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 .
Claims Status
Claims 1-11, 14, and 16-23 are pending. Claims 1-5, 7-11, 14, 21, and 23 are withdrawn from consideration. Claims 6, 16-20, and 22 are under examination on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-11 and 16-23, and the required species: (1) SARS-CoV-2 as the target virus; (2) 3’-deoxy-3’,4’-didehydro-cytidine (ddhC) as the furanose derivative of formula (I); (3) NMR spectroscopy as the method of biomarker detection; and (4) a urine sample as the sample type, in the reply filed on 8/4/2026 is acknowledged.
Claim 14 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 1-5, 7-11, 21, and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/4/2026.
Claims 6, 16-20, and 22 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 4/5/2024 is in compliance with 37 CFR 1.97. Accordingly, the references listed in the IDS are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on p. 46. 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://, www., or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 18 is objected to because of the following informalities: claim 18 recites “with a RNA-dependent RNA polymerase”, but should instead recite “with an RNA-dependent RNA polymerase”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
Claims 6, 16-20, and 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for diagnosing a generic viral infection known to induce elevated ddhC levels, by determining ddhC in a human subject and comparing the amount with a reference to diagnose a viral infection, does not reasonably provide enablement for similar methods for any generic or specific, viral infection or disease associated therewith, in any and every type of subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claim 6.
The nature of the invention a method for diagnosing a viral infection or a disease associated therewith in a subject comprising the steps of: (A) determining in a sample of said subject the amount of 3’-deoxy-3’,4’-didehydro-cytidine (ddhC); and (B) comparing the amount of the ddhC determined in (A) with a reference, thereby diagnosing a viral infection; wherein the determination in (a) is done by NMR spectroscopy and the sample of the subject is a urine sample of said subject.
The level of skill of one skilled in this art is high.
The specification teaches that acute SARS-CoV-2 infection is associated with a distinct urinary metabolic phenotype, shown by 1H NMR spectroscopy of urine or plasma samples of SARS-CoV-2 positive and SARS-CoV-2 negative human subjects (Example 2), and analysis revealed that 3’-deoxy-3’,4’-didehydrocytidine (ddhC) was one of the biomarkers observed (Example 3). However, the specification does not measure ddhC to diagnose other viral infections, or in non-human subjects.
The state of the prior art is such that ddhC is a metabolomic discriminator for viral infections, in both COVID-19 cases and pre-COVID-19 viral infections, relative to other groups of bacteremia, non-infected unwell controls, and healthy controls, as demonstrated by LC-MS metabolomics of human sera (Mehta, et al. Med. 2022 Mar 11;3(3):204-215.e6. Epub 2022 Jan 31. PMID: 35128501, on IDS; Fig. 2E). However, as shown in Mehta Fig. 2E, not all pre-COVID-19 human subjects exhibited increased ddhC levels, and there is no information regarding the specific virus that the subject was infected with.
Biomarkers for a disease must be experimentally shown to function in the context of the samples in which they are used (e.g., urine). Micallef (US9222937, priority to 09/01/2011) teaches that a variety of non-cancer causes raise circulating nucleosome level, and in some cancers, their level varies greatly, encompassing levels of healthy patients (Column 2, last para.). Therefore, circulating nucleosome level cannot be used predictably to prognose any condition barring experimental validation. In short, no one of ordinary skill in this art assumes any protein, nucleotide, or metabolite is a functional biomarker. They need experimental support. In this case, there is insufficient data to show that ddhC is a generic biomarker for any and all viral infections. Along those lines, to further highlight the unpredictability of the art, post-filing art demonstrates that not all viral infections are associated with elevated ddhC levels, as RSV challenge did not result in elevated ddhC levels (Mehta II. Npj Viruses. 2025 Jun 20;3(1):50. PMID: 40542254; Fig. 2). Additionally Mehta II discloses that while ddhC levels increase in SARS-CoV-2 and influenza-infected subjects’ plasma, so it is unpredictable whether a specific viral infection would result in elevated ddhC levels.
