US Pat. No. 9,267,158

BIOLOGICAL PRODUCTION OF MULTI-CARBON COMPOUNDS FROM METHANE

Intrexon Corporation, Bl...

1. A method for producing isobutanol from a methane substrate comprising the steps of:
(a) providing a methanotrophic host microorganism that metabolizes methane (CH4) to methanol (CH3OH) and methanol to formaldehyde (H2C?O);

(b) introducing into the methanotroph host and expressing at least one exogenous polynucleotide open reading frame (ORF) under
the control of suitable regulatory-sequences, wherein the at least one polynucleotide ORF encodes a polypeptide that catalyzes
a reaction in an isobutanol pathway,

wherein the at least one polynucleotide ORF is selected from the group consisting of acetolactate synthase (ALS), ketol-acid
reductoisomerase (KARI), dihydroxy-acid dehydratase (DHAD), ketoacid decarboxylase (KDC) and alcohol dehydrogenase (ADH),
and wherein the ALS polypeptide comprises an amino acid sequence having at least 90% sequence homology to SEQ ID NO:2, the
KARI polypeptide comprises an amino acid sequence having at least 90% sequence homology to SEQ ID NO:4, the DHAD polypeptide
comprises an amino acid sequence having at least 90% sequence homology to SEQ ID NO:6, the KDC polypeptide comprises an amino
acid sequence having at least 90% sequence homology to SEQ ID NO:8 and the ADH polypeptide comprises an amino acid sequence
having at least 90% sequence homology to SEQ ID NO:10;

(c) feeding the methanotroph host produced according to step (b) a methane substrate under suitable growth conditions, wherein
the host metabolizes methane to formaldehyde as set forth in step (a), wherein the formaldehyde is converted to pyruvate by
means of an endogenous type I RuMP pathway or a type II serine pathway and the host metabolizes pyruvate to produce isobutanol;
and

(d) recovering the isobutanol produced.
US Pat. No. 9,447,387

MODIFIED FORMS OF PSEUDOMONAS EXOTOXIN A

INTREXON CORPORATION, Bl...

1. A polypeptide having at least one Pseudomonas exotoxin A (PE-A) biological activity, wherein said polypeptide comprises one or more amino acid substitutions compared to
a wild-type PE-A polypeptide, wherein said one or more amino acid substitutions is a substitution of a different amino acid
at one or more positions corresponding to amino acid residues in the polypeptide of SEQ ID NO:1, wherein one of said substitutions
is selected from the group consisting of:
a) arginine (R) at position 146 is substituted with a different basic amino acid;
b) arginine (R) at position 146 is substituted with a different polar amino acid residue wherein the substitution at position
146 is not lysine (K) or histidine (H).

US Pat. No. 9,492,482

ENGINEERED CELLS EXPRESSING MULTIPLE IMMUNOMODULATORS AND USES THEREOF

Intrexon Corporation, Bl...

1. An in vitro engineered immune cell comprising an adenoviral vector for conditionally expressing proteins, the vector comprising
a polynucleotide encoding an ecdysone gene switch, wherein said polynucleotide comprises
(1) a polynucleotide sequence comprising a first transcription factor sequence and a second transcription factor sequence
under the control of a promoter, wherein the proteins encoded by the first transcription factor sequence and second transcription
factor sequence interact to form a ligand-dependent transcription factor complex,

wherein the first transcription factor sequence comprises a nucleic acid encoding a VP-16 transactivation domain and a retinoic
acid-X-receptor (RXR) polypeptide,

wherein the RXR polypeptide is a genetically engineered chimera comprising vertebrate RXR and invertebrate RXR domains,
wherein said vertebrate RXR ligand binding domain is a human RXR ligand binding domain,
wherein the second transcription factor sequence comprises a nucleic acid encoding a GAL-4 DNA binding domain and an ecdysone
receptor protein,

wherein said ecdysone receptor ligand binding domain is derived from a Choristoneura fumiferna ecdysone receptor ligand binding domain, and

wherein said Choristoneura fumiferna ecdysone receptor ligand binding domain further comprises a genetically engineered substitution mutation compared to the naturally
occurring Choristoneura fumiferna ecdysone receptor ligand binding domain from which it was derived;

(2) a polynucleotide encoding a polypeptide at least 90% identical to IL-12; and
(3) a polynucleotide encoding a polypeptide at least 90% identical to IL-21;
wherein at least one polynucleotide of (2) or (3) are linked to a promoter capable of being activated by said ligand dependent
transcription factor complex.

US Pat. No. 9,127,024

BORON-CONTAINING DIACYLHYDRAZINES

Intrexon Corporation, Bl...

1. A compound having Formula I:

wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and haloalkyl; or

R1 and R2 taken together with the carbon atom to which they are attached form a 4- to 8-membered cycloalkyl;

R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted alkenyl, optionally substituted aryl, and optionally substituted heteroaryl;

R4 is selected from the group consisting of:


X1 is selected from the group consisting of —O— and —N(R8a)—;

Y1 is —(CR9aR9b)m—;

Z1 is selected from the group consisting of —O— and —N(R8b)—, or Z1 is absent;

R6a is selected from the group consisting of hydroxy, alkyl, and alkoxy; or

R6a forms a hydroxy acid adduct or an amino acid adduct;

R7a and R7b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R7a? and R7b? are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8a and R8b are each independently selected from the group consisting of hydrogen and alkyl;

R9a and R9b are each independently selected from the group consisting of hydrogen and alkyl;

m is 1, 2, 3, or 4;
X2 is selected from the group consisting of —O— and —N(R8c)—;

Y2 is —(CR9cR9d)n—;

Z2 is selected from the group consisting of —O— and —N(R8d)—, or Z2 is absent;

R6b is selected from the group consisting of hydroxy, alkyl, and alkoxy; or

R6b forms a hydroxy acid adduct or an amino acid adduct;

R7c and R7d are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8c and R8d are each independently selected from the group consisting of hydrogen and alkyl;

R9c and R9d are each independently selected from the group consisting of hydrogen and alkyl;

n is 1, 2, 3, or 4;
X is selected from the group consisting of —O— and —N(R8e)—;

R6c is selected from the group consisting of hydroxy, alkyl, and alkoxy; or

R6c forms a hydroxy acid adduct or an amino acid adduct;

R7e and R7f are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8e is selected from the group consisting of hydrogen and alkyl;

R6d is selected from the group consisting of hydroxy, alkyl, and alkoxy; or

R6d forms a hydroxy acid adduct or an amino acid adduct;

R6f is selected from the group consisting of hydrogen, alkyl, amino, and hydroxy;

X5 is selected from the group consisting of —O— and —N(R8k)—;

R7g and R7h are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8k is selected from the group consisting of hydrogen and alkyl;

X6 is selected from the group consisting of —O— and —N(R8l)—;

X7 is selected from the group consisting of —O— and —N(R8n)—;

R8l is selected from the group consisting of hydrogen and alkyl;

R8m is selected from the group consisting of hydrogen and alkyl;

R8n is selected from the group consisting of hydrogen and alkyl;

R10a is selected from the group consisting of hydrogen and —(CR11aR11b)o—B(R12a)(R12b); and

R10b, R10c, and R10d are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN,
optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted
heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino; or

R10b is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, —N(H)CHO, —N(H)CN, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy,
arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino; and/or

R10c and R10d taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo,
or optionally substituted heteroaryl group;

R11a and R11b are each independently selected from the group consisting of hydrogen and alkyl;

R12a and R12b are selected from the group consisting of hydroxy and alkoxy; or

R12a and R12b taken together form a linkage —O(CR13aR13b)pO—; or

—B(R12a)(R12b) forms a fluoride adduct;

R13a and R13b are each independently selected from the group consisting of hydrogen and C1-4 alkyl;

o is 0, 1, 2, 3, 4, or 5;
p is 2, 3, or 4;
R5 is R4-3, R4-4, R4-8, R4-9, or R4-10; or R5 is selected from the group consisting of:


X3 is selected from the group consisting of —O— and —N(R8f)—;

Y3 is —(CR9eR9f)q—;

Z3 is selected from the group consisting of —O— and —N(R8g)—, or Z3 is absent;

R6e is selected from the group consisting of hydroxy and alkyl; or

R6e forms a hydroxy acid adduct or an amino acid adduct;

R7i and R7j are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8f and R8g are each independently selected from the group consisting of hydrogen and alkyl;

R9e and R9f are each independently selected from the group consisting of hydrogen and alkyl;

q is 1, 2, 3, or 4;
X4 is selected from the group consisting of —O— and —N(R8h)—;

Y4 is —(CR9gR9h)r—;

Z4 is selected from the group consisting of —O— and —N(R8i)—, or Z4 is absent;

R6g is selected from the group consisting of hydroxy and alkyl; or

R6g forms a hydroxy acid adduct or an amino acid adduct;

R7k and R7l are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8h and R8i are each independently selected from the group consisting of hydrogen and alkyl;

R9g and R9h are each independently selected from the group consisting of hydrogen and alkyl;

r is 1, 2, 3, or 4;
R10e is selected from the group consisting of hydrogen and —(CR11cR11d)s—B(R12c)(R12d); and

R10f, R10g, and R10h are independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally
substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,
alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino; or

R10f is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy,
arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino; and

R10g and R10h taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo,
or optionally substituted heteroaryl group; or

R11c and R11d are each independently selected from the group consisting of hydrogen and alkyl;

R12c and R12d are selected from the group consisting of hydroxy and alkoxy; or

R12c and R12d taken together form a linkage —O(CR13cR13d)tO—; or

—B(R12c)(R12d) forms a fluoride adduct;

R13c and R13d are each independently selected from the group consisting of hydrogen and C1-4 alkyl;

s is 0, 1, 2, 3, 4, or 5;
t is 2, 3, or 4;
R14a and R14b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN,
optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted
heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamide, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino;

R15a and R15b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN,
optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted
heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino;

R16 is selected from the group consisting of hydrogen, hydroxy, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted
heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, and arylalkyloxy;

R17 is selected from the group consisting of haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally
substituted aryl, and optionally substituted heteroaryl;

R18 is selected from the group consisting of hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle,
optionally substituted aryl, and optionally substituted heteroaryl;

R19 is selected from the group consisting of hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle,
optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, arylalkyloxy, and amino;

R20 is selected from the group consisting of haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally
substituted aryl, optionally substituted heteroaryl, and amino;

R21 is selected from the group consisting of hydrogen, alkyl, aryl, cyano, and nitro;

with the provisos:
a) when R4 is R4-5, R4-6, or R4-7 and R5 is R5-3, then one of R10a or R10e is not hydrogen; and

b) when R4 is R4-5, R4-6, or R4-7 and R5 is R5-4 or R5-5, then R10a is not hydrogen,

or a pharmaceutically acceptable salt or solvate thereof.
US Pat. No. 9,102,648

BIOAVAILABLE DIACYLHYDRAZINE LIGANDS FOR MODULATING THE EXPRESSION OF EXOGENOUS GENES VIA AN ECDYSONE RECEPTOR COMPLEX

Intrexon Corporation, Bl...

