Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-6, and species in the reply filed on 05/26/2026 is acknowledged.
Applicant elected the following species:
Claim 1: virus
Claim 2: SARS-CoV-2
Claim 3: TNF
Claim 4: IL1B
Claim 5: CRH
Claim 6: STAT
Claims 12-13, 17-20, 22-26, 28, 31, 33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/26/2026.
Claims 1-6 are under consideration.
Priority
Priority to provisional application 63/181,215 with a filing date of 04/28/2021 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/28/2024 and 06/09/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 3, 5, and 6 are objected to because of the following informalities:
Claim 3: For increased clarity, write tumor necrosis factor (TNF) at first recitation before abbreviating.
Claim 5: For increased clarity, write corticotropin-releasing hormone (CRH) at first recitation before abbreviating.
Claim 6: For increased clarity, write signal transducer and activator of transcription (STAT) at first recitation before abbreviating.
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.
Claim 1 is 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 virus, SARS-CoV-2 (COVID-19) and associated biomarkers indicative of a chronic or long-term infection of that virus, the specification does not reasonably provide enablement for all other viruses and the associated biomarkers indicative of a chronic or long-term infection of all other viruses.
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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Here, the instant claims are broadly drawn to a method of diagnosing or classifying a subject as having a chronic or long-term infection of a virus, comprising determining the level of one or more biomarkers in a biological sample obtained from a subject.
The level of skill in the art is high and would include, e.g., Ph.D. level scientists. Sampson et al. (Sampson)(2017)(See PTO-892: Notice of References Cited) evidences that “increasing attention is being paid to an alternative approach: that of identifying biomarkers that reflect the differential host response to underlying non-infectious, bacterial, or viral conditions…[their] investigation builds upon and extends previous host biomarker studies by identifying a molecular signature that is demonstrably specific to SI [systemic inflammation] caused by a broad range of pathogenic viruses that represent all seven Baltimore virus classification groups and that cause infection in different tissues in multiple mammalian species…Notably, this viral signature relies on only four biomarkers, and this high degree of parsimony should help to ensure the performance robustness necessary for effective translation to a rapid point-of-care format (p.2).
Mayne et al. (Mayne)(2023)(See PTO-892: Notice of References Cited) evidences “some biomarkers which have been investigated in diagnosis and prognosis of key viral infections including inflammatory cytokines, markers of endothelial dysfunction and activation and coagulation, and the role that more conventional diagnostic markers, such as C-reactive protein and procalcitonin, can play in predicting these secondary compli-cations, as markers of severity and to distinguish viral and bacterial infection. Although many of these are still only available in the research setting, these markers show promise for incorporation in diagnostic algorithms which may assist to predict adverse outcomes and to guide therapy” (p. 159). Mayne also teaches “[s]equential CRP levels are a sensitive and specific biomarker to improve the dif-ferential diagnosis between acute bacterial and viral infections, although this may be less accurate in severe viral disease cases and with prolonged inflammation”(p.165)… Although relatively specific for bacterial infections, serum PCT levels also cor-relate with disease severity and thus cannot reliably distinguish between bacterial and nonbacterial infections in the setting of critical illness, particularly in cases of severe influenza and SARS-CoV-2 infection” (p. 166).
Van der Steen et al. (van der Steen)(2022)(PTO-892: Notice of References Cited) evidences the challenge of accurately distinguishing MIS-C from other more common inflammatory pediatric diseases, and the need to act with caution to avoid misdiagnoses in the current pandemic (p. 3549, Abstract). Van der Steen also evidences “multi-organ involvement, abnormalities on the echocardiogram, inflammatory, and hematologic markers did not differ substantially between non-MIS-C patients and MIS-C patients, in contrast to previous findings” (p. 3552). Furthermore, Van der Steen evidences “[t]here is no definitive diagnostic test for MIS-C; therefore, a case definition for MIS-C has been formulated by the RCPCH, WHO and CDC, using broad criteria. At presentation, [their] non-MIS-C patients all met the RCPCH criteria for MIS-C and two met the WHO and CDC criteria as well based on (possible) contact with a COVID-19 positive subject, illustrating the non-specificity of these definitions” (p. 3552).
