US Pat. No. 9,261,517

DIAGNOSIS OF ACUTE CORONARY SYNDROME, MYOCARDIAL INFARCTION, OR ANGINA PECTORIS BY MEANS OF NEUROPHYSIN II

B.R.A.H.M.S GmbH, Hennig...

1. A method for in vitro diagnosis of acute coronary syndrome, myocardial infarction, or angina pectoris, comprising
a) determining the level of neurophysin II in at least one sample from a patient, wherein said neurophysin II is a fragment
of preprovasopressin, said fragment consisting of the polypeptide of SEQ ID NO: 2; and b) diagnosing the presence of acute
coronary syndrome, myocardial infarction or angina pectoris in said patient based on the result in step a) .

US Pat. No. 9,116,153

ARGININE VASOPRESSIN PRO-HORMONE AS PREDICTIVE BIOMARKER FOR DIABETES

B.R.A.H.M.S GMBH, Hennig...

1. A method for predicting the risk of a subject for contracting diabetes mellitus and/or metabolic syndrome or for identifying
a subject having an enhanced risk for contracting diabetes mellitus and/or metabolic syndrome or for diagnosing metabolic
syndrome in a subject wherein said subject is non-diabetic, comprising:
(a) detecting and quantitating the level of a marker consisting of arginine vasopressin pro-hormone or fragments thereof in
a sample from said patient,

wherein said detection and quantitation comprises contacting the sample with a diagnostic assay reagent comprising a capture
probe that specifically binds to arginine vasopressin pro-hormone or a fragment thereof selected from copeptin and neurophysin
II, and detecting and quantitating thus-formed complexes of capture probe and arginine vasopressin pro-hormone, copeptin or
neuorphysin II, and

(b) predicting the risk of the subject for contracting diabetes mellitus and/or metabolic syndrome or inferring from it a
risk for contracting diabetes mellitus and/or metabolic syndrome for said subject or for diagnosing metabolic syndrome in
said subject by comparing the level of arginine vasopressin pro-hormone, copeptin or neurophysin II in the patient to the
level of arginine vasopressin pro-hormone, copeptin or neurophysin II in an ensemble of pre-determined samples in a population
of comparable apparently healthy subjects who later contracted diabetes mellitus or metabolic syndrome or did not contract
said conditions, wherein said prediction or inference is based on a statistically significant correlation of the level of
the marker in the patient sample with the levels of the marker in the pre-determined samples.

US Pat. No. 9,810,699

RISK ASSESSMENT FOR ANTIBIOTICS TREATMENT IN PATIENTS SUFFERING FROM PRIMARY NON-INFECTIOUS DISEASE BY DETERMINING THE LEVEL OF PROCALCITONIN

B.R.A.H.M.S GMBH, Hennig...

1. A method for diagnosing whether a subject suffering from a primary non-infectious disease has an increased risk of an adverse
outcome potentially being induced by administration of an antibiotic to said subject, comprising:
(a) detecting and quantifying in a sample of a bodily fluid from the subject the level of Procalcitonin (PCT) consisting of
the amino acid sequence 2-116 or 3-116 of the PCT of SEQ ID NO:1, wherein said detection and quantitation comprises

(i) contacting said sample with a diagnostic assay capture molecule which specifically binds to the PCT consisting of the
amino acid sequence 2-116 or 3-116 to form a capture molecule:PCT complex and

(ii) quantitating the capture molecule:PCT complex, and thereby determining the level of PCT in the sample;
(b) comparing the thus-determined level of PCT in the sample with a predetermined value for diagnosing of whether the subject
has an increased risk of an adverse outcome induced by the administration of an antibiotic,

wherein the predetermined value indicates a statistically significant adverse outcome risk if the sample contains less than
200 pg/mL of PCT, whereby if the sample contains less than 200 pg/mL of PCT, said subject is diagnosed as having a statistically
significant increased risk of having an adverse outcome induced by administration of an antibiotic, and whereby treatment
with antibiotics is contraindicated, or if the prescribed treatment includes antibiotics, the subject is further monitored
for symptoms of an adverse outcome, and

wherein the sample of the bodily fluid of the subject is selected from the group consisting of: a blood sample, a serum sample,
a plasma sample, a cerebrospinal fluid sample, a saliva sample, a urine sample and an extract of any of these samples.

