Opinion ID: 209563
Heading Depth: 2
Heading Rank: 3

Heading: Perera at 2130.

Text: 2008-1119 7 See MEHL/Biophile Int'l Corp. v. Milgraum, 192 F.3d 1362, 1366 (Fed. Cir. 1999). His gnotobiotic pig model is therefore of little relevance to the obviousness inquiry. 9 Tzipori also argues that [a]n important aspect of the studies conducted by Tzipori was the use of a virulent strain of E. coli (the 0157:H7 strain) that infects and causes disease in humans. Krivan does not recognize that the strains of E. coli infect different hosts differently, and therefore that one cannot extrapolate from therapeutics in one species, such as cattle, for use in humans, even though the organism, E. coli, is the same, because there are differences in the toxins different strains produce, and between the host species, which are infected differently and have different diseases. Krivan, however, did recognize that differences existed among various strains of SLTproducing E. coli: The SLT-producing E. coli is a heterogeneous group of bacteria that belong to several different O:H:K serotypes, but they all have in common the ability to discharge one or more SLTs. Krivan at 1:43-46. Krivan also observed that SLTproducing E. coli cause a spectrum of diseases in humans from mild, uncomplicated diarrhea and bloody diarrhea to two life-threatening complications, hemorrhagic colitis and hemolytic uremic syndrome (HUS). Id. at 1:46-50. The Krivan patent recited that one object of its invention was to provide pharmaceutical compositions for the prevention, amelioration, or treatment of disease in a human or animal caused by an SLT. Id. at 6:3-6. 9 Furthermore, the Director questions the novelty of the gnotobiotic pig model. He points out that the declaration of Dr. Florian Gunzer—which Tzipori submitted during prosecution—indicates that Gunzer has worked since 1994 with the swine model for human infection with enteric pathogens. The Director also calls attention to an article published in 1989 entitled Nature and distribution of mucosal lesions associated with enteropathogenic and enterohemorrhagic Escherichia coli in piglets and the role of plasmid-mediated factors. Tzipori asserts the '958 application is entitled to a priority date of November 15, 1996. However, because Tzipori's claims do not cover the gnotobiotic pig model, we need not decide whether these two references disclose it. 2008-1119 8 Again, Tzipori's claims are no more specific than Krivan's patent on this point. Tzipori merely claims antibodies against a single subunit of the Shiga like toxin II produce[d] by Escherichia coli which causes hemolytic uremic syndrome to prevent or treat hemolytic uremic syndrome in a human. His claims do not specify that the antibodies bind specifically to SLT-II from the 0157:H7 strain of E. coli, 10 nor do they make clear how or whether the claimed antibodies differ from antibodies, such as those claimed by Krivan, which would be suitable for animal treatment. Furthermore, as the Director points out, Krivan discloses that in cows, SLTs do not cause the ill effects that they do in humans. Krivan at 8:11-14. And Williams recognizes different strains of E. coli infect hosts differently. Williams contains a table dividing various E. coli strains into four different categories: enterotoxigenic, enteropathogenic, enteroinvasive, and verotoxin-producing. Williams, Table 1. Tzipori is incorrect that the prior art does not disclose that different strains of E. coli infect different hosts differently. Tzipori argues that there is no teaching in Krivan of the need in treating humans to make human or humanized antibodies to SLT II. However, Tzipori appears to conflate using human(ized) antibodies with using antibodies to treat disease in humans. Human antibodies are antibodies made by humans. And while there may be reasons to 10 Even if Tzipori's claims were limited to antibodies against SLT-II made by the O157:H7 strain, it does not appear that using this strain for research was novel. Among the cited references in Perera are a pair entitled Two toxin-converting phages from Escherichia coli O157:H7 strain 933 encode antigenically distinct toxins with similar biological activities and Purification and some properties of a Verotoxin from Escherichia coli O157:H7 that is immunologically unrelated to Shiga toxin. Perera at 2131. Other scientists in this field clearly used the O157:H7 strain in research. The table in Williams dividing E. coli strains into four categories places strain O157:H7 into the verotoxin-producing category. Williams, Table 1. 2008-1119 9 prefer human antibodies for human treatment, Tzipori has not proven that non-human antibodies are necessarily ineffective for human treatment. Krivan notes that bovine IgG1 antibodies are relatively protease-resistant and highly homologous with human immunoglobulin G. Krivan at 3:32-34. And, as shown by claims 1, 17, and 18, Krivan claims bovine antibodies to SLT-II effective for treatment and prevention of human disease: 1. Purified IgG, comprising high titer, monospecific polyclonal antibodies to Shiga-like toxin (SLT) obtained by a process comprising the steps of: inoculating a bovine animal with a purified, active SLT, derived from E. coli and selected from the group consisting of SLT I, SLT II, SLT IIV and mixtures thereof; and recovering and purifying IgG from said animal after said animal has had an immune response to said purified active SLT. ... 17. A method for the passive immunization of a human or animal against SLT toxemia comprising administering to said human or animal a prophylactically effective amount of the purified IgG of claim 1 to prevent said toxemia. 