US Pat. No. 9,216,178

DRY BLEND FORMULATION OF TETRAHYDROBIOPTERIN

BioMarin Pharmaceutical I...

1. A pharmaceutical composition, comprising a dry blend powder that comprises about 32% by weight of (6R)-L-erythro-tetrahydrobiopterin
dihydrochloride, about 54% by weight of mannitol, about 1.9% by weight of sucrolose, about 10.4% by weight of potassium citrate,
and about 1.6% by weight of ascorbic acid; wherein at least 90% of the initial amount of (6R)-L-erythro-tetrahydrobiopterin
dihydrochloride in the pharmaceutical composition remains after the pharmaceutical composition is stored at 40° C. and 75%
relative humidity for a period of three months.
US Pat. No. 9,200,264

MANUFACTURE OF ACTIVE HIGHLY PHOSPHORYLATED HUMAN LYSOSOMAL SULFATASE ENZYMES AND USES THEREOF

BIOMARIN PHARMACEUTICAL I...

1. A method for measuring the activity of a recombinant human lysosomal enzyme to degrade natural substrates, comprising:
(a) culturing an isolated human cell deficient in the lysosomal enzyme under conditions in which natural substrates for the
lysosomal enzyme accumulate;

(b) contacting the cell with the lysosomal enzyme;
(c) lysing the cell;
(d) adding to the cell lysate an enzyme that (i) is specific for natural substrates and (ii) cleaves small oligosaccharides
from the natural substrates;

(e) labeling the small oligosaccharides with a detectable moiety;
(f) optionally separating the labeled small oligosaccharides;
(g) detecting the labeled small oligosaccharides; and
(h) determining the activity of the lysosomal enzyme to degrade natural substrates by comparing (i) the amount of labeled
small oligosaccharides from cells contacted with the lysosomal enzyme with (ii) the amount of labeled small oligosaccharides
from cells not contacted with the lysosomal enzyme, wherein a reduction in (h)(i) as compared to (h)(ii) indicates the activity
of the lysosomal enzyme to degrade natural substrates.

US Pat. No. 9,504,762

ADENO-ASSOCIATED VIRUS FACTOR VIII VECTORS

BIOMARIN PHARMACEUTICAL I...

1. An adeno-associated virus (AAV) vector, comprising an AAV2 5? inverted terminal repeat (ITR), a liver specific transcriptional
regulatory region, a functionally active FVIII coding region, a polyadenylation sequence, an AAV2 3? ITR, and optionally one
or more introns, wherein the functionally active FVIII coding region comprises nucleotides 923-5296 of SEQ ID NO: 9.
US Pat. No. 9,376,480

TARGETED THERAPEUTIC LYSOSOMAL ENZYME FUSION PROTEINS AND USES THEREOF

BIOMARIN PHARMACEUTICAL I...

1. A targeted therapeutic fusion protein comprising (i) a human ?-N-acetylglucosaminidase (Naglu) protein comprising amino
acids 1-743 or 24-743 of SEQ ID NO:1, (ii) a peptide tag comprising SEQ ID NO: 2 or amino acids 8-67 of SEQ ID NO:5and (iii)
a spacer peptide located between the Naglu protein and the peptide tag, wherein the spacer peptide comprises the amino acid
sequence GAPGGGSPAPAPTPAPAPTPAPAGGGPSGAP (SEQ ID NO: 51).
US Pat. No. 9,340,822

METHODS OF DIAGNOSING A DISEASE AND METHODS OF MONITORING TREATMENT OF A DISEASE BY QUANTIFYING A NON-REDUCING END GLYCAN RESIDUAL COMPOUND AND COMPARING TO A SECOND BIOMARKER

BIOMARIN PHARMACEUTICAL I...

1. A method of determining in an individual the presence, identity, and/or severity of a disease or condition associated with
abnormal glycan biosynthesis, degradation, or accumulation, the method comprising:
(a) generating a first biomarker comprising a glycan residual compound, wherein the first biomarker is generated by treating
a population of glycans, in or isolated from a biological sample from the individual, with at least one digesting glycan enzyme,
wherein prior to enzyme treatment, the first biomarker is not present in abundance in samples from individuals with the disease
or condition relative to individuals without the disease or condition, and wherein the first biomarker is a non-reducing end
biomarker;

(b) generating a second biomarker comprising a glycan residual compound, wherein the second biomarker is generated by treating
a population of glycans, in or isolated from a biological sample from the individual, with at least one digesting glycan enzyme
in the same or different digestion step as provided in step (a), wherein prior to enzyme treatment, the second biomarker is
not present in abundance in samples from individuals with the disease or condition relative to individuals without the disease
or condition, and wherein:

1) the second biomarker is a non-reducing end biomarker different from the first biomarker,
2) the second biomarker is a reducing end biomarker,
3) the second biomarker is an internal glycan biomarker, or
4) when the disease or condition is caused by an abnormal function of a glycan degradation enzyme in the individual, the second
biomarker is a biomarker generated by treating the first biomarker with the glycan degradation enzyme that is functioning
abnormally in the individual;

(c) using an analytical instrument to detect the presence of and/or measure the amount of the first and second biomarker produced
and displaying or recording the presence of or a measure of a population of the first and second biomarkers; and

(d) monitoring and/or comparing the amounts of the first and second biomarkers in a biological sample;
wherein the presence of and/or measure of the amounts of the first and second biomarkers are utilized to determine the presence,
identity, and/or severity of the disease or condition; and

wherein the disease or condition is a lysosomal storage disease, cancer, an inflammatory disease, liver disease, bone diseases,
an infectious disease, a central nervous system disease, or a cardiovascular disease.

US Pat. No. 9,089,566

DELIVERY OF THERAPEUTIC COMPOUNDS TO THE BRAIN AND OTHER TISSUES

BIOMARIN PHARMACEUTICAL I...

1. A method for treating Sanfilippo syndrome type B (Mucopolysaccharidosis type IIIB or MPS IIIB) comprising the step of administering
intrathecally to a human subject in need of treatment a pharmaceutical composition comprising a fusion protein comprising
recombinant human ?-N-acetylglucosaminidase and a moiety that facilitates high uptake of a lysosomal enzyme, wherein the moiety
is an IGF-II polypeptide that allows the lysosomal enzyme to bind to the mannose-6-phosphate receptor, and wherein the fusion
protein is administered in an amount effective to ameliorate one or more central nervous system (CNS) symptoms of Sanfilippo
syndrome type B.

US Pat. No. 9,512,143

HISTONE DEACETYLASE INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A compound having a structure of formula (II):

wherein:
R3 is H or F;

Rp is Cl or F;

Cy is a saturated heterocyclyl having 4-8 ring atoms, where at least one hetero atom is NH or N(C1-6 alkyl) to form a secondary amine or tertiary amine, respectively, and optionally one or two additional heteroatoms are independently
selected from the group consisting of O, NH, and N(C1-6 alkyl); wherein a ring atom of Cy is bonded to the exocyclic double bond;

V is C(Ry)2;

each Ry is independently selected from the group consisting of H, F, C1-6 alkyl, and C3-6 cycloalkyl;

R1 is H, phenyl, or monocyclic or bicyclic heteroaryl, where the phenyl and heteroaryl are each optionally substituted with 1-3
Rq; and

Rq is independently halogen, OH, C1-6 alkyl, fluoro(C1-6 alkyl), hydroxy(C1-4 alkyl), C1-6 alkoxy, or fluoro(C1-6 alkoxy);

or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,044,473

DELIVERY OF THERAPEUTIC COMPOUNDS TO THE BRAIN AND OTHER TISSUES

BIOMARIN PHARMACEUTICAL I...

