DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of the following species:
Parkinson’s disease as the disease diagnosed and treated;
Cerebrospinal fluid as the sample type;
RNA associated with human pegivirus as the biomarker;
RT-PCR as the assay type;
SEQ ID NOs: 5-9 as the primers;
SEQ ID NOs: 10-12 as the probes;
Tegobuvir as the anti-HCV drug;
in the reply filed on 02 July 2026 is acknowledged.
Claim 11 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
3. Claim 11 is withdrawn.
Claims 1-10 and 12-20 are under consideration.
Priority
4. The Instant Application claims priority to U.S. Provisional Application 63/486,951 filed 24 February 2023. Priority is granted to U.S. Provisional Application 63/486,951 for claims 1-10 and 12-20 of the Instant Application. Thus, the U.S. effective filing date of the Instant Application is 24 February 2023.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 28 March 2024 was filed before the mailing date of the Non-Final Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
6. 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
7. The disclosure is objected to because of the following informalities: pages 39 and 41-42 appear to have Chinese characters. The specification must fully be in English.
Appropriate correction is required.
8. The use of the terms “RiboMAX” (Page 21, line 31), “Quantstudio” (Page 22, line 4 and page 25, line 22), “Qubit” (Page 25, line 19; page 26, line 15; and page 27, line 12), and Vectastain (Page 28, line 7), which are trade names or marks used in commerce, has 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 ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that these are merely examples and all improper uses of trademarks in the specification should be identified by Applicant and properly addressed.
Claim Objections
9. Claims 1, 4, 8, and 17 are objected to because of the following informalities:
Regarding claims 1 and 8, the colon should be removed as there is only one step in each method.
Regarding claims 4 and 17, “an” before “RNA” should be removed for clarity.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
10. 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.
11. Claims 1-7, 15, and 17 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 “associated” in claims 1, 4, 15, and 17 is a relative term which renders the claim indefinite. The term “associated” 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. An associated biomarker could be any structure/part of the virus or an upregulated protein in response to the virus. Therefore, there are multiple interpretations. See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
Claims 2-7, which are dependent on claim 1, are similarly rejected.
Claim 17, which is dependent on claim 15, is similarly rejected.
Claim Rejections – Improper Markush Grouping
12. Claims 1-10 and 12-20 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 1 and 8 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: human pegivirus infection and Parkinson’s disease do not share a common cause or a resulting structure or directly affected cell type. Claims 2-7; and 9-10 and 12-20, which are dependent on claims 1 and 8, respectively, are similarly rejected.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112 – Enablement
13. 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.
14. In making a determination as to whether an application has met the requirements forenablement under 35 U.S.C. 112 ¶ 1, the courts have put forth a series of factors. See, In reWands, 8 USPQ2d 1400, at 1404 (CAFC 1988). The factors considered include: (1) the breadth of the claims, (2) the nature of the invention, (3) the relative skill of those in the art, (4) the presence or absence of working examples, (5) the amount of direction or guidance provided, (6) the state of the prior art, (7) the level of predictability in the art, and (8) the quantity of experimentation necessary.
15. Claims 1-10 and 12-20 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 the method of diagnosing or treating a subject having Parkinson’s disease (PD) with at least one PD biomarker and human pegivirus (HPgV) biomarkers in CSF or brain tissue from human subjects, does not reasonably provide enablement for similar methods using just any sample type such from just any species, and/or with solely a biomarker associated with HPgV. 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 and/or use the invention commensurate in scope with these claims.
The claims recite a method of diagnosing and treating a subject having HPgV or PD, wherein HPgV associated biomarkers are used to detect the presence of PD prior to treatment.
The nature of the invention is methods of diagnosing and treating HPgV or PD.
The level of skill of one of ordinary skill in this art is high.
The specification states that the subject may be a mammal or non-mammalian animal (Page 7, lines 16-22) However, the examples appear to only test human subjects. The working examples nor the drawings seem to imply that subjects other than humans were tested. The specification also states that the sample refers to a sample taken from the subject (Page 7, lines 10-15) and gives examples, but not a specific definition. The examples state that the patients had CSF samples taken (Page 11, line 17), as well as brain tissue samples (Page 19, lines 4-9). However, the examples also appear to disclose that HPgV RNA was not detected in any of the plasma samples (Page 13, lines 2-3), despite testing positive in CSF samples taken from the same patients (Table 2). The working examples do not discuss any other sample type. Furthermore, the results appear to show a correlation between HPgV infection and PD rather than causation, as not every PD patient showed signs of a current or previous HPgV infection (Example 1).