US Pat. No. 9,753,039

PROGNOSIS OF ADVERSE EVENTS IN PATIENTS WITH SUSPECTED CHRONIC HEART FAILURE

B.R.A.H.M.S GmbH, Hennig...

1. A method for determining an enhanced risk of a patient with stable chronic heart failure or suspected of having stable
chronic heart failure suffering an adverse event, comprising:
(a) detecting and quantitating the level of procalcitonin (PCT), or a fragment thereof consisting of amino acids 1 to 116
or 2 to 116 or 3 to 116 of SEQ ID NO:1, in a sample of bodily fluid of said patient, wherein the detection and quantitation
comprises a PCT detection assay wherein the sample is contacted with an antibody that specifically binds to PCT to form a
detectable PCT:antibody complex, and detecting and quantitating the complex; and

(b) comparing said level of PCT or fragments thereof to a statistically significant predetermined threshold level,wherein, when said level of procalcitonin or fragments thereof exceeds said threshold level, said patient is determined to
have an enhanced risk of suffering an adverse event.
US Pat. No. 9,664,689

METHOD FOR THE SELECTIVE DETECTION AND MEASUREMENT OF PROCALCITONIN 1-116 AND AMINO-TERMINAL PEPTIDES OF PROCALCITONIN COMPRISING AMINO ACIDS 1 AND 2 OF PROCALCITONIN 1-116

B.R.A.H.M.S GMBH, Hennig...

1. A method for detecting procalcitonin 1-116 (SEQ ID NO: 1) and N-terminal procalcitonin peptides comprising amino acids
alanine and proline (Ala-Pro or AP) in positions 1 and 2 of the amino terminus of procalcitonin 1-116 (SEQ ID NO: 1) in a
sample, the method comprising contacting said sample with an antibody that specifically binds an epitope of procalcitonin
1-116 comprising amino acids 1 and 2 of procalcitonin 1-116 and binds selectively to intact procalcitonin 1-116 (SEQ ID NO:
1) or procalcitonin partial peptides comprising amino acids 1 and 2 of SEQ ID NO: 1, said antibody comprising a detectable
label or being detectable by a molecule comprising a detectable label; and
detecting the concentration of procalcitonin 1-116 and N-terminal procalcitonin peptides comprising amino acids alanine and
proline (Ala-Pro or AP) in positions 1and 2 of the amino terminus of procalcitonin 1-116 in said sample by measuring the amount
of bound detectable label in said sample.

US Pat. No. 9,261,516

DIAGNOSIS AND RISK STRATIFICATION USING NT-PROET-1

B.R.A.H.M.S GmbH, Hennig...

1. A method for the in-vitro diagnosis and/or risk stratification of heart diseases and/or diseases of the lungs and respiratory
tract selected from the group consisting of cardiac insufficiency, post myocardial infarction, pneumonia and exacerbated chronic
obstructive pulmonary disease comprising
(a) contacting at least one sample of bodily fluid from a patient with an antibody specific for the polypeptide consisting
of the amino acid sequence APETAVLGAELSAVGENGGEKPTPSPPWRLRRSKR (SEQ ID NO: 6), known as NT-proET-1,

(b) detecting binding of said antibody to NT-proET-1 using an immunoassay to determine the level of NT-proET-1 in said at
least one sample, and

(c) diagnosing the presence or stratifying the risk of heart diseases and/or diseases of the lungs and respiratory tract in
the patient based on the result in steps (a) and (b), wherein the presence of a higher level of NT-proET-1 in said at least
one sample compared to healthy controls indicates the presence of a heart disease or disease of the lungs and respiratory
tract in said patient, or an increased risk of an unfavorable prognosis for heart disease or disease of the lungs and respiratory
tract and wherein said heart disease or disease of the lungs and respiratory tract are selected from the group consisting
of cardiac insufficiency, post myocardial infarction, pneumonia and exacerbated chronic obstructive pulmonary disease.

US Pat. No. 9,513,301

METHOD FOR RISK STRATIFICATION IN STABLE CORONARY ARTERY DISEASE

B.R.A.H.M.S GmbH, Hennig...