1. A method of modulating the expression of a target gene in a host cell, wherein the host cell comprises:
(i) a transactivation domain;
(ii) a DNA-binding domain; and
(iii) a Choristoneura fumiferana ecdysone receptor (EcR) ligand binding domain;

and a gene expression cassette comprising:
(i) a response element capable of binding to said DNA binding domain;
(ii) a promoter that is activated by the transactivation domain; and
(iii) said target gene;the method comprising contacting said host cell with a compound selected from the group consisting of:
5-Methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(3,5-dimethyl-benzoyl)-N?-(1-ethyl-2,2-dimethyl-propyl)-hydrazide;
5-Methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(3,5-dimethoxy-4-methyl-benzoyl)-N?-(1-ethyl-2,2-dimethyl-propyl)-hydrazide;
5-Methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(1-tert-butyl-butyl)-N?-(3,5-dimethyl-benzoyl)-hydrazide;
5-Methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(1-tert-butyl-butyl)-N?-(3,5-dimethoxy-4-methyl-benzoyl)-hydrazide;
5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(3,5-dimethyl-benzoyl)-N?-(1-ethyl-2,2-dimethyl-propyl)-hydrazide;
5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(3,5-dimethoxy-4-methyl-benzoyl)-N?-(1-ethyl-2,2-dimethyl-propyl)-hydrazide;
5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(1-tert-butyl-butyl)-N?-(3,5-dimethyl-benzoyl)-hydrazide;
5-Ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(1-tert-butyl-butyl)-N?-(3,5-dimethoxy-4-methyl-benzoyl)-hydrazide;
3,5-Dimethyl-benzoic acid N-(1-ethyl-2,2-dimethyl-propyl)-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide;
3,5-Dimethoxy-4-methyl-benzoic acid N-(1-ethyl-2,2-dimethyl-propyl)-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide;
3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide;
3,5-Dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide;
3,5-Dimethyl-benzoic acid N-(1-ethyl-2,2-dimethyl-propyl)-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
3,5-Dimethoxy-4-methyl-benzoic acid N-(1-ethyl-2,2-dimethyl-propyl)-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
3,5-Dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
3,5-Dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
2-Methoxy-nicotinic acid N-(1-tert-butyl-pentyl)-N?-(4-ethyl-benzoyl)-hydrazide;
3,5-Dimethyl-benzoic acid N-(2,2-dimethyl-1-phenyl-propyl)-N?-(4-ethyl-benzoyl)-hydrazide;
3,5-Dimethyl-benzoic acid N-(1-tert-butyl-pentyl)-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide; and
3,5-Dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-pentyl)-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide.
US Pat. No. 9,493,525

AKT LIGANDS AND POLYNUCLEOTIDES ENCODING AKT LIGANDS

Intrexon Corporation, Bl...

1. An isolated polynucleotide comprising a polynucleotide sequence encoding a polypeptide heteropolyligand wherein said polypeptide
heteropolyligand comprises
(a) a sequence at least 90% identical to SEQ ID NO:90 and SEQ ID NO:174;
(b) a sequence at least 90% identical to SEQ ID NO:102 and SEQ ID NO:174;
(c) a sequence at least 90% identical to SEQ ID NO:194 and SEQ ID NO:174; or
(d) a sequence at least 90% identical to SEQ ID NO:195 and SEQ ID NO:174;
wherein Xaa is any amino acid, and wherein the polypeptide heteropolyligand inhibits the kinase activity of mammalian protein
kinase B (AKT).

US Pat. No. 9,322,026

SUBSTITUTION MUTANT RECEPTORS AND THEIR USE IN A NUCLEAR RECEPTOR-BASED INDUCIBLE GENE EXPRESSION SYSTEM

Intrexon Corporation, Bl...

1. A gene expression cassette comprising a polynucleotide that encodes a polypeptide selected from the group consisting of:
a) a polypeptide comprising a transactivation domain, a DNA-binding domain, and a Drosophila melanogaster EcR (DmEcR) ligand binding domain comprising a substitution mutation,

b) a polypeptide comprising a DNA-binding domain and a Drosophila melanogaster EcR (DmEcR) ligand binding domain comprising a substitution mutation, and

c) a polypeptide comprising a transactivation domain and a Drosophila melanogaster EcR (DmEcR) ligand binding domain comprising a substitution mutation,

wherein the DmEcR ligand binding domain is encoded by a polynucleotide comprising a codon mutation that results in a substitution
at amino acid residue 107, 121, 213, or 217 of the DmEcR in SEQ ID NO: 2.

US Pat. No. 9,096,680

MTOR LIGANDS AND POLYNUCLEOTIDES ENCODING MTOR LIGANDS

Intrexon Corporation, Bl...

1. An isolated polynucleotide comprising a nucleotide sequence encoding a polypeptide heteropolyligand, wherein a heteropolyligand
monomer therein is an amino acid sequence at least 97% identical to any one of SEQ ID NO: 37, wherein Xaa is any amino acid,
and wherein said polypeptide heteropolyligand inhibits mTOR activity.
US Pat. No. 9,371,517

MODIFIED FORMS OF PSEUDOMONAS EXOTOXIN A

INTREXON CORPORATION, Bl...

1. A polypeptide having at least one Pseudomonas exotoxin A (PE-A) biological activity, wherein said polypeptide comprises one or more amino acid substitutions compared to
a wild-type PE-A polypeptide, wherein said one or more amino acid substitutions is a substitution of a different amino acid
at one or more positions corresponding to amino acid residues in the polypeptide of SEQ ID NO:1, wherein one of said substitutions
is selected from the group consisting of:
a) isoleucine (I) at position 141 is substituted with a different non-polar amino acid; and
b) isoleucine (I) at position 141 is substituted with a different aliphatic amino acid.
US Pat. No. 9,359,289

BIOAVAILABLE DIACYLHYDRAZINE LIGANDS FOR MODULATING THE EXPRESSION OF EXOGENOUS GENES VIA AN ECDYSONE RECEPTOR COMPLEX

Intrexon Corporation, Bl...

1. A compound selected from the group consisting of:
5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(3,5-dimethyl-benzoyl)-N?-(1-ethyl-2,2-dimethyl-propyl)-hydrazide;
5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(1-tert-butyl-butyl)-N?-(3,5-dimethyl-benzoyl)-hydrazide;
5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(3,5-dimethyl-benzoyl)-N?-(1-ethyl-2,2-dimethyl-propyl)-hydrazide;
5-ethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N?-(1-tert-butyl-butyl)-N?-(3,5-dimethyl-benzoyl)-hydrazide;
3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide; and
3,5-dimethyl-benzoic acid N-(1-ethyl-2,2-dimethyl-propyl)-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide.
US Pat. No. 9,301,992

MTOR LIGANDS AND POLYNUCLEOTIDES ENCODING MTOR LIGANDS

Intrexon Corporation, Bl...

1. An isolated polynucleotide comprising a nucleotide sequence encoding a polypeptide heteropolyligand, wherein a heteropolyligand
monomer therein is an amino acid sequence at least 90% identical to SEQ ID NO:42, wherein Xaa is any amino acid, and wherein
said polypeptide heteroligand inhibits mTOR activity.
US Pat. No. 9,222,121

METHODS AND COMPOSITIONS FOR DIAGNOSING DISEASE

Intrexon Corporation, Bl...

1. A method of detecting kidney transplant rejection in a subject that has received a kidney transplant, comprising:
introducing into cells of said organ or tissue transplant (1) a polynucleotide encoding a gene switch, said gene switch comprising
at least one transcription factor sequence, wherein said at least one transcription factor sequence encodes a ligand-dependent
transcription factor, operably linked to a diagnostic ADAM-17 switch promoter, wherein the activity of the promoter is modulated
during transplant rejection, and (2) a polynucleotide encoding a CD95-ADAM8 dual reporter or a alkaline phosphatase—c terminal
CD40 reporter gene linked to a promoter which is activated by said ligand-dependent transcription factor, to produce modified
cells;

administering ligand to said modified cells; and
detecting reporter gene expression;
wherein expression of the CD95-ADAM8 dual reporter or the alkaline phosphatase—c terminal CD40 reporter gene indicates that
transplant rejection has been detected.

US Pat. No. 9,181,314

MTOR LIGANDS AND POLYNUCLEOTIDES ENCODING MTOR LIGANDS

Intrexon Corporation, Bl...

1. An isolated polynucleotide comprising a nucleotide sequence encoding a polypeptide heteropolyligand, wherein a heteropolyligand
monomer therein is an amino acid sequence at least 90% identical to SEQ ID NO:24 or SEQ ID NO:25, wherein Xaa is any amino
acid, and wherein said polypeptide heteroligand inhibits mTOR activity.
US Pat. No. 9,493,540

ECDYSONE RECEPTOR/INVERTEBRATE RETINOID X RECEPTOR-BASED INDUCIBLE GENE EXPRESSION SYSTEM

Intrexon Corporation, Bl...

1. A viral vector comprising a gene expression modulation system comprising:
a) a first gene expression cassette that is capable of being expressed in a host cell, comprising a polynucleotide that encodes
a first hybrid polypeptide comprising a DNA-binding domain that recognizes a response element associated with a gene whose
expression is to be modulated; and

b) a second gene expression cassette that is capable of being expressed in the host cell comprising a polynucleotide that
encodes a second hybrid polypeptide comprising a transactivation domain,

wherein said first hybrid polypeptide or said second hybrid polypeptide further comprises an ecdysone receptor ligand binding
domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 43, and SEQ ID NO:
59, and

wherein said first hybrid polypeptide or said second hybrid polypeptide that does not comprise said ecdysone receptor ligand
binding domain further comprises a retinoid X receptor ligand binding domain comprising an amino acid sequence selected from
the group consisting of SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO:
27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32.

US Pat. No. 9,402,919

VECTORS CONDITIONALLY EXPRESSING PROTEIN

Intrexon Corporation, Bl...

1. A method of inducing, regulating, or enhancing erythropoietin (EPO) expression in a mammal, wherein the method comprises
(a) administering an adeno-associated virus to the mammal, wherein the virus comprises a polynucleotide encoding EPO; and
(b) administering an activator ligand which induces EPO expression from the virus polynucleotide encoding EPO,
wherein the adeno-associated virus is administered intramuscularly,
wherein the adeno-associated virus further comprises an ecdysone receptor (EcR)-based gene switch, wherein the gene switch
comprises at least one transcription factor sequence operably linked to a first promoter, wherein at least one transcription
factor encoded by the at least one transcription factor sequence is a ligand-dependent transcription factor,

wherein the adeno-associated virus further comprises a second promoter operably linked to the polynucleotide encoding EPO,
wherein the second promoter is activated by the at least one ligand-dependent transcription factor following administration
of activator ligand,

wherein EPO expression is increased in the mammal, and
wherein the hematocrit or volume percentage of red blood cells in blood is increased in the mammal by at least 25%, compared
with the hematocrit or volume percentage of red blood cells prior to administration of ligand.

US Pat. No. 9,272,986

DIACYLHYDRAZINE LIGANDS FOR MODULATING THE EXPRESSION OF EXOGENOUS GENES IN MAMMALIAN SYSTEMS VIA AN ECDYSONE RECEPTOR COMPLEX

Intrexon Corporation, Bl...

1. A method of modulating the expression of a target gene in a host cell, wherein the host cell includes a first gene expression
cassette comprising a first polynucleotide encoding a first polypeptide comprising:
(i) a transactivation domain;
(ii) a DNA-binding domain; and
(iii) a Group H nuclear receptor ligand binding domain;
a second gene expression cassette comprising:
(i) a response element capable of binding to said DNA binding domain;
(ii) a promoter that is activated by the transactivation domain; and
(iii) said target gene;the method comprising contacting said host cell with a compound of the formula:

wherein X and X? are independently O or S;
Y is:
(a) substituted or unsubstituted phenyl wherein the substituents are independently 1-5H, (C1-C4)alkyl, (C1-C4)alkoxy, (C2-C4)alkenyl, halo (F, Cl, Br, I), (C1-C4)haloalkyl, hydroxy, amino, cyano, or nitro; or

(b) substituted or unsubstituted 2-pyridyl, 3-pyridyl, or 4-pyridyl, wherein the substituents are independently 1-4H, (C1-C4)alkyl, (C1-C4)alkoxy, (C2-C4)alkenyl, halo (F, Cl, Br, I), (C1-C4)haloalkyl, hydroxy, amino, cyano, or nitro;

R1 and R2 are independently: H; cyano; cyano-substituted or unsubstituted (C1-C7) branched or straight-chain alkyl; cyano-substituted or unsubstituted (C2-C7) branched or straight-chain alkenyl; cyano-substituted or unsubstituted (C3-C7) branched or straight-chain alkenylalkyl; or together the valences of R1 and R2 form a (C1-C7) cyano-substituted or unsubstituted alkylidene group (RaRbC?) wherein the sum of non-substituent carbons in Ra and Rb is 0-6;

R3 is H, methyl, ethyl, n-propyl, isopropyl, or cyano;

R4, R7, and R8 are independently: H, (C1-C4)alkyl, (C1-C4)alkoxy, (C2-C4)alkenyl, halo (F, Cl, Br, I), (C1-C4)haloalkyl, hydroxy, amino, cyano, or nitro; and

R5 and R6 are independently: H, (C1-C4)alkyl, (C2-C4)alkenyl, (C3-C4) alkenylalkyl, halo (F, Cl, Br, I), (C1-C4)haloalkyl, (C1-C4)alkoxy, hydroxy, amino, cyano, or nitro;

wherein the number of carbon atoms, excluding those of cyano substitution, for either or both of groups R1 or R2 is greater than 4, and the number of carbon atoms, excluding those of cyano substitution, for the sum of groups R1, R2, and R3 is 10, 11, or 12.

