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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Mar. 30, 2026 has been entered.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 30, 2026. Claims 1, 3-4, 7-9, 13-14 and 19-31 are pending and currently examined.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
(Previous Rejection – Withdrawn) Claims 1-3, 7-9, 13-14 and 19-25 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01.
This rejection is withdrawn in view of the amendment filed on Mar. 30, 2026.
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.
(Previous Rejection – Maintained) Claims 1, 3-4, 7-9, 13-14 and 19-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter because it is directed to a judiciary exception (JE).
A claim directed to a judicial exception must be analyzed to determine whether the elements of the claim, considered both individually and as an ordered combination, are sufficient to ensure that the claim as a whole amounts to significantly more than the exception itself. To be patent-eligible, a claim that is directed to a judicial exception must include additional features to ensure that the claim describes a process or product that applies the exception in a meaningful way, such that it is more than a drafting effort designed to monopolize the exception.
The claimed invention is based on a correlation between the level of GDF-15 in a sample from a patient with COVID-19 and disease conditions in the patient. Such correlation is a natural phenomenon, and thus is a JE. The active steps of the claims would be the determination of the GDF-15 levels of the patient and healthy subjects. Since the determining step is a highly general necessary data gathering procedure, it would not add significantly more to the claimed method than the JE. Therefore, the additional elements do not add meaningful limitations to the claimed process. The method is therefore not drawn to significantly more than the indicated JE.
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 of this title, 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.
(Previous Rejection – Maintained) Claims 1, 3-4, 7-9, 13-14 and 19-31 are rejected under 35 U.S.C. 103 as being unpatentable over Spanuth et al. (US 2010/0261284 A1, published on Oct. 14, 2010) in view of Lippi et al. (Prog Cardiovasc Dis. 2020 Mar 10;63(3):390–391).
These claims are directed to a method for predicting the disease severity or risk mortality for a patient with COVID-19, comprising a) determining the level of GDF-15 in a sample from the patient with COVID-19, b) comparing the level determined in step a) to a reference obtained for healthy individuals, and c) predicting the disease severity in the patient with COVID-19, wherein an increased level of GDF-15 in the sample from the patient compared to the reference is indicative of increased disease severity of the patient with COVID-19.
Spanuth teaches an invention relating to a method of identifying if a subject is to be admitted to the hospital or intensive care unit, the method comprising a) determining the amount of GDF 15 in a sample of the subject, and b) comparing the amount of GDF 15 determined in step a) to a reference amount, whereby a subject to be admitted to the hospital or intensive care unit is to be identified. Also described is a method for predicting the risk of mortality based on determining the amount of GDF 15 in a subject. Also described are devices and kits for carrying out the aforementioned methods. See Abstract. Spanuth teaches that a preferred reference amount serving as a threshold may be derived from the upper limit of normal (ULN), i.e., the upper limit of the physiological amount to be found in a population of apparently healthy subjects. See [0042].
Spanuth teaches that peptide of GDF-15 can be detected by ELISA assays using polyclonal or monoclonal antibodies specifically recognizing the GDF-15 polypeptides. See [0030]. Spanuth teaches that a kit for carrying out the methods of the invention, for identifying a subject to be admitted to the hospital, deciding about admitting a subject to the hospital, or predicting the risk of mortality in a subject is envisaged by the disclosed invention. Said kit comprising means for determining the amount of GDF-15 in a sample of a subject and means for comparing said amounts to reference amounts, wherein a subject to be admitted to the hospital is identified, a decision about admitting the subject to the hospital or intensive care unit is made, or the risk of mortality in the subject is predicted. See [0073].
Accordingly, Spanuth teaches a method comprising the steps of a) determining the amount of GDF 15 in a sample of a patient subject, and b) comparing the amount of GDF 15 determined in step a) to a reference amount, and c) predicting the risk of mortality (i.e., severity) of the subject – steps that are indistinguishable from those recited in the instant claims. However, Spanuth is silent on if the patient subject to be tested by the method is a COVID-19 patient. Instead, Spanuth is generic on diseases of the subject of the tested as long as there is risk of mortality that potentially require the patient to be hospitalized or put into intensive care unit.
