, 5 – 7, 9 – 13 and 18. Maher goes on to teach that a particular gene in the first virus, i.e., HPV, and its associated methylation status are determined first and compared to a reference/cutoff value that is based upon a subject without cancer, followed by the same methodology for the second virus, i.e., read of a gene and its methylation status, wherein if the viral load of the second targeted gene exceeds a predetermined value, i.e., the reference/cutoff value, relative to the viral load of the first targeted gene, then the subject has cancer or likely has cancer (pages 2 and 3; paragraphs 0015 – 0019; page 4, paragraph 0026; claim 14; see also figure 2E as reproduced above), as required in instant claims 1, 4, 6 – 9, 12, and 18.
While Maher does teach that the nucleic acids are sequenced via analytical methods that include polymerase chain reaction (PCR), massively parallel sequencing, and whole genome bisulfite sequencing (page 1, paragraph 0010; page 10, paragraph 0096); and that the cancer is that of the breast, lung, prostate, colorectal, renal, uterine, pancreatic, esophagus, lymphoma, head/neck, ovarian, a hepatobiliary, melanoma, cervical, multiple myeloma, leukemia, thyroid, bladder, and gastric (page 21, paragraphs 0187 and 0188; page 35, paragraph 0322; claims 31 and 33), it fails to teach the explicit steps involved in sodium bisulfite conversion of the nucleic acids, as stated in instant claim 8; or the types of cancer defined in instant claim 17. Millar is drawn to the detection of a virus in combination with genomic markers, including methylation, in a sample to determine the health state of a subject (page 1, lines 3 – 5; page 12, lines 7 – 12; page 16, lines 9 – 14; claim 16). It is further taught that methylation is a stable change inherited over many cell divisions, wherein alteration of a usually stable methylome can be predictive of the pre–cancerous or cancerous state (page 5, lines 28 – 30), as required in instant claim 8. Millar continues to teach that sodium bisulfite (NaHSO3) reacts readily with cytosine in the presence of water to yield uracil sulfite, unless the cytosine is methylated as the methylation provides protection from the NaHSO3 (page 19, lines 25 – 31; claims 8 – 10), as defined in instant claim 8. Pages 39 – 51 teach an in–depth protocol for the NaHSO3 treatment of a sample followed by amplification of viral nucleic acids via PCR that is employed to determine the presence of unmethylated versus methylated cytosines in target locations to indicate the likelihood of cancer in a subject (page 10, lines 7 – 24), as stated in instant claim 8. Page 34, lines 1 – 9 and 30 – 33 further describes the usage of massively parallel signature sequencing to evaluate the change status, as defined in instant claim 8. It is further taught that HPV is commonly implicated in cancers of the cervix and contribute to cancers of the vagina, vulvae, penis, and anus (page 6, lines 28 and 29), as defined in instant claim 17.
Maher does teach that the first virus is selected from a list that includes HPV (page 25, paragraph 0230; see also figure 2B as reproduced above). Additionally, Millar teaches that the detected virus can be from the Papillomaviridae family, which includes HPV (page 14, lines 11 and 12; page 82, claim 15), or the Coronaviridae family, which includes human coronaviruses (page 14, lines 32 and 33). Both Maher and Millar fail to explicitly teach that the second virus is severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) or that the subject has long coronavirus disease 2019 (COVID–19), as recited in instant claims 1, 2, 4, 5 – 7, and 18. However, Liang taught that SARS–CoV–2 is a novel betacoronavirus and the causative agent of COVID–19 (page 335) and subjects with cancer have a significantly higher rate of hospitalization or death due to SARS–CoV–2 infections (page 336), as recited in instant claims 1, 2, 4, 5 – 7, and 18.
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Maher, Millar, and Liang fail to teach the relationship between T–cell and B–cell receptors and DNA methylation in the context of cancer, as required in instant claims 8, 10, and 13. Maher does teach that the nucleic acid employed can be DNA, RNA, or any hybrid or fragment thereof (page 10, paragraph 0091), but fails to teach that the can be messenger RNA (mRNA), microRNA (miRNA), or non–coding RNA (ncRNA), as stated in instant claim 8. However, the relationship between DNA/ RNA methylation and cancer is known in the art with numerous research and review articles written on the topic. For example, Medhi teaches that a large number of diverse, but very specific receptors on T–cells and B–cells are useful in response to foreign pathogens and can be influenced by DNA methylation (pages 3 and 4), as recited in instant claims 8, 10, and 13. It is further taught that alterations in the pattern of DNA methylation results in the up or downregulation of different genes, wherein the differentiation of T–cells is either inactivated or activated as a result, leading to tumor growth and cancer progression (section 2.2: adaptive immunity; pages 8 – 13; see also figure 3 as reproduced above). Page 11 gives an explicit example of the evaluation of methylation status for different gene loci in colon cancer subject samples to determine cancer prognosis. Medhi also teaches that the RNA involved in methylation and cancer can be ncRNA (page 1), mRNA (page 6), and miRNA (page 6), as discussed in instant claim 8.
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Maher, Millar, Liang, and Medhi fail to a microbiota differential for samples relative to unaffected subjects, as recited in instant claim 11. However, microbiota differentials are known in the art to influence a variety of disease states, including cancer, with numerous research and review articles written on the topic. For example, Bhatt teaches that Fusobacterium sp. are overexpressed in colon cancer samples in comparison to non–cancerous samples (page 331), as required in instant claim 11. It is further taught that numerous other bacteria, including Lactobacillus sp., Streptococcus sp., Prevotella sp., and Parvimonas sp., are enriched or reduced in various types of cancers over unaffected subjects (see table 2 as reproduced below). While the
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instant application does not explicitly claim the involvement of Fusobacterium sp., Lactobacillus sp., Streptococcus sp., Prevotella sp., and Parvimonas sp. in the microbiota differential of instant claim 11, paragraph 0127 on page 36 of the instant specification indicates that these bacteria are acceptable embodiments.
Maher, Millar, Liang, Medhi, and Bhatt are considered to be analogous to the claimed invention because assessing a subject's cancer or the likelihood that they will develop cancer. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined detecting cancer in a subject based on the presence or absence of genetic material that are derived from one or more pathogens, including HPV, of Maher with the sodium bisulfite protocol of Millar and apply it to the SARS–CoV–2 of Liang in the context of the altered T–cell and B–cell receptor expression of Mehdi and microbiota differentials of Bhatt before the effective filing date of the claimed invention to provide an early detection method for HPV–mediated tumors and cancers in subjects co–infected with SARS–CoV–2 to monitor for relapses and the effectiveness of treatments (instant application; page 1, paragraph 0003). All the claimed elements were known in the prior art. It would have been obvious to a person having ordinary skill in the art to have combined the elements as claimed by known methods with no change in their respective functions. The combination would have yielded nothing more than predictable results to one having ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143A and 2143.02.
Conclusion
21. Claims 1 – 18 are rejected. No claims are allowed.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Hallie N. Pennington, Ph.D. whose telephone number is (571)272–6781. The examiner can normally be reached M–Th 7:30–5:30 ET.
Examiner interviews are available via telephone, in–person, and video conferencing using a USPTO supplied web–based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at (571)270–3497. The fax phone number for the organization where this application or proceeding is assigned is 571–273–8300.
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/HALLIE N. PENNINGTON, PH.D./Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671