US Pat. No. 9,604,913

CRYSTALLINE DIACYLHYDRAZINE AND THE USE THEREOF

Intrexon Corporation, Bl...

1. Crystalline (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide hydrate Form
IV,
characterized as having a powder x-ray diffraction pattern with peaks at 6.83, 10.31, 11.30, 12.18, 12.98, 13.69, 15.11, 16.23,
17.60, 17.99, 20.70, 21.15, 21.68, 22.71, 23.79, and 24.86 degrees 2?.

US Pat. No. 9,512,148

BORON-CONTAINING DIACYLHYDRAZINES

Intrexon Corporation, Bl...

1. A compound having Formula I-A:

wherein:
R1 and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and haloalkyl; or

R1 and R2 taken together with the carbon atom to which they are attached form a 4- to 8-membered cycloalkyl;

R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl,
optionally substituted alkenyl, optionally substituted aryl, and optionally substituted heteroaryl;

R4a is selected from the group consisting of:


X1 is selected from the group consisting of —O— and —N(R8a)—;

Y1 is —(CR9aR9b)m—;

Z1 is selected from the group consisting of —O— and —N(R8b)—, or Z1 is absent;

R6a is selected from the group consisting of hydroxy, alkyl, and alkoxy; or

R6a forms a hydroxy acid adduct or an amino acid adduct;

R7a and R7b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R7a? and R7b? are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8a and R8b are each independently selected from the group consisting of hydrogen and alkyl;

R9a and R9b are each independently selected from the group consisting of hydrogen and alkyl;

m is 1, 2, 3, or 4;
X2 is selected from the group consisting of —O— and —N(R8c)—;

Y2 is —(CR9cR9d)n—;

Z2 is selected from the group consisting of —O— and —N(R8d)—, or Z2 is absent;

R6b is selected from the group consisting of hydroxy, alkyl, and alkoxy; or

R6b forms a hydroxy acid adduct or an amino acid adduct;

R7c and R7d are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8c and R8d are each independently selected from the group consisting of hydrogen and alkyl;

R9c and R9d are each independently selected from the group consisting of hydrogen and alkyl;

n is 1, 2, 3, or 4;
X is selected from the group consisting of —O— and —N(R8e)—;

R6c is selected from the group consisting of hydroxy, alkyl, and alkoxy; or

R6c forms a hydroxy acid adduct or an amino acid adduct;

R7e and R7f are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8e is selected from the group consisting of hydrogen and alkyl;

R6d is selected from the group consisting of hydroxy, alkyl, and alkoxy; or

R6d forms a hydroxy acid adduct or an amino acid adduct;

R6f is selected from the group consisting of hydrogen, alkyl, amino, and hydroxy;

X5 is selected from the group consisting of —O— and —N(R8k)—;

R7g and R7h are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8k is selected from the group consisting of hydrogen and alkyl;

X6 is selected from the group consisting of —O— and —N(R8l)—;

X7 is selected from the group consisting of —O— and —N(R8n)—;

R8l is selected from the group consisting of hydrogen and alkyl;

R8m is selected from the group consisting of hydrogen and alkyl;

R8n is selected from the group consisting of hydrogen and alkyl;

R10a is selected from the group consisting of hydrogen and —(CR11aR11b)o—B(R12a)(R12b); and

R10i, R10j, and R10k are each independently selected from the group consisting of hydrogen, halo, optionally substituted alkyl, haloalkyl, alkoxyalkyl,
hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy,
alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino; or

R10i is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, —N(H)CHO, —N(H)CN, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy,
arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino; and/or

R10j and R10k taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo,
or optionally substituted heteroaryl group;

R11a and R11b are each independently selected from the group consisting of hydrogen and alkyl;

R12a and R12b are selected from the group consisting of hydroxy and alkoxy; or

R12a and R12b taken together form a p linkage —O(CR13aR13b)pO—; or

—B(R12a)(R12b) forms a fluoride adduct;

R13a and R13b are each independently selected from the group consisting of hydrogen and C1-4 alkyl;

o is 0, 1, 2, 3, 4, or 5;
p is 2, 3, or 4;
R5 is R4-3, R4-4, R4-8, R4-9, or R4-10; or R5 is selected from the group consisting of:


X3 is selected from the group consisting of —O— and —N(R8f)—;

Y3 is —(CR9eR9f)q—;

Z3 is selected from the group consisting of —O— and —N(R8g)—, or Z3 is absent;

R6e is selected from the group consisting of hydroxy and alkyl; or

R6e forms a hydroxy acid adduct or an amino acid adduct;

R7i and R7j are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8f and R8g are each independently selected from the group consisting of hydrogen and alkyl;

R9e and R9f are each independently selected from the group consisting of hydrogen and alkyl;

q is 1, 2, 3, or 4;
X4 is selected from the group consisting of —O— and —N(R8h)—;

Y4 is —(CR9gR9h)r—;

Z4 is selected from the group consisting of —O— and —N(R8i)—, or Z4 is absent;

R6g is selected from the group consisting of hydroxy and alkyl; or

R6g forms a hydroxy acid adduct or an amino acid adduct;

R7k and R7l are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;

R8h and R8i are each independently selected from the group consisting of hydrogen and alkyl;

R9g and R9h are each independently selected from the group consisting of hydrogen and alkyl;

r is 1, 2, 3, or 4;
R10e is selected from the group consisting of hydrogen and —(CR11cR11d)s—B(R12c)(R12d); and

R10f, R10g, and R10h are independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally
substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,
alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino; or

R10f is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally substituted
alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy,
arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino; and

R10g and R10h taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo,
or optionally substituted heteroaryl group; or

R11c and R11d are each independently selected from the group consisting of hydrogen and alkyl;

R12c and R12d are selected from the group consisting of hydroxy and alkoxy; or

R12c and R12d taken together form a linkage —O(CR13cR13d)tO—); or

—B(R12c)(R12d) forms a fluoride adduct;

R13c and R13d are each independently selected from the group consisting of hydrogen and C1-4 alkyl;

s is 0, 1, 2, 3, 4, or 5;
t is 2, 3, or 4;
R14a and R14b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN,
optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted
heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino;

R15a and R15b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN,
optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted
heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C?N(R21)-amino;

R16 is selected from the group consisting of hydrogen, hydroxy, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted
heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, and arylalkyloxy;

R17 is selected from the group consisting of haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally
substituted aryl, and optionally substituted heteroaryl;

R18 is selected from the group consisting of hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle,
optionally substituted aryl, and optionally substituted heteroaryl;

R19 is selected from the group consisting of hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle,
optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, arylalkyloxy, and amino;

R20 is selected from the group consisting of haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally
substituted aryl, optionally substituted heteroaryl, and amino;

R21 is selected from the group consisting of hydrogen, alkyl, aryl, cyano, and nitro;

with the provisos:
a) when R4 is R4-11, R4-12, or R4-13 and R5 is R5-3, then one of R10a or R10e is not hydrogen; and

b) when R4 is R4-11, R4-12, or R4-13 and R5 is R5-4 or R5-5, then R10a is not hydrogen,

or a pharmaceutically acceptable salt or solvate thereof.
US Pat. No. 9,399,783

BIOLOGICAL PRODUCTION OF MULTI-CARBON COMPOUNDS FROM METHANE

INTREXON CORPORATION, Bl...

1. An isobutanol producing methanotroph host microorganism that metabolizes methane (CH4) to methanol (CH3OH) and methanol to formaldehyde (H2C?O), said host microorganism manufactured according to the steps of:
(a) introducing into a methanotroph host at least one polynucleotide open reading frame (ORF), under the control of suitable
regulatory sequences, wherein the at least one polynucleotide ORF encodes a polypeptide that catalyzes a reaction in an isobutanol
pathway, and

wherein the at least one polynucleotide ORF is acetolactate synthase (ALS), ketol-acid reductoisomerase (KARI), dihydroxy-acid
dehydratase (DHAD), ketoacid decarboxylase (KDC) or alcohol dehydrogenase (ADH), and wherein the ALS polypeptide comprises
an amino acid sequence having at least 90% sequence homology to SEQ ID NO:2, the KARI polypeptide comprises an amino acid
sequence having at least 90% sequence homology to SEQ ID NO:4, the DHAD polypeptide comprises an amino acid sequence having
at least 90% sequence homology to SEQ ID NO:6, the KDC polypeptide comprises an amino acid sequence having at least 90% sequence
homology to SEQ ID NO:8 and the ADH polypeptide comprises an amino acid sequence having at least 90% sequence homology to
SEQ ID NO: 10, and

(b) wherein the methanotroph host microorganism metabolizes methane to methanol and methanol to formaldehyde, and wherein
the formaldehyde is converted to pyruvate by means of an endogenous type I RuMP pathway or a type II serine pathway and the
host metabolizes pyruvate to produce isobutanol.

US Pat. No. 9,255,125

POLYNUCLEOTIDES ENCODING EXTRACELLULAR-SIGNAL-REGULATED KINASE (ERK) HETEROPOLYLIGAND POLYPEPTIDES

Intrexon Corporation, Bl...

1. An isolated polynucleotide comprising a nucleotide sequence encoding a polypeptide polyligand comprising a first amino
acid sequence selected from the group consisting of SEQ ID NOS: 28, 32, 36, 48, and 49 and one or more additional amino acid
sequences that are at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOS: 28,
32, 36, 48, 49, 91, 93-96 and 102,
wherein Xaa of SEQ ID NOS: 28, 32, 36, 48, and 49 is any naturally occurring amino acid other than serine or threonine, and
wherein the polypeptide polyligand inhibits the kinase activity of extracellular-signal-regulated kinase (ERK).
US Pat. No. 9,063,140

WHITEFLY ECDYSONE RECEPTOR NUCLEIC ACIDS, POLYPEPTIDES, AND USES THEREOF

Intrexon Corporation, Bl...

1. An isolated polynucleotide operatively linked to an expression control sequence that permits expression of the isolated
polynucleotide in an expression competent host cell comprising a cDNA sequence at least 90% identical to a sequence selected
from the group consisting of SEQ ID NO: 1, nucleotides 102-1349 of SEQ ID NO: 1, nucleotides 102-258 of SEQ ID NO: 1, nucleotides
259-457 of SEQ ID NO: 1, nucleotides 458-677 of SEQ ID NO: 1, nucleotides 678-1349 of SEQ ID NO: 1, nucleotides 259-1349 of
SEQ ID NO: 1, nucleotides 458-1349 of SEQ ID NO: 1, and nucleotides 648-1349 of SEQ ID NO: 1, wherein the polynucleotide further
comprises a sequence that encodes a heterologous polypeptide comprising a DNA binding domain or a transactivation domain.
US Pat. No. 9,315,786

GSK3 LIGANDS AND POLYNUCLEOTIDES ENCODING GSK3 LIGANDS

Intrexon Corporation, Bl...