Lippi teaches that coronavirus disease 2019 (COVID-19) is an emerging outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In up to 15% of infected patients the clinical course of COVID-19 may be complicated by the onset of a severe form of interstitial pneumoniae, which may then progress towards acute respiratory distress syndrome (ARDS) and/or multi organ failure (MOF) and death. People with underlying cardiovascular disease are among the highest risk individuals for severe disease and death. Importantly, among the COVID-19 knowledge gaps are laboratory and diagnostics issues as well as the clinical management of severe and critically ill patients. Since major cardiac complications have been reported to develop in a considerable number of patients with pneumonia, the authors performed an analysis of the current scientific literature to investigate whether the measurement of cardiac troponin I (cTnI) or cardiac troponin T (cTnT) may help predict clinical severity in patients with COVID-19. See page 390, left column. Teachings of Lippi indicate that there is a risk of mortality for COVID-19 patients, suggesting that patients may potentially need to be hospitalized or put into intensive care unit.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to apply the method of Spanuth to patients with COVID-19. One would have been motivated to do so to use the method of testing GDF-15 disclosed in Spanuth in determining if a COVID-19 patient has the risk of mortality or is potentially in need to be hospitalized or put into intensive care unit. Indeed, since Spanuth teaches testing of GDF-15 in patients with diseases for mortality risk in general, there is no reason to leave out patients with COVID-19, who, according to Lippi, are at high risk of mortality and may need to be hospitalized or put under intensive care.
Regarding claim 4, Spanuth is silent on determining level of GDF-15 in a first sample and a second sample obtained at different times. It would have been prima facie obvious for one of ordinary skill in the art to do the GDF-15 test on different samples, including ones obtained at different time points, and compare the results. One would have been motivated to do so, e.g., to reduce potential errors in individual tests and obtain results with better statistical significance.
Regarding claims 29 and 30, one of skill in the art would have found it obvious to test GDF-15 levels of samples obtained at multiple different time points, including those as claimed, to improve statistical significance and/or to obtain expression information at different time points, unless there is evidence that the claimed sampling time points are critical.
(Previous Rejection – Maintained) Claims 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (Am J Physiol Lung Cell Mol Physiol 314: L514–L527, 2018) in view of Polidoro et al. (Frontiers in Immunology, June 2020, volume 11, article 1626).
These claims are directed to a method for detecting or measuring GDF-15 concentration in a sample from a COVID-19 patient, comprising providing a sample (a multiple samples obtained at different time points) and contacting the sample(s) with an agent that specifically binds to GDF-15.
Wu teaches that human rhinovirus (HRV) is the most common virus contributing to acute exacerbations of chronic obstructive pulmonary disease (COPD) nearly year round, but the mechanisms have not been well elucidated. Recent clinical studies suggest that high levels of growth differentiation factor 15 (GDF15) protein in the blood are associated with an increased yearly rate of all-cause COPD exacerbations. The authors investigated whether GDF15 promotes HRV infection and virus-induced lung inflammation. They first examined the role of GDF15 in regulating host defense and HRV-induced inflammation using human GDF15 transgenic mice and cultured human GDF15 transgenic mouse tracheal epithelial cells. Next, they determined the effect of GDF15 on viral replication, antiviral responses, and inflammation in human airway epithelial cells with GDF15 knockdown and HRV infection. Finally, they explored the signaling pathways involved in airway epithelial responses to HRV infection in the context of GDF15. Human GDF15 protein overexpression in mice led to exaggerated inflammatory responses to HRV, increased infectious particle release, and decreased IFN-l2/3 (IL-28A/B) mRNA expression in the lung. Moreover, GDF15 facilitated HRV replication and inflammation via inhibiting IFN-l1/IL-29 protein production in human airway epithelial cells. Lastly, Smad1 cooperated with interferon regulatory factor 7 (IRF7) to regulate airway epithelial responses to HRV infection partly via GDF15 signaling. Their results reveal a novel function of GDF15 in promoting lung HRV infection and virus-induced inflammation, which may be a new mechanism for the increased susceptibility and severity of respiratory viral (i.e., HRV) infection in cigarette smoke-exposed airways with GDF15 overproduction. See Abstract.