1. A method for treating a human suffering from a lysosomal storage disease, comprising administering directly into cerebrospinal
fluid (CSF) of the human a pharmaceutical composition comprising an amount of enzyme effective to ameliorate one or more central
nervous system (CNS) symptoms of said lysosomal storage disease, wherein the enzyme comprises or has been engineered to comprise
a moiety that binds the mannose-6-phosphate (M6P) receptor, wherein the moiety is a mannose-6-phosphate residue or an IGF-2
polypeptide, thereby ameliorating one or more CNS symptoms of said lysosomal storage disease.
US Pat. No. 9,834,588

TARGETED THERAPEUTIC LYSOSOMAL ENZYME FUSION PROTEINS AND USES THEREOF

BIOMARIN PHARMACEUTICAL I...

1. A targeted therapeutic fusion protein comprising (a) a human ?-N-acetylglucosaminidase (Naglu) protein comprising amino
acids 1-743 or 24-743 of SEQ ID NO: 1, (b) a peptide tag having an amino acid sequence at least 70% identical to amino acids
8-67 of SEQ ID NO: 5 (mature human IGF-II) and (c) a spacer peptide between the lysosomal enzyme and the peptide tag, wherein
the spacer peptide comprises the amino acid sequence of SEQ ID NO: 55.
US Pat. No. 9,567,572

MANUFACTURE OF ACTIVE HIGHLY PHOSPHORYLATED HUMAN N-ACETYLGALACTOSAMINE-6-SULFATASE AND USES THEREOF

BioMarin Pharmaceutical I...

1. A method of purifying a recombinant human N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, said GALNS enzyme comprising
an amino acid sequence at least 95% identical to amino acids 27 to 522 of SEQ ID NO:4, wherein said GALNS enzyme:
has a purity of at least about 95% as determined by Coomassie Blue staining when subjected to SDS-PAGE under non-reducing
conditions, has at least about 50% conversion of the cysteine residue at position 53 to Ca-formylglycine (FGly), and optionally, has between 0.5 to 0.8 bis-phosphorylated oligomannose chains per monomeric protein
chain, and wherein at least 97% of said GALNS enzyme is in the precursor form as determined by SDS-capillary gel electrophoresis
(SDS-CGE), comprising:

a) filtering a culture medium containing the GALNS enzyme secreted from a mammalian cell line that expresses human sulfatase
modifying factor 1 (SUMF1) and the recombinant human GALNS enzyme, ultrafiltering/diafiltering the filtered culture medium,
and charcoal filtering the ultrafiltered/diafiltered culture medium;

b) loading the charcoal filtered ultrafiltered/dialfiltered culture medium from step a) onto a capture column, washing the
capture column under conditions such that the GALNS enzyme is retained on the capture column, and eluting the GALNS enzyme
from the capture column;

c) optionally, filtering the eluate from the capture column in step b) through a filter to remove viruses;
d) adjusting the pH of the eluate from the capture column from step b) or the filtrate from step c) to an acid pH, and filtering
the acid pH-adjusted eluate from the capture column or acid pH-adjusted filtrate;

e) loading the acid pH-adjusted eluate from the capture column or acid pH-adjusted Q filtrate from step d) onto an intermediate
column, washing the intermediate column under conditions such that the GALNS enzyme is retained on the intermediate column,
and eluting the GALNS enzyme from the intermediate column;

f) adjusting the eluate from the intermediate column in step e) to low pH for viral inactivation;
g) loading the low pH viral inactivated eluate from step f) onto a polishing column, washing the polishing column under conditions
such that the GALNS enzyme is retained on the polishing column, and eluting the GALNS enzyme from the polishing column; and

h) buffer exchanging the eluate from the polishing column in step g) into a formulation comprising
(i) an amount of phosphate buffer effective to reduce dephosphorylation of said GALNS enzyme, wherein the phosphate buffer
is NaH2PO4 at a concentration from about 25 mM to 75 mM; and

(ii) a stabilizing amount of the following stabilizers: an arginine salt or buffer, optionally arginine hydrochloride, wherein
the arginine salt or buffer is at a concentration from about 10 mM to 50 mM; a polysorbate, optionally polysorbate 20; and
a trihydric or higher sugar alcohol, optionally sorbitol; wherein said formulation is at a pH of about 5.0-5.8.

US Pat. No. 9,222,120

QUANTIFICATION OF NON-REDUCING END GLYCAN RESIDUAL COMPOUNDS FOR DETERMINING THE PRESENCE, IDENTITY, OR SEVERITY OF A DISEASE OR CONDITION

BioMarin Pharmaceutical I...

1. A method of determining the presence, identity, and/or severity of a disease or condition in an individual, where the disease
or condition is associated with abnormal glycan biosynthesis, degradation, or accumulation, the method comprising:
(a) generating a biomarker comprising of one or more non-reducing end glycan residual compound(s), wherein the biomarker is
generated by treating a population of glycans, in or isolated from a biological sample from the individual, with at least
one digesting glycan enzyme(s), wherein prior to enzyme treatment, the biomarker is not present in abundance in samples from
individuals with the disease or condition relative to individuals without the disease or condition, and

(b) detecting the presence of and/or measuring the amount of the biomarker produced using an analytical instrument and displaying
or recording the presence of or the measure of the biomarker produced;

(c) correlating the presence of and/or the measure of the amount of the biomarker with the presence, identity, and/or severity
of the disease or condition for determining the presence, identity, and/or severity of the disease or condition;

wherein the disease or condition is a lysosomal storage disease, cancer, an inflammatory disease, a liver disease, a bone
disease, an infectious disease, a central nervous system disease, or a cardiovascular disease; and

wherein when the lysosomal storage disease is an MPS disorder or when the disease or condition is osteoarthritis, then the
digesting glycan enzyme is not a lyase.

US Pat. No. 9,993,481

METHODS AND COMPOSITIONS FOR THE TREATMENT OF METABOLIC DISORDERS

BIOMARIN PHARMACEUTICAL I...

1. A method for treating a subject comprising administering to said subject (1) tetrahydrobiopterin (BH4) or pharmaceutically acceptable salt thereof and (2) a protein-restricted diet, wherein the administering of BH4 is multiday, oral, and only once per day, and the subject suffers from hyperphenylalaninemia (HPA) due to BH4-responsive phenylketonuria (PKU).
US Pat. No. 9,796,999

DETECTION OF OLIGOSACCHARIDES

BIOMARIN PHARMACEUTICAL I...

1. A method of determining in an individual the presence, identity, and/or severity of an MPS III disorder, the method comprising:
(a) generating a biomarker comprising one or more saturated non-reducing end oligosaccharides, wherein the biomarker is generated
by treating a population of heparan sulfate oligosaccharides, in or isolated from a biological sample from the individual,
with at least one digesting glycosaminoglycan lyase, wherein prior to lyase treatment, the biomarker is not present in abundance
in samples from individuals with the MPS III disorder relative to individuals without the MPS III disorder; and

(b) using an analytical instrument to detect the presence of and/or measure the amount of the biomarker produced and displaying
or recording the presence of or the measure of the biomarker produced;

wherein the presence of and/or measure of the amounts of the biomarker are utilized to determine the presence, identity, and/or
severity of the MPS III disorder; and

wherein the biomarker is selected from a group consisting of
Formula III: [GlcNS-IdoA-GlcN(Ac)0-1](SO3R)0-3;

Formula IV: [GlcNS-GlcA-GlcN(Ac)0-1](SO3R)0-2;

Formula V: [GlcNAc-IdoA-GlcN(Ac)0-1](SO3R)0-3;

Formula VI: [GlcNAc-GlcA-GlcN(Ac)0-1](SO3R)0-2;

Formula VIII: [GlcN-GlcA-GlcN(Ac)0-1](SO3R)0-4;

Formula IX: [GlcNAc6S-IdoA-GlcN(Ac)0-1](SO3R)0-3;

Formula X: [GlcNAc6S-GlcA-GlcN(Ac)0-1](SO3R)0-2;

GlcN-IdoA-GlcNAc;
GlcN-IdoA2S-GlcNAc;
GlcN-IdoA-GlcNS;
GlcN-IdoA-GlcNAc6S;
GlcN-IdoA2-GlcNAc6S; and
GlcN-IdoA-GlcNS6S.

