# US 10,478,400 B2 · Immediate-release tablets containing combimetinib and methods of making and using the same

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- Number: US 10,478,400 B2
- Document ID: US10478400B2
- Status: Granted
- Kind: B2
- Application number: 15/852,125
- Filed: 2017-12-22
- Published: 2018-05-03
- Granted: 2019-11-19
- Earliest claimed: 2015-06-30
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Sanjeev Kothari; Priscilla Mantik; Alexander Mauerer; Hamid Rezaei
- Web page: https://patentgrep.com/patent/US10478400B2

## CPC

- A61K 9/2095: {Tabletting processes}
- A61J 3/10: into the form of compressed tablets (tablet presses B30B11/00)
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- 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 31/4523: containing further heterocyclic ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)
- A61J: CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates generally to rapid-release pharmaceutical dosage unit tablets containing a drug that is an inhibitor of the mitogen-activated protein kinase enzyme, a filler and a disintegrant, and to processes for forming the tablets. More specifically, the present disclosure relates to pharmaceutical dosage unit tablets containing cobimetinib, a least one filler, at least one lubricant and at least one disintegrant, and to methods for preparing the tablets from granules formed by dry granulation.

## Claims

### Claim 1

A process for preparing a pharmaceutical dosage unit tablet core, the process comprising:
(1) blending a particulate pharmaceutical active drug, an intragranular filler, an intragranular disintegrant and an intragranular lubricant to form a pre-blend, wherein the particulate pharmaceutical drug active has a particle size D[v, 0.5] of from about 25 μm to about 65 μm, from about 25 μm to about 50 μm, or from about 30 μm to about 40 μm;
(2) compacting the pre-blend by application of a compaction force of from about 1 kN/cm to about 8 kN/cm, from about 2 kN/cm to about 5 kN/cm, or from about 2 kN/cm to about 4 kN/cm;
(3) milling and screening the compacted pre-blend to form granules; and
(4) tableting the granules by application of a tableting compression force of from about 5 kN to about 20 kN, from about 14 kN to about 19 kN, from about 14 kN to about 18 kN, or from about 8 kN to about 13 kN to form the pharmaceutical dosage unit tablet core, wherein the particulate pharmaceutical active drug is cobimetinib hemifumarate polymorph Form A.

### Claim 2 (depends on 1)

The process of claim 1, wherein the pharmaceutical active drug has a particle size D[v, 0.9] of from about 45 μm to about 500 μm, from about 45 μm to about 400 μm, from about 45 μm to about 300 μm, from about 45 μm to about 200 μm, from about 45 μm to about 100 μm, from about 50 μm to about 60 μm, from about 65 μm to about 100 μm, from about 45 μm to about 80 μm, or from about 75 μm to about 100 μm.

### Claim 3 (depends on 1)

The process of claim 1, further comprising applying a film coating on the surface of the pharmaceutical dosage unit tablet core.

### Claim 4 (depends on 1)

The process of claim 1, further comprising, prior to tableting, blending the granules with extragranular disintegrant and extragranular lubricant to form a final blend, wherein the final blend is tableted.

### Claim 5 (depends on 1)

The process of claim 1, wherein the total lubricant content based on pharmaceutical dosage unit tablet core weight is from about 0.5 wt. % to about 5 wt. %, from about 0.5 wt. % to about 3 wt. %, from about 1 wt. % to about 3 wt. %, from about 1 wt. % to about 2.5 wt. %, or from about 1.5 wt. % to about 2 wt. %.

### Claim 6 (depends on 4)

The process of claim 4, wherein
(1) the intragranular lubricant content based on tablet core weight is from about 0.1 wt. % to about 1 wt. %, from about 0.2 wt. % to about 0.75 wt. %, or from about 0.25 wt. % to about 5 wt. %; and
(2) the extragranular lubricant content based on tablet core weight is from about 0.5 wt. % to about 2.5 wt. %, from about 0.75 wt. % to about 2.25 wt. %, from about 0.75 wt. % to about 2 wt. %, from about 1 wt. % to about 1.75 wt. %, or from about 1.25 wt. % to about 1.5 wt. %.