1. An isolated polynucleotide encoding a polypeptide comprising an amino acid sequence that is at least 98% identical to the
amino acid sequence of SEQ ID NO:7 and wherein the polypeptide inhibits kinase activity of glycogen synthase kinase-3.
US Pat. No. 9,243,263

STEROIDAL LIGANDS AND THEIR USE IN GENE SWITCH MODULATION

Intrexon Corporation, Bl...

1. A composition comprising a plurality of individually operable recombinant gene switches, wherein each individually operable
recombinant gene switch comprises:
a first recombinant cassette comprising first polynucleotide encoding a first polypeptide comprising:
a DNA-binding domain that recognizes a response element operatively linked with a gene of interest whose expression is to
be modulated; and

a E274V/V390I/Y410E mutant of the Choristoneura fumiferana ecdysone receptor ligand binding domain; and

a second recombinant cassette comprising:
a response element capable of binding to said DNA binding domain;
a promoter that is activated by the transactivation domain; and
a gene of interest;
wherein the composition comprises a plurality of ligands, wherein at least one ligand is:
20-hydroxyecdysone-2-methyl ether;
20-hydroxyecdysone-3-methyl ether;
20-hydroxyecdysone-14-methyl ether;
20-hydroxyecdysone-2,22-dimethyl ether;
20-hydroxyecdysone-3,22-dimethyl ether;
20-hydroxyecdysone-14,22-dimethyl ether;
20-hydroxyecdysone-22,25-dimethyl ether;
20-hydroxyecdysone-2,3,14,22-tetramethyl ether;
20-hydroxyecdysone-22-n-propyl ether;
20-hydroxyecdysone-22-n-butyl ether;
20-hydroxyecdysone-22-allyl ether;
20-hydroxyecdysone-22-benzyl ether;
20-hydroxyecdysone-22-(28R,S)-2?-ethyloxiranyl ether;
ponasterone A-2-methyl ether;
ponasterone A-14-methyl ether;
ponasterone A-22-methyl ether;
ponasterone A-2,22-dimethyl ether;
ponasterone A-3,22-dimethyl ether;
ponasterone A-14,22-dimethyl ether;
dacryhainansterone-22-methyl ether;
25,26-didehydroponasterone A (iso-stachysterone C (?25(26)));
shidasterone (stachysterone D);
stachysterone C;
22-deoxy-20-hydroxyecdysone (taxisterone);
ponasterone A;
polyporusterone B;
22-dehydro-20-hydroxyecdysone;
20-hydroxyecdysone;
pterosterone;
(25R)-inokosterone;
(25S)-inokosterone;
pinnatasterone;
25-fluoroponasterone A;
24(28)-dehydromakisterone A;
24-epi-makisterone A;
makisterone A;
20-hydroxyecdysone-22-methyl ether;
20-hydroxyecdysone-25-methyl ether;
abutasterone;
22,23-di-epi-geradiasterone;
20,26-dihydroxyecdysone (podecdysone C);
24-epi-abutasterone;
geradiasterone;
29-norcyasterone;
ajugasterone B;
24(28)[Z]-dehydroamarasterone B;
amarasterone A;
makisterone C;
rapisterone C;
20-hydroxyecdysone-22-ethyl ether;
carthamosterone;
24(25)-dehydroprecyasterone;
leuzeasterone;
cyasterone;
24(28)[Z]-dehydro-29-hydroxymakisterone C;
20-hydroxyecdysone-22-acetate;
viticosterone E (20-hydroxyecdysone 25-acetate);
24-hydroxycyasterone;
ponasterone A 22-hemisuccinate;
22-acetoacetyl-20-hydroxyecdysone;
canescensterone;
20-hydroxyecdysone-22-hemisuccinate;
inokosterone-26-hemisuccinate;
20-hydroxyecdysone-22-benzoate;
20-hydroxyecdysone-22-?-D-glucopyranoside;
20-hydroxyecdysone-25-?-D-glucopyranoside;
sileneoside A (20-hydroxyecdysone-22?-galactoside);
3-deoxy-1?,20-dihydroxyecdysone (3-deoxyintegristerone A);
2-deoxyintegristerone A;
1-epi-integristerone A;
integristerone A;
sileneoside C (integristerone A 22?-galactoside);
2,22-dideoxy-20-hydroxyecdysone;
2-deoxy-20-hydroxyecdysone;
2-deoxy-20-hydroxyecdysone-3-acetate;
2-deoxy-20,26-dihydroxyecdysone;
2-deoxy-20-hydroxyecdysone-22-acetate;
2-deoxy-20-hydroxyecdysone-3,22-diacetate;
2-deoxy-20-hydroxyecdysone-22-benzoate;
ponasterone A 2-hemisuccinate;
20-hydroxyecdysone-2-acetate;
20-hydroxyecdysone-2-hemisuccinate;
20-hydroxyecdysone-2-?D-glucopyranoside;
2-dansyl-20-hydroxyecdysone;
ponasterone A 3?-D-xylopyranoside (limnantheoside B);
20-hydroxyecdysone-3-acetate;
20-hydroxyecdysone-3?-D-xylopyranoside (limnantheoside A);
20-hydroxyecdysone-3-?-D-glucopyranoside;
sileneoside D (20-hydroxyecdysone-3?-galactoside);
20-hydroxyecdysone 3?-D-glucopyranosyl-[1-3]-?-D-xylopyranoside (limnantheoside C);
cyasterone-3-acetate;
2-dehydro-3-epi-20-hydroxyecdysone;
3-epi-20-hydroxyecdysone (coronatasterone);
rapisterone D;
3-dehydro-20-hydroxyecdysone;
5?-hydroxy-25,26-didehydroponasterone A;
5?-hydroxystachysterone C;
25-deoxypolypodine B;
polypodine B;
25-fluoropolypodine B;
5?-hydroxyabutasterone;
26-hydroxypolypodine B;
29-norsengosterone;
sengosterone;
6?-hydroxy-20-hydroxyecdysone;
6?-hydroxy-20-hydroxyecdysone;
20-hydroxyecdysone-6-oxime;
ponasterone A 6-carboxymethyloxime;
20-hydroxyecdysone-6-carboxymethyloxime;
ajugasterone C;
rapisterone B;
muristerone A;
atrotosterone B;
atrotosterone A;
turkesterone-2-acetate;
punisterone (rhapontisterone);
turkesterone;
atrotosterone C;
25-hydroxyatrotosterone B;
25-hydroxyatrotosterone A;
paxillosterone;
turkesterone-2,22-diacetate;
turkesterone-22-acetate;
turkesterone-11?-acetate;
turkesterone-2,11?-diacetate;
turkesterone-11?-propionate;
turkesterone-11?-butanoate;
turkesterone-11?-hexanoate;
turkesterone-11?-decanoate;
turkesterone-11?-laurate;
turkesterone-11?-myristate;
turkesterone-11?-arachidate;
22-dehydro-12?-hydroxynorsengosterone;
22-dehydro-12?-hydroxycyasterone;
22-dehydro-12?-hydroxysengosterone;
14-deoxy(14?-H)-20-hydroxyecdysone;
14?-perhydroxy-20-hydroxyecdysone;
20-hydroxyecdysone 14,22-dimethyl ether;
(20S)-22-deoxy-20,21-dihydroxyecdysone;
22,25-dideoxyecdysone;
(22S)-20-(2,2?-dimethylfuranyl)ecdysone;
(22R)-20-(2,2?-dimethylfuranyl)ecdysone;
22-deoxyecdysone;
25-deoxyecdysone;
22-dehydroecdysone;
ecdysone;
22-epi-ecdysone;
24-methylecdysone (20-deoxymakisterone A);
ecdysone-22-hemisuccinate;
25-deoxyecdysone-22-?-D-glucopyranoside;
ecdysone-22-myristate;
22-dehydro-20-iso-ecdysone;
20-iso-ecdysone;
20-iso-22-epi-ecdysone;
2-deoxyecdysone;
sileneoside E (2-deoxyecdysone 3?-glucoside; blechnoside A);
2-deoxyecdysone-22-acetate;
2-deoxyecdysone-3,22-diacetate;
2-deoxyecdysone-22-?-D-glucopyranoside;
2-deoxyecdysone 25-?-D-glucopyranoside;
2-deoxy-21-hydroxyecdysone;
3-epi-22-iso-ecdysone;
3-dehydro-2-deoxyecdysone (silenosterone);
3-dehydroecdysone;
3-dehydro-2-deoxyecdysone-22-acetate;
ecdysone-6-carboxymethyloxime;
ecdysone-2,3-acetonide;
14-epi-20-hydroxyecdysone-2,3-acetonide;
20-hydroxyecdysone-2,3-acetonide;
20-hydroxyecdysone-20,22-acetonide;
14-epi-20-hydroxyecdysone-2,3,20,22-diacetonide;
paxillosterone-20,22-p-hydroxybenzylidene acetal;
poststerone;
(20R)-dihydropoststerone;
(20S)dihydropoststerone;
poststerone-20-dansylhydrazine;
(20S)-dihydropoststerone-2,3,20-tribenzoate;
(20R)-dihydropoststerone-2,3,20-tribenzoate;
(20R)-dihydropoststerone-2,3-acetonide;
(20S)-dihydropoststerone-2,3-acetonide;
(5?-H)-dihydrorubrosterone;
2,14,22,25-tetradeoxy-5?-ecdysone-5?-ketodiol;
bombycosterol;
2?,3?,22S,25-tetrahydroxy-5?-cholestan-6-one;
(5?-H)-2-deoxy-21-hydroxyecdysone;
castasterone;
24-epi-castasterone;
(5?-H)-2-deoxyintegristerone A;
(5?-H)-22-deoxyintegristerone A;
(5?-H)-20-hydroxyecdysone;
24,25-didehydrodacryhaininansterone;
25,26-didehydrodacryhainansterone;
5-deoxykaladasterone (dacryhainansterone);
(14?-H)-14-deoxy-25-hydroxydacryhainansterone;
25-hydroxydacryhainansterone;
rubrosterone;
(5?-H)-dihydrorubrosterone;
dihydrorubrosterone-17?-acetate;
sidisterone;
20-hydroxyecdysone-2,3,22-triacetate;
14-deoxy(14?-H)-20-hydroxyecdysone;
14-epi-20-hydroxyecdysone;
9?,20-dihydroxyecdysone;
malacosterone;
2-deoxypolypodine B-3-?-D-glucopyranoside;
ajugalactone;
cheilanthone B;
2?,3?,6?-trihydroxy-5?-cholestane;
2?,3?,6?-trihydroxy-5?-cholestane;
14-dehydroshidasterone;
stachysterone B;
2?,3?,9?,20R,22R,25-hexahydroxy-5?-cholest-7,14-dien-6-one;
kaladasterone;
(14-?H)-14-deoxy-25-hydroxydacryhainansterone;
4-dehydro-20-hydroxyecdysone;
14-methyl-12-en-shidasterone;
14-methyl-12-en-15,20-dihydroxyecdysone;
podecdysone B;
2?,3?,20R,22R-tetrahydroxy-25-fluoro-5?-cholest-8,14-dien-6-one (25-fluoropodecdysone B);
calonysterone;
14-deoxy-14,18-cyclo-20-hydroxyecdysone;
9?,14?-epoxy-20-hydroxyecdysone;
9??,14?-epoxy-20-hydroxyecdysone;
9?,14?-epoxy-20-hydroxyecdysone 2,3,20,22-diacetonide;
28-homobrassinolide; or
iso-homobrassinolide.
US Pat. No. 9,169,306

ENDOPLASMIC RETICULUM LOCALIZATION SIGNALS

Intrexon Corporation, Bl...

