Is there any disadvantage running a k64 as 4 single k16?
Ok you need 4 USB-cable but is there a speed decrease?
Not different. a k64 is just 4 k16, not cut up into 4 boards but kept as 1. They are connected between each board, not by usb but by a ribbon cable. All you will need is one usb cable, and i think you can connect/chain up to 8 boards in one ribbon cable or was it even 16 boards.
I would assume 8 of them, since that is 128 chips (USB hosts can accept 128 devices, and i would assume that the controller on the K16 either follows this rule or applies a similar rule to the chips it controls)
No, the USB protocol is not used when communicating with the chips. Each 16-chip board is shown as a single device when connected via USB. If you use the built-in chaining capability of the boards (which uses the i2c protocol, not USB) it still shows up as a single USB device, regardless of how many boards you have chained together.