1. A method for assessing the risk of future cardiovascular events in an individual with stable coronary artery disease (CAD),
the method comprising:
(a) contacting a blood, plasma, or serum sample from the individual having stable coronary disease (CAD) with antibodies of
a dual antibody assay for the determination of procalcitonin (PCT) with a functional assay sensitivity of <0.007 ng/ml PCT
to determine the level of procalcitonin (PCT) in said plasma or serum sample from the individual; and

(b) identifying the individual as being at highest risk of experiencing future adverse cardiovascular events when the PCT
level is equal to or greater than 0.05 ng/ml.

US Pat. No. 9,046,532

RISK ASSESSMENT FOR ANTIBIOTICS TREATMENT IN PATIENTS SUFFERING FROM PRIMARY NON-INFECTIOUS DISEASE BY DETERMINING THE LEVEL OF PROCALCITONIN

B.R.A.H.M.S GMBH, Hennig...

1. A method for diagnosing whether a subject suffering from a primary non-infectious disease has an increased risk of an adverse
outcome induced by administration of an antibiotic in order to treat potential bacterial infections to said subject, comprising:
(a) detecting and quantifying in a sample of a blood from the subject the level of Procalcitonin (PCT) or a fragment thereof
having an amino acid sequence 2-116 or 3-116 of the PCT of SEQ ID NO:1, wherein said detection and quantitation comprises

i. contacting said sample with a diagnostic assay capture molecule which specifically binds to the PCT or fragment, and
ii. quantitating the capture molecule:PCT or fragment thereof complex,
thereby determining the level of the PCT or fragment thereof in the sample;
(b) comparing the thus-determined level of PCT or fragment thereof in the sample with a predetermined value obtained by a
statistical analysis of calibration levels for the prediction of a potential risk of an adverse outcome induced by the administration
of an antibiotic;
wherein the predetermined value resulting from the statistical analysis indicate a statistically significant adverse outcome
risk if the sample contains less than 200 pg/mL of PCT or fragment thereof, whereby if the sample contains less than 200 pg/mL
of PCT or fragment thereof, said subject is diagnosed as having a statistically significant increased risk of having an adverse
outcome induced by administration of an antibiotic in order to treat or prevent potential bacterial infections, andwherein
when the subject is determined to have a statistically significant risk of an adverse outcome, treatment which excludes administration
of antibiotics in order to treat potential bacterial infections is performed, and

when the subject is determined to not have a statistically significant risk of an adverse outcome, administration of antibiotics
in order to treat potential bacterial infections is performed.

US Pat. No. 9,229,013

VASOACTIVE HORMONE-BASED STRATIFICATION OF PATIENTS SUFFERING FROM DISEASES RELATED TO ENDOTHELIAL FUNCTION/DYSFUNCTION

B.R.A.H.M.S GMBH, Hennin...

1. A method for the stratification of a subject having an acute or a chronic disease for response to or risk of unfavorable
effect from administration of a medication, wherein said disease affects endothelial function, comprising:
(i) detecting and quantitating in a sample of bodily fluid from said subject the concentration of a vasoactive hormone, a
precursor of said vasoactive hormone, or a fragment of said hormone or precursor, selected from the group consisting of

a. a peptide hormone a precursor of said peptide hormone, and a fragment of said peptide hormone or precursor of said peptide
hormone, selected from the group consisting of Adrenomedullin (ADM), proADM, Midregional proADM (MR-proADM), Atrial Natriuretic
Peptide (ANP), proANP, Midregional proANP (MR-proANP), Brain natriuretic peptide (BNP), proBNP, N-Terminal proBNP (NT-proBNP),
C-type natriuretic peptide (CNP), proCNP, Endothelin-1 (ET-1), proET-1, C-Terminal proET-1 (CT-proET-1), Endothelin-2 (ET-2),
proET-2, Endothelin-3 (ET-3), proET-3, Arginine-Vasopressin (AVP), proAVP, C-Terminal-proAVP (CT-proAVP or Copeptin), Dendroaspis
natriuretic peptide (DNP), proDNP, Urodilatin, proUrodilatin, Angiotensin II, pro-Angiotensin-II, Urocortin, proUrocortin,
Urocortin-2 (Stresscopin-related peptide), proUrocortin-2, Urocortin-3 (Stresscopin), proUrocortin-3, Urotensin-II, proUrotensin-II,
Urotensin II-related protein (URP), proURP, Neuropeptide Y (NPY), proNPY, Vasoactive intestinal peptide (VIP), proVIP, Calcitonin
gene-related peptide I (CGRP I), proCGRP I, Calcitonin gene-related peptide II (CGRP II), proCGRP II, Relaxin, proRelaxin,
Endokinin A, and proEndokinin A;

