Yes, you can use USB, but you can't simply copy the ISO to the flash drive. You can use a tool like rufus or the Microsoft USB tool, or you can do it from within Windows: Mount ISO. In Windows 8+, just double-click the ISO to mount it. In Windows 7, use something like MagicISO to mount it. Assume the ISO mounts as drive E:. From the Command Prompt: diskpart select disk 1cleancreate partition primaryactiveformat fs=fat32 quickassignexit xcopy E:\*.* /s/e/f F: exit This assumes that your flash drive is assigned the drive letter F:. This also assumes that disk 1 is your flash drive. In diskpart, type "list disk" to make sure you "select" the right "disk". The 5GB ISO is not a standard installation ISO and probably includes extras. The standard ISO will be under 4GB. Most current DVD drives will read DL DVD's ... you could also use that. OR you can install over the network. 
I have a PowerEdge T410 server that I had purchased in July 2009.  I want to change the operating system from SBS 2008 to Windows Server 2012 R2.  Since the iso file for the new operating system is about 5.1 GB, I won't be able to use a DVD to install the new operating system.  I have created the iso file on a USB drive.  Will I be able to boot from and install Windows Server 2012 R2 using my flash drive?  If yes, what steps should I follow? Thanks for your assistance.  i would like to work on this project over the upcoming long weekend. 
Booting a T410 using a USB drive