### Claim 7 (depends on 1)

The process of claim 1, wherein the total disintegrant content based on pharmaceutical dosage unit tablet core weight is from about 2 wt. % to about 7 wt. %, from about 2 wt. % to about 6 wt. %, from about 2 wt. % to about 5 wt. %, from about 3 wt. % to about 6 wt. %, or from about 3 wt. % to about 5 wt. %.

### Claim 8 (depends on 1)

The process of claim 1, wherein the pharmaceutical dosage unit tablet core comprises intragranular disintegrant and extragranular disintegrant, wherein
(1) the intragranular disintegrant content based on tablet core weight is from about 0.1 wt. % to about 3 wt. %, from about 0.25 wt. % to about 2.5 wt. %, from about 0.25 wt. % to about 2 wt. %, from about 0.25 wt. % to about 1.5 wt. %, from about 0.25 wt. % to about 1 wt. %, from about 0.5 wt. % to about 3 wt. %, from about 0.5 wt. % to about 2 wt. %, from about 0.5 wt. % to about 1.5 wt. %, from about 1 wt. % to about 3 wt. %, or from about 1.5 wt. % to about 2.5 wt. %; and
(2) the extragranular disintegrant content based on tablet core weight is from about 0.5 wt. % to about 3 wt. %, from about 1 wt. % to about 3 wt. %, from about 1.25 wt. % to about 3 wt. %, from about 1.25 wt. % to about 2.5 wt. %, from about 1.25 wt. % to about 2 wt. %, from about 1.25 wt. % to about 1.5 wt. %, from about 1.5 wt. % to about 3 wt. %, or from about 1.5 wt. % to about 2.5 wt. %.

### Claim 9 (depends on 8)

The process of claim 8, wherein the weight ratio of the intragranular disintegrant to the extragranular disintegrant is about 1:5, about 1:3, about 1:1, or about 2:1.

### Claim 10 (depends on 1)

The process of claim 1, wherein the total filler content based on pharmaceutical dosage unit tablet core weight is from about 60 wt. % to about 78 wt. %, from about 65 wt. % to about 78 wt. %, from about 65 wt. % to about 77 wt. %, from about 70 wt. % to about 77 wt. %, or from about 71 wt. % to about 75 wt. %.

### Claim 11 (depends on 1)

The process of claim 1, wherein the bulk density of the final blend is from about 0.4 g/mL to about 0.75 g/mL, from about 0.45 g/mL to about 0.7 g/mL, or from about 0.5 g/mL to about 0.65 g/mL.

### Claim 12 (depends on 1)

The process of claim 1, wherein the screen size is from about 0.5 mm to about 2.0 mm, from about 0.5 mm to about 1.5 mm, from about 0.5 mm to about 1.25 mm, from about 0.75 mm to about 2.0 mm, from about 0.75 mm to about 1.5 mm, from about 0.75 mm to about 1.25 mm, or about 1 mm.

### Claim 13 (depends on 1)

The process of claim 1, wherein the filler comprises (1) lactose or (2) lactose and microcrystalline cellulose wherein the weight ratio of lactose to microcrystalline cellulose is from about 1:1.5 to about 4:1, from about 1.25 to about 4:1, from about 1:1 to about 4:1, from about 1:1 to about 3:1, from about 1.5:1 to about 3:1, or from about 2:1 to about 2.5:1.

### Claim 14 (depends on 1)

The process of claim 1, wherein the disintegrant comprises sodium starch glycolate, croscarmellose sodium, or a combination thereof.

### Claim 15 (depends on 1)

The process of claim 1, wherein the lubricant comprises magnesium stearate, sodium stearyl fumarate, or a combination thereof.

### Claim 16 (depends on 1)

The process of claim 1, wherein the pre-blend further comprises a binder at a total binder content based on pharmaceutical dosage unit tablet core weight of from about 1 wt. % to about 10 wt. %, from about 1 wt. % to about 7 wt. %, from about 1 wt. % to about 6 wt. %, or from about 1 wt. % to about 5 wt. %.

### Claim 17 (depends on 16)

The process of claim 16, wherein the binder comprises povidone, copovidone, pregelatinized starch, hydroxypropyl methylcellulose, or a combination thereof.