US Pat. No. 9,796,664

COMPOSITIONS INCLUDING 6-AMINOHEXANOIC ACID DERIVATIVES AS HDAC INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A method of treating a disorder selected from cutaneous T cell lymphoma, B cell lymphoma, colorectal cancer, psoriasis,
rheumatoid arthritis, osteoarthritis, Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome,
Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular
atrophy, and Alzheimer's disease in a patient in need thereof, the method comprising administering to said patient a therapeutically
effective amount of a compound having a structure of Formula (I):
wherein
Ar2 is selected from C6-10 aryl and benzo[d][1,3]dioxolyl; wherein said C6-10 aryl and benzo[d][1,3]dioxolyl are each substituted at one ortho position by NH2 and by m independently selected Rz groups;

L2 is selected from straight chain C4-6 alkylene and straight chain C4-6 alkenylene; wherein 1 or 2 carbon atoms of said straight chain C4-6 alkylene, or straight chain C4-6 alkenylene is optionally replaced by a group independently selected from —O—, —S—, —S(?O)—, —S(?O)2—, —C(?O)—, and —NRa—;

each Ra is independently selected from H and C1-3 alkyl;

Cy1 is selected from C6-10 aryl and C1-9 heteroaryl; each of which is substituted with n independently selected Ry groups;

R1 is H or C1-4 alkyl;

each Ry is independently selected from halogen, cyano, nitro, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 haloalkylcarbonyl, C6-10 arylcarbonyl, C1-6 alkylsulfonyl, sulfonamido, C1-6 alkylthio, carbamyl, C1-6 alkylcarbamyl, di-C1-6 alkylcarbamyl, C1-6 alkylcarbonylamino, C1-6 alkylcarbonyl-(C1-4-alkyl)amino, C1-6 alkoxycarbonylamino, amino, C1-6 alkylamino, di-C1-6 alkylamino, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 alkylcarbamyl, di-C1-6 alkylcarbamyl, C1-6 alkylcarbonylamino, C1-6 alkylcarbonyl-(C1-4-alkyl)amino, C1-6 alkoxycarbonylamino, C1-6 alkylamino, di-C1-6 alkylamino are each optionally substituted by 1, 2, or 3 independently selected Ry? groups; and wherein said C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, or 3 independently selected Ry? groups;

provided that only one Ry is selected from the optionally substituted groups C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl;

each Rz is independently selected from halogen, cyano, nitro, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-10 aryloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, carbamyl, C1-6 alkylcarbamyl, di-C1-6 alkylcarbamyl, C1-6 alkylcarbonylamino, C1-6 alkylcarbonyl-(C1-4-alkyl)amino, C1-6 alkoxycarbonylamino, amino, C1-6 alkylamino, di-C1-6 alkylamino, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 alkylcarbamyl, di-C1-6 alkylcarbamyl, C1-6 alkylcarbonylamino, C1-6 alkylcarbonyl-(C1-4-alkyl)amino, C1-6 alkoxycarbonylamino, C1-6 alkylamino, di-C1-6 alkylamino are each optionally substituted by 1, 2, or 3 independently selected Rz? groups; and wherein said C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, or 3 independently selected Rz? groups;

provided that only one Rz is selected from the optionally substituted groups C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl;

each Ry? and Rz? is independently selected from hydroxyl, cyano, nitro, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino;

each Ry? and Rz? is independently selected from halogen, hydroxyl, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino;

n is an integer selected from 0, 1, 2, 3, and 4 when Cy1 is C1-9 heteroaryl and n is an integer selected from 1, 2, 3, and 4 when Cy1 is C6-10 aryl; and

m is an integer selected from 0, 1, 2, and 3;or pharmaceutically acceptable salt thereof.
US Pat. No. 9,572,870

DELIVERY OF THERAPEUTIC COMPOUNDS TO THE BRAIN AND OTHER TISSUES

BioMarin Pharmaceutical I...

1. A method for treating a human suffering from a lysosomal storage disease, comprising administering directly into cerebrospinal
fluid (CSF) of the human a pharmaceutical composition comprising an amount of enzyme effective to ameliorate one or more central
nervous system (CNS) symptoms of said lysosomal storage disease, wherein the enzyme comprises or has been engineered to comprise
a moiety that binds the mannose-6-phosphate (M6P) receptor, wherein the moiety is a mannose-6-phosphate residue or an IGF-2
polypeptide, wherein the enzyme is human ?-N-acetylglucosaminidase and wherein the lysosomal storage disease is Mucopolysaccharidosis
IIIB (MPS IIIB or Sanfilippo Syndrome B), thereby ameliorating one or more CNS symptoms of said lysosomal storage disease.
US Pat. No. 9,433,624

METHODS AND COMPOSITIONS FOR THE TREATMENT OF METABOLIC DISORDERS

BIOMARIN PHARMACEUTICAL I...

1. A method for treating a subject suffering from hyperphenylalaninemia (HPA) due to BH4-responsive phenylketonuria (PKU)
comprising administering to said subject tetrahydrobiopterin (BH4) or pharmaceutically acceptable salt thereof at a daily
dose of 10 mg/kg to 20 mg/kg, wherein the administering is multiday, oral, and only once per day.

US Pat. No. 9,265,734

COMPOSITIONS INCLUDING 6-AMINOHEXANOIC ACID DERIVATIVES AS HDAC INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A compound of Formula (I):

or pharmaceutically acceptable salt thereof; wherein:
Y is C(?O);
Ar2 is selected from the group consisting of C6-10 aryl and benzo[d][1,3]dioxolyl; wherein said C6-10 aryl and benzo[d][1,3]dioxolyl are each substituted at one ortho position by NH2 and at additional positions by m independently selected Rz groups;

L2 is selected from straight chain C4-6 alkylene and straight chain C4-6 alkenylene wherein 1 or 2 carbon atoms of said straight chain C4-6 alkylene or straight chain C4-6 alkenylene is optionally replaced by a group independently selected from the group consisting of —O—, —S—, —S(?O)—, —S(?O)2—, —C(?O)—, and —NRa—;

each Ra is independently selected from the group consisting of H and C1-3 alkyl;

Cy1 is selected from the group consisting of C6-10 aryl and C1-9 heteroaryl;

each of which is substituted with n independently selected Ry groups;

L1 is a bond;