As such, there appears to be no predictability for a method of diagnosing or classifying a subject as having a chronic or long-term infection of a virus, even in the case of SARS-CoV-2 infection and MIS-C development in child subjects.
The specification only exemplifies and reduces to practice the different biomarkers associated with long-term infection of SARS-CoV-2. The specification offers no other working examples demonstrating the methods with other viruses.
In view of the foregoing, a vast quantity of experimentation and biomarker analysis in the context of different viruses would be required to use the invention based on the content of the disclosure.
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 1-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
See claims 1-6 as submitted 05/24/2024.
In view of the 2019 PEG (“The 2019 Revised Patent Subject Matter Eligibility Guidance” (2019 PEG) found at https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf ), based upon an analysis with respect to the claims as a whole, claim 1 does not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
The claims are directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more (these claims are interpreted in light of the most recent Guidelines (See “Subject Matter Eligibility” found at https://www.uspto.gov/patent/laws-and-regulations/examination-policy/subject-matter-eligibility; as well as Subject Matter Eligibility Examples: Life Sciences at https://www.uspto.gov/sites/default/files/documents/ieg-may-2016-ex.pdf).
These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation. In view of the Subject Matter Eligibility Test for Products and Processes and the Steps cited below (See flowchart at pages 10-11 at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf ), the claims are directed to an abstract idea as further detailed below.
In view of the Subject Matter Eligibility Test for Products and Processes and the Steps cited below, the claims are directed to a process or processes (Step 1); an abstract idea, which sets forth a judicial exception.
In this case, claim 1 recites or is directed to a process (Step 1) and recites a method of “diagnosing or classifying”…as well as “determining the level” that are directed to judicial exceptions (in this case, an abstract idea)(Step 2A). The step of “diagnosing or classifying” or “determining the level” could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams). Thus, the claim is directed to at least one exception (Step 2A: YES), which may be termed an abstract idea. Claims 2-6 are dependent on claim 1 and further limit the virus and the biomarkers.
Thus the claim is directed to a judicial exception, and the claim as a whole is focused on an abstract idea (See also 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).
The claim as a whole is focused on “diagnosing or classifying” and “determining the level of one or more biomarkers” and not on the products per se. Thus, there is no need to perform the markedly different characteristics analysis.
Further as to Step 2A in view of the 2019 PEG, in view of Prong 1 of Revised Step 2A, the claim recites an abstract idea.
As to Prong 2 of Step 2A, the instant claim does not recite additional elements that integrate the judicial exception (abstract idea) into a practical application. “Integration into a practical application’ requires an additional element(s) or combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception (See for example, Slide 18 of 2019 PEG training at http://ptoweb.uspto.gov/patents/exTrain/101.html).
Further, in view of Step 2B and the “No” pathway, the claim does not recite additional elements that amount to significantly more than the judicial exception.
Consideration of the additional elements as a combination also adds no other meaningful limitations to the exception not already present when the elements are considered separately. The claim does not invoke any of the considerations that courts have identified as providing significantly more than the exceptions. Even when viewed as a combination, the additional elements fail to transform the exceptions into a patent eligible application of that exception. Thus, the claim as a whole does not amount to significantly more than the exception.
Thus, it is asserted that the claim is directed to judicial exceptions (by reciting mental steps) without reciting more or additional elements that amount to significantly more than the judicial exception.
Therefore, claim 1 does not recite eligible subject matter under 35 U.S.C. 101 in view of the Subject Matter Eligibility Test for Products and Processes, and the claimed invention is directed to non-statutory subject matter.
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 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Consiglio et al. (Consiglio)(as cited on the IDS submitted 06/28/2024).