1. An isolated polypeptide localization signal comprising two amino acid sequences at least 90% identical to SEQ ID NO: 49.
US Pat. No. 9,255,273

BIOAVAILABLE DIACYLHYDRAZINE LIGANDS FOR MODULATING THE EXPRESSION OF EXOGENOUS GENES VIA AN ECDYSONE RECEPTOR COMPLEX

Intrexon Corporation, Bl...

1. A method of modulating the expression of a target gene in a host cell, wherein the host cell comprises recombinant DNA
encoding:
(i) a transactivation domain;
(ii) a DNA-binding domain; and
(iii) a Choristoneura fumiferana ecdysone receptor ligand binding domain;
and a gene expression cassette comprising:
(i) a response element capable of binding to said DNA binding domain;
(ii) a promoter that is activated by the transactivation domain; and
(iii) said target gene;the method comprising contacting said host cell with a compoundselected from the group consisting of:
3,5-Dimethyl-benzoic acid N?-(2-ethyl-3-methoxy-benzoyl)-N-(2-hydroxyimino-1,1-dimethyl-ethyl)-hydrazide;
Acetic acid 2-[N-(3,5-dimethyl-benzoyl)-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazino]-2-methyl-propyl ester;
2-Ethyl-3-methoxy-benzoic acid N?-tert-butyl-N?-(1-methyl-1H-indole-2-carbonyl)-hydrazide;
3-(H2NC(O)NHN?CH-5-methyl-benzoic acid N-tert-butyl-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;

3-(H2NC(O)C(O)NHN?CH-5-methyl-benzoic acid N-tert-butyl-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;

2-Methoxy-6-trifluoromethyl-nicotinic acid N-tert-butyl-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide;
3-Methoxy-2-methy-benzoic acid N?-tert-butyl-N?-(1-methyl-2-oxo-6-trifluoromethyl-1,2-dihydro-pyridine-3-carbonyl)-hydrazide;
1H-Benzoimidazole-5-carboxylic acid, N-tert-butyl-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
1-Trityl-1H-benzoimidazole-5-carboxylic acid N-tert-butyl-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
3-Trityl-1H-benzoimidazole-5-carboxylic acid N-tert-butyl-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
1H-Indazole-3-carboxylic acid N-tert-butyl-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
1-Trityl-1H-indazole-3-carboxylic acid N-tert-butyl-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
3,5-Dimethyl-benzoic acid N-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
3,5-Dimethyl-benzoic acid N?-(2-ethyl-3-methoxy-benzoyl)-N-[2-(2-hydroxy-ethylimino)-1,1-dimethyl-ethyl]-hydrazide;
3,5-Dimethyl-benzoic acid N-[(H2NC(O)NHN?CH)(CH3)2C-]N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide; and

3,5-Dimethyl-benzoic acid N-[(H2NC(O)C(O)NHN?CH)(CH3)2C-]-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide.

US Pat. No. 9,249,207

SUBSTITUTION MUTANT RECEPTORS AND THEIR USE IN AN ECDYSONE RECEPTOR-BASED INDUCIBLE GENE EXPRESSION SYSTEM

Intrexon Corporation, Bl...

1. A gene expression modulation system comprising
(a) a polynucleotide that encodes a first polypeptide comprising a Group B nuclear receptor ligand binding domain comprising
a substitution mutation at a position selected from the group consisting of

(i) 401 or 429 of SEQ ID NO:1,
(ii) 401 and 429 of SEQ ID NO:1,
(iii) 337, 462, 470, or 473 of SEQ ID NO:2,
(iv) 450, 451, and 452 of SEQ ID NO:2,
(v) 455, 456, 457, and 458 of SEQ ID NO:2,
(vi) 475, 476, 477, 478, and 479 of SEQ ID NO:2, and
(vii) 481, 482, and 483 of SEQ ID NO:2; and
(b) a polynucleotide that encodes a second polypeptide comprising a nuclear receptor ligand binding domain that dimerizes
with said Group B nuclear receptor ligand binding domain comprising a substitution mutation.

US Pat. No. 9,115,361

METHODS FOR DYNAMIC VECTOR ASSEMBLY OF DNA CLONING VECTOR PLASMIDS

Intrexon Corporation, Bl...

1. A method for simultaneously synthesizing an array of transgenes, comprising:
a. providing a primary cloning vector plasmid comprising a first and a second docking point,
wherein each docking point comprises at least one endonuclease site of greater than six nucleotides, and
wherein the cloning vector plasmid further comprises a unique homing endonuclease site in a forward orientation located upstream
from the 5? end of the first docking point and a unique homing endonuclease site in a reverse orientation located downstream
from the 3? end of the second docking point;

b. introducing at least one Promoter nucleotide sequence into a corresponding Promoter shuttle vector;
c. introducing at least one Expression nucleotide sequence into a corresponding Expression shuttle vector;
d. introducing at least one Regulatory nucleotide sequence into a corresponding Regulatory shuttle vector;
e. simultaneously ligating the Promoter, Expression, and Regulatory nucleotide sequences from the Promoter, Expression, and
Regulatory shuttle vectors to the cloning vector plasmid, between the first and second docking points, thereby forming a transgene
construct comprising the Promoter, Expression, and Regulatory nucleotide sequences;

f. digesting the cloning vector plasmid with homing endonucleases that recognize the unique homing endonuclease sites in (a),
thereby releasing the transgene construct;

g. providing a second cloning vector plasmid comprising the same unique homing endonuclease site in a forward orientation
and the same unique homing endonuclease site in a reverse orientation as the first cloning vector plasmid;

h. digesting the second cloning vector plasmid with the homing endonuclease used in (f); and
i. ligating the transgene construct of (f) into the second cloning vector plasmid.
US Pat. No. 9,163,256

MUTANT RECEPTORS AND THEIR USE IN A NUCLEAR RECEPTOR-BASED INDUCIBLE GENE EXPRESSION SYSTEM

Intrexon Corporation, Bl...

1. A method of modulating the expression of a gene in a host cell comprising:
(a) introducing into the host cell a polynucleotide encoding a gene expression modulation system comprising a transactivation
domain, a DNA binding domain and a Group H nuclear receptor ligand binding domain that is capable of binding a diacylhydrazine
and comprises an amino acid residue substitution mutation at

(i) at least one of amino residues 54, 119, and 132 of SEQ ID NO: 1,
(ii) both of amino acid residues 96 and 119 of SEQ ID NO: 1,
(iii)
both of amino acid residues 52 and 110 of SEQ ID NO: 1,
(iv) both of amino acid residues 132 and 125 of SEQ ID NO: 1,
(v) all three of amino acid residues 107, 110 and 127 of SEQ ID NO: 1,
(vi) all three of amino acid residues 52, 107 and 127 of SEQ ID NO: 1,
(vii) both of amino acid residues 107, 127 and an insertion at 259 of SEQ ID NO: 1, or
(viii) an amino acid substitution at least one of the mutations F48Y, F48W, F48L, F48N, F48R, F48K, I51M, I51N, I51L, T52M,
T52E, T52P, T52R, T52W, T52G, T52Q, M92L, M92E, R95H, R95M, R95W, V96L, V96W, V96S, V96E, F109W, F109P, F109L, F109M, F109N,
Y120W, Y120M, M219K, M219W, M219Y, M219A, L223K, L223R, L223Y, L234M, L234I, L234R, L234W, W238P, W238E, W238Y, W238M and
W238L of SEQ ID NO: 1;

said gene expression modulation system further comprising a gene expression cassette comprising:
(i) a response element recognized by the DNA binding domain;
(ii) a promoter that is activated by the transactivation domain; and
(iii) a gene whose expression is to be modulated; and
(b) introducing into the host cell a ligand;
whereby upon introduction of the ligand into the host cell, expression of the gene whose expression is to be modulated is
induced, compared to the expression of said gene by a gene expression modulation system in which the same Group H nuclear
receptor ligand binding domain does not contain said mutation.

US Pat. No. 9,169,210

BIOAVAILABLE DIACYLHYDRAZINE LIGANDS FOR MODULATING THE EXPRESSION OF EXOGENOUS GENES VIA AN ECDYSONE RECEPTOR COMPLEX

Intrexon Corporation, Bl...

1. A compound of the general formula:

wherein X and X? are independently O or S;
A is unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy;
amino (—NRaRb); alkylaminolkyl (—(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4)alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (—OCORa); carboxamido (—CONRaRb); amido (—NRaCORb); alkoxycarbonylamino (—NRaCO2Rb); alkylaminocarbonylamino (—NRaCONRbRc); mercapto; (C1-C6)alkylthio; (C1-C6) alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (—S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl —(CH2)nS(O)Ra); sulfamido (—SO2NRaRb); —SO3H; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6) alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted, the attached atoms may
form the phenyl-connecting termini of a linkage selected from the group consisting of (—OCH2O—), (—OCH(CH3)O—), (—OCH2CH2O—), (—OCH(CH3)CH2O—), (—S—CH?N—), (—CH2OCH2O—), (—O(CH2)3—), (?N—O—N?), (—CH?CH—NH—), (—OCF2O—), (—NH—CH?N—), (—CH2CH2O—), and (—(CH2)4—);

B is
(a) unsubstituted or substituted phenyl wherein the substituents are independently 1 to 5H; halo; nitro; cyano; hydroxy; amino
(—NRaRb); alkylaminolkyl (—(CH2)nNRaRb); (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)cyanoalkyl; (C1-C6)hydroxyalkyl; (C1-C6)alkoxy; phenoxy; (C1-C6)haloalkoxy; (C1-C6)alkoxy(C1-C6)alkyl; (C1-C6)alkenyloxy(C1-C6)alkyl; (C1-C6)alkoxy(C1-C6)alkoxy; (C1-C6)alkanoyloxy(C1-C6)alkyl; (C2-C6)alkenyl optionally substituted with halo, cyano, (C1-C4) alkyl, or (C1-C4)alkoxy; (C2-C6)alkynyl optionally substituted with halo or (C1-C4)alkyl; formyl; carboxy; (C1-C6)alkylcarbonyl; (C1-C6)haloalkylcarbonyl; benzoyl; (C1-C6)alkoxycarbonyl; (C1-C6)haloalkoxycarbonyl; (C1-C6)alkanoyloxy (—OCORa); carboxamido (—CONRaRb); amido (—NRaCORb); alkoxycarbonylamino (—NRaCO2Rb); alkylaminocarbonylamino (—NRaCONRbRe); mercapto; (C1-C6)alkylthio; (C1-C6) alkylsulfonyl; (C1-C6)alkylsulfonyl(C1-C6)alkyl; (C1-C6)alkylsulfoxido (—S(O)Ra); (C1-C6)alkylsulfoxido(C1-C6)alkyl (—CH2)nS(O)Ra); sulfamido (—SO2NRaRb); —SO3H; —CH?N—NHC(O)NRaRb; —CH?N—NHC(O)C(O)NRaRb; or unsubstituted or substituted phenyl wherein the substituents are independently 1 to 3 halo, nitro, (C1-C6) alkoxy, (C1-C6)alkyl, or amino; or when one or both of two adjacent positions on the phenyl ring are substituted, the attached atoms may
form the phenyl-connecting termini of a linkage selected from the group consisting of (—OCH2O—), (—OCH(CH3)O—), (—OCH2CH2O—), (—OCH(CH3)CH2O—), (—S—CH?N—), (—CH2OCH2O—), (—O(CH2)3—), (?N—O—N?), (—CH?CH—NH—), (—OCF2O—), (—NH—CH?N—), (—CH2CH2O—), and (—(CH2)4—);

(b) unsubstituted 6-membered heterocycle or substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon
atoms where the substituents are from one to three of the same or different halo; nitro; hydroxy; (C1-C6)alkyl; (C1-C6)alkoxy; (C1-C6)thioalkoxy; carboxy; (C1-C6)alkoxycarbonyl; (C1-C6)carboxyalkyl; (C1-C6)alkoxycarbonylalkyl having independently the stated number of carbon atoms in each alkyl group; —CONRaRb; amino; (C1-C6)alkylamino; (C1-C6)dialkylamino having independently the stated number of carbon atoms in each alkyl group; haloalkyl; —CH?N—NHC(O)NRaRb; or —CH?N—NHC(O)C(O)NRaRb; or

