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
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 19-34 are pending and currently examined.
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).
This rejection is extended to new claims 32-34.
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.
New claims 32-34 depend from claim 9, further specifying that predicting the need for intensive care of the patient with COVID-19 comprises predicting that the patient will need intensive care when a level of GDF-15 in the sample from patient is at least 3000, 4000 or 4500 pg/ml.
The additional limitation of predicting the need for intensive care is a mental process based on the correlation of GDF-15 level and disease severity, not an active step. Therefore, it is not considered as adding significant more to the 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).
This rejection is extended to new claims 32-34.
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.
New claims 32-34 depend from claim 9, further specifying that the predicting the need for intensive care of the patient with COVID-19 comprises predicting that the patient will need intensive care when a level of GDF-15 in the sample from patient is at least 3000, 4000 or 4500 pg/ml.
The new limitation of predicting the need for intensive care is a mental process based on the correlation of GDF-15 level and disease severity, not an active step. One of skill in the art would have found it obvious to make mental predictions for intensive care need of a patient based on any information known in the art that is related with disease severity, including GDF-15 levels in COVID-19 patients. As to the claimed values of GDF-15 level, one of skill in the art would have found it obvious to obtain them based on routine clinical observation and/or professional judgments.
(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 Jul. 7, 2026 have been fully considered and are addressed as follows.
To the 101 rejection, Applicant provides the following two arguments:
1) Applicant argues that the claims integrate any JE into a practical application under Step 2A, Prong two, stating that the claims address a specific, documented unmet medical need and that the specification demonstrates a concrete, previously unavailable clinical benefit.
2) Applicant argues that the Office’s Step 2B analysis is not supported under Berkheimer, stating that the Office characterizes the determining step as “highly general necessary data gathering” but cites none of the four categories of evidence required by the Berkheimer Memorandum - no express statement in the specification, no court decision from MPEP 2016.05(d)(II), no supporting publication, and no statement of official notice. Applicant argues that the Office’s own 103 rejections supply affirmative factual evidence that the claimed methods were not well-understood, routine, and conventional.
Applicant’s arguments are not persuasive.
Regarding argument (1), MPEP 2106.04(d) explains integration of a Judicial Exception into a practical application. “The analysis under Step 2A Prong Two is the same for all claims reciting a judicial exception, whether the exception is an abstract idea, a law of nature, or a natural phenomenon (including products of nature). Examiners evaluate integration into a practical application by: (1) identifying whether there are any additional elements recited in the claim beyond the judicial exception(s); and (2) evaluating those additional elements individually and in combination to determine whether they integrate the exception into a practical application, using one or more of the considerations introduced in subsection I supra, and discussed in more detail in MPEP §§ 2106.04(d)(1), 2106.04(d)(2), 2106.05(a) through (c) and 2106.05(e) through (h).” Here, the JE is the correlation of the GDF-15 level of a COVID-19 patient with disease severity of the patient. The claims do not recite additional element that is significant more that the JE.
Regarding argument (2), MPEP 2016.05(d)(II) indicates that the courts have recognized determining the laboratory techniques the level of a biomarker in blood by any means, as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity (Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017)). Here, the claims recite a highly general step for determining the level of a biomarker, GDF-15, without specifying how the test is performed and what sample is analyzed.
As to Applicant’s argument that the Office’s own 103 rejections supply affirmative factual evidence that the claimed methods were not well-understood, routine, and conventional, the examiner does not agree. First, the 103 rejections aim to establish that the claimed invention is obvious over the cited prior art. There is no indication that the rejections supply affirmative factual evidence that the claimed methods were not well-understood, routine, and conventional. Additionally, the analysis for 101 rejection does not rely on if the claimed methods are well-understood, routine, and conventional. Instead, the analysis relies on if the claimed elements additional to the JE amount to significant more to the JE.