See claims 1-3 as submitted 05/24/2024.
Consiglio teaches the rare multisystem inflammatory syndrome in children (MIS-C)(reads on “diagnosing or classifying a subject as having a chronic or long-term infection”) associated with COVID-19 (reads on “of a virus”, in this case SARS-CoV-2), presenting 4–6 weeks (reads on “long term”; defined in the specification as 30 days to 2 years, p. 4) after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation (reads on “one or more biomarkers in a biological sample”)…[found] that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage (reads on “determining the level of one or more biomarkers in a biological sample obtained from a subject”). Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C. (p.968, Summary).
Consiglio teaches “all serum samples of COVID-19 patients in Italy were investigated for presence of SARS-CoV-2 antibodies. IgG antibodies were quantitatively tested by LIAISON® SARS-CoV-2 S1/S2 IgG test (Diasorin)(Supplemental, Method Details, Confirmation of SARS-CoV-2 Infection) …Serum proteins were analyzed using a multiplex technology based upon proximity-extension assays (Supplemental Method Details, Serum Protein Profiling)(reads on “biological samples obtained from a subject”).
Regarding claim 2, Consiglio teaches “Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)(reads on instant claim 2, “SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4–6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation”(p. 968, Summary).
Regarding claim 3, Consiglio “assessed the cytokine changes upon treatment and found that tumor necrosis factor beta (TNF-β)(reads on instant claim 3, “TNF”), ITGA11, and CCL25 levels decreased, whereas HEXIM1, PSP1, and CXCL10 levels increased in response to treatment in the seven MIS-C patients with available pre/post samples (Figures 5B and 5C). These results indicate that there is a particular cytokine profile associated with MIS-C, which differs from Kawasaki disease hyperinflammation and that changes in response to immunomodulatory treatment”(p.974).
In view of the foregoing, all the claimed limitations are found in one reference and are taught to be optional variations to a base process they exemplify. As such, the claimed process, recited in claims 1-3, is within the scope of Consiglio’s invention, and thus Consiglio’s invention renders claims 1-3 prima facie obvious. The rationale to support this conclusion of obviousness is that Consiglio provides a teaching, suggestion, and motivation to substitute different variables disclosed within the reference. Furthermore, there is no evidence on the record that indicates that the claimed method exhibits any unexpected results compared to the prior art.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Consiglio as applied to claims 1-3 above, and further in view of McMurray et al. (McMurray)(See PTO-892 Notice of References Cited).
See claim 4 as submitted 05/24/2024.
Consiglio teaches claim 1 but does not teach wherein the cytokines, chemokines, and/or immunomodulatory proteins comprise IL1β.
McMurray, however, teaches “MIS-C is a newly defined post-viral myocarditis and inflammatory vasculopathy of children following COVID-19 infection” (p. 1, Abstract) and “cases of MIS-C were emerging around 4–5 weeks on average following the peak incidence of COVID-19 in each particular region”(p. 1, Introduction). McMurray teaches elevated IL-1β in MIS-C as well as other MIS-C like conditions (p. 5, Table 2)(reads on instant claim 4, “IL1β”). McMurray also teaches “when secreted, IL-1β remains mostly in the tissue microenvironment and serum levels of free IL-1β remain low as reported on patients with MIS-C…Therefore, assays based on RNA expression are preferred. Children with MIS-C invariably show increased IL-18, which is produced along with IL-1β and converted from pro-IL-18 to IL-18 through activation of caspase 1”(p. 5). McMurray further teaches “administration of an anti-IL-1 antagonist, Anakinra which was demonstrated as safe and efficacious in a small pilot study on COVID-19 patients (p. 10).