A search of the art shows that protein biomarkers are often species-specific in both presence and host response. Kawanishi (22 July 2019, PNAS, 116(32): 16036-16045) teaches a human-specific loss of CMP-N-acetylneuraminic acid hydroxylase which relates to an increase in risk for cardiovascular disease when compared to closely-related chimpanzees (Abstract). Nutma (28 August 2023, Nature Communications, 14: 5247) teaches “We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.” (Page 1, ¶ 1). Mishra (07 April 2025, Cellular and Molecular Life Sciences, 82: 147) teaches in relation to neurological degenerative diseases (NDDs) “In case of NDDs, animal models show multiple differences, including genetics, with human patients, for example some hereditary disease causing genes are not found in animal models, such as the gene APOE ε4 allele responsible for AD is not found in mice.” (Introduction, ¶ 1) and “Interestingly, in PD, CRISPR/Cas9 mediated disruption of PINK1 and Parkin in monkeys showed degenerative phenotypes, while they did not make significant differences in transgenic pigs.” (Page 10, right column, ¶ 2). In summary, the art shows that not all subjects will have the same biomarkers as many are species-specific, even between closely related species. Furthermore, even if different species have the same biomarkers, they will not necessarily affect both species in the same way.
In addition, it was unpredictable whether or not a biomarker detected in any biological specimen could be used to specifically identify a cancer or a subject suffering from a cancer. Ludwig (2005, Nature Reviews: Cancer, 5: 845-856) teaches that a marker for cancer to be used in screening the general population must have an extremely high specificity to minimize false positives that necessitate costly or invasive follow-up studies (Page 850, column 2, ¶ first full). This specificity refers in part to the cancer's tissue of origin. A tumor’s anatomical location usually indicates its tissue of origin. Thus, molecular markers are generally not required for classification of origin (Page 847, column 2, ¶ first full). By extension, for a biomarker to function as an indicator of cancer in a specimen containing no tumor cells, it is helpful if said marker is tissue-specific. Ludwig further teaches that relevant immunohistochemical markers may have prognostic or therapeutic value as in the case of breast cancer wherein estrogen receptor (ER) and HER2/NEU receptor status can help predict a patient's response to certain therapies (Page 849, column 2, ¶ first full). Taken together, even though some biomarkers allow for prognosis, not all are specific enough for diagnosis in just any type of biological specimen.
Mantovani (1994, European Journal of Cancer, 30A(3): 363-369) teaches that a biomarker that functions in one sample type need not function in another. They teach that folate binding protein levels in serum were significantly different in ovarian cancer patients compared to healthy donors (Abstract). However, the same cannot be said when urine was used as sample type (Figure 5 and page 368, column 2, ¶ 2). This is further supported by Williamson (30 April 2012, Nurs. Res. Pract., 2912: 246178), which teaches “We undertook this comparison of levels of biomarkers (27 specific cytokines) in 3 sample types (plasma, passive drool saliva, and saliva collected on filter paper) […] Passive drool saliva samples were significantly associated with plasma samples for only 3 biomarkers. No significant associations between filter paper saliva and plasma samples were found.” (Discussion, ¶ 1).
Since the art teaches that biomarker presence is unpredictable across multiple species and sample types, and the specification does not provide ample guidance with respect to diagnosing and treating a subject having a HPgV or PD by detecting only HPgV associated biomarkers in anything other than CSF or brain tissue samples from human subjects, one would be burdened with undue experimentation to use the claimed invention to use similar methods with any sample type from any species.
16. Claims 6 and 19 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 RT-PCR with one forward and one reverse primer, does not reasonably provide enablement for RT-PCR with anything less than one forward and one reverse primer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claims recite a method of detecting a biomarker via RT-PCR using one or more primers and/or one or more probes.
The nature of the invention is methods of diagnosing and treating HPgV or PD.
The level of skill of one of ordinary skill in this art is high.
The specification states the primers and probes in Table 4. The specification goes on to state that the primer pairs were validated and tested (Page 21, lines 19-31).
A search of the art shows that both a forward primer and a reverse primer are required in PCR to flank the target region to be amplified (AAT Bioquest, 22 June 2020).
Since the art teaches that a forward and reverse primer are required for PCR and the specification does not provide ample guidance with respect to performing PCR with less than one forward and reverse primer, one would be burdened with undue experimentation to use the invention as so broadly claimed.