### Claim 18 (depends on 1)

The process of claim 1, wherein the particulate pharmaceutical active drug content based on the weight of the tablet core is at least 5 wt. %, from about 15 wt. % to about 25 wt. %, or about 20 wt. %.

### Claim 19 (depends on 1)

The process of claim 1, wherein the pharmaceutical dosage unit tablet core comprises:
(1) from 17.6 wt. % to 19.4 wt. % cobimetinib hemifumarate polymorph Form A;
(2) from 43.3 wt. % to 47.9 wt. % microcrystalline cellulose;
(3) from 28.9 wt. % to 31.9 wt. % lactose monohydrate;
(4) from 3.8 wt. % to 4.2 wt. % croscarmellose sodium; and
(5) from 1.4 wt. % to 1.6 wt. % magnesium stearate.

### Claim 20 (depends on 1)

The process of claim 1, wherein the pre-blend is compacted between at least two rotating rolls having a gap width of from about 2 mm to about 5 mm, from about 2 mm to about 4 mm, from about 3 mm to about 5 mm, or from about 4 mm to about 5 mm to form a ribbon, wherein the ribbon is milled and screened to form granules.

### Claim 21 (depends on 20)

The process of claim 20, wherein the ribbon has an at-gap density selected from:
from about 0.85 g/mL to about 0.95 g/mL from about 0.9 g/mL to about 0.95 g/mL, from about 0.95 g/mL to about 1.1 g/mL, from about 0.95 g/mL to about 1.05 g/mL, from about 1 g/mL to about 1.10 g/mL, from about 1 g/mL to about 1.05 g/mL, from about 1.1 g/mL to about 1.3 g/mL, from about 1.1 g/mL to about 1.25 g/mL, from about 1.1 g/mL to about 1.2 g/mL, from about 1.1 g/mL to about 1.15 g/mL, from about 1.15 g/mL to about 1.3 g/mL, from about 1.15 g/mL to about 1.25 g/mL, and from about 1.15 g/mL to about 1.2 g/mL.

### Claim 22 (depends on 20)

The process of claim 20, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 27 μm to about 37 μm, the roller compaction gap force is about 2 kN/cm, and the gap width is about 5 mm.

### Claim 23 (depends on 20)

The process of claim 20, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 38 μm to about 65 μm, the roller compaction gap force is from about 2 kN/cm to about 4 kN/cm, and the gap width is from about 4 mm to about 5 mm.

### Claim 24

A pharmaceutical dosage unit tablet core, the tablet core comprising:
(1) about 5 wt. % or more of a particulate pharmaceutical active drug;
(2) a lubricant at a content based on the pharmaceutical dosage unit tablet core weight of from about 0.5 wt. % to about 5 wt. %, from about 0.5 wt. % to about 3 wt. %, from about 1 wt. % to about 3 wt. %, from about 1 wt. % to about 2.5 wt. %, or from about 1.5 wt. % to about 2 wt. %;
(3) a disintegrant at a content based on the pharmaceutical dosage unit tablet core weight of from about 2 wt. % to about 7 wt. %, from about 2 wt. % to about 6 wt. %, from about 2 wt. % to about 5 wt. %, from about 3 wt. % to about 6 wt. %, or from about 3 wt. % to about 5 wt. %;
(4) a filler at a content based on the pharmaceutical dosage unit tablet core weight of from about 60 wt. % to about 78 wt. %, from about 65 wt. % to about 78 wt. %, from about 65 wt. % to about 77 wt. %, from about 70 wt. % to about 77 wt. %, or from about 71 wt. % to about 75 wt. %; and
(5) optionally, up to 10 wt. % of a binder,
wherein the particulate pharmaceutical active drug is cobimetinib hemifumarate polymorph Form A.

### Claim 25 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug content based on the weight of the tablet core is from about 15 wt. % to about 25 wt. %, or about 20 wt. %.

### Claim 26 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 25 μm to about 65 μm, from about 25 μm to about 50 μm, or from about 30 μm to about 40 μm.