(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or
1-(C1-C6)alkyl-1H-indole-2-yl;

E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C5-C6)cycloalkyl; phenyl; (C2-C3)alkenyl; hydroxy, (C1-C6)alkoxy; carboxy; (C1-C6)alkoxycarbonyl; formyl; (C1-C6)trialkylsilyloxy having independently the stated number of carbon atoms in each alkyl group; —CH?N—ORa; —CH?N—Rd; —CH?N—NHC(O)NRaRb; or —CH?N—NHC(O)C(O)NRaRb;

wherein Ra, Rb, and Rc are independently H, (C1-C6)alkyl, or phenyl; Rd is hydroxy(C1-C6)alkyl; and n=1-4; and

G is H or CN;
provided that:
1) when E is unsubstituted or substituted (C4-C10) branched alkyl wherein the substituents are independently 1-4 cyano; halo; (C2-C3)alkenyl; carboxy; or (C1-C6)alkoxycarbonyl;

then B is:
(a) substituted phenyl which bears at least one —CH?N—NHC(O)NRaRb or —CH?N—NHC(O)C(O)NRaRb group;

(b) substituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms which bears at least one haloalkyl
group; or

(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or
1-(C1-C6)alkyl-1H-indole-2-yl;

wherein Ra, Rb are independently H, (C1-C6)alkyl, or phenyl; or

2) when E is a substituted (C4-C10) branched alkyl which bears at least one of phenyl; hydroxy, (C1-C6)alkoxy; or formyl;

then B is:
(a) substituted phenyl which bears at least one —CH?N—NHC(O)NRaRb or —CH?N—NHC(O)C(O)NRaRb group;

(b) substituted or unsubstituted 6-membered heterocycle having 1-3 nitrogen atoms and 3-5 nuclear carbon atoms; or
(c) 5-benzimidazolyl; 1-trityl-5-benzimidazolyl; 3-trityl-5-benzimidazolyl; 1H-indazole-3-yl; 1-trityl-1H-indazole-3-yl; or
1-(C1-C6)alkyl-1H-indole-2-yl;

wherein Ra and Rb are independently H, (C1-C6)alkyl, or phenyl.

US Pat. No. 9,617,317

ENDOPLASMIC RETICULUM LOCALIZATION SIGNALS

Intrexon Corporation, Bl...

1. An isolated polynucleotide comprising a sequence encoding a polypeptide localization signal comprising:
(a) an amino acid sequence at least 90% identical to SEQ ID NO: 42;
(b) the amino acid sequence of SEQ ID NO: 72; and
(c) the amino acid sequence of SEQ ID NO:75.
US Pat. No. 9,598,355

CHIRAL DIACYLHYDRAZINE LIGANDS FOR MODULATING THE EXPRESSION OF EXOGENOUS GENES VIA AN ECDYSONE RECEPTOR COMPLEX

Intrexon Corporation, Bl...

1. A method of modulating the expression of a gene of interest in a host cell, wherein the host cell comprises a first recombinant
gene expression cassette comprising a first polynucleotide encoding a first polypeptide comprising:
i) a DNA-binding domain; and
ii) a Group H nuclear receptor ligand binding domain;and a second recombinant gene expression cassette comprising:
i) a response element capable of binding to said DNA binding domain;
ii) a promoter; and
iii) said gene of interest;the method comprising contacting said host cell with a compound selected from the group consisting of:
(R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(2-ethyl-3-methoxy-benzoyl)-hydrazide;
(R)-3,5-dimethyl-benzoic acid N?-benzoyl-N-(1-tert-butyl-butyl)-hydrazide;
(R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(2-methyl-benzoyl)-hydrazide;
(R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(2-fluoro-benzoyl)-hydrazide;
(R)-3,5-dimethyl-benzoic acid N?-(2-bromo-benzoyl)-N-(1-tert-butyl-butyl)-hydrazide;
(R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(3-methyl-benzoyl)-hydrazide;
(R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(4-methyl-benzoyl)-hydrazide; and
(R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N?-(3-methoxy-2-methyl-benzoyl)-hydrazide,
wherein the expression of the gene of interest is modulated.
US Pat. No. 9,605,316

METHODS AND COMPOSITIONS FOR DIAGNOSING DISEASE

Intrexon Corporation, Bl...

1. A method of monitoring the level of a factor that is being administered to a subject for treatment of a kidney disease
or disorder, comprising:
administering said treatment to said subject;
introducing into cells of said subject (1) a polynucleotide encoding a gene switch, said gene switch comprising at least one
transcription factor sequence, wherein said at least one transcription factor sequence encodes a ligand-dependent transcription
factor, linked to a diagnostic ADAM-17 switch promoter, wherein the activity of the promoter is modulated by said factor that
is being administered for treatment, and (2) a polynucleotide encoding a CD95-ADAM8 dual reporter or an alkaline phosphatase-c
terminal CD40 reporter gene linked to a promoter which is activated by said ligand-dependent transcription factor, to produce
modified cells;

administering ligand to said modified cells; and
detecting reporter gene expression;
wherein the level of expression of the CD95-ADAM8 dual reporter or the alkaline phosphatase-c terminal CD40 reporter gene
indicates that the level of the factor being administered for treatment is not high enough to effect treatment of the kidney
disease or disorder.

US Pat. No. 9,802,936

KETONE LIGANDS FOR MODULATING THE EXPRESSION OF EXOGENOUS GENES VIA AN ECDYSONE RECEPTOR COMPLEX

Intrexon Corporation, Bl...

1. A compound of formula I:

wherein Q1 is selected from the group consisting of O and S;

R1 is selected from the group consisting of 2-methyl-3,4-methylenedioxyphenyl, 2-ethyl-3,4-methylenedioxyphenyl, 2-methyl-3,4-ethylenedioxyphenyl,
2-ethyl-3,4-ethylenedioxyphenyl, and 2-methyl-3,4-oxydimethylenephenyl;

R2 and R3 are independently:

(a) cyano, aminocarbonyl, carboxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C1-C6)alkyl, (C3-C6)halocycloalkyl, (C2-C6)alkenyl, (C3-C6)cycloalkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C1-C6)alkylsulfonyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, cyano(C1-C6)alkyl, hydroxy(C1-C6)alkyl, or carboxy(C1-C6)alkyl; or

(b) unsubstituted or substituted phenyl, phenyl(C1-C6)alkyl, benzoyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thiophenyl, benzothiophenyl, benzofuranyl,
isoxazolyl, or imidazolyl, heterocyclylcarbonyl, wherein the substituents are independently selected from the group consisting
of cyano, nitro, halo, aminocarbonyl, aminothiocarbonyl, carboxy, formyl, hydroxy, amino, carbamoyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, (C1-C3)alkythio, (C1-C3)haloalkylthio, (C1-C3)alkylsulfonyl, (C1-C3)alkylamino, di(C1-C3)alkylamino, (C1-C2)alkoxy(C1-C2)alkyl, (C1-C2)alkylthio(C1-C2)alkyl, (C1-C2)alkylsulfonyl(C1-C2)alkyl, (C1-C2)alkylamino(C1-C2)alkyl, di(C1-C2)alkylamino(C1-C2)alkyl, (C1-C3)alkylcarbonyl, (C1-C3)alkoxycarbonyl, (C1-C3)alkylaminocarbonyl, di(C1-C3)alkylaminocarbonyl, and cyano(C1-C3)alkyl; or

R2 and R3 may be joined together with the carbon to which they are attached to form an unsubstituted or substituted, partially unsaturated
or saturated 3-, 4-, 5-, 6-, 7- or 8-membered carbocyclic or heterocyclic ring wherein the heterocyclic ring contains from
one to three heteroatoms selected from O, N, or S; and the substituents are independently selected from the group consisting
of cyano, nitro, halo, aminocarbonyl, aminothiocarbonyl, carboxy, formyl, hydroxy, amino, carbamoyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, (C1-C3)alkythio, (C1-C3)haloalkylthio, (C1-C3)alkylsulfonyl, (C1-C3)alkylamino, di(C1-C3)alkylamino, (C1-C2)alkoxy(C1-C2)alkyl, (C1-C2)alkylthio(C1-C2)alkyl, (C1-C2)alkylsulfonyl(C1-C2)alkyl, (C1-C2)alkylamino(C1-C2)alkyl, di(C1-C2)alkylamino(C1-C2)alkyl, (C1-C3)alkylcarbonyl, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxycarbonyl(C1-C4)alkyl, (C1-C4)alkoxycarbonylcarbonyl, (C1-C3)alkylaminocarbonyl, di(C1-C3)alkylaminocarbonyl, cyano(C1-C3)alkyl, oxo, methoxyimino, and spiro-(C1-C4)alkadioxy; and

R4 is unsubstituted or substituted phenyl or pyridyl, wherein the substituents are independently selected from the group consisting
of cyano, nitro, halo, aminocarbonyl, aminothiocarbonyl, carboxy, formnyl, hydroxy, amino, carbamoyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)haloalkyl, (C3-C6)halocycloalkyl, (C2-C6)alkenyl, (C3-C6)cycloalkenyl, (C3-C6)alkadienyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C3-C6)cycloalkoxy, (C1-C6)haloalkoxy, (C3-C6)cyclohaloalkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C1-C6)alkythio, (C3-C6)cycloalkylthio, (C1-C6)haloalkylthio, (C3-C6)halocycloalkythio, (C2-C6)alkenylthio, (C2-C6)alkynylthio, (C1-C6)alkylsulfinyl, (C3-C6)cycloalkysulfinyl, (C1-C6)haloalkylsulfinyl, (C3-C6)halocycloalkylsulfinyl, (C2-C6)alkenylsulfinyl, (C3-C6)cycloalkenylsulfinyl, (C2-C6)alkynylsulfinyl, (C1-C6)alkylsulfonyl, (C3-C6)cycloalkysulfonyl, (C1-C6)haloalkylsulfonyl, (C3-C6)halocycloalkylsulfonyl, (C1-C6)alkylsulfinyl, (C3-C6)cycloalkysulfinyl, (C1-C6)haloalkylsulfinyl, (C3-C6)halocycloalkylsulfinyl, (C1-C6)alkylamino, (C3-C6)cycloalkylamino, di(C1-C6)alkylamino, di(C3-C6)(cycloalkyl)amino, (C1-C6)alkoxy(C1-C6)alkyl, (C3-C6)cycloalkoxyalkyl, (C1-C6)alkoxy(C3-C6)cycloalkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C6)cycloalkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylaminocarbonyl, (C3-C6)cycloalkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, di(C3-C6)(cycloalkyl)aminocarbonyl, cyano(C1-C6)alkyl, and tri(C1-C6)alkylsilyl;

wherein in said substituted phenyl or pyridyl, two adjacent substituted positions may be joined together with the atoms to
which they are attached to form an unsubstituted or substituted, unsaturated, partially unsaturated, or saturated 4-, 5-,
6- or 7-membered carbocyclic or heterocyclic ring wherein the heterocyclic ring contains from one to three heteroatoms selected
from N, O, or S; and the substituents are independently selected from the group consisting of cyano, nitro, halo, aminocarbonyl,
aminothiocarbonyl, carboxy, fonnuyl, hydroxy, amino, carbamoyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, (C1-C3)haloalkoxy, (C1-C3)alkythio, (C1-C3)haloalkylthio, (C1-C3)alkylsulfonyl, (C1-C3)alkylamino, di(C1-C3)alkylamino, (C1-C2)alkoxy(C1-C2)alkyl, (C1-C2)alkylthio(C1-C2)alkyl, (C1-C2)alkylsulfonyl(C1-C2)alkyl, (C1-C2)alkylamino(C1-C2)alkyl, di(C1-C2)alkylamino(C1-C2)alkyl, (C1-C3)alkylcarbonyl, (C1-C3)alkoxycarbonyl, (C1-C3)alkylaminocarbonyl, di(C1-C3)alkylaminocarbonyl, cyano(C1-C3)alkyl, oxo, and methoxyimino.