One of ordinary skill in the art would have been motivated to combine the method of Consiglio, particularly in the context of MIS-C, with the inclusion of the cytokine biomarker IL1β as taught by McMurray because upregulation of IL-1β pathway and activation of endothelial cells are likely to be the key determinants in disease pathogenesis, particularly with respect to myocarditis and systemic vasculitis which have been noted as conditions associated with MIS-C (See MPEP 2143 Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for including IL1β as a biomarker as taught by McMurray. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of immunology and proteomics, and commonly used as evidenced by the applied prior art.
Therefore the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Consiglio as applied to claims 1-3 above, and further in view of Samprathi et al. (Samprathi)(See PTO-892 Notice of References Cited) and Chen et al. (Chen)(See PTO-892 Notice of References Cited).
See claim 6 as submitted 05/24/2024.
Consiglio teaches claim 1 but does not teach wherein the transcription factors and motifs thereof comprise STAT.
Samprathi, however, teaches “the different classes of biomarkers – immunological, inflammatory, coagulation, hematological, cardiac, biochemical and miscellaneous – in terms of their pathophysiological basis followed by the current evidence” (p. 1., Abstract). Samprathi also teaches “Laboratory biomarkers play a major role in the diagnosis, prognosis and management of children with MIS-C…biomarkers are a valuable adjunct in timely diagnosis; appropriate therapy is lifesaving. Several diagnostic criteria have been proposed…Mandatory investigations for all children with suspected MIS-C, which are an essential part of the WHO criteria are the (i) inflammatory markers – ESR, C-reactive protein, or procalcitonin, and ferritin, (ii) cardiac biomarkers – troponin/NT-proBNP, and (iii) markers of coagulopathy – PT, PTT, and d-dimers. Elevated fibrinogen, LDH, or IL-6, elevated neutrophils, reduced lymphocytes and low albumin, proteinuria, high CK, high TG, and transaminitis are present in a variable number of children (p. 7). Additionally, Samprathi teaches “Cytokine storm, the hallmark of SARS CoV2 infection, evolves through several pathways, like the NF-κB, JAK/STAT (reads on instant claim 6, “STAT”) and the macrophage activation pathway, leading to the release of interleukin-6 (IL-6) and TNF-alpha...IL-6 is a key player in the cytokine storm, activating several cell types and forming a positive feedback loop. The large-scale unregulated production of interleukins, particularly IL-6, further stimulates several downstream pathways, increasing the production of acute-phase reactants like C-reactive protein (CRP)”(p. 3).
Chen additionally teaches “[i]nflammatory pathways impact the pathogenesis of a number of chronic diseases, and involve common inflammatory mediators and regulatory pathways. Inflammatory stimuli activate intracellular signaling pathways that then activate production of inflammatory mediators. Primary inflammatory stimuli, including microbial products and cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), mediate inflammation through interaction with the TLRs, IL-1 receptor (IL-1R), IL-6 receptor (IL-6R), and the TNF receptor (TNFR)…Receptor activation triggers important intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways”(p. 7205)(reads on instant claim 6, “STAT”). Chen also teaches Figure 4. which shows the JAK-STAT pathway where binding of IL-6 family members to plasma membrane receptors activates the JAK-STAT proteins. STAT proteins translocated into the nucleus bind target gene promoter regions to regulate transcription of inflammatory genes”(p. 7210). Further, Chen teaches “Elevated oxidative stress can induce production of reactive oxygen species (ROS), malondialdehyde (MDA), 8-Hydroxy-2-deoxyguanosine (8-OHdG) and isoprostanes…each of which can activate various transcription factors, including NF-κB, AP-1, p53, and STAT…Thus, this cascade can increase expression of genes encoding growth factors, inflammatory cytokines, and chemokines…Oxidative stress is associated with the pathogenesis of multiple diseases, such as cardiovascular disease, cancer, diabetes, hypertension, aging, and atherosclerosis…Therefore, oxidative stress products can also be used as markers of the inflammatory response (p. 7207).