R1 is H or C1-4 alkyl;

each Ry is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 haloalkylcarbonyl, C6-10 arylcarbonyl, C1-6 alkylsulfonyl, sulfonamido, C1-6 alkylthio, carbamyl, C1-6 alkylcarbamyl, di-C1-6 alkylcarbamyl, C1-6 alkylcarbonylamino, C1-6 alkylcarbonyl-(C1-4-alkyl)amino, C1-6 alkoxycarbonylamino, amino, C1-6 alkylamino, di-C1-6 alkylamino, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 alkylcarbamyl, di-C1-6 alkylcarbamyl, C1-6 alkylcarbonylamino, C1-6 alkylcarbonyl-(C1-4-alkyl)amino, C1-6 alkoxycarbonylamino, C1-6 alkylamino, di-C1-6 alkylamino are each optionally substituted by 1, 2, or 3 independently selected Ry? groups; and wherein said C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, or 3 independently selected Ry? groups;

provided that only one Ry is selected from the group consisting of optionally substituted C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl;

each Rz is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-10 aryloxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, carbamyl, C1-6 alkylcarbamyl, di-C1-6 alkylcarbamyl, C1-6 alkylcarbonylamino, C1-6 alkylcarbonyl-(C1-4-alkyl)amino, C1-6 alkoxycarbonylamino, amino, C1-6 alkylamino, di-C1-6 alkylamino, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 alkylcarbamyl, di-C1-6 alkylcarbamyl, C1-6 alkylcarbonylamino, C1-6 alkylcarbonyl-(C1-4-alkyl)amino, C1-6 alkoxycarbonylamino, C1-6 alkylamino, di-C1-6 alkylamino are each optionally substituted by 1, 2, or 3 independently selected Rz? groups; and wherein said C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, or 3 independently selected Rz? groups;

provided that only one Rz is selected from the group consisting of optionally substituted C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, C1-6 heteroaryl, C3-7 cycloalkyl-C1-4-alkyl, C2-6 heterocycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, and C1-6 heteroaryl-C1-4-alkyl;

each Ry? and Rz? is independently selected from the group consisting of hydroxyl, cyano, nitro, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino;

each Ry? and Rz? is independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4-alkylamino;

n is an integer selected from 0, 1, 2, 3, and 4 when Cy1 is C1-9 heteroaryl and n is an integer selected from the group consisting of 1, 2, 3, and 4 when Cy1 is C6-10aryl; and

m is an integer selected from the group consisting of 0, 1, 2, and 3;
provided that the compound is not N-(7-(2 aminophenylamino)-7-oxoheptyl)biphenyl-3-carboxamide; N-(7-(2-aminophenylamino)-7-oxoheptyl)biphenyl-4-carboxamide;
or N-(7-(2-aminophenylamino)-7-oxoheptyl)-6-phenylnicotinamide.

US Pat. No. 9,557,340

ASSAYS FOR DETECTION OF PHENYLALANINE AMMONIA-LYASE AND ANTIBODIES TO PHENYLALANINE AMMONIA-LYASE

BIOMARIN PHARMACEUTICAL I...

1. A method for detecting the presence of pegylated Anabaena variabilis phenylalanine ammonia-lyase (AvPAL-PEG)-specific antibodies in a sample, said method comprising:
(a) contacting the sample with recombinant AvPAL-PEG enzyme, wherein the recombinant AvPAL-PEG enzyme is immobilized on a
solid support via a PEG-specific antibody;

(b) optionally removing unbound sample;
(c) adding a phenylalanine substrate; and
(d) detecting the presence of enzymatic activity between the immobilized recombinant AvPAL-PEG enzyme and phenylalanine substrate;
wherein a reduction of enzymatic activity as compared to a reference sample having no neutralizing AvPAL-PEG-specific antibodies
indicates the presence of neutralizing AvPAL-PEG-specific antibodies in the sample.

US Pat. No. 9,540,395

HISTONE DEACETYLASE INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A compound of the formula (I):
wherein
Ar/Het is selected from the group consisting of pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furanyl, isoxazolyl,
isothiazolyl, thiadiazolyl, oxadiazolyl, and 1,2,4-triazolyl;

Y is bond, CRc?CRd, O, NRe, or S(O)m;

a is 1-3;
b is 0-3;
m is 0-2;
each occurrence of Ra and Rb is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;

each of Rc and Rd is, independently, selected from H, F, OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;

each occurrence of Re is independently selected from H, C1-C6 alkyl, —C(?O)H, —C(?O)Rh, C(?O)O(C1-C6 alkyl), C(?O)N(Ri)2, SO2—Rh, wherein Rh is selected from C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Ri is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl and the aryl or heteroaryl portion in Rh and Ri can be optionally substituted with one or more independently selected substituents selected from the group consisting of F,
C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;

each of R4 and R5 is, independently, selected from H, C1-C6 alkyl and F;
R1 is:
(i) hydrogen; or
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 Ro; or

(iii) monocyclic or bicyclic heteroaryl having from 5-10 ring atoms, which is optionally substituted with from 1-3 Ro; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—Ro, and S; or

(iv) heterocyclyl having from 4-10 ring atoms, which is optionally substituted with from 1-3 Ro; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—Ro, and S; and

each occurrence of Ro is independently selected from the group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6alkyl); hydroxyl; hydroxy(C1-C4alkyl);
C1-C6 alkoxy; fluoro(C1-C6alkoxy); (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; formyl; formyl(C1-C4alkyl); cyano; cyano(C1-C4alkyl); benzyl; benzyloxy; SO2—(C1-C6alkyl); SO—(C1-C6alkyl); and nitro;

R2 is selected from H, F, Cl, CF3, CF2CF3, CH2CF3, OCF3, OCHF2, phenyl; phenyl substituted with from 1-3 substituents independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6 alkyl)
C3-C6 cycloalkyl, NH2, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; thienyl; thiazolyl; and pyrazol-1-yl; and

R3 is H, F, or Cl;or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,469,683

LYSOSOMAL TARGETING PEPTIDES AND USES THEREOF

BIOMARIN PHARMACEUTICAL I...

1. A targeted therapeutic fusion protein comprising:
a lysosomal enzyme which is ?-N-Acetylglucosaminidase (Naglu);
an IGF-II mutein comprising amino acids 8-67 of SEQ ID NO: 1 and an Ala substitution at position Arg37 of SEQ ID NO:1, wherein
the IGF-II mutein (i) has diminished binding affinity for the insulin receptor relative to the affinity of naturally-occurring
human IGF-II for the insulin receptor, (ii) is resistant to furin cleavage and (iii) binds to the human cation-independent
mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner; and

a spacer between the lysosomal enzyme and the IGF-II mutein, wherein the spacer comprises the amino acid sequence Gly-Ala-Pro.
US Pat. No. 9,814,762

TARGETED THERAPEUTIC PROTEINS

BioMarin Pharmaceutical I...

1. A nucleic acid encoding a targeted therapeutic fusion protein comprising: a lysosomal enzyme; and a lysosomal targeting
domain that binds human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner; wherein
the lysosomal targeting domain comprises a mutein of mature human IGF-II having an amino acid sequence at least 70% identical
to mature human IGF-II (SEQ ID NO:8).