Thus, the state of the art recognized that it would be highly unpredictable that a viral infection or a disease associated therewith could be diagnosed by measuring ddhC and comparing the amount to a reference. One of skill in the art would neither expect nor predict the appropriate functioning of the method as broadly as currently claimed. Specifically, there is insufficient support for the method working for any specific viral infection, a generic viral infection, a disease associated with a specific or generic viral infection, or any subject other than human.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Mehta and Mehta II, the lack of guidance and direction provided by applicants, and the absence of working examples, undue experimentation would be required to use the claimed method for a generic viral infection and subject, with a reasonable expectation of success, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed methods are functional, commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 6, 16-20, and 22 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.
The term “disease associated therewith” in claim 6 is a relative term which renders the claim indefinite. The term “disease associated therewith” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 6 is drawn to “[a] method for diagnosing a viral infection or a disease associated therewith in a subject” (lines 1-2); however, the disclosure does not define which diseases are “associated” with a viral infection. For example, the disease could be caused by the viral infection in-and-of-itself, have some frequency correlation with viral disease, or be caused by treating the viral disease (but not arising from the infection itself). Therefore, the metes and bounds of claim 6 are unclear. Claims 16-20 and 22 depend on claim 6 but do not remedy this deficiency.
Claim 19 recites the limitation "the at least one biomarker" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112 - Failure to Further Limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 17 recites “the method of claim 6, wherein the method is an ex vivo method.” However, claim 6 encompasses a method for diagnosing a viral infection or a disease associated therewith comprising determining in a sample (urine) of said subject the amount of ddhC, done by NMR spectroscopy. It appears that such a method would necessarily be performed ex vivo, so claim 17 does not appear to further limit claim 6. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 6, 16-20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Mehta, et al. (Med. 2022 Mar 11;3(3):204-215.e6. Epub 2022 Jan 31. PMID: 35128501, on IDS) as evidenced by Hillen, et al. (Nature. 2020 Aug;584(7819):154-156. Epub 2020 May 21. PMID: 32438371), in view of Bouatra, et al. (PLoS One. 2013 Sep 4;8(9):e73076. PMID: 24023812) and Langley, et al. (PGPub US 20100273207, published 10/28/2010).
The claimed invention encompasses a method for diagnosing a viral infection or a disease associated therewith in a subject comprising the steps of: (A) determining in a sample of said subject the amount of 3’-deoxy-3’,4’-didehydro-cytidine (ddhC); and (B) comparing the amount of the ddhC determined in (A) with a reference, thereby diagnosing a viral infection; wherein the determination in (a) is done by NMR spectroscopy and the sample of the subject is a urine sample of said subject (claim 6).
The Prior Art
Mehta teaches that ddhC identifies acute viral infections, including COVID-19 (Title), and that biomarkers can better guide therapeutic and infection control decisions (p. 205, para. 1). Mehta teaches methods of untargeted high-resolution liquid chromatography coupled with mass spectrometry to compare the admission serum metabolome of emergency department patients with viral infections (including COVID-19), bacterial infections, inflammatory conditions, and healthy controls (p. 204, Methods). 3’-Deoxy-3’,4’-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), was detected for the first time in serum, and when comparing 60 viral with 101 non-viral cases in the discovery cohort, ddhC was the most significantly differentially abundant metabolite (p. 204, Findings). Mehta explains that a robust serum biomarker of viral infection would provide real-time determination of infectious etiology, aiding patient triage and decision-making regarding antimicrobial prescription, and could prove vital in infection prevention and control measures, especially in the context of a viral pandemic, where rapid detection of an acute viral illness, not dependent on nucleotide amplification via PCR, would enable prompt patient isolation while awaiting definitive pathogen identification (p. 211, para. 2). Mehta also teaches that technologies for large-scale characterization of low-molecular-weight metabolites have the potential to aid discovery of novel biomarkers of infectious diseases, and that liquid chromatography coupled with mass spectrometry (LC-MS) and nuclear magnetic resonance spectroscopy stand out among the most commonly employed techniques in the field (p. 205, para. 2). Mehta contemplates that further work will be required to determine whether ddhC is detectable in minimally invasive samples such as urine or saliva (p. 212, para. 4).