b. a small peptide hormone selected from the group consisting of Bradykinin, proBradykinin, Apelin, proApelin, Neurotensin,
proNeurotensin, Substance P, Neurokinin A (Substance K), proTachykinin A, N-terminal proTachykinin A (NT-proPTA), Endokinin
A/B, proEndokinin A/B, Endokinin C, proEndokinin C, Methionine-Enkephalin, Leucine-Enkephalin, proenkephalin (PENK), and Mid-Regional-PENK
(MR-PENK); or

c. a hormone selected from the group consisting of Serotonin, Prostaglandins and Thromboxane;
wherein said detection and quantitation comprises a diagnostic assay, said assay comprising
a?. contacting the sample with a diagnostic assay reagent comprising a capture probe that specifically binds to vasoactive
hormone, precursor of said vasoactive hormone or fragment of said hormone or precursor, and

b?. detecting and quantitating thus-formed complexes of capture probe and vasoactive hormone, precursor of said vasoactive
hormone or fragment of said hormone or precursor, and;

(ii) stratifying said subject based on the thus-determined concentration of the vasoactive hormone, precursor of said vasoactive
hormone or fragment of said hormone or precursor into one of the following categories by comparison to pre-determined threshold
concentration values correlated to the categories:

(a) a responder to a medication for treatment of said disease;
(b) a non-responder to a medication for treatment of said disease not showing an unfavorable effect after having received
said medication;

(c) a subject showing an unfavorable effect after having received said medication,
wherein the vasoactive hormone is ADM, pro-ADM or MR-proADM,
wherein the disease is selected from the group consisting of chronic obstructive pulmonary disease (COPD), post stroke condition
and post myocardial infarct condition, and

wherein the medication is selected from the group consisting of an anti-coagulant, warfarin, a thrombolytic drug, a platelet
aggregation inhibitor, a ?-blocker, a lipid lowering substance, a statin, a diuretic, an Angiotensin-Converting Enzyme (ACE)
inhibitor, a calcium channel blocker, a prostacyclin derivative, a hormone therapeutic agent, a steroid, a nitrate, acetylsalicylic
acid and an antibiotic;

(d) a subject showing an unfavorable effect after having received said medication,
wherein the vasoactive hormone is ANP, pro-ANP, or MR-proANP),
wherein the disease is selected from the group consisting of COPD, post stroke condition and post myocardial infarct condition,
and

wherein the medication is selected from the group consisting of an anti-coagulant, warfarin, a thrombolytic drug, a platelet
aggregation inhibitor, a ?-blocker, a lipid lowering substance, a statin, a diuretic, an ACE inhibitor, a calcium channel
blocker, a prostacyclin derivative, a hormone therapeutic agent, a steroid, a nitrate, acetylsalicylic acid and antibiotic;

(e) a subject showing an unfavorable effect after having received said medication,
wherein the vasoactive hormone is Endothelin-1, proET-1 or CT-proET-1,
wherein the disease is selected from the group consisting of COPD, post stroke condition and post myocardial infarct condition,
and

wherein the medication is selected from the group consisting of an anti-coagulant, warfarin, a thrombolytic drug, a platelet
aggregation inhibitor, a ?-blocker, an anti-oxidant, a lipid lowering substance, a statin, a diuretic, an ACE inhibitor, a
calcium channel blocker, an endothelin-receptor antagonist, a prostacyclin derivative, a hormone therapeutic agent, a steroid,
a nitrate, acetylsalicylic acid, and an antibiotic; or

(f) a subject showing an unfavorable effect after having received said medication,
wherein the vasoactive hormone is AVP, proAVP, or CT-proAVP (Copeptin),
wherein the disease is selected from the group consisting of COPD, post stroke condition and post myocardial infarct condition,
and

wherein the medication is selected from the group consisting of an anti-coagulant, warfarin, a thrombolytic drug, a platelet
aggregation inhibitor, a ?-blocker, an anti-oxidant, a lipid lowering substance, a statin, a diuretic, an ACE inhibitor, a
calcium channel blocker, a prostacyclin derivative, a hormone therapeutic agent, a steroid, a nitrate, acetylsalicylic acid
and an antibiotic.