Claim Rejections - 35 USC § 101
17. 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.
18. Claims 1-5 and 7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation without significantly more.
The claims recite a method for diagnosing HPgV or PD in a subject by detecting a biomarker associated with HPgV. See MPEP 2106 for analysis framework.
The instant claims are drawn to a method for diagnosing HPgV or PD by detecting a biomarker associated with HPgV. As such, the instant claims are drawn to a process, which is statutory category of matter (Step 1: Yes).
The instant claims are drawn to a judicial exception of a natural correlation or law of nature. This correlation is diagnosing HPgV or PD by detecting a biomarker that would naturally be elevated in the subject. Thus, the claims are directed to at least one exception (Step 2A, Prong 1: Yes).
The instant claims are drawn solely to a judicial exception which is not integrated into a practical application because the claimed invention is not used to provide a particular treatment or prophylaxis for a disease or medical condition. Further, the claimed invention does not apply or use the judicial exception in a meaningful way so as to prevent monopoly of the natural correlation. Generally linking the use of the judicial exception to a particular technological environment or field of use is not indicative of integration into a practical application (see MPEP 2106.05(h) and Example 29, Claim 2 (Diagnosing and Treating Julitis) of the Subject Matter Eligibility Examples: Life Sciences found at https://www.uspto.gov/sites/default/files/documents/ieg-may-2016-ex.pdf)). Therefore, the instant claims do not recite any additional elements that integrate the exception into a practical application (Step 2A, Prong 2: No). Claim 1 recites mere application of the correlation of biomarker in a sample with PD. Claim 2 only specifies nuance of the correlation that infection is indicative of PD. Claim 3 only narrows the correlation to biomarker in specific sample types. Claim 4 only further limits the marker used in the correlation. Claim 5 does add specific assays for the marker but covers all reasonably functional assays with which the correlation can be assessed. Claim 7 only further limits the correlation to samples in humans.
The instant claims are drawn to a judicial exception and do not recite any additional elements that amount to significantly more than the judicial exception. “Laws of nature, natural phenomena, and abstract ideas are not patentable.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116 (2013) (quoting Mayo, 132 S. Ct. at 1293). “Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972). “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Myriad, 133 S. Ct. at 2117. The only claim that adds an additional element(s) to the correlation is claim 5 as stated above. However, these assay types are well-known, routine, and conventional in this art as evidenced by Slapina (21 November 2022, Bioimage, Accessed via WayBack Machine). Slapina teaches that “Traditionally, biomarkers have been identified using various laboratory techniques, such as immunohistochemistry, ELISA, and PCR.” (Where does scRNA-seq come in?, ¶ 1) and that RNA sequencing provides unprecedented insight when it comes to biomarker identification (Where does scRNA-seq come in?, ¶ 2-4) (Step 2B: No).
In view of the foregoing, the instant claims do not constitute patent eligible subject matter under 35 U.S.C. § 101.
Other Prior Art
19. Examiner notes that the following reference, while not currently enabled, could constitute as prior art under 35 U.S.C. § 102(a)(1) depending on Applicant’s arguments over the 112(a) rejections supra:
Hanson, 2021, Human Pegivirus in Parkinson’s Disease, Rush University (See IDS filed 28 March 2024).
It is noted that while the Instant Specification (Page 11, lines 19-22) reference the publishing date as 2022, the reference itself is labeled as 2021 and it is unclear which date would apply. Examiner is currently considering 2021 as the public availability date. Applicant is encouraged to clarify the public availability date in response to this action.
20. Examiner notes Lin (05 June 2019, JAMA Neurol., 76(9): 1019-1027) as uncited prior art. Lin teaches “This study found that PD incidence appeared to be lower in patients who were receiving interferon-based antiviral therapy for chronic HCV infection. The results seem to support the theory that HCV infection is a risk factor for developing PD. Antiviral therapy has shown potential in lowering this risk.” (Conclusion), wherein they excluded patients that had a PD diagnosis from their study (Methods, ¶ 2). Their results are found below in Table 2, wherein they saw a statistically significant difference at the 5 year follow-up in the risk of PD between the treated and untreated groups (Results, ¶ 3).
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Conclusion
21. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA E LY whose telephone number is (571)272-5169. The examiner can normally be reached Monday - Thursday, 8:00 am - 5:00 pm EST.
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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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/KRISTINA E. LY/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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