Accordingly, Wu teaches a method for detecting or measuring concentration of GDF-15 in a subject. Wu teaches that the level of GDF-15 is related with virus-induced lung inflammation associated with HRV infection. However, Wu is silent on patients with COVID-19.
Polidoro reviews studies on systemic inflammatory response derived from lung injury caused by SARS-CoV-2 infection. Polidoro teaches that most SARS-CoV2 infections will not develop into severe COVID-19. However, in some patients, lung infection leads to the activation of alveolar macrophages and lung epithelial cells that will release proinflammatory cytokines. IL-6, TNF, and IL-1b increase expression of cell adhesion molecules (CAMs) and VEGF, thereby increasing permeability of the lung endothelium and reducing barrier protection, allowing viral dissemination and infiltration of neutrophils and inflammatory monocytes. In the blood, these cytokines will stimulate the bone marrow to produce and release immature granulocytes, that return to the lung and further increase inflammation, leading to acute respiratory distress syndrome (ARDS). This lung-systemic loop leads to cytokine storm syndrome (CSS). Concurrently, the acute phase response increases the production of platelets, fibrinogen and other pro-thrombotic factors. Systemic decrease in ACE2 function impacts the Renin-Angiotensin-Kallikrein-Kinin systems (RAS-KKS) increasing clotting. The combination of acute lung injury with RAS-KKS unbalance is called COVID-19 Associated Lung Injury (CALI). This conservative two-hit model of systemic inflammation due to the lung injury allows new intervention windows and is more consistent with the current knowledge. See Abstract.
Accordingly, teachings of Polidoro indicate that COVID-19 may cause cytokine storm and inflammation in patients which may be associated to lung injury - COVID-19 Associated Lung Injury (CALI). The teachings of Polidoro provide a nexus between GDF-15 levels in a patient with a respiratory viral infection and COVID-19, which is also a respiratory viral infection with risk of lung inflammation and injury.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Wu and Polidoro to arrive at the invention as claimed. One would have been motivated to do so, e.g., to analyze the GDF-15 expression status in patients of COVID-19 and determine if GDF-15 can be a useful marker for COVID-19, in a way similar to the study performed for HRV infection taught in Wu. There is a reasonable expectation of success that GDF-15 expression levels can be determined for COVID-19 patients based on the teachings of Wu.
Regarding claims 29 and 30, one of skill in the art would have found it obvious to test GDF-15 levels of samples obtained at multiple different time points, including those as claimed, to improve statistical significance and/or to obtain expression information at different time points, unless there is evidence that the claimed sampling time points are critical.
(Previous Rejection – Maintained) Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (Am J Physiol Lung Cell Mol Physiol 314: L514–L527, 2018) in view of Polidoro et al. (Frontiers in Immunology, June 2020, volume 11, article 1626), and further in view of Ruan et al. (Intensive Care Med (2020) 46:846–848) and Gaze, D.C. (Annals of Clinical BiochemistryVolume 57, Issue 3, May 2020, Pages 202-205).
Claim 31 is directed to a method for measuring a panel of biomarkers in a patient, comprising: providing a sample from the patient, wherein the patient has COVID-19, measuring levels of a panel of biomarkers in the sample, wherein the panel comprises GDF-15 and at least one biomarker selected from cardiac troponin T (cTnT), N-terminal pro-B- type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and/or D-dimer.