US Pat. No. 10,067,063

PROGNOSIS AND RISK ASSESSMENT IN STROKE PATIENTS BY DETERMINING THE LEVEL OF MARKER PEPTIDES

B.R.A.H.M.S GMBH, Hennig...

1. A method for diagnosing and treating a stroke or a transient ischemic attack in a patient suspected of having a stroke or a transient ischemic attack within 5 days to a year after said patient has previously suffered a stroke or transient ischemic attack, said method comprising:a. obtaining a sample of bodily fluid from said patient,
b. detecting and quantitating in said sample from said patient the level of at least one cardiovascular peptide, wherein said cardiovascular peptide is selected from the group consisting of MR-proANP (mid-regional fragment of proANP), CT-proAVP (C-terminal fragment of arginine vasopressin precursor proAVP), MR-proADM (mid-regional fragment of adrenomedullin), CT-proET-1 (C-terminal fragment of endothelin-1 precursor pro-ET-1), PCT (calcitonin precursor procalcitonin), and hGH (human growth hormone),
wherein said detection and quantitation comprises contacting the sample with a diagnostic assay reagent comprising a capture probe that specifically binds to said cardiovascular peptide, and detecting and quantitating the thus-formed complexes of said capture probe and cardiovascular peptide, and
c. diagnosing said patient as having had a stroke or a transient ischemic attack by comparing the level of the cardiovascular peptide in the patient to a threshold level, wherein a level value of the cardiovascular peptide below the threshold is indicative for transient ischemic attack and a level value of the cardiovascular peptide above the threshold is indicative for stroke, and wherein the threshold level for MR-proANP is from about 90 to about 140 pmol/l, the threshold level for CT-proAVP is from about 9.5 to about 11.5 pmol/l, the threshold level for MR-proADM is from about 0.5 to about 0.8 nmol/l, the threshold level for CT-pro-ET-1 is from about 65 to about 90 pmol/l, the threshold level for PCT is from about 0.0230 to about 0.0260 ng/ml, and the threshold level for hGH is from about 0.10 to about 0.3 ng/ml, and
d. treating said patient for a stroke or transient ischemic attack.
US Pat. No. 10,048,280

IMMUNOASSAY FOR THE DETECTION OF PROCALCITONIN

B.R.A.H.M.S GMBH, Hennig...

4. An antibody or an antigen binding fragment thereof directed against an epitope in the sequence spanning amino acid residues 25 to 37 of SEQ ID NO:1 (Procalcitonin), wherein the antibody is produced by a hybridoma cell line that is deposited at the DSMZ under accession number DSM ACC2993.
US Pat. No. 10,024,872

AUGURIN IMMUNOASSAY

B.R.A.H.M.S GmbH, Hennig...

1. An immunoassay method for the detection of augurin or a precursor or fragment thereof comprising(a) contacting a sample suspected of comprising augurin or a precursor or fragment thereof with a first antibody or an antigen-binding fragment thereof specific for augurin or a precursor or fragment thereof and a second antibody or an antigen-binding fragment thereof specific for augurin or a precursor or fragment thereof under conditions allowing for the binding of the two antibodies or antigen-binding fragments thereof to augurin or a precursor or fragment thereof,
wherein said first and second antibodies or antigen-binding fragments thereof are specific for epitopes contained within the sequence spanning amino acids 71 to 107 of pre-augurin according to SEQ ID NO:1, wherein said first and second antibodies or antigen-binding fragments thereof are specific for different and non-overlapping epitopes,
wherein the first antibody or antigen-binding fragment is produced by a hybridoma cell line selected from the group consisting of cell line 482/H2 deposited as DSM ACC3208, cell line 482/H10 deposited as DSM ACC3209, cell line 482/H7 deposited as DSM ACC3210, and cell line 482/G9 deposited as DSM ACC3211, and
wherein the second antibody or antigen-binding fragment is produced by hybridoma cell line 439/F4 deposited as DSM ACC3206 or hybridoma cell line 439/H10 deposited as DSM ACC3207, and
(b) detecting the binding of the first and second antibodies or antigen-binding fragments thereof to augurin or a precursor or fragment thereof.
US Pat. No. 10,921,330