To the 103 rejection of claims 1, 3-4, 7-9, 13-14 and 19-31 over Spanuth in view of Lippi, Applicant argues that Spanuth in view of Lippi does not render the prognostic claims obvious, stating that nothing in Spanuth suggests that GDF-15 would perform differently – let alone superiorly – in any particular disease. Applicant argues, referring to teachings in the Specification, that GDF-15 provided prognostic information superior to and independent of the cardiovascular and inflammatory biomarkers then under investigation for COVID-19, including cardiac troponin T, NT-proBNP, CRP and D-dimer. Applicant argues that the specification further reports that GDF-15 was the only biomarker independently associated with SARS-CoV-2 viremia. Applicant argues that Spanuth’s disease-agnostic teaching provides no basis from which a person having ordinary skill in the art would have predicted this result.
Applicant argues that there was no reasonable expectation of success as to the claimed prediction, stating that the claims do not merely require measuring GDF-15, they require predicting disease severity, mortality, or the need for intensive care in patient with COVID-19, which at the effective filing date was a novel disease. Applicant argues that the field was investigating numerous candidate biomarkers, including cardiac troponins that are of subject of Lippi, with variable results. Applicant argues that Spanuth’s teaching of GDF-15 as a general admission/mortality marker provides no reasonable expectation that GDF-15 would yield a superior, independent prediction of outcomes in COVID-19.
Applicant’s arguments are not persuasive.
As indicated in the rejection body, Spanuth teaches a method for predicting the risk of mortality (i.e., severity) of the subject with a disease and accessing potential need to be hospitalized or put into intensive care unit for the subject, comprising the same steps as instantly claimed, except that the disease is a generic disease, suggesting that the method can be used for any disease with a risk of mortality and/or severity. 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. Therefore, one of skill in the art would have found it obvious to apply the prognostic/predicting method of Spanuth to a patient with COVID-19 patient, which is a disease with risk of mortality and the patient may need to be hospitalized.
As to the argument that GDF-15 was the only biomarker independently associated with SARS-CoV-2 viremia, the examiner does not agree. As taught in Lippi, other biomarkers can also be associated with SARS-CoV-2 infections. Moreover, Spanuth already teaches that GDF-15 alone can be associated with severity and risk of motility of a disease in general.
As to Applicant’s arguments that the Specification demonstrates that GDF-15 is superior than other biomarkers for patients with COVID-19, applicant points to paragraphs [0014], [0665] and [0689]. These paragraphs are presented below:
[0014] Surprisingly, the inventors could show that GDF- 15 is elevated in a high percentage of patients with COVID-19, and higher concentrations are associated with SARS-CoV-2 viremia and worse clinical outcome. GDF-15 provides prognostic information that is superior to known risk markers in COVID-19, including cTnT, NT-proBNP, CRP and D-dimer. Increased GDF-15 levels were inversely related to blood oxygenation levels. Greater increases in GDF-15 during hospitalization are also independently associated with worse outcomes.
[0665] In regression models including all biomarkers and baseline characteristics, ferritin (p=0.03) and GDF-15 (p=0. 006) were the only biomarkers associated with the primary endpoint. The ROC AUC for GDF-15 to discriminate patients with the primary endpoint was 0.78 (95% CI 0.70-0.86) (FIG. 1).
[0689] GDF-15 is known to be a robust predictor of poor outcome in critically ill patients. In animal models, GDF-15 deficiency is known to augment the inflammatory response and to exacerbate renal and cardiac injury induced by lipopolysaccharide, while over-expression of GDF-15 protects from these endotoxin-induced mechanisms. GDF-15 expression is induced by lung injury, and is suggested to be a hallmark for tissue injury in many organs. In the present invention, it was found that SARS-CoV-2 viremia is associated with higher levels of GDF-15. In models including all the cardiovascular and inflammatory biomarkers, only GDF-15 remained associated with viremia. This novel finding may suggest a direct link between SARS-CoV-2 cytopathic effects and the expression of GDF-15 in multiple tissues. GDF-15 correlated moderately (rho 0.45-0.64) with all the investigated inflammatory and cardiovascular biomarkers, but provided prognostic information beyond this. The present invention supports the current, integrated understanding on GDF-15, reflecting a spectrum of pathophysiological effects related to inflammation and cardiovascular dysfunction.