One of ordinary skill in the art would have been motivated to combine the method of Consiglio, particularly in the context of MIS-C, with the inclusion of the transcription factor STAT as a biomarker as taught by Samprathi and Chen because of its important role in regulating the inflammatory response and because of the exceptional likelihood of its elevation in a long term infection, such as MIS-C (See MPEP2143 Rationale A. Combining prior art elements according to known methods to yield predictable results and Rationale G. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference teachings to arrive at the claimed invention).
One of ordinary skill in the art would have had a reasonable expectation of success for using the transcription factor, STAT, as one of the biomarkers for classifying a subject as having a chronic or long-term infection of a virus. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of immunology and proteomics, and commonly used as evidenced by the applied prior art.
Therefore the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over WHO (See PTO-892 Notice of References Cited).
See claim 1 as submitted 05/24/2024.
The WHO teaches different case definitions and criteria for both acute and chronic/advanced HIV infection or disease (reads on instant claim, “chronic or long-term infection”). The WHO teaches Box 2. or Criteria for diagnosis of advanced HIV (including AIDSa)(reads on instant claim 1, “diagnosing or classifying a subject”) for reporting for adults and children. The WHO teaches “Advanced HIV infection is diagnosed based on clinical or immunological (CD4) criteria (reads on instant claim 1, “one or more biomarkers”) among people with confirmed HIV infection” and more specifically:
- Clinical criteria for diagnosis of advanced HIV in adults and children with confirmed HIV infection: Presumptive or definitive diagnosis of any stage 3 or stage 4 condition (reads on instant claim 1, “chronic or long-term infection”) and/or;
- Immunological criteria for diagnosing advanced HIV in adults and children five years or older with confirmed HIV infection: CD4 count less than 350 per mm3 of blood in an HIV-infected adult or child and/or;
- Immunological criteria for diagnosing advanced HIV in a child younger than five years of age with confirmed HIV infection:
%CD4+ <30 among those younger than 12 months
%CD4+ <25 among those younger than 12-35 months
%CD4+ <20 among those younger than 36-59 months (p.9)
In view of the foregoing, all the claimed limitations are found in one reference and are taught to be optional variations to a base process they exemplify. As such, the claimed process, recited in claim 1, is within the scope of WHO’s invention, and thus WHO’s invention renders claim 1 prima facie obvious. The rationale to support this conclusion of obviousness is that WHO provides a teaching, suggestion, and motivation to substitute different variables disclosed within the reference. Furthermore, there is no evidence on the record that indicates that the claimed method exhibits any unexpected results compared to the prior art.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over WHO as applied to claim 1 above, and further in view of Nicolaides et al. (Nicolaides)(See PTO-892 Notice of References Cited) and Contoreggio et al. (Contoreggio)(See PTO-892 Notice of References Cited).
See claim 5 as submitted 05/24/2024.
The WHO teaches claim 1 but does not teach wherein the hormones and hormone receptors comprise CRH (corticotropin-releasing hormone).
Nicolaides, however, teaches “The Acquired Immunodeficiency Syndrome (AIDS), caused by infection with the Human Immunodeficiency Virus Type-1 (HIV), is characterized by profound immunosuppression, particularly of the innate, and T-helper (Th) 1-directed immunity. AIDS causes multisystem dysfunction, including impairment of the hypothalamic-pituitary-adrenal (HPA) axis, a major system coordinating the resting state and the adaptive response to stress. This neuroendocrine axis consists of three components: the hypothalamus, the pituitary gland, and the adrenal cortex with its end-effector molecules, the glucocorticoids. AIDS/HIV influence the HPA axis directly, through modulation of the host immune activity and alterations of the cellular biological pathways via HIV-encoded proteins, as well as indirectly, through immunodeficiency-associated opportunistic infections and various side effects of the therapeutic compounds employed, including those used in the highly active antiretroviral therapy (HAART)”(p. 1, Abstract). Nicolaides teaches Figure 1, showing the HPA axis and the hypothalamic PVN parvocellular corticotropin-releasing hormone (CRH) (reads on instant claim 5, “CRH”) and arginine vasopressin (AVP)-secreting neurons, the corticotrophs of the pituitary gland, and the adrenal gland cortex…Secreted CRH and AVP reach the pituitary gland and synergistically stimulate secretion of the adrenocorticotropic hormone (ACTH) from corticotrophs…ACTH released into systemic circulation finally stimulates both production and secretion of glucocorticoids (cortisol in humans and corticosterone in rodents) from the zona fasciculata of the adrenal cortex… Secreted glucocorticoids modulate activity of virtually all organs and tissues to adjust their functions. In addition, these hormones suppress higher regulatory centers of the HPA axis, the PVN and the pituitary gland, ultimately forming a closed negative feedback loop that aims to reset the activated HPA axis and restore its homeostasis (p. 3).