Relevance of Wu and Polidoro is set forth above. However, they are silent on biomarkers cardiac troponin T (cTnT), N-terminal pro-B- type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and D-dimer.
Ruan teaches a study on clinical predictors of mortality due to COVID‑19 based on an analysis of data of 150 patients from Wuhan, China. Ruan teaches that using the database of Jin Yin-tan Hospital and Tongji Hospital, the authors conducted a retrospective multicenter study of 68 death cases (68/150, 45%) and 82 discharged cases (82/150, 55%) with laboratory-confirmed infection of SARS-CoV-2. See page 846, left column, para 2. Ruan teaches that laboratory results showed that there were significant differences in white blood cell counts, absolute values of lymphocytes, platelets, albumin, total bilirubin, blood urea nitrogen, blood creatinine, myoglobin, cardiac troponin, C-reactive protein (CRP) and interleukin-6 (IL-6) between the two groups (Fig. 1b and Supplementary Table 1). See page 846, right column, para 1.
Gaze reviews studies on clinical utility of cardiac troponin measurement in COVID-19 infection. Gaze teaches that evidence of COVID-19-associated increases in circulating cardiac troponin T (cTnT) and cardiac troponin I (cTnl) above the 99th percentile reference limit are emerging in the literature. Detectable cTnl has been observed in most COVID-19 patients. In a retrospective cohort analysis, cTnl was significantly elevated in 54 subjects who died compared with 137 survivors (median [IQR] cTnl 22 [5.6-83.1] ng/L vs. 3 [1.1-5.5] ng/L, P~0.0001). See page 204, left column, para 3.
Accordingly. Teachings of Ruan and Gaze indicate that measurements of cardiac troponin (cTn) and C-reactive protein (CRP) were performed for COVID-19 patients as potential biomarkers.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Wu, Polidoro, Ruan and Gaze to arrive at the invention as claimed. One would have been motivated to do so to measure the expression of other biomarkers known to be studied with potential association of COVID-19, such as cTn and CRP taught in Ruan and Gaze, in addition to GDF-15 taught in Wu. There is a reasonable expectation of success that the cTnT and CRP levels in COVID-19 patients can be measured based on the teachings of Ruan and Gaze.
Response to Applicant’s Arguments
Applicant’s arguments filed on Mar. 30, 2026 have been fully considered and are addressed as follows.
To the 101 rejection, Applicant argues that claims 1, 4 and 13 are directed to methods, which fall within the statutory category of process under 35 USC 101. Applicant argues that under Step 2A, Prong 1 the claims should not be characterized as directed to a JE. Applicant argues that claim 1 is directed to a technological diagnostic method for a specific disease (COVID-19), not to an abstract concept or law of nature. Applicant argues that the Office’s analysis identifies the correlation between GDF-15 levels and COVID-19 disease severity as a natural phenomenon. Applicant quotes “Alice Corp. v. CLS Bank Int’l, 573 US 208, 217 (2014”) and “[t]hat one way of describing the [invention] is to describe the natural ability of the subject matter to undergo the process does not make the claim ‘directed to’ that natural ability”, arguing that just as the claims in CellzDirect were directed to a new method of preserving hepatocytes (not the natural ability of hepatocytes to survive multiple freeze-thaw cycles), the instant claims are directed to a new diagnostic method for COVID-19 disease severity prediction (not any underlying natural correlation between biomarkers and disease).
Applicant argues that even assuming argundo that the claims recite a judicial exception, the claims integrate this exception into a practical application through several meaningful limitations. Applicant argues that the claims are specifically directed to a “patient with COVID-19”, that the claims provide a specific, practical solution to the clinical need to identify patients at risk of severe disease progression, and that by the claimed process clinicians can predict disease severity in COVID-19 patients. Applicant argues that the claimed invention is not an abstract application of a natural correlation, it is a specific diagnostic method tailored to the unique clinical challenges presented by the COVID-19 pandemic.