US Pat. No. 10,029,988

HDAC INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A compound having formula (I), or a pharmaceutically acceptable salt thereof:wherein:R1—X is attached to only one of the ring nitrogen atoms;
X is:
(i) —Y—[C(Ra)2]a-A-[C(Rb)2]b—B—;
(ii) direct bond; or
(iii) C?O, C(Rj)2—C(?O), C(?O)—C(Rj)2, SO2—NRk, NRk—SO2, C(?O)NRk or NRk—C(?O);wherein:Y is bond, CRc?CRd, O, NRe, or S(O)m;
each of A and B is, independently, a bond, O, NRf, or S(O)m;
a is 1, 2, or 3;
b is 0, 1, 2, or 3;
m is 0, 1, or 2;
each occurrence of Ra and Rb is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or
one or more of the following can apply with respect to Ra and Rb:
any two Ra, together with the carbons to which each is attached, together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O, S(O)m, and NRg; or
one Ra and one Rb, together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NRg; or
any two Rb, together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the ring atoms is selected from O; S(O)m and NRg;
each of Rc and Rd is independently selected from H, F, OH, C1-6 alkyl, C3-C5 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-6 fluoroalkoxy, and cyano;
or Rc and Rd, together with the carbons to which each is attached form a C5-C7 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which from 1-2 of the heterocyclyl ring atoms are independently selected from O, S(O)m and NRg?;
each occurrence of Re, Rf, Rg and Rg? is independently selected from H, C1-6 alkyl, —C(?O)H, —C(?O)Rh, C(?O)O(C1-C6 alkyl), C(?O)N(Ri)2, and SO2—Rh; wherein Rh is selected from C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Ri is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl;
each occurrence of Rj is independently selected from H, F, OH, C1-6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or Rj—C—Rj together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NRj?;
each occurrence of Rj? and Rk is independently selected from H, C1-C6 alkyl, —C(?O)H, —C(?O)Rm, C(?O)O(C1-C6 alkyl), C(?O)N(Rn)2, and SO2—Rm, wherein Rm is selected from C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Rn is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl, and wherein the aryl and heteroaryl portion in Rm and Rn can be optionally substituted with 1-3 independently selected substituents F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano;further wherein:(a) when each of A and B is a bond, and b is 0, then X has the following formula:
—Y—[C(Ra)2]a—;
(b) when b is 0 or 1, then A and B cannot both be heteroatoms; and
(c) when A or B serves as the point of connection of X to the nitrogen ring atoms, then A or B cannot be a heteroatom;
R1 is:
(i) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 Ro; wherein from 1-4 of the ring atoms are a heteroatom independently selected from 0, N, N—H, N—Ro, and S;
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 Ro;
(iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is optionally substituted with from 1-6 Ro; or
(iv) hydrogen;
R4 is H or Ro and each occurrence of Ro is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; —N*(Ro?)2, wherein Ro?—N*—Ro? together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms are optionally a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl; benzyl; benzyloxy; (heterocyclyl)—(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—Ro?, and S, each of which is optionally substituted with from 1-3 Ro?; SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
each occurrence of Ro? is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl; benzyl; benzyloxy; (heterocyclyl)—(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—(C1-C6 alkyl), and S; SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
R5 is selected from the group consisting of: hydrogen, halogen; C1-06 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; (C1-C6 alkyl)C(O)—; formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl; benzyl; (heterocyclyl)-(C0-C6)alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, and S; SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
R2 is selected from H, F, CI, CF3, CF2CF3, CH2CF3, OCF3, OCHF2, phenyl; or phenyl substituted with 1-3 Ro; and
R3 is H, F, or Cl.
US Pat. No. 9,907,834

USE OF C-TYPE NATRIURETIC PEPTIDE VARIANTS TO TREAT SKELETAL DYSPLASIA

BioMarin Pharmaceutical I...


and
(b) citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine and polysorbate 80.
US Pat. No. 9,834,587

TARGETED THERAPEUTIC LYSOSOMAL ENZYME FUSION PROTEINS AND USES THEREOF

BIOMARIN PHARMACEUTICAL I...

1. A targeted therapeutic fusion protein comprising (a) a human ?-N-acetylglucosaminidase (Naglu) protein comprising amino
acids 1-743 or 24-743 of SEQ ID NO: 1, (b) a peptide tag having an amino acid sequence at least 70% identical to amino acids
8-67 of SEQ ID NO: 5 (mature human IGF-II) and (c) a spacer peptide between the lysosomal enzyme and the peptide tag, wherein
the spacer peptide comprises the amino acid sequence of SEQ ID NO:47.