Contoreggio teaches “Corticotropin-releasing hormone (CRH) is critical in neuroendocrine immune regulation. CRH, a neuropeptide, is distributed in the central and peripheral nervous systems and acts principally on CRH receptor type 1 (CRHR1). CRH in the brain modulates neuropsychiatric disorders. CRH and stress modulation of immunity is two-pronged; there is a direct action on hypothalamic–pituitary–adrenal secretion of glucocorticoids and through immune organ sympathetic innervation. CRH is a central and systemic proinflammatory cytokine. Glucocorticoids and their receptors have gene regulatory actions on viral replication and cause central and systemic immune suppression. CRH and stress activation contributes to central nervous system (CNS) viral entry important in HIV-associated neurocognitive disorders and HIV-associated dementia. CNS CRH overproduction short-circuits reward, executive, and emotional control, leading to addiction, cognitive impairment, and psychiatric comorbidity. CRHR1 is an important therapeutic target for medication development” (p. 53, Abstract). Contoreggio also teaches “CRH stimulates the HPA axis, and excess GC/cortisol modulates immune responsivity. Under chronic stress, integrated daily cortisol secretion is elevated; compared to normal individuals, GC/cortisol concentrations may approach pharmacologic levels…When the stress system and the HPA axis are chronically activated, immune responsivity can convert to a smoldering proinflammatory state; this can be seen in autoimmune disorders, malignancy, atherosclerosis, and metabolic conditions. Responses to acute inflammation and infectious insults may be blunted, resulting in a suboptimal host defense during chronic stress-related proinflammatory states”(p. 56). Contoreggio further teaches “Chronic exposure to elevated levels of cortisol can adversely shift cytokine production and cellular immunity. In addition, in the setting of inflammation and infection, peripheral CRH together with other immune activators, such as histamine and catecholamines, induces production of IL-1, IL-6, IL-8, IL-18, TNF-alpha, and C-reactive protein, thereby driving inflammatory processes (p.60).
One of ordinary skill in the art would have been motivated to combine WHO’s method which involves using clinical criteria for diagnosis of advanced HIV in adults and children, with corticotropin-releasing hormone (CRH) as taught by Nicolaides and Contoreggio as a biomarker of HIV/AIDS disease chronicity because advanced HIV infection and AIDS causes multisystem dysfunction, including impairment of the hypothalamic-pituitary-adrenal (HPA) axis and thus measurable changes could potentially be seen in CRH levels in circulation indicating progression of disease, aiding in diagnosing or classifying a subject as having a chronic or long-term infection (See MPEP 2143 Rationale G. Some teaching, suggestion or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
One of ordinary skill in the art would have had a reasonable expectation of success for including corticotropin releasing hormone (CRH) as a biomarker to diagnose or classify a subject as having a chronic or long-term infection of a virus, such as the human immunodeficiency virus (HIV). There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of HIV endocrinology and immunology, and commonly used as evidenced by the applied prior art.
Therefore the invention as a whole would have been prima facie obvious to one of
ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims allowed.
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/C.C./Examiner, Art Unit 1672
/M FRANCO G SALVOZA/Primary Examiner, Art Unit 1672
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