18. A method for the treatment of SLT toxemia in a human or animal comprising administering a therapeutically effective amount of the purified IgG of claim 1 to treat said toxemia to said human or animal. Krivan's claims are presumed enabled, Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1355 (Fed. Cir. 2003), and Tzipori has not proven that they are not. Tzipori does point out correctly that two aspects of claim 26 are not present in Krivan, namely, that the antibodies are monoclonal and human or humanized. Krivan instead discloses monospecific, purified polyclonal antibodies. See, e.g., Krivan at 1:10-12. And rather than human or humanized antibodies, Krivan discloses 2008-1119 10 bovine antibodies. Id. at 15:30-19:16. Krivan thus contains disclosure corresponding to all aspects of Tzipori's claim 26 except monoclonal antibodies and human or humanized antibodies. 11 b. Disclosure of Queen Tzipori admits that Queen discloses a method of making humanized antibodies. See, e.g., Queen at 5:8-31, 6:21-25 (When combined into an intact antibody, the humanized light and heavy chains of the present invention will be substantially nonimmunogenic in humans and retain substantially the same affinity as the donor immunoglobulin to the antigen . . .). Tzipori instead argues that [t]hese techniques do not incorporate the use of an intact immune system to produce such humanized monoclonal antibodies. Tzipori does not explain why this is relevant; claim 26 does not require the antibodies be produced by an intact immune system. Given that the Board stated that the point of this argument of Tzipori’s was less than clear, we would have expected him to attempt to elucidate the issue on appeal. He has not, and we, like the Board, cannot accept the argument. Queen thus discloses one of the limitations of claim 26—human or humanized antibodies—not disclosed by Krivan. c. Engleman The Board mentioned in passing Engleman but did not discuss this reference in detail. Although the Board recited that the evidence on this record weighs in favor of the Examiner's conclusion that claim 26 is prima facie obvious over the combination of 11 The precise distinction between monoclonal antibodies and monospecific polyclonal antibodies is not critical to this appeal. For simplicity, we merely note that a group of monoclonal antibodies all bind to the same portion of the same antigen (and are identical), while a group of monospecific polyclonal antibodies all bind to different portions of the same antigen (and are not identical to each other). 2008-1119 11 Krivan, Perera, Williams, Queen and Engelman [sic], it does not appear that the Board actually relied on Engleman in upholding the obviousness rejection of claim 26. The content of Engleman is not pertinent to whether the invention of claim 26 would have been obvious, and that the Board mentioned it is harmless. 12 d. Disclosure of Perera Perera discloses the manufacture of murine hybridomas that made monoclonal antibodies which immunoprecipitated the isolated A subunit of SLT-II but not the B subunit. Perera at 2127. The E. coli strains that were the basis of the work in Perera were collected from humans with diarrhea, hemorrhagic colitis, or hemolytic-uremic syndrome, calves with diarrhea, and pigs with edema disease. Id. Perera also described these antibodies as neutralizing. Id. at 2130. Perera thus discloses the other limitation of claim 26—monoclonal antibodies—absent from Krivan. e. Disclosure of Williams The abstract of Williams begins, [t]he present invention includes methods for generating neutralizing antitoxin directed against verotoxins. '400 Pat. at [57]. Williams further recites that [t]hese antitoxins are useful in the treatment of humans and other animals intoxicated with at least one bacterial toxin, as well as for preventive treatment. Id. The disclosure of Williams is cumulative of references already discussed. f. Combination of References The combination of familiar elements according to known methods is likely— although not certain—to be obvious when it does no more than yield predictable 12 Engleman recounts the manufacture of a number of prior immunoglobulinsecreting human-human hybridomas. Engleman at 23-27. 2008-1119 12 results. KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1739 (2007). The level of skill in the art is important to obviousness analysis because a more skilled artisan will have more general knowledge on which to rely in combining teachings from multiple references. See DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1370 (Fed. Cir. 2006). Tzipori admits that the ordinary level of skill in the art is high, that of one with both (1) a doctorate or medical degree, and (2) experience in the treatment or research in infectious disease. All art cited by the Board discusses making antibodies to SLT-II, and each of the individual limitations of claim 26 were known to those of skill in the art at the time Tzipori filed the '958 application. Tzipori argues that one of ordinary skill in the art would not combine the teachings of the references because some of the references, such as Williams, are directed to using antibodies to detect SLT-II-producing E. coli, not treating infection by SLT-II-producing E. coli. The Board stated that combining Krivan, Queen, Williams, Perera, and Engleman would have been obvious to one of ordinary skill in the art (as did the examiner 13 ). The Board explained that a person of ordinary skill would have been motivated to combine Perera's antibodies, which are capable of neutralizing the toxicity of the SLT II toxin with the teachings of Krivan because the combination would result in a more effective therapy. The Board merely stated that the substantially decreased immunogenicity of Queen's method of humanizing antibodies would have motivated the combination with Krivan. It appears that the Board believed one of skill in 13 Many documents, including the examiner's final rejection of Tzipori's claims, do not appear in the parties' joint appendix despite being listed in its table of contents. A portion of the examiner's answer to the Board, however, does appear in the