US Pat. No. 10,059,723

HISTONE DEACETYLASE INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A method of treating (i) a neurological disease or disorder selected from Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease; (ii) an inflammatory disease; (iii) a memory impairment condition or (iv) a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure of formula (I):
wherein n=0 or 1;
I. when n=1, Z is R1—X—Ar/Het wherein:
Ar/Het is:
(i) a 5 membered heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furanyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, and 1,2,4-triazolyl; or
(ii) a bicyclic 8-, 9-, or 10-membered heteroaryl selected from the group consisting of benzofuranyl, benzothienyl, benzothiazolyl, indolyl, indazolyl, quinolonyl, naphthyridinyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, triazolothiazolyl, and triazolooxazolyl;
X is:
(i) —Y—[C(Ra)2]a-A-[C(Rb)2]b—B—;
wherein:
Y is bond, CRc?CRd, O, NRe, or S(O)m;
each of A and B is, independently, a bond, O, NRf, or S(O)m;
a is 1-3;
b is 0-3;
m is 0-2;
each occurrence of Ra and Rb is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or
any two Ra, together with the carbons to which each is attached, together form C3-C6 cycloalkyl or heterocyclyl having 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O, S(O)m, and NRg; or
one Ra and one Rb, together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl having 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O, S(O)m, and NRg; or
any two Rb, together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl having 3-6 ring atoms, in which one of the ring atoms is selected from O, S(O)m, and NRg;
each of Rc and Rd is, independently, selected from H, F, OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or Rc and Rd, together with the carbons to which each is attached form a C5-C7 cycloalkenyl or heterocyclenyl having 3-6 ring atoms, in which from 1-2 of the heterocyclenyl ring atoms is/are independently selected from O, S(O)m, and NRg?;
each occurrence of Re, Rf, Rg and Rg? is independently selected from H, C1-C6 alkyl, C(?O)H, C(?O)Rh, C(?O)O(C1-C6 alkyl), C(?O)N(Ri)2, SO2—Rh; wherein Rh is selected from C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Ri is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl and wherein the aryl or heteroaryl groups in Rh and Ri can be optionally substituted with one or more groups independently selected from the group consisting of F, C1-C6 alkyl, fluoro(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
further wherein:
(a) when b is 0 or 1, then A and B cannot both be heteroatoms; and
(b) when A or B serves as the point of connection of X to Ar/Het, and the Ar/Het is linked to X via a nitrogen ring atom in Ar/Het, then the A or B connector cannot be a heteroatom;
or X is:
(ii) direct bond; or
(iii) C?O, C(Rj)2—C(?O), C(?O)—C(Rj)2, SO2—NRk, NRk—SO2, C(?O)NRk or NRk—C(?O); wherein:
each occurrence of Rj is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or Rj—C—Rj together form C3-C6 cycloalkyl or heterocyclyl having 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O, S(O)m, and NRj?;
each occurrence of Rj? and Rk is independently selected from H, C1-C6 alkyl, C(?O)H, C(?O)Rm, C(?O)O(C1-C6 alkyl), C(?O)N(Rn)2, and SO2—Rm, wherein Rm is selected from C1-C6 alkyl, CH2-heteroaryl, CH2-aryl, and aryl; and each occurrence of Rn is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl, and wherein the aryl and heteroaryl groups in Rm and Rn are optionally substituted with one or more groups independently selected from F, C1-C6 alkyl, fluoro(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
each of R4 and R5 is, independently, selected from H, C1-C6 alkyl and F;
R1 is:
(i) hydrogen; or
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 Ro; or
(iii) monocyclic or bicyclic heteroaryl having from 5-10 ring atoms, which is optionally substituted with from 1-3 Ro; wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—Ro, and S; or
(iv) heterocyclyl having from 4-10 ring atoms, which is optionally substituted with from 1-3 Ro; wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—Ro, and S; and
each occurrence of Ro is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6 alkyl); hydroxyl; hydroxy(C1-C4 alkyl); C1-C6 alkoxy; fluoro(C1-C6 alkoxy); (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; —N*(Ro?)2, wherein Ro?—N*—Ro? together form a saturated ring having 5 or 6 ring atoms, wherein 1 or 2 ring atoms in addition to the N* ring atom is/are optionally a heteroatom independently selected from NH, N(C1-C6 alkyl), O, or S; formyl; formyl(C1-C4 alkyl); cyano; cyano(C1-C4 alkyl); benzyl; benzyloxy; heterocyclyl-(C0-C6 alkyl), wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are independently selected from NH, N(C1-C6 alkyl), O, or S; phenyl or heteroaryl having from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—Ro?, and S, wherein the phenyl or heteroaryl are each optionally substituted with from 1-3 Ro?; SO2—(C1-C6 alkyl); SO—(C1-C6 alkyl); and nitro;
each occurrence of Ro? is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6 alkyl); hydroxyl; hydroxy(C1-C4 alkyl); C1-C6 alkoxy; fluoro(C1-C6 alkoxy); (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; formyl; formyl(C1-C4 alkyl); cyano; cyano(C1-C4 alkyl); benzyl; benzyloxy; heterocyclyl-(C0-C6 alkyl), wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are independently selected from NH, N(C1-C6 alkyl), O, and S; phenyl or heteroaryl having from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—(C1-C6 alkyl), and S; SO2—(C1-C6 alkyl); SO—(C1-C6 alkyl); and nitro;
II. when n=0, Z is R1—V-Cy-U—Ar?/Het? wherein:
Ar?/Het? is:
(i) phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted with from 1-3 Rp; provided that the point of connection on said phenyl, pyridyl, or pyrimidinyl to U and the point of connection on said phenyl, pyridyl, or pyrimidinyl to the amide carbonyl do not result in 1,2-relation to one another on said phenyl, pyridyl, or pyrimidinyl; wherein Rp at each occurrence is, independently, selected from H, F, chloro, CH3, CF3, OCH3, OCF3, and OCHF2;
(ii) a 5-membered heteroaryl selected from pyrazolyl, pyrrolyl, thiazolyl, thienyl, furanyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, each of which is optionally substituted with from 1-3 Rp; provided that the point of connection on said 5-membered heteroaryl to U and the point of connection on said 5-membered heteroaryl to the amide carbonyl do not result in 1,2-relation to one another on said 5-membered heteroaryl;
(iii) a 8-, 9- or 10-membered bicyclic heteroaryl selected from benzothienyl, benzofuranyl, benzothioazolyl, benzoxazolyl, indolyl, isoindolonyl, indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, triazolopyridinyl, imidazothiazolyl, imidazooxazolyl, quinolinyl, and naphthyridinyl;
each of which is optionally substituted with from 1-3 Rp;
R1 is:
(i) hydrogen; or
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 Rq; or
(iii) monocyclic or bicyclic heteroaryl having from 5-10 ring atoms, which is optionally substituted with from 1-3 Rq; wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—Rq, and S; or
(iv) heterocyclyl having from 4-10 ring atoms, which is optionally substituted with from 1-3 Rq; wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—Rq, and S; and
each occurrence of Rq is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6 alkyl); hydroxyl; hydroxy(C1-C4 alkyl); C1-C6 alkoxy; fluoro(C1-C6 alkoxy); (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; —N*(Rq?)2, wherein Rq?—N*—Rq? together form a saturated ring having 5 or 6 ring atoms, wherein 1 or 2 ring atoms in addition to the N* ring atom is/are optionally a heteroatom independently selected from NH, N(C1-C6 alkyl), O, or S; formyl; formyl(C1-C4 alkyl); cyano; cyano(C1-C4 alkyl); benzyl; benzyloxy; heterocyclyl-(C0-C6 alkyl), wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are independently selected from NH, N(C1-C6 alkyl), O, or S; phenyl or heteroaryl having from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—Rq?, and S, wherein the phenyl or heteroaryl are each optionally substituted with from 1-3 Rq?; SO2—(C1-C6 alkyl); SO—(C1-C6 alkyl); and nitro;
each occurrence of Rq? is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6alkyl); hydroxyl; hydroxy(C1-C4 alkyl); C1-C6 alkoxy; fluoro(C1-C6alkoxy); (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; formyl; formyl(C1-C4 alkyl); cyano; cyano(C1-C4 alkyl); benzyl; benzyloxy; heterocyclyl-(C0-C6 alkyl), wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are independently selected from NH, N(C1-C6 alkyl), O, or S; phenyl or heteroaryl having from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are independently selected from O, N, N—H, N—(C1-C6 alkyl), and S; SO2—(C1-C6 alkyl); SO—(C1-C6 alkyl); and nitro;
U is:
(i) ?CRr, wherein the carbon atom in ?CRr is doubly bonded to a ring atom of Cy, thereby forming an exocyclic double bond; or
(ii) —U?—C(Rs)2— or —C(Rs)2—U?—;
wherein:
Rr is hydrogen, F, C1-C6 alkyl, fluoro(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano;
each occurrence of Rs is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or
Rs—C—Rs together form C3-C6 cycloalkyl or heterocyclyl having 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m, wherein m is 0-2; and NRU;
each occurrence of Ru is independently selected from H, C1-C6 alkyl, C(?O)H, C(?O)Rv, C(?O)O(C1-C6 alkyl), C(?O)N(Rw)2, and SO2—Rv, wherein Rv is selected from C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Rw is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl wherein the aryl and heteroaryl portion in Rv and Rw can be optionally substituted with one or more groups independently selected from F, C1-C6 alkyl, fluoro(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
U? is a bond; O; NRu; S(O)m; CH2; or U?—CH2—; wherein U? is O; NRu; or S(O)m; and m is 0-2;
Cy is C4-C10 cycloalkyl or saturated heterocyclyl having 4-10 ring atoms, wherein from 1-3 heteroatoms are independently selected from N—H, NRx?, and S(O)m; m is 0-2; Rx? is defined as Rq?; and Cy is optionally substituted with from 1-3 Rx; and each occurrence of Rx is independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6 alkyl), C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; and wherein when the heterocyclyl contains a secondary amine as part of its structure, then:
(i) V is linked through the nitrogen of the secondary amine portion of the heterocyclyl; and
(ii) U is linked to Cy via a Cy ring carbon atom; wherein the bond between U and the Cy ring carbon is a single or double bond; and
(iii) the Cy ring carbon atom that is attached to U is not adjacent to Cy ring nitrogen atom that is attached to V;
V is:
(i) —V?—C(Ry)2— or —C(Ry)2—V?—; or
(ii) O, NRz, or S(O)m, wherein m is 0-2; or
(iii) —CH?CH—, C?O, C(Ry)2—C(?O), C(?O)—C(Ry)2—, —SO2NRz, NRzSO2, C(?O)NRz, or NRzC(?O); wherein:
each occurrence of Ry is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or
Ry—C—Ry together form C3-C6 cycloalkyl or heterocyclyl having 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O, S(O)m, and NRaa, and m is 0-2;
each occurrence of Rz and Raa is independently selected from H, C1-C6 alkyl, C(?O)H, C(?O)Rv, C(?O)O(C1-C6 alkyl), C(?O)N(Rw)2, and SO2—Rv, wherein Rv is selected from C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Rw is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl;
V? is a bond; O; NRu; S(O)m; —C(O)—O—(CRy2)0-2—, —(CRy2)0-2—O—C(O)—, C(Ry)2, C(Ry)2—C(Ry)2; —(Ry)2—V?; or V?—C(Ry)2—; wherein V? is O; NRz; or S(O)m, and m is 0-2; wherein Ru is independently selected from H, Cl—C6 alkyl, C(?O)H, C(?O)Rv, C(?O)O(Cl—C6 alkyl), C(?O)N(Rw)2 and SO2—Rv, wherein Rv is selected from Cl—C6 alkyl, CH2-(heteroaryl having 5-10 ring atoms), CH2—(C6-Cl0 aryl), and C6-C10 aryl, and each occurrence of Ry is independently selected from H, F, OH, Cl—C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(Cl—C6 alkyl), OCO—(C3-C6 cycloalkyl), Cl—C6 alkoxy, Cl—C6 fluoroalkoxy, and cyano;
R2 is selected from H, F, Cl, CF3, CF2CF3, CH2CF3, OCF3, OCHF2, phenyl; phenyl substituted with from 1-3 substituents independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6 alkyl), C3-C6 cycloalkyl, NH2, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; thienyl; thiazolyl; and pyrazol-1-yl; and
R3 is H, F, or Cl,
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,908,899

HISTONE DEACETYLASE INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A method of inhibiting HDAC1, HDAC2, or HDAC3 in a subject, comprising administering to the subject an effective amount
of a compound having a structure of formula (II):
wherein:
RA is H or F;

RC is H, Cl, or F;

Het is selected from oxetanyl, azetindinyl, piperidinyl, and 8-azabicyclo[3.2.1]octanyl, and when Het is azetindinyl, piperidinyl,
or 8-azabicyclo[3.2.1]octanyl, the ring nitrogen is substituted with RB; and

RB is C1-C6alkyl, C1-C6hydroxyalkyl, C1-C3alkylene-C3-C6cycloalkyl, C1-C3alkylene-phenyl, or C1-C3alkylene-pyridyl; wherein the phenyl or pyridyl ring is optionally substituted with methyl;
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,873,867

MANUFACTURE OF ACTIVE HIGHLY PHOSPHORYLATED HUMAN LYSOSOMAL SULFATASE ENZYMES AND USES THEREOF

BIOMARIN PHARMACEUTICAL I...