Applicant argues that the claimed methods have direct clinical utility for COVID-19 patient management, that GDF-15 measurement enables disease severity prediction, mortality risk assessment, hospital resource allocation and treatment guidance, and that all these are concrete, practical applications that go far beyond merely observing a natural correlation. Applicant argues that the specification demonstrate that GDF-15 levels are significantly associated with oxygen saturation, enabling identification of patients with silent hypoxia.
Applicant argues that the examiner’s characterization of the measurement step as “highly general necessary data gathering” is incorrect and distinguishable from Mayo Collaborative Services V. Prometheus Laboratories, Inc., 566 U.S. 66 (2012). Applicant argues that in Mayo, the Court held that the claims, taken as a whole, effectively did no more than inform physicians of a natural correlation and suggest that they consider it when making treatment decisions. Applicant argues that the present claims are fundamentally different. The claims do not merely inform a physician of a correlation and suggest they "consider" it, instead, the amended claims explicitly define what the measured result means.
Applicant argues that the present claims are analogous to diagnostic claims that have been found patent-eligible. Applicant argues that, in CellzDirect, the Federal Circuit found claims directed to a method of preserving hepatocytes patent-eligible, even though the method relied on the natural ability of hepatocytes to survive multiple freeze-thaw cycles. Applicant argues that, similarly, the present claims are directed to a new and improved way of predicting disease severity in COVID-19 patients-not to any underlying natural correlation.
Applicant’s arguments above are not persuasive.
The JE is the naturally occurring correlation between disease severity or risk of mortality in a subject with COVID-19 and the GDF-15 level of the subject. The active steps of the claims would be the determination of the GDF-15 level and comparing it with a reference level obtained for healthy control subjects. Since the steps are highly general necessary data gathering and analysis procedure, they would not add significantly more to the claimed method than the JE. Therefore, the additional elements do not add meaningful limitations to the claimed process. The method is therefore not drawn to significantly more than the indicated JE.
As to Applicant’s arguments about the clinical applications, to be patent-eligible, a claim that is directed to a judicial exception must include additional features to ensure that the claim describes a process or product that applies the exception in a meaningful way, such that it is more than a drafting effort designed to monopolize the exception. Here, the JE is the naturally occurring correlation between the level of GDF-15 in a subject with COVID-19 and severity of COVID-19 or risk of mortality for the subject, such clinical applications presented in Applicant’s arguments do not alter the fact that the claimed invention are based on the correlation, and the claims are no more than a drafting effort designed to monopolize the correlation.
As to Applicant’s argument comparing the instant invention to the method of preserving hepatocytes in CellzDirect, which the Federal Circuit found claims directed to a method of preserving hepatocytes patent-eligible, Applicant does not elaborate how a diagnostic/prognostic method based on the correlation between the GDF-15 level and COVID-19 severity and mortality risk is comparable to a method of preserving hepatocytes in the cited court ruling.
As to Applicant argument that the examiner’s characterization of the measurement step as “highly general necessary data gathering” is incorrect and distinguishable from Mayo Collaborative Services V. Prometheus Laboratories, Inc., 566 U.S. 66 (2012), the examiner presents that the only active steps of claim 1 are “a) measuring the level of growth differentiation factor 15 (GDF-15) in a sample from the patient with COVID-19, b) comparing the level measured in step a) to a reference, wherein the reference is established from healthy control individuals”, these steps are highly general and are necessary data gathering steps for applying the JE.
As to Applicant’s argument that under Step 2B, the specification discloses a specific implementation for assessing COVID-19 disease severity that goes beyond routine and conventional activities, it is noted that the implementation disclosed in the specification is not sufficient to establish that the claims contain eligible subject matter under 35 USC 101. Instead, Step 2B recites “DOES THE CLAIM RECITE ADDITIONAL ELEMENTS THAT AMOUNT TO SIGNIFICANYLY MORE THAN THE JUDICIAL EXCEPTION?” As indicated above, the steps of measuring the levels of GDF-15 and comparing it to a reference established from healthy control individuals are highly general and necessary data gathering and data analyzing steps. They are not considered as amounting to significant more than the JE.