Hillen provides evidence that Coronaviruses (e.g., SARS-CoV-2) use an RdRp complex for the replication of their genome and for the transcription of their genes (p. 154, col. 1, para. 1).
However, Mehta does not teach comparing the amount of ddhC with a reference, thereby diagnosing a viral infection, nor does it disclose where the determination is done by NMR spectroscopy or the sample of the subject is a urine sample.
Langley teaches methods for diagnosis of sepsis and high risk of sepsis death (Abstract), which may compare one or more of the subject’s clinic-metabolomic classifier values to (i) a reference characteristic determined from the same clinic-metabolomic classifiers obtained from subjects with sepsis and to (ii) a reference characteristic determined from the same clinic-metabolomic classifier obtained from non-infected subjects with systemic inflammatory response, which may comprise measuring the amount or level of clinic-metabolomic classifiers including specific metabolites (para. [0033]). Langley also teaches that biomarkers or reference characteristics are needed to stratify patients at presentation and identify patient subsets that need additional or more aggressive treatment (para. [0004]).
Accordingly, it would have been obvious to one of ordinary skill in the art to utilize a reference amount from subjects suffering from a viral disease to diagnose a viral infection in the subject.
Bouatra teaches that urine has long been a “favored” biofluid among metabolomics researchers, because it is sterile, easy-to-obtain in large volumes, largely free from interfering proteins or lipids, and chemically complex (Abstract). Bouatra further teaches that, in an effort to improve understanding of urine, they undertook a comprehensive, quantitative, metabolome-wide characterization of human urine, and utilized the analytical platform of NMR to identity and quantify 209 metabolites (Abstract).
It would have been obvious to one of ordinary skill in the art to modify the methods of diagnosing SARS-CoV-2 taught by Mehta to incorporate a reference value, as disclosed by Langley, and use of NMR of urine, as taught by Bouatra. While Mehta focuses primarily on LC-MS, they do teach that nuclear magnetic resonance spectroscopy stands out among the most commonly employed techniques for large-scale characterization of low-molecular-weight metabolites that have the potential to aid discovery of novel biomarkers of infectious diseases. Additionally, though Mehta focuses on sera for detecting ddhC for purposes of SARS-CoV-2 diagnosis, they indicate that further work will be required to determine whether ddhC is detectable in minimally invasive samples such as urine. Bouatra demonstrates that NMR can be used to identity and quantify metabolites in human urine. Langley demonstrates that comparing the amount of a metabolite in a subject with a reference is known in methods of diagnosing diseases. It would have been obvious for the subject to be a mammal, or specifically a human, because Mehta’s methods are performed on humans. Similarly, the method being ex vivo would be obvious, because each of Mehta and Langley appear to utilize ex vivo methods. Also, because SARS-CoV-2 has an RNA-dependent RNA polymerase, it would be obvious that the viral infection is associated with an RNA-dependent RNA polymerase. It would have been further obvious for the reference to be derived from the amount of the biomarker from a subject or group of subjects known to suffer from the viral infection and/or associated disease to be diagnosed, because Langley discloses use of a reference characteristic determined from the same clinic-metabolomic classifiers obtained from subjects with a disease that is to be diagnosed. Regarding claim 20’s step of identifying a subject in need of a viral infection therapy, Mehta teaches that ddhC identifies acute viral infections, including COVID-19, and that biomarkers can better guide therapeutic and infection control decisions, and Langley teaches that biomarkers or reference characteristics are needed to stratify patients at presentation and identify patient subsets that need additional or more aggressive treatment. One of ordinary skill in the art would have been motivated to diagnose SARS-CoV-2 infection. There would be a reasonable expectation of success because Mehta discloses that ddhC is a metabolic marker for SARS-CoV-2 infection, contemplates urine testing for ddhC for minimally invasive assays, states that NMR stands out among the most commonly employed techniques for large-scale characterization of low-molecular-weight metabolites that have the potential to aid discovery of novel biomarkers of infectious diseases, and Bouatra discloses NMR methods to characterize urine metabolites. Therefore, claims 6, 16-20, and 22 were prima facie obvious before the priority date of the instant invention.
Conclusion
No claim is allowed.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