### Claim 27 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 45 μm to about 500 μm, from about 45 μm to about 400 μm, from about 45 μm to about 300 μm, from about 45 μm to about 200 μm, from about 44 μm to about 100 μm, from about 50 μm to about 60 μm, from about 65 μm to about 100 μm, from about 45 μm to about 80 μm, or from about 75 μm to about 100 μm.

### Claim 28 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein said tablet core comprises intragranular lubricant and extragranular lubricant, wherein:
(1) the intragranular lubricant content based on said tablet core weight is from about 0.1 wt. % to about 1 wt. %, from about 0.2 wt. % to about 0.75 wt. %, or from about 0.25 wt. % to about 5 wt. %; and
(2) the extragranular lubricant content based on said tablet core weight is from about 0.5 wt. % to about 2.5 wt. %, from about 0.75 wt. % to about 2.25 wt. %, from about 0.75 wt. % to about 2 wt. %, from about 1 wt. % to about 1.75 wt. %, or from about 1.25 wt. % to about 1.5 wt. %.

### Claim 29 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the lubricant comprises magnesium stearate, sodium stearyl fumarate, or a combination thereof.

### Claim 30 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein said tablet core comprises intragranular disintegrant and extragranular disintegrant, wherein:
(1) the intragranular disintegrant content based on said tablet core weight is from about 0.1 wt. % to about 3 wt. %, from about 0.25 wt. % to about 2.5 wt. %, from about 0.25 wt. % to about 2 wt. %, from about 0.25 wt. % to about 1.5 wt. %, from about 0.25 wt. % to about 1 wt. %, from about 0.5 wt. % to about 3 wt. %, from about 0.5 wt. % to about 2 wt. %, from about 0.5 wt. % to about 1.5 wt. %, from about 1 wt. % to about 3 wt. %, or from about 1.5 wt. % to about 2.5 wt. %; and
(2) the extragranular disintegrant content based on said tablet core weight is from about 0.5 wt. % to about 3 wt. %, from about 1 wt. % to about 3 wt. %, from about 1.25 wt. % to about 3 wt. %, from about 1.25 wt. % to about 2.5 wt. %, from about 1.25 wt. % to about 2 wt. %, from about 1.25 wt. % to about 1.5 wt. %, from about 1.5 wt. % to about 3 wt. %, or from about 1.5 wt. % to about 2.5 wt. %.

### Claim 31 (depends on 30)

The pharmaceutical dosage unit tablet core of claim 30, wherein the weight ratio of the intragranular disintegrant to the extragranular disintegrant is about 1:5, about 1:3, about 1:1, or about 2:1.

### Claim 32 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the disintegrant comprises sodium starch glycolate, croscarmellose sodium, or a combination thereof.

### Claim 33 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the filler comprises (1) lactose or (2) lactose and microcrystalline cellulose, wherein the weight ratio of lactose to microcrystalline cellulose is from about 1:1.5 to about 4:1, from about 1:1.25 to about 4:1, from about 1:1 to about 4:1 from about 1:1 to about 3:1, from about 1.5:1 to about 3:1, or from about 2:1 to about 2.5:1.

### Claim 34 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 25 μm to about 40 μm.

### Claim 35 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the particulate pharmaceutical active drug has a particle size D[v, 0.5] of from about 40 μm to about 65 μm.

### Claim 36 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein the tablet core further comprises a binder at a total binder content based on said tablet core weight of from about 1 wt. % to about 10 wt. %, from about 1 wt. % to about 7 wt. %, from about 1 wt. % to about 6 wt. %, or from about 1 wt. % to about 5 wt. %.

### Claim 37 (depends on 36)

The pharmaceutical dosage unit tablet core of claim 36, wherein the binder comprises povidone, copovidone, pregelatinized starch, hydroxypropyl methylcellulose, or a combination thereof.

### Claim 38 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, wherein said tablet core comprises:
(1) from about 17.6 wt. % to about 19.4 wt. % cobimetinib hemifumarate polymorph Form A;
(2) from about 43.3 wt. % to about 47.9 wt. % microcrystalline cellulose;
(3) from about 28.9 wt. % to about 31.9 wt. % lactose monohydrate;
(4) from about 3.8 wt. % to about 4.2 wt. % croscarmellose sodium; and
(5) from about 1.4 wt. % to about 1.6 wt. % magnesium stearate.