1. A method for producing an active highly phosphorylated recombinant human lysosomal sulfatase enzyme, comprising the steps
of:
(a) culturing a Chinese Hamster Ovary (CHO)-derived END3 complementation group cell defective in endosomal acidification;
(b) preparing a first mammalian expression vector capable of expressing said active highly phosphorylated recombinant human
lysosomal sulfatase enzyme in said END3 complementation group cell;

(c) preparing a second mammalian expression vector capable of expressing recombinant human sulfatase modifying factor 1 (SUMF1)
in said END3 complementation group cell;

(d) transfecting said END3 complementation group cell with said first and second expression vectors;
(e) selecting and cloning of a transfectant of said END3 complementation group cell that expresses said active highly phosphorylated
recombinant human lysosomal sulfatase enzyme; and

(f) optimizing a cell culture process method for manufacturing said highly phosphorylated recombinant human lysosomal sulfatase
enzyme,

wherein the recombinant human lysosomal sulfatase enzyme is selected from the group consisting of arylsulfatase A (ARSA),
arylsulfatase B (ARSB), iduronate-2-sulfatase (IDS), sulfamidase/heparin-N-sulfatase (SGSH), N-acetylglucosamine-sulfatase
(G6S) and N-acetylgalactosamine-6-sulfatase (GALNS).

US Pat. No. 9,771,408

TARGETED THERAPEUTIC LYSOSOMAL ENZYME FUSION PROTEINS AND USES THEREOF

BioMarin Pharmaceutical I...

1. A targeted therapeutic fusion protein comprising (a) a human ?-N-acetylglucosaminidase (Naglu) protein comprising amino
acids 1-743 or 24-743 of SEQ ID NO: 1, (b) a peptide tag having an amino acid sequence at least 70% identical to amino acids
8-67 of SEQ ID NO: 5 (mature human IGF-II), and (c) a spacer peptide between the lysosomal enzyme and the peptide tag, wherein
the spacer peptide comprises the amino acid sequence of SEQ ID NO: 71.

US Pat. No. 10,308,608

HISTONE DEACETYLASE INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A compound selected from the group consisting of:or a pharmaceutically acceptable salt thereof.
US Pat. No. 10,300,113

TARGETED THERAPEUTIC PROTEINS

BioMarin Pharmaceutical I...

1. A formulation for parenteral administration comprising: a target therapeutic comprising a therapeutic agent that is therapeutically active in a mammalian lysosome and a variant of human IGF-II having an amino acid sequence at least 70% identical to mature human IGF-II (SEQ ID NO:8) that binds an extracellular domain of human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner; and a pharmaceutically acceptable carrier.

US Pat. No. 10,227,312

GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES

BIOMARIN PHARMACEUTICAL I...

1. A compound of Formula I:
wherein
R1 is H; or R1 and R2 together form —OCH2CH2O—;
R2 is C3-6 cycloalkyloxy or 3-6 membered heterocycloalkyloxy;
R3 is H or halogen;
R4 is H or C1-4 alkyl;
R5 and R5A are each independently H or C1-4 alkyl;
X is N or O, and when X is N, the dashed line is a bond to form a double bond, and when X is O, the dashed line is not a bond to form a single bond;
Y is C(R6)2 or O; with the proviso that X and Y are not both O;
R6 at each occurrence is independently H or C1-4 alkyl;
Ring A is phenylene, naphthylene, or 5-10 membered heteroarylene;
R7 at each occurrence is independently halogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyloxy, (C3-6 cycloalkyl)C1-6 alkoxy, phenyl, or 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are each optionally substituted with 1, 2, or 3 R8;
p is 0, 1, or 2;
R8 at each occurrence is independently halogen, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, aminocarbonyl, C1-6 alkylaminocarbonyl, or C1-6 dialkylaminocarbonyl;
Ring B is a 4-6 membered heterocycloalkyl ring;
R9 at each occurrence is independently halogen, OR10, or N(R10)2;
R10 at each occurrence is independently H or C1-4 alkyl;
q is 0, 1, 2, 3, or 4; and
optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

US Pat. No. 10,227,323

GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES

BIOMARIN PHARMACEUTICAL I...

1. A compound of Formula I:
wherein
R1 is —C(O)C(R6)(R6a)R1a or —C(O)C(R6)(R6a)—X1—R1a;
X1 is alkylene, alkenylene, or cycloalkylene;
R1a is alkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R7 groups; wherein when R1a is phenyl, R1a is substituted with 1, 2, or 3 R7 groups;
R2 and R3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R8;
R4 is phenyl substituted with a halo and a cycloalkyloxy group;
R5 is —OH, and R5a is hydrogen;
R6 and R6a are halo; R6 and R6a are deuterium; or R6 and R6a together with the carbon to which they are attached form C(?NOH) or C(O);
each R7, when present, is independently nitro, cyano, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or heteroaryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1, 2 or 3 R7a;
each R7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;
each R8, when present, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl; or two R8 together with the carbon to which they are attached form C(O); and
R12 is hydrogen or C1-5 alkyl;
optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

US Pat. No. 10,301,323

HISTONE DEACETYLASE INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A compound selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

US Pat. No. 10,239,832

N-(1-HYDROXY-3-(PYRROLIDINYL)PROPAN-2-YL)PYRROLIDINE-3-CARBOXAMIDE DERIVATIVES AS GLUCOSYLCERAMIDE SYNTHASE INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A compound of Formula I:
where
R1 is N—(R6)-azetidinyl, N—(R6)-pyrrolidinyl, or N—(R6)-piperidinyl, each of which is attached to the C(O) group by a carbon atom and is optionally substituted with hydroxy;
R2 and R3 together with the nitrogen to which they are attached form a 4-6 membered heterocycloalkyl ring with 1 or 2 nitrogen atoms, which is optionally substituted with 1 or 2 R8;
R4 is aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R9 groups;
R5 is halo, hydroxy, —N3, —NH2, —NHC(O)CH3, —NH(OCH3), or —NHC(O)H and R5a is hydrogen, halo, alkyl, or deuterium; or R5 and R5a together with the carbon to which they are attached form C(O) or C(NOH);
R6 is alkyl, alkoxycarbonyl, aryl, arylalkyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, or —C(O)NR6aR6b; wherein each aryl and heteroaryl, whether alone or as part of another group, is optionally substituted with 1 or 2 R10 groups; and wherein each heterocycloalkyl and cycloalkyl, whether alone or as part of another group, is optionally substituted with 1 or 2 groups independently selected from hydroxy, halo, haloalkyl, alkoxy, alkyl, alkylcarbonyl, and alkoxycarbonyl;
R6a is hydrogen or alkyl, and R6b is aryl or heteroaryl each of which is optionally substituted with 1 or 2 halo; or R6a and R6b together with the nitrogen to which they are attached form a heterocycloalkyl optionally substituted with alkyl, hydroxy, alkylcarbonyl, or alkoxycarbonyl;
each R8, when present, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl;
each R9, when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, —NR11C(O)NR11aR11b, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyloxy, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylthio, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the phenyl is optionally substituted with 1 or 2 R9a; where each heterocycloalkyl, either alone or as part of another group, is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy, alkylcarbonyl, and alkoxycarbonyl;
each R9a, when present, is independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino;
each R10, when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl, —NR11C(O)NR11aR11b, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, hydroxy, alkoxy, haloalkoxy, hydroxyalkoxy, alkenyloxy, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylthio, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkyloxy, or heterocycloalkylalkyloxy; where each aryl or heteroaryl either alone or as part of another group, is independently optionally substituted with 1, 2 or 3 R10a; and each heterocycloalkyl, either alone or as part of another group, is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy, alkylcarbonyl, and alkoxycarbonyl groups;
each R10a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl; and
R11, R11a, and R11b are independently hydrogen, alkyl, or cycloalkyl; and
optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
US Pat. No. 10,301,369