Applicant argues that (about Step 2B) the claims recite an inventive concept, that the Office has failed to provide adequate evidentiary support, that COVID-19 was a novel disease with no established biomarker protocols, that the prior art does not establish routine and conventional practice, that the claimed method achieves unexpected results, and that the specific combination of elements provides and inventive concept. Applicant argues that the Office has not provide evidence against these characteristics.
Applicant’s arguments are not persuasive. These characterizations are not germane to the 101 rejection since they do not argue against the fact that the claimed invention are based on a JE and that the active steps recited in the claimed do not amount to significantly more to the JE.
To the 103 rejection of claims 1-4, 7-9, 13-14 and 19-27 over Spanuth in view of Lippi, Applicant argues that (A) Lippi does not teach or suggest GDF-15, (B) no motivation to combine Spanuth with Lippi, (C) Spanuth is directed to a different technical problem, (D) there is no reasonable expectation of success, (E) unexpected results demonstrate nonobviousness. Applicant argues that, additionally, GDF-15 demonstrated superior prognostic performance compared to other biomarkers being investigated for COVID-19, that GDF-15 outperformed cTnT, NT-proBNP, CRP, and D-dimer in regression models, and that in multivariant analysis, GDF-15 (p=0.006) was one of only two biomarkers significantly associated with ICU admission or death after adjustment for other factors, and that GDF-15 outperformed the cardiac troponins that are the focus of Lippi. Applicant argues that these results demonstrate that the claimed invention provides more than a predictable application of prior art elements.
Applicant’s arguments are not persuasive.
Regarding arguments (A) and (B), it is not required that the cited references must teach or suggest combination of prior arts as long as there is a rationale to support a conclusion of obviousness. A "motivation to combine may be found explicitly or implicitly in market forces; design incentives; the ‘interrelated teachings of multiple patents’; ‘any need or problem known in the field of endeavor at the time of invention and addressed by the patent’; and the background knowledge, creativity, and common sense of the person of ordinary skill." Zup v. Nash Mfg., 896 F.3d 1365, 1371, 127 USPQ2d 1423, 1427 (Fed. Cir. 2018) (quoting Plantronics, Inc. v. Aliph, Inc., 724 F.3d 1343, 1354 [107 USPQ2d 1706] (Fed. Cir. 2013) (citing Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324, 1328 [92 USPQ2d 1849] (Fed. Cir. 2009) (quoting KSR, 550 U.S. at 418-21)). See MPEP § 2143.01. Secondly, teachings of Lippi indicate that there is a risk of mortality for COVID-19 patients, suggesting that patients may potentially need to be hospitalized or put into intensive care unit. These teachings present a nexus between the invention of Spanuth and patients of COVID-19 – the teachings of Spanuth indicate the use of GDF-15 testing in prognosing patients of risk of mortality in general while teachings of Lippi suggest that COVID-19 patients have significant risk of mortality. One of skill in the art would have found it obvious to combine the teachings of the two references to arrive at the invention as claimed.
Regarding argument (C) that Spanuth is directed to a different technical problem, the examiner does not agree, Spanuth teaches a method comprising the steps of a) determining the amount of GDF 15 in a sample of a patient subject, and b) comparing the amount of GDF 15 determined in step a) to a reference amount, and c) predicting the risk of mortality (i.e., severity) of the subject – steps that are indistinguishable from those recited in the instant claims. The method of Spanuth is generic to the diseases of the subject to be tested. It is known in the art that a subject with COVID-19 has a potential risk of severe disease and mortality, therefore, one of skill in the art would have found it obvious to apply the method of Spanuth in a subject with COVID-19; at least there would be no reason to deny a subject with COVID-19 of the method of assessing severity/mortality risk by measuring the GDF-15 level.