### Claim 39 (depends on 24)

The pharmaceutical dosage unit tablet core of claim 24, further comprising a film-coating on the surface of said tablet core, wherein the coated pharmaceutical dosage unit tablet core is characterized by:
(1) a dissolution profile such that 80% of the tablet dissolves in 20 minutes;
(2) a minimum hardness of 45 N;
(3) a disintegration time of no more than 300; and
(4) an abrasion of less than 1.0%.

### Claim 40 (depends on 39)

The pharmaceutical dosage unit tablet core of claim 39, wherein the coated pharmaceutical dosage unit tablet core comprises from about 2 wt. % to about 6 wt. % or from about 3 wt. % to about 5 wt. % of the film-coating based on the weight of said tablet core, and, wherein the film-coating comprises:
(1) from about 38 wt. % to about 42 wt. % polyvinyl alcohol;
(2) from about 23.8 wt. % to about 26.3 wt. % titanium dioxide;
(3) from about 19.2 wt. % to about 21.2 wt. % macrogol/PEG3350; and
(4) from about 14.1 wt. % to about 15.5 wt. % talc.

### Claim 41 (depends on 39)

A pharmaceutical product comprising:
(1) a first tablet comprising the coated pharmaceutical dosage unit tablet core of claim 39; and
(2) a second tablet comprising propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (vemurafenib), or a pharmaceutically acceptable salt thereof.

### Claim 42 (depends on 41)

The pharmaceutical product of claim 41, wherein the first tablet comprises 20 mg cobimetinib, 40 mg cobimetinib, or 60 mg cobimetinib.

### Claim 43 (depends on 41)

A method of treating BRAFV600 mutation-positive unresectable or metastatic melanoma comprising administering to a patient a therapeutically effective amount of the pharmaceutical product of claim 41.

### Claim 44 (depends on 43)

The method of claim 43, wherein one or more first tablets are administered to provide a total dose of 60 mg cobimetinib, on days 1-21 of a 28 day cycle, and wherein one or more second tablets are administered to provide a total dose of 960 mg vemurafenib, twice daily each day of the 28 day cycle.

### Claim 45 (depends on 43)

The method of claim 43, wherein the first tablet is administered sequentially with the second tablet.

### Claim 46 (depends on 43)

The method of claim 43, wherein the first tablet is administered concurrently with the second tablet.

### Claim 47 (depends on 43)

The method of claim 43, wherein the unresectable or metastatic melanoma is BRAFV600E mutation-positive melanoma.

### Claim 48 (depends on 43)

The method of claim 43, wherein the unresectable or metastatic melanoma is metastatic melanoma.

### Claim 49 (depends on 43)

The method of claim 43, wherein the BRAFV600 mutation-positive unresectable or metastatic melanoma has not been previously treated.

### Claim 50

A pharmaceutical dosage unit tablet core, the tablet core comprising:
(1) 18.5 wt. % cobimetinib hemifumarate polymorph Form A;
(2) 45.6 wt. % microcrystalline cellulose;
(3) 30.4 wt. % lactose monohydrate;
(4) 4 wt. % croscarmellose sodium; and
(5) 1.5 wt. % magnesium stearate.

### Claim 51 (depends on 50)

The pharmaceutical dosage unit tablet core of claim 50, comprising:
(1) 2 wt. % intragranular croscarmellose sodium and 2 wt. % extragranular croscarmellose sodium; and
(2) 0.25 wt. % intragranular magnesium stearate and 1.25 wt. % extragranular magnesium stearate.

### Claim 52 (depends on 50)

The pharmaceutical dosage unit tablet core of claim 50, wherein the microcrystalline cellulose has a bulk density from 0.26 to 0.31 g/mL, a degree of polymerization of not more than 350, and a particle size measured by air jet of not more than 1 wt. %+60 mesh (250 microns) and not more than 30 wt. %+200 mesh (75 microns).