US Pat. No. 9,745,603

BIOLOGICAL PRODUCTION OF MULTI-CARBON COMPOUNDS FROM METHANE

Intrexon Corporation, Bl...

1. A genetically modified methanotroph that is capable of producing 2,3-butanediol from methane (CH4), the genetically modified methanotroph comprising exogenous polynucleotides encoding acetolactate synthase and 2,3-butanediol
dehydrogenase, wherein the acetolactate synthase has acetolactate synthase activity and comprises an amino acid sequence having
at least 90% sequence homology to SEQ ID NO:2, and the 2,3-butanediol dehydrogenase has 2,3-butanediol dehydrogenase activity
and comprises an amino acid sequence having at least 90% sequence homology to SEQ ID NO: 157, wherein said methanotroph is
capable of converting methane to pyruvate through an endogenous type I RuMP pathway or a type II serine pathway.
US Pat. No. 9,724,430

THERAPEUTIC GENE-SWITCH CONSTRUCTS AND BIOREACTORS FOR THE EXPRESSION OF BIOTHERAPEUTIC MOLECULES, AND USES THEREOF

Intrexon Corporation, Bl...

1. A composition comprising: (1) a first polynucleotide encoding a gene switch, said gene switch comprising at least one transcription
factor sequence, wherein said at least one transcription factor sequence encodes a ligand-dependent transcription factor in
operable association with a hypoxia-inducible promoter, wherein the hypoxia-inducible promoter is a nucleic acid sequence
at least 95% identical to the sequence from nucleotide 4958 to nucleotide 5535 of SEQ ID NO: 7, and
(2) a second polynucleotide encoding a therapeutic polypeptide or therapeutic polynucleotide operably associated with a transcription
factor-regulated promoter which is activated by said ligand-dependent transcription factor, wherein a ligand is capable of
inducing expression of said therapeutic polypeptide or therapeutic polynucleotide, wherein said composition is for use in
treating, ameliorating, or preventing a disease or disorder.

US Pat. No. 10,036,026

METHODS FOR DYNAMIC VECTOR ASSEMBLY OF DNA CLONING VECTOR PLASMIDS

Intrexon Corporation, Bl...

1. A method for making a transgene, comprising:(a) providing a cloning vector plasmid comprising first and second docking points, wherein each docking point comprises at least one endonuclease site of greater than six nucleotides, wherein the cloning vector plasmid further comprises a unique homing endonuclease site in a forward orientation located upstream from the 5? end of the first docking point and a unique homing endonuclease site in a reverse orientation located downstream from the 3? end of the second docking point;
(b) introducing a first nucleotide sequence into a first shuttle vector;
(c) introducing a second nucleotide sequence into a second shuttle vector; and
(d) transferring simultaneously the first nucleotide sequence and the second nucleotide sequence from the shuttle vectors to the cloning vector plasmid, between the first and second docking points.
US Pat. No. 10,046,049

ENGINEERED CELLS EXPRESSING MULTIPLE IMMUNOMODULATORS AND USES THEREOF

Intrexon Corporation, Bl...

1. A method for treating a tumor in a mammal, comprising:(a) administering intratumorally to tumor microenvironments a population of in vitro engineered immune cells wherein the in vitro engineered immune cells comprise an adenoviral vector for conditionally expressing proteins, the vector comprising a polynucleotide encoding an ecdysone gene switch, wherein said polynucleotide comprises
(1) polynucleotide sequence comprising a first transcription factor sequence and a second transcription factor sequence under the control of a promoter, wherein the proteins encoded by the first transcription factor sequence and second transcription factor sequence interact to form a ligand-dependent transcription factor complex,
wherein the first transcription factor sequence comprises a nucleic acid encoding a VP-16 transactivation domain and a retinoic acid-X-receptor (RXR) polypeptide,
wherein the RXR polypeptide is a genetically engineered chimera comprising vertebrate RXR and invertebrate RXR domains,
wherein said vertebrate RXR ligand binding domain is a human RXR ligand binding domain,
wherein the second transcription factor sequence comprises a nucleic acid encoding a GAL-4 DNA binding domain and an ecdysone receptor protein,
wherein said ecdysone receptor protein comprises a ecdysone receptor ligand binding domain derived from a Choristoneura fumiferna ecdysone receptor ligand binding domain, and
wherein said Choristoneura fumiferna ecdysone receptor ligand binding domain further comprises a genetically engineered substitution mutation compared to the naturally occurring Choristoneura fumiferna ecdysone receptor ligand binding domain from which it was derived;
(2) a polynucleotide encoding a polypeptide at least 90% identical to IL-12; and
(3) a polynucleotide encoding a polypeptide at least 90% identical to IL-21; wherein at least one polynucleotide of (2) or (3) are linked to a promoter capable of being activated by said ligand dependent transcription factor complex; and
(b) administering to said mammal a therapeutically effective amount of an activating ligand; thereby inducing expression of at least one polynucleotide of (2) or (3).

US Pat. No. 9,944,659

BORON-CONTAINING DIACYLHYDRAZINE COMPOUNDS

INTREXON CORPORATION, Bl...

1. A compound having Formula I:
or a pharmaceutically acceptable salt, solvate, or boronic anhydride thereof, wherein:
A is selected from the group consisting of hydrogen and —C(R1)(R2)(R3);
R1, R2, and R3 are each independently selected from the group consisting of hydrogen and optionally substituted alkyl;
R4 is selected from the group consisting of:

X is selected from the group consisting of —O— and —N(R8a)—;
X1 is selected from the group consisting of —O— and —N(R8b)—;
X2 is selected from the group consisting of —O— and —N(R8c)—;
X3 is selected from the group consisting of —O— and —N(R8d)—;
Y1 is —(CR9aR9b)m—;
m is 0, 1, 2, or 3;
Z1 is selected from the group consisting of —O— and —N(R8e)—, or Z1 is absent;
Z2 is selected from the group consisting of O, S, and NH;
R6a is selected from the group consisting of hydrogen, —B(OH)2, and pinacolborane;
R6b, R6c, and R6d are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, —N(H)(cyano)alkyl, —CHO, optionally substituted alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR10, —SO2R11, —N(R12)COR13, —N(R12)SO2R14 or N(R12)C?N(R15)-amino; or
R6b is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, —N(H)CHO, —N(H)CN, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR10, —SO2R11, —N(R12)COR13, —N(R12)SO2R14 or N(R12)C?N(R15)-amino; and/or
R6c and R6d taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo, or optionally substituted heteroaryl group;
R6f is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino, and hydroxy;
R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, and R7j are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
R8a, R8b, R8c, R8d, R8e, R8f, and R8g are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, and arylcarbonyl;
R9a and R9b are each independently selected from the group consisting of hydrogen, alkyl, and cyano;
R5 is selected from the group consisting of:

X4 is selected from the group consisting of —O— and —N(R8h)—;
X5 is selected from the group consisting of —O— and —N(R8i)—;
X6 is selected from the group consisting of —O— and —N(R8j)—;
X7 is selected from the group consisting of —O— and —N(R8k)—;
Y2 is —(CR9cR9d)n—;
n is 0, 1 2, or 3;
Z3 is selected from the group consisting of —O— and —N(R8l)—, or Z3 is absent;
Z4 is selected from the group consisting of O, S, and NH;
R6e is selected from the group consisting of hydrogen, —B(OH)2, and pinacolborane;
R6g, R6h, and R6i are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, —N(H)(cyano)alkyl, —CHO, optionally substituted alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR10, —SO2R11, —N(R12)COR13, —N(R12)SO2R14 or N(R12)C?N(R15)-amino; or
R6g is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, —N(H)CHO, —N(H)CN, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR10, —SO2R11, —N(R12)COR13, —N(R12)SO2R14 or N(R12)C?N(R15)-amino; and/or
R6h and R6i taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo, or optionally substituted heteroaryl group;
R6j is selected from the group consisting of hydrogen, alkyl, amino, and hydroxy;
R7k, R7l, R7m, R7n, R7o, R7p, R7q, R7r, R7s, and R7t are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
R8h, R8i, R8j, R8k, R8l, R8m, and R8n are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, and arylcarbonyl;
R9c and R9d are each independently selected from the group consisting of hydrogen, alkyl, and cyano;
R10 is selected from the group consisting of hydrogen, hydroxy, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, and arylalkyloxy;
R11 is selected from the group consisting of haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
R12 is selected from the group consisting of hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
R13 is selected from the group consisting of hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, arylalkyloxy, and amino;
R14 is selected from the group consisting of haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and amino; and
R15 is selected from the group consisting of hydrogen, alkyl, aryl, cyano, and nitro, with the provisos that:
1) when R4 is R4-1 or R4-2 and R5 is R5-1 or R5-2, then one of R6a or R6e is —B(OH)2 or pinacolborane; and
2) said compound having Formula I is not:
(3-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-2-methylphenyl)boronic acid;
(R)-(2-chloro-3-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)phenyl)boronic acid;
(4-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)phenyl)boronic acid;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-3-isopropylphenyl)boronic acid;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-3-fluorophenyl)boronic acid;
(R)-(4-(2-(2,6-dimethylisonicotinoyl)-2-(2,2-dimethylpentan-3-yl)hydrazine-1-carbonyl)-3-fluorophenyl)boronic acid;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-2-fluorophenyl)boronic acid;
(4-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-3,5-difluorophenyl)boronic acid;
(2-(1-(2,2-dimethylpentan-3-yl)-2-(3-methoxy-2-methylbenzoyl)hydrazine-1-carbonyl)phenyl)boronic acid;
(3-(1-(2,2-dimethylpentan-3-yl)-2-(3-methoxy-2-methylbenzoyl)hydrazine-1-carbonyl)-4-fluorophenyl)boronic acid;
(3-(1-(2,2-dimethylpentan-3-yl)-2-(3-methoxy-2-methylbenzoyl)hydrazine-1-carbonyl)-5-methoxyphenyl)boronic acid;
(4-(1-(tert-butyl)-2-(2-ethyl-3-methoxybenzoyl)hydrazine-1-carbonyl)phenyl)boronic acid;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
N?-(3-chloro-5-methylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
N-(2,2-dimethylhexan-3-yl)-N?-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-2-oxo-1,2-dihydropyridine-3-carbohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
(S)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbohydrazide;
N?-(3,5-dimethylbenzoyl)-1-hydroxy-N?-isopropyl-6-methyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
N?-(3,5-dimethylbenzoyl)-1-hydroxy-6-methyl-N?-(tert-pentyl)-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-1-hydroxy-6-methyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
N?-(3,5-dimethylbenzoyl)-N?-(1-fluorobutan-2-yl)-1-hydroxy-6-methyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-2-methyl-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-3-(2-methoxyethoxy)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
N?-(tert-butyl)-3-(cyanomethoxy)-N?-(3,5-dimethylbenzoyl)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylpentan-3-yl)hydrazine-1-carbonyl)-3-fluorophenyl)boronic acid;
(3-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-2-fluoro-6-(methoxymethyl)phenyl)boronic acid;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-1-hydroxy-6-methyl-1,2,3,4-tetrahydrobenzo[f][1,4,5]oxazaborepine-7-carbohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-2-fluoro-4-(methoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)-(3-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-2-methylphenyl)boronic acid;
(3-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-2-fluorophenyl)boronic acid;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)phenyl)boronic acid;
(4-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-3-isopropylphenyl)boronic acid;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(6-fluoro-2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-3-fluorophenyl)boronic acid;
(R)-(4-(2-(2,2-dimethylpentan-3-yl)-2-(4,6-dimethylpyrimidine-2-carbonyl)hydrazine-1-carbonyl)-3-fluorophenyl)boronic acid;
(R)-(3-chloro-4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)phenyl)boronic acid;
(4-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-2-fluorophenyl)boronic acid;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylpentan-3-yl)hydrazine-1-carbonyl)-2-(2-methoxyethoxy)-3-methylphenyl)boronic acid;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-3-methoxy-2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)benzohydrazide;
(3-(1-(2,2-dimethylpentan-3-yl)-2-(3-methoxy-2-methylbenzoyl)hydrazine-1-carbonyl)phenyl)boronic acid;
(3-(1-(2,2-dimethylpentan-3-yl)-2-(3-methoxy-2-methylbenzoyl)hydrazine-1-carbonyl)-5-fluorophenyl)boronic acid;
N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
N-(2,2-dimethylpentan-3-yl)-3,5-dimethoxy-4-methyl-N?-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)benzohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
(S)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
(R)—N-(2,2-dimethylpentan-3-yl)-N?-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-4,6-dimethylpyrimidine-2-carbohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
(S)—N?-(3,5-bis(methyl-d3)benzoyl)-N?-(2,2-dimethylpentan-3-yl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbohydrazide;
N?-(3,5-dimethylbenzoyl)-1-hydroxy-6-methyl-N?-neopentyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
N?-(3,5-bis(methyl-d3)benzoyl)-1-hydroxy-6-methyl-N?-(tert-pentyl)-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
(S)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-1-hydroxy-6-methyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
N?-(3,5-dimethylbenzoyl)-N?—((R)-2,2-dimethylpentan-3-yl)-2-methyl-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)-3-(cyanomethoxy)-N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)-(3-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylpentan-3-yl)hydrazine-1-carbonyl)-2-fluoro-6-(methoxymethyl)phenyl)boronic acid;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-1-hydroxy-6-methyl-1,2,3,4-tetrahydrobenzo[f][1,4,5]oxazaborepine-7-carbohydrazide;
(3-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-2-chlorophenyl)boronic acid;
(R)-(3-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-2-fluorophenyl)boronic acid;
(4-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-3-methylphenyl)boronic acid;
(4-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-3-fluorophenyl)boronic acid;
(R)-(4-(2-(3,5-bis(methyl-d3)benzoyl)-2-(2,2-dimethylpentan-3-yl)hydrazine-1-carbonyl)-3-fluorophenyl)boronic acid;
(4-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-3-chlorophenyl)boronic acid;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-3,5-difluorophenyl)boronic acid;
(R)-(3-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-2-methoxy-3-methylphenyl)propyl)boronic acid;
(R)-3-(difluoromethoxy)-N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)benzohydrazide;
(R)-(3-(1-(2,2-dimethylpentan-3-yl)-2-(3-methoxy-2-methylbenzoyl)hydrazine-1-carbonyl)-5-methylphenyl)boronic acid;
(3-(1-(2,2-dimethylpentan-3-yl)-2-(3-methoxy-2-methylbenzoyl)hydrazine-1-carbonyl)-5-nitrophenyl)boronic acid;
(R)—N?-(2,2-dimethylpentan-3-yl)-3-methoxy-2-methyl-N?-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)benzohydrazide;
(R)-(3-(2-(3-borono-5-methylbenzoyl)-1-(2,2-dimethylpentan-3-yl)hydrazine-1-carbonyl)-5-methylphenyl)boronic acid;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
N?-(2,5-dimethoxybenzoyl)-N?-(2,2-dimethylhexan-3-yl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
(S)—N?-benzoyl-N?-(2,2-dimethylpentan-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
N-(tert-butyl)-N?-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-2, 6-dimethylisonicotinohydrazide;
(R)—N?-benzoyl-N?-(2,2-dimethylpentan-3-yl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbohydrazide;
N-(tert-butyl)-N?-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-2,6-dimethylisonicotinohydrazide;
N?-(3,5-bis(methyl-d3)benzoyl)-N?-(tert-butyl)-4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-2-hydroxy-9-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]oxaborepine-8-carbohydrazide;
N?-(3-chloro-5-methylbenzoyl)-1-hydroxy-6-methyl-N?-neopentyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-1-hydroxy-6-methyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
N?-(3,5-dimethylbenzoyl)-N?-(2,3-dimethylbutan-2-yl)-1-hydroxy-6-methyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
(S)—N?-(3,5-bis(methyl-d3)benzoyl)-N?-(2,2-dimethylpentan-3-yl)-1-hydroxy-6-methyl-3,4-dihydro-1H-benzo[c][1,5,2]dioxaborepine-7-carbohydrazide;
(R)—N?-(3,5-bis(methyl-d3)benzoyl)-N?-(2,2-dimethylpentan-3-yl)-4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbohydrazide;
N?-(3,5-dimethylbenzoyl)-N?-(1-fluorobutan-2-yl)-2-methyl-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylpentan-3-yl)hydrazine-1-carbonyl)-2-hydroxy-3-methylphenyl)boronic acid;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylpentan-3-yl)-2-fluoro-4-(methoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide;
(R)-(3-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylpentan-3-yl)hydrazine-1-carbonyl)-6-(ethoxymethyl)-2-fluorophenyl)boronic acid;
potassium (R)-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-3-fluorophenyl)trifluoroborate;
(R)—N?-(3,5-dimethylbenzoyl)-N?-(2,2-dimethylhexan-3-yl)-3-hydroxy-2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)benzohydrazide;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-3-hydroxy-2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)benzohydrazide;
(R)-(3-(4-(2-(3,5-dimethylbenzoyl)-2-(2,2-dimethylhexan-3-yl)hydrazine-1-carbonyl)-2-hydroxy-3-methylphenyl)propyl)boronic acid;
(3-(4-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-2-hydroxy-3-methylphenyl)propyl)boronic acid;
tert-butyl (2-(3-(2-(tert-butyl)-2-(3,5-dimethylbenzoyl)hydrazine-1-carbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)carbamate;
N?-(tert-butyl)-N?-(3,5-dimethylbenzoyl)-3-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzohydrazide; or

US Pat. No. 10,087,231

SUBSTITUTION MUTANT RECEPTORS AND THEIR USE IN AN ECDYSONE RECEPTOR-BASED INDUCIBLE GENE EXPRESSION SYSTEM

Intrexon Corporation, Bl...

1. A method of modulating the expression of a gene in a host cell comprising the steps of:(a) introducing into the host cell a gene expression modulation system; comprising:
(i) a first gene expression cassette comprising a polynucleotide that encodes a first polypeptide, comprising:
(1) a DNA-binding domain that recognizes a response element associated with a gene whose expression is to be modulated; and
(2) a first nuclear receptor ligand binding domain; and
(ii) a second gene expression cassette comprising a polynucleotide that encodes a second polypeptide, comprising:
(1) a transactivation domain; and
(2) a second nuclear receptor ligand binding domain,
wherein one of the first and second nuclear receptor ligand binding domains is a Group B nuclear receptor ligand binding domain comprising a substitution mutation at a position selected from the group consisting of
(1) 401 or 429 of SEQ ID NO:1,
(2) 401 and 429 of SEQ ID NO:1,
(3) 337, 462, 470, or 473 of SEQ ID NO:2,
(4) 450, 451, and 452 of SEQ ID NO:2,
(5) 455, 456, 457, and 458 of SEQ ID NO:2,
(6) 475, 476, 477, 478, and 479 of SEQ ID NO:2, and
(7) 481, 482, and 483 of SEQ ID NO:2; and
the other of said nuclear receptor ligand binding domains is a nuclear receptor ligand binding domain that dimerizes with said Group B nuclear receptor ligand binding domain, and
(b) introducing into the host cell a ligand; wherein the gene to be modulated is a component of a gene expression cassette comprising:
(i) a response element recognized by the DNA binding domain;
(ii) a promoter that is activated by the transactivation domain; and
(iii) a gene whose expression is to be modulated;
whereby upon introduction of the ligand into the host cell, expression of the gene of (b)(iii) is modulated.
US Pat. No. 10,131,916

REGULATORY ELEMENT FOR HETEROLOGOUS PROTEIN PRODUCTION IN THE FRUITING BODY OF FILAMENTOUS FUNGI

Intrexon Corporation, Bl...

1. A nucleotide sequence comprising the regulatory element set forth in SEQ ID NO:4 operably linked to a heterologous nucleotide sequence.
US Pat. No. 10,081,817

SITE-SPECIFIC SERINE RECOMBINASES AND METHODS OF THEIR USE

Intrexon Corporation, Bl...

1. A method for obtaining site-specific recombination in a eukaryotic cell, the method comprising: providing a eukaryotic cell that comprises a first recombination site and a second recombination site; a stop sequence positioned between said first recombination site and said second recombination site; contacting the first and second recombination sites with a prokaryotic recombinase polypeptide, resulting in recombination between the recombination sites and deletion of said stop sequence, wherein the recombinase polypeptide can mediate recombination between the first and second recombination sites, the first recombination site is a phage genomic recombination attachment site (attP) or a bacterial genomic recombination attachment site (attB), the second recombination site is attB or attP, and the recombinase is a Mycobacterium smegmatis Bxb1 phage recombinase, provided that when the first recombination attachment site is attB, the second recombination attachment site is attP, and when the first recombination attachment site is attP, the second recombination attachment site is attB.
US Pat. No. 10,190,124

SUBSTITUTION MUTANT RECEPTORS AND THEIR USE IN A NUCLEAR RECEPTOR-BASED INDUCIBLE GENE EXPRESSION SYSTEM

Intrexon Corporation, Bl...

1. A method of modulating the expression of a gene in a host cell comprising the steps of:a) introducing into the host cell a gene expression modulation system comprising
i) a first polynucleotide that encodes a first polypeptide comprising: (1) a DNA-binding domain that recognizes a response element associated with a gene whose expression is to be modulated; and 2) a first nuclear receptor ligand binding domain; and
ii) a second polynucleotide that encodes a second polypeptide comprising: 1) a transactivation domain; and 2) a second nuclear receptor ligand binding domain;
wherein one of the first or second nuclear receptor ligand binding domains comprises the amino acid sequence of SEQ ID NO: 1 wherein the amino acid sequence of SEQ ID NO: 1 has
a single amino acid substitution mutation at amino acid residue 20, 21, 48, 51, 58, 59, 61, 62, 92, 93, 95, 109, 120, 123, 125, 175, 223, 230, 234, or 238 of SEQ ID NO: 1;
b) introducing into the host cell a ligand;
wherein the gene to be modulated is a component of a gene expression cassette comprising:
i) a response element recognized by the DNA binding domain;
ii) a promoter that is activated by the transactivation domain; and
iii) a gene whose expression is to be modulated;
whereby upon introduction of the ligand into the host cell, expression of the gene of b) iii) is modulated.
US Pat. No. 10,314,926

THERAPEUTIC GENE-SWITCH CONSTRUCTS AND BIOREACTORS FOR THE EXPRESSION OF BIOTHERAPEUTIC MOLECULES, AND USES THEREOF

Intrexon Corporation, Bl...

1. A composition comprising: (1) a first polynucleotide encoding a gene switch, said gene switch comprising at least one transcription factor sequence, wherein said at least one transcription factor sequence encodes a ligand-dependent transcription factor in operable association with a hypoxia-inducible promoter, wherein the hypoxia-inducible promoter is a nucleic acid sequence at least 95% identical to the sequence from nucleotide 5446 to nucleotide 6315 of SEQ ID NO: 8, and(2) a second polynucleotide encoding a therapeutic polypeptide or therapeutic polynucleotide operably associated with a transcription factor-regulated promoter which is activated by said ligand-dependent transcription factor, wherein a ligand is capable of inducing expression of said therapeutic polypeptide or therapeutic polynucleotide.