NUCLEIC ACIDS ENCODING TARGETED THERAPEUTIC LYSOSOMAL ENZYME FUSION PROTEINS

BioMarin Pharmaceutical I...


US Pat. No. 10,260,084

QUANTIFICATION OF NON-REDUCING END GLYCAN RESIDUAL COMPOUNDS FOR DETERMINING THE PRESENCE, IDENTITY, OR SEVERITY OF A DISEASE OR CONDITION

BIOMARIN PHARMACEUTICAL I...

1. A method of determining the presence, identity, and/or severity of a disease or condition in an individual, wherein the disease or condition is associated with abnormal glycan biosynthesis, degradation, or accumulation, the method comprising:(a) generating a biomarker comprising of one or more non-reducing end glycan residual compound(s), wherein the biomarker is generated by treating a population of glycans, in or isolated from a biological sample from the individual, with at least one digesting glycan enzyme(s), wherein prior to enzyme treatment, the biomarker is not present in abundance in samples from individuals with the disease or condition relative to individuals without the disease or condition;
(b) detecting the presence of and/or measuring the amount of the biomarker produced using an analytical instrument and displaying or recording the presence of or the measure of the biomarker produced; and
(c) correlating the presence of and/or the measure of the amount of the biomarker with the presence, identity, and/or severity of the disease or condition for determining the presence, identity, and/or severity of the disease or condition in the individual,
wherein the disease or condition is mucopolysaccharidosis I (MPS I); and
wherein at least one digesting glycan enzyme is iduronidase.

US Pat. No. 10,428,028

HDAC INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A method of treating a disease or disorder wherein the disease or disorder is a neurological disorder selected from myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins, spinal and bulbar muscular atrophy, and Alzheimer's disease; an inflammatory disease; a memory impairment condition; or a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
R1—X is attached to only one of the ring nitrogen atoms;
X is:
(i) —Y—[C(Ra)2]a-A-[C(Rb)2]b—B—;
(ii) direct bond; or
(iii) C?O, C(Rj)2—C(?O), C(?O)—C(Rj)2, SO2—NRk, NRk—SO2, C(?O)NRk or NRk—C(?O);wherein:Y is bond, CRc?CRd, O, NRe, or S(O)m;
each of A and B is, independently, a bond, O, NRe, or S(O)m;
a is 1, 2, or 3;
b is 0, 1, 2, or 3;
m is 0, 1, or 2;
each occurrence of Ra and Rb is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or
one or more of the following can apply with respect to Ra and Rb:
any two Ra, together with the carbons to which each is attached, together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O, S(O)m and NRg; or
one Re and one Rb, together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NRg; or
any two Rb, together with the carbons to which each is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the ring atoms is selected from O; S(O)m and NRg;
each of Rc and Rd is independently selected from H, F, OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or Rc and Rd, together with the carbons to which each is attached form a C5-C7 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which from 1-2 of the heterocyclyl ring atoms are independently selected from O, S(O)m and NRg?;
each occurrence of Re, Rf, Rg and Rg? is independently selected from H, C1-C6 alkyl, —C(?O)H, —C(?O)Rh, C(?O)O(C1-C6 alkyl), C(?O)N(Rj)2, and SO2—Rh; wherein Rh is selected from C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of Ri is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl;
each occurrence of Rj is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH2, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
or Rj—C—Rj together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O)m and NRj?;
each occurrence of Rj? and Rk is independently selected from H, C1-C6 alkyl, —C(?O)H, —C(?O)Rm, C(?O)O(C1-C6 alkyl), C(?O)N(Rn)2, and SO2—Rm, wherein Rm is selected from C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10aryl), and C6-C10aryl; and each occurrence of Rn is independently selected from H, C1-C6 alkyl, CH2-(heteroaryl including 5-10 ring atoms), CH2—(C6-C10 aryl), and C6-C10 aryl, and wherein the aryl and heteroaryl portion in Rm and Rn can be optionally substituted with 1-3 independently selected substituents F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano;further wherein:(a) when each of A and B is a bond, and b is 0, then X has the following formula: —Y—[C(Ra)2]a—;
(b) when b is 0 or 1, then A and B cannot both be heteroatoms; and
(c) when A or B serves as the point of connection of X to the nitrogen ring atoms, then A or B cannot be a heteroatom;
R1 is:
(i) monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, which is optionally substituted with from 1-3 Ro; wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—Ro, and S;
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 Ro;
(iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is optionally substituted with from 1-6 Ro; or
(iv) hydrogen;
R4 is H or Ro and each occurrence of Ro is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; —N*(Ro?)2, wherein Ro?—N*—Ro? together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms are optionally a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl; benzyl; benzyloxy; (heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—Ro?, and S, each of which is optionally substituted with from 1-3 Ro?; SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
each occurrence of Ro? is independently selected from the group consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)2N—; formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl; benzyl; benzyloxy; (heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(C1-C6alkyl), 0, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, N—(C1-C6 alkyl), and S; SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
R5 is selected from the group consisting of: hydrogen, halogen; C1-C6 alkyl;
fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C1-C4)alkyl; (C1-C6 alkyl)C(O)—; formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl; benzyl; (heterocyclyl)-(C0-C6)alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatom independently selected from NH, N(C1-C6alkyl), O, or S; phenyl; heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ring atoms are a heteroatom independently selected from O, N, N—H, and S; SO2—(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;
R2 is selected from H, F, Cl, CF3, CF2CF3, CH2CF3, OCF3, OCHF2, phenyl; or phenyl substituted with 1-3 Ro; and
R3 is H, F, or Cl.

US Pat. No. 10,279,015

TPP-1 FORMULATIONS AND METHODS FOR TREATING CLN2 DISEASE

BioMarin Pharmaceutical I...

1. A formulation comprising non-aggregated recombinant human tripeptidyl peptidase-1 (rhTPP1) for intracerebroventricular, intrathecal, or intraocular administration, wherein the rhTPP1 comprises the amino acid sequence of SEQ ID NO: 1 or a fragment thereof, wherein the formulation comprises rhTPP1 at a concentration of from about 25 mg/mL to about 35 mg/mL, further comprising potassium chloride at a concentration of about 0.01 mg/mL to about 1 mg/mL, magnesium chloride hexahydrate at a concentration of about 0.01 mg/mL to about 1 mg/mL, and calcium chloride dehydrate at a concentration of about 0.01 mg/mL to about 1 mg/mL, and wherein the formulation has a pH of 6.5 and the rhTTP1 is not aggregated.

US Pat. No. 10,280,182

HISTONE DEACETYLASE INHIBITORS

BIOMARIN PHARMACEUTICAL I...

1. A compound selected from the group consisting of:or a pharmaceutically acceptable salt thereof.