### Claim 53

A coated pharmaceutical dosage unit tablet core, the coated tablet comprising:
(1) 17.79 wt. % cobimetinib hemifumarate polymorph Form A;
(2) 43.85 wt. % microcrystalline cellulose;
(3) 29.23 wt. % lactose monohydrate;
(4) 3.84 wt. % croscarmellose sodium;
(5) 1.45 wt. % magnesium stearate; and
(6) 3.85 wt. % film coating.

### Claim 54 (depends on 53)

The coated pharmaceutical dosage unit tablet of claim 53, comprising:
(1) 1.92 wt. % intragranular croscarmellose sodium and 1.92 wt. % extragranular croscarmellose sodium; and
(2) 0.24 wt. % intragranular magnesium stearate and 1.21 wt. % extragranular magnesium stearate.

### Claim 55 (depends on 53)

The coated pharmaceutical dosage unit tablet of claim 53, wherein the film coating comprises:
(1) 40 wt. % polyvinyl alcohol;
(2) 25 wt. % titanium dioxide;
(3) 20.2 wt. % macrogol/PEG 3350; and
(4) 14.8 wt. % talc.

### Claim 56 (depends on 53)

A pharmaceutical product comprising:
(1) a first tablet comprising the coated tablet of claim 53; and
(2) a second tablet comprising propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (vemurafenib), or a pharmaceutically acceptable salt thereof.

### Claim 57 (depends on 56)

The pharmaceutical product of claim 56, wherein the first tablet comprises 20 mg cobimetinib, 40 mg cobimetinib, or 60 mg cobimetinib.

### Claim 58 (depends on 56)

A method of treating BRAFV600 mutation-positive unresectable or metastatic melanoma comprising administering to a patient a therapeutically effective amount of the pharmaceutical product of claim 56.

### Claim 59 (depends on 58)

The method of claim 58, wherein one or more first tablets are administered to provide a total dose of 60 mg cobimetinib, on days 1-21 of a 28 day cycle, and wherein one or more second tablets are administered to provide a total dose of 960 mg vemurafenib, twice daily each day of the 28 day cycle.

### Claim 60 (depends on 58)

The method of claim 58, wherein the first tablet is administered sequentially with the second tablet.

### Claim 61 (depends on 58)

The method of claim 58, wherein the first tablet is administered concurrently with the second tablet.

### Claim 62 (depends on 58)

The method of claim 58, wherein the unresectable or metastatic melanoma is BRAFV600E mutation-positive melanoma.

### Claim 63 (depends on 58)

The method of claim 58, wherein the unresectable or metastatic melanoma is metastatic melanoma.

### Claim 64 (depends on 58)

The method of claim 58, wherein the BRAFV600 mutation-positive unresectable or metastatic melanoma has not been previously treated.

### Claim 65

A process for preparing a coated pharmaceutical dosage unit tablet, the process comprising the following steps:
(1) combining a particulate filler component, a first particulate disintegrant component and cobimetinib hemifumarate polymorph Form A in a blender and admixing said components to form a primary pre-blend;
(2) combining a particulate first lubricant component with the primary pre-blend in a blender and admixing said first lubricant component and primary pre-blend to form a finished preblend;
(3) dry granulating the finished pre-blend to form granules;
(4) combining the granules and a second particulate disintegrant component in a blender and admixing said granules and disintegrant component to form a primary final blend;
(5) combining a second particulate lubricant component and the primary final blend in a blender and admixing said second lubricant component and primary final blend to form a finished final blend;
(6) tableting the finished final blend to form tablet cores; and
(7) coating the tablet cores.

### Claim 66 (depends on 65)

The process of claim 65, further comprising suspending a film-coat solid mixture in water to form a coating slurry mixture and coating the tablet cores with the coating mixture slurry.

### Claim 67 (depends on 65)

The process of claim 65, wherein:
(1) the particulate filler component is selected from lactose, microcrystalline cellulose, and combinations thereof;
(2) the first particulate disintegrant and second particulate disintegrant are each selected from sodium starch glycolate, croscarmellose sodium, and combinations thereof;
and
(3) first lubricant component and the second lubricant component are each selected from magnesium stearate, sodium stearyl fumarate, and combinations thereof.