# US 10,478,439 B2 · Use of inhibitors of bruton's tyrosine kinase (Btk)

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- Number: US 10,478,439 B2
- Document ID: US10478439B2
- Status: Granted
- Kind: B2
- Application number: 15/965,114
- Filed: 2018-04-27
- Published: 2018-09-13
- Granted: 2019-11-19
- Earliest claimed: 2010-06-03
- Assignees: Pharmacyclics, Inc.
- Applicants: Pharmacyclics LLC
- Inventors: Lee Honigberg; David J. Loury
- Web page: https://patentgrep.com/patent/US10478439B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0031: {Rectum, anus}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/007: {Pulmonary tract; Aromatherapy}
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 31/195: having an amino group
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/606: having amino groups
- A61K 31/664: Amides of phosphorus acids
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/69: Boron compounds
- A61K 31/7032: attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/39533: {against materials from animals}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
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- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 487/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed herein are methods for treating a cancer comprising: a. administering a Btk inhibitor to a subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping; b. determining the expression profile of one or more biomarkers from one or more subpopulation of lymphocytes; and c. administering a second agent based on the determined expression profile.

## Claims

### Claim 1

A method of inhibiting proliferation and survival of activated B-cells in a human subject suffering from a B-cell proliferative disorder, comprising: orally administering to the human subject suffering from a B-cell proliferative disorder a therapeutically effective amount of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13), on a continuous once-daily regimen until progression of the disorder or unacceptable toxicity,
wherein said administration of the therapeutically effective amount results in an AUC(0-24) of >about 100 ng*h/ml; and
wherein said administration of the therapeutically effective amount results in >90% of the Btk active sites in the peripheral blood mononuclear cells of the human subject being occupied by Compound 13 twenty-four hours following said administration.

### Claim 2 (depends on 1)

The method of claim 1, wherein the once daily regimen is continued for at least 6 months.

### Claim 3 (depends on 1)

The method of claim 1, wherein the B-cell proliferative disorder is a hematological malignancy.

### Claim 4 (depends on 3)

The method of claim 3, wherein the hematological malignancy is a non-Hodgkin lymphoma.

### Claim 5 (depends on 3)

The method of claim 3, wherein the hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia.

### Claim 6 (depends on 3)

The method of claim 3, wherein the hematological malignancy is selected from the group consisting of mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, and ABC-diffuse large B-cell lymphoma.

### Claim 7 (depends on 1)

The method of claim 1, wherein the human subject has previously undergone a bone marrow transplant.

### Claim 8 (depends on 7)

The method of claim 7, wherein the human subject has previously undergone an autologous bone marrow transplant.

### Claim 9 (depends on 3)

The method of claim 3, wherein the hematological malignancy is relapsed or refractory.

### Claim 10

A method of inhibiting proliferation and survival of activated B-cells in a human subject suffering from a B-cell proliferative disorder, comprising:
orally administering to the human subject suffering from a B-cell proliferative disorder a therapeutically effective amount of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13),
wherein the therapeutically effective amount of Compound 13 is an amount that results in >90% of the Btk active sites in the peripheral blood mononuclear cells of the human subject being occupied by Compound 13 twenty-four hours following said administration, and
wherein proliferation and survival of the activated B-cells in the human are inhibited.

### Claim 11 (depends on 10)

The method of claim 10, wherein the B-cell proliferative disorder is a hematological malignancy.

### Claim 12 (depends on 11)

The method of claim 11, wherein the hematological malignancy is a non-Hodgkin lymphoma.

### Claim 13 (depends on 11)

The method of claim 11, wherein the hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic lymphoma, and Waldenstrom's macroglobulinemia.

### Claim 14 (depends on 11)

The method of claim 11, wherein the hematological malignancy is selected from the group consisting of mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, and ABC-diffuse large B-cell lymphoma.

### Claim 15 (depends on 10)

The method of claim 10, wherein the human subject has previously undergone a bone marrow transplant.

### Claim 16 (depends on 15)

The method of claim 15, wherein the human subject has previously undergone an autologous bone marrow transplant.

### Claim 17 (depends on 11)

The method of claim 11, wherein the hematological malignancy is relapsed or refractory.