METHOD FOR DIAGNOSIS OF DEMENTIAS AND NEUROINFLAMMATORY DISEASES BASED ON AN INCREASED LEVEL OF PROCALCITONIN IN CEREBROSPINAL FLUID

B.R.A.H.M.S GMBH, Hennig...

1. A method for assisting in the detection and diagnosis of dementias selected from the group consisting of Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and various forms of vascular dementia (VAD), said method comprising:determining the level of procalcitonin (PCT) in a sample of cerebrospinal fluid (CSF) from an adult patient who is suffering from or, based on clinical manifestations, is suspected of having a dementia selected from the group consisting of Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and various forms of vascular dementia (VAD with the aid of a highly sensitive PCT immunoassay having a functional assay sensitivity (FAS) of 10 ng of PCT per liter (10 ng/1 or 10 pg/ml) or better, said immunoassay comprising contacting the sample of CSF from the adult patient with a pair of antibodies, wherein one of the pair of antibodies binds to calcitonin and the other of the pair of antibodies binds to katacalcin, and at least one of the pair of antibodies is an affinity-purified polyclonal antibody, wherein an increased level of procalcitonin in said sample when compared to levels of PCT in CSF from healthy individuals indicates dementia.
US Pat. No. 10,101,326

METHOD FOR DETERMINING A MARKER IN SMALL VOLUME OF A SAMPLE OF A BODILY FLUID

B.R.A.H.M.S GMBH, Hennig...

1. A method for determining correct use of a flow test element, comprising:providing a flow test element having a plurality of functional zones (3, 4, 5, 6, and optionally 7), the plurality of functional zones (3, 4, 5, 6, and optionally 7) being at least partially fluidly connected and comprising an application zone (3), a bridging zone (4), a testing zone (5) fluidly connected to the application zone (3) and configured for determination of a marker in a whole blood sample, a control zone (6) and optionally an optional sample determination zone (7), wherein the bridging zone (4) is located between and fluidly connected to the application zone (3) and the testing zone (5), and wherein the bridging zone (4) comprises a bridge membrane fluidly connected to the application zone (3) and the testing zone (5) configured to hinder migration of erythrocytes to the testing zone (5), and
applying a small volume of a whole blood sample to the sample application zone (3) of the flow test element and determining if the flow test element is being correctly used by:
(a) measuring at least one optical parameter for one or more of the functional zones (3; 4; 5; 6; 7), and
(b) comparing the at least one optical parameter determined in (a) to at least one predefined optical parameter assigned to the one or more functional zones (3; 4; 5; 6; 7), thereby optically determining whether a part of the applied whole blood sample reaching one of the zones of the plurality of functional zones (3, 4, 5, 6, 7) is a whole blood sample;
wherein the method includes:
making an optical determination in control zone (6) of whether the correct sample material was used, and
optionally making an optical determination of a marker in the sample in testing zone (5).
US Pat. No. 10,857,129

V1B RECEPTOR ANTAGONIST FOR USE IN THE TREATMENT OF PATIENTS HAVING AN ELEVATED AVP LEVEL AND/OR AN ELEVATED COPEPTIN LEVEL

B.R.A.H.M.S GMBH, Hennig...

1. Method for predicting a treatment response to a V1B receptor antagonist in a human patient with depressive symptoms and/or anxiety symptoms, wherein the copeptin concentration in a blood sample of said patient is determined, wherein an elevated copeptin concentration compared to copeptin concentration in individuals not suffering from anxiety and/or depressive symptoms and being at least 5 pmol/L is indicative for the patient responding to a treatment with a V1B receptor antagonist, wherein the patient is determined to have the elevated copeptin concentration and wherein a V1B receptor antagonist is administered to the patient.