Regarding argument (D) that there is no reasonable expectation of success, it is noted that the claimed invention is based on the measurement of the GDF-15 level of a subject with COVID-19; there is no requirement that the subject has to have a high level of GDF-15. Based on the teachings of Spanuth, a high level of GDF-15 is found to be associated with high risk of disease severity/mortality; it does not matter what disease the subject may have. Therefore, there is a reasonable expectation of success and predictability that levels of GDF-15 in subjects with COVID-19 can be measured and comparison with a reference level be made.
Regarding argument (E) that unexpected results demonstrate nonobviousness, Applicant argues that GDF-15 levels correlate with detectable SARS-CoV-2 viral RNA in blood (viremia), that the specification demonstrates that GDF-15 levels are significantly associated with oxygen saturation, and that this enables detection of silent hypoxia, a critical COVID-19 complication not suggested by the reference.
As an initial matter, “the burden of showing unexpected results rests on he who asserts them. Thus it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted). Applicant’s attention is directed to MPEP 716.02(b)-(e) for how unexpected results can be established. E.g., to evaluate if the claimed invention produces unexpected results, one must consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art. See MPEP Section 716.02(d) and (e). Here, Applicant has not provided sufficient information for the Office to consider if the results produced by the claimed invention are commensurate in scope with the claims and how the results compare with the closest prior art.
To the 103 rejection of claims 28-30 over Wu in view of Polioro, Applicant argues that (A) Wu teaches human rhinovirus, not COVID-19, (B) Polidoro does not teach or suggest GDF-15, and (C) the Office’s combination relies on impermissible hindsight reasoning.
Applicant’s arguments are not persuasive.
Wu teaches a method for detecting or measuring concentration of GDF-15 in a subject. Wu teaches that the level of GDF-15 is related with virus-induced lung inflammation associated with HRV infection. Teachings of Polidoro indicate that COVID-19 may cause cytokine storm and inflammation in patients which may be associated to lung injury - COVID-19 Associated Lung Injury (CALI). The teachings of Polidoro provide a nexus between GDF-15 levels in a patient with a respiratory viral infection and COVID-19, which is also a respiratory viral infection with risk of lung inflammation and injury. It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Wu and Polidoro to arrive at the invention as claimed. One would have been motivated to do so, e.g., to analyze the GDF-15 expression status in patients of COVID-19 and determine if GDF-15 can be a useful marker for COVID-19, in a way similar to the study performed for HRV infection taught in Wu.
As to hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, the rejection has explained why a skilled artisan would have been motivated to combine the teachings of the cited references to arrive at the invention as claimed, without taking into account “knowledge gleaned only from applicant’s disclosure.”
To the 103 rejection of claim 31 over Wu in view of Polioro, Ruan and Gaze, Applicant argues that additional references do not cure the deficiency. Applicant argues that the combination of Wu, Polidoro, Ruan and Gaze suffers from the same fundamental deficiency: none of these references teaches or suggests using GDF-15 for COVID-19 prognosis, that adding more references that discuss COVID-19 biomarkers other than GDF-15 does not provide motivation to use GDF-15.
Applicant’s arguments are not persuasive. This rejection is not an anticipation rejection, and does not require any one of the cited references teaches each and every element of the claimed invention. As indicated in the rejection body, teachings of Ruan and Gaze indicate that measurements of cardiac troponin (cTn) and C-reactive protein (CRP) were performed for COVID-19 patients as potential biomarkers. One of skill in the art would have found it obvious to combine the teachings of Wu, Polidoro, Ruan and Gaze to arrive at the invention as claimed. One would have been motivated to do so to measure the expression of other biomarkers known to be studied with potential association of COVID-19, such as cTn and CRP taught in Ruan and Gaze, in addition to GDF-15 taught in Wu.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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