circumstances. The industry has slowly recovered, by focusing on pharming in simple plants grown in bioreactors and on growing GM crops in greenhouses. Some companies and academic groups have continued with open-field trials of GM crops that produce drugs. In 2006 Dow AgroSciences received USDA approval to market a vaccine for poultry against Newcastle disease, produced in plant cell culture – the first plant-produced vaccine approved in the U.S. In mammals Historical development Milk is presently the most mature system to produce recombinant proteins from transgenic organisms. Blood, egg white, seminal plasma, and urine are other theoretically possible systems, but all have drawbacks. Blood, for instance, as of 2012 cannot store high levels of stable recombinant proteins, and biologically active proteins in blood may alter the health of the animals. Expression in the milk of a mammal, such as a cow, sheep, or goat, is a common application, as milk production is plentiful and purification from milk is relatively easy. Hamsters and rabbits have also been used in preliminary studies because of their faster breeding. One approach to this technology is the creation of a transgenic mammal that can produce the biopharmaceutical in its milk (or blood or urine). Once an animal is produced, typically using the pronuclear microinjection method, it becomes efficacious to use cloning technology to create additional offspring that carry the favorable modified genome. In February 2009 the US FDA granted marketing approval for the first drug to be produced in genetically modified livestock. The drug is called ATryn, which is antithrombin protein purified from the milk of genetically modified goats. Marketing permission was granted by the European Medicines Agency in August 2006. Patentability issues As indicated above, some mammals typically used for food production (such as goats, sheep, pigs, and cows) have been modified to produce non-food products, a practice sometimes called pharming. Use of genetically modified goats has been approved by the FDA and EMA to produce ATryn, i.e. recombinant antithrombin, an anticoagulant protein drug. These products "produced by turning animals into drug-manufacturing 'machines' by genetically modifying them" are sometimes termed biopharmaceuticals. The patentability of such biopharmaceuticals and their process of manufacture is uncertain. Probably, the biopharmaceuticals themselves so made are unpatentable, assuming that they are chemically identical to the preexisting drugs that they imitate. Several 19th century United States Supreme Court decisions hold that a previously known natural product manufactured by artificial means cannot