These teachings confirm that GDF-15 can be a biomarker that can be associated with risk of mortality and disease severity of a patient with COVID-19. Such conformation is predicted based on the teachings of Spunuth and Lippi that GDF-15 is a biomarker associated with increased disease severity and risk of mortality in general and patients with COVID-19 are with increase disease severity and risk of mortality.
As to applicant’s argument that GDF-15 is superior to other biomarkers then tested, this argument suggest that the other biomarkers do not predict disease severity and risk of mortality as well as GDF-15. Indeed, Spunuth does not teach that other biomarkers can be used for better predicting disease severity and risk of mortality.
Moreover, MPEP 2145 II teaches that prima facie obviousness is not rebutted by merely recognizing additional advantages or latent properties present but not recognized in the prior art.
Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) “would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art.” 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991) (Appellant argued that the presence of DEHP as the plasticizer in a blood collection bag unexpectedly suppressed hemolysis and therefore rebutted any prima facie showing of obviousness, however the closest prior art utilizing a DEHP plasticized blood collection bag inherently achieved same result, although this fact was unknown in the prior art.).
Here the combined teachings of Spunuth and Lippi suggest the method as claimed. The results provided in the Specification, e.g., GDF-15 is a better marker for predicting disease severity and risk of mortality than other biomarkers compared in the studies of the instant invention is a latent property that is silent in the cited references and does not rebuttal the obviousness of the claimed invention.
To the 103 rejection of claims 28-31 over Wu et al. in view of Polidoro et al. (claims 28-30), and further in view of Ruan et al. (claim 31), Applicant argues that those references concern GDF-15 measurement and COVID-19 generally and do not teach the viremia limitation (claim 30), the serial-sampling structure (claims 29-30), or the specific panel.
Applicant’s arguments are not persuasive.
Wu teaches a method for detecting or measuring concentration of GDF-15 in a subject. Even though Wu is silent on patients with COVID-19, Wu teaches that the level of GDF-15 is related with virus-induced lung inflammation associated with HRV infection. Polidoro teaches 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. Therefore, one of skill in the art when reading the references of Wu and Polidoro would have found it obvious to determine the GDF-15 level in a COVID-19 patient who may also have virus-caused lung injuries. Moreover, since it is a known practice in the art to detect the GDF-15 in a patient with one viral infection, it would have been obvious to do the same detection assay for a patient with a different viral infection which has similar symptoms.
As to the claimed limitation of viremia, viremia is one of the symptoms of COVID-19, one of skill in the art would have found it obvious to include patients with viremia (or at least not to exclude those patients) in the GDF-15 detection assays so that the GDF-15 levels in those patients can be measure. As to the time points samples are obtained, one of skill in the art would have found it obvious to do so to determine GDF-15 at different time points to see if there is any difference in the process of disease progression. As to the panels of biomarkers to be determined together with GDF-15, since all of the biomarkers are known in the art to be associated with virus infections, one of skill in the art would have found it obvious to detect them to find out their association with disease progress.
Applicant argues that combinations reflect impermissible hindsight. Applicant argues that the Office's combinations are sustainable only by using the present application as a template and that only with knowledge of the inventors' discovery - that GDF-15 provides superior, independent prognostic information specifically in COVID-19 - would a PHOSITA have assembled these references to arrive at the claimed methods.
Applicant’s argument is not persuasive. 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 the current case, the rejections have explained why a skilled artisan would have been motivated to use the GDF-15 level in a subject in the prognosis/prediction of disease severity and risk of mortality for a patient with COVID-19 based on the teachings of the cited prior art references.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
Prosecution Insights