Opinion ID: 477880
Heading Depth: 2
Heading Rank: 3

Heading: Obviousness, 35 U.S.C. Sec. 103

Text: 77 A section 103 obviousness determination--whether the claimed invention would have been (not would be as the court repeatedly stated because Monoclonal's pretrial papers used that improper language) obvious at the time the invention was made is reviewed free of the clearly erroneous standard although the underlying factual inquiries--scope and content of the prior art, level of ordinary skill in the art, 3 and differences between the prior art and the claimed invention--integral parts of the subjective determination involved in Sec. 103, are reviewed under that standard. Objective evidence such as commercial success, failure of others, long-felt need, and unexpected results must be considered before a conclusion on obviousness is reached and is not merely icing on the cake, as the district court stated at trial. See Lindemann, supra, 730 F.2d at 1461, 221 USPQ at 488; Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed.Cir.1983); Kansas Jack, Inc. v. Kuhn, 719 F.2d 1144, 219 USPQ 856 (Fed.Cir.1983); W.L. Gore & Associates v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303, 314 (Fed.Cir.1983). 78
Monoclonal Antibodies 79 Before discussing the more pertinent references in this case--the Oi/Herzenberg and Frankel works--we cull the other prior art references relied on by the trial court. 80 First, the latest four of the eight articles that the court stated were of the utmost importance because they predicted that the breakthrough in production of monoclonal antibodies by Kohler and Milstein would lead to widespread use of monoclonal antibodies in immunoassays are neither 102(a)/103 nor 102(b)/103 prior art because they are dated between late 1979 and March 6, 1980, well after the date of conception and within one year of the filing date of the '110 patent. 81 The earliest four of the eight articles, on the other hand, although clearly prior art, discuss production of monoclonal antibodies--admittedly old after Kohler and Milstein showed how to produce them--but none discloses sandwich assays. At most, these articles are invitations to try monoclonal antibodies in immunoassays but do not suggest how that end might be accomplished. To the extent the district court relied upon these references to establish that it would have been obvious to try monoclonal antibodies of 10 8 liters/mole affinity in a sandwich immunoassay that detects the presence of or quantitates antigen, the court was in error. See Jones v. Hardy, 727 F.2d 1524, 1530, 220 USPQ 1021, 1026 (Fed.Cir.1984) (Obvious to try is improper consideration in adjudicating obviousness issue). 4 82
83 Jeong, Piasio, and Schurr Patents Considered by 84 the Examiner 85 The district court's finding that Kohler and Milstein developed a method for producing monoclonal antibodies in vitro is correct, but that finding proves no more; although it made possible all later work in that it paved the way for a supply of monoclonal antibodies, it indisputably does not suggest using monoclonal antibodies in a sandwich assay in accordance with the invention claimed in the '110 patent. 86 The Cuello reference discloses monoclonal antibodies but not in a sandwich assay. The competitive assay in Cuello, moreover, uses only one monoclonal antibody and thus in no way suggests the claimed invention wherein a ternary complex of two monoclonal antibodies and an antigen form a sandwich. Furthermore, the court did not explain how this art, by itself or in combination with any of the other art, suggests the claimed subject matter and thus why that combination would have been obvious. We are of the opinion that it does not. 87 The district court correctly found that the use of polyclonal antibodies in sandwich assays was well known. The Jeong patent discloses the use of polyclonal antibodies in a simultaneous sandwich assay, with no suggestion that monoclonal antibodies be so used. It is prior art by virtue of Sec. 102(e), application for the patent having been filed September 5, 1978, its effective date as a reference. The Piasio patent, disclosing a reverse sandwich assay using polyclonal antibodies, and Schurrs, disclosing a forward sandwich assay using the same, both Sec. 102(a) prior art, are likewise devoid of any suggestion that monoclonal antibodies can be used in a similar fashion. 88
89 Clearly, the most pertinent items of prior art not cited by the examiner are the Oi/Herzenberg work, as described in section A, 3, supra, and the Frankel article. As stated in the discussion of Prior Invention of Another (section III, 2, supra), the Oi/Herzenberg work involved mapping epitopes on a known quantity of antigen. It was not concerned with and does not disclose using monoclonal antibodies of at least 10 8 liters/mole affinity. Oi and Herzenberg testified that they did not know the affinity of the antibodies used, and Ciotti testified that nowhere in that work is there mention of monoclonal antibody affinity of at least 10 8 liters/mole. On this basis, we conclude that the Oi/Herzenberg work is qualitatively different than the claimed invention; the former is directed to mapping epitopes on a known quantity of antigen and the latter to determining the presence or concentration of an antigenic substance in a sample of fluid.... We disagree with Monoclonal that these are essentially the same thing. Furthermore, it is perfectly clear that this work in no way suggests using monoclonal antibodies of the affinity claimed in the '110 patent. It is because of these differences between the Oi/Herzenberg work and the claimed invention that the fact that an antigen was sandwiched between two monoclonal antibodies in the course of Oi's and Herzenberg's work is not sufficient basis to conclude that the claimed invention would have been obvious at the time it was made to a person of ordinary skill in the art. 90 Likewise, a conclusion that the invention would have been obvious cannot properly be reached when the Oi/Herzenberg work is considered in view of the Frankel article. Frankel teaches a method for rapid determination of affinity constants for monoclonal antibodies, some of which clearly have affinities of the order defined by the claims, but does not in any way suggest using two of those antibodies in a sandwich to assay an antigen by forming a ternary complex of labelled antibody, the antigenic substance, and a bound antibody wherein the presence of the antigenic substance is determined by measuring either the amount of labelled antibody bound to a solid carrier or the amount of unreacted labelled antibody. The mere existence of prior art disclosing how to measure the affinity of high affinity monoclonal antibodies is insufficient to support a holding of obviousness. Hybritech's claims define a process that employs monoclonal antibodies, and does not merely claim antibodies of high affinity. In view of the fact that the Oi/Herzenberg work is not directed to an assay as claimed and does not disclose antibodies of at least 10 8 liters/mole affinity, and further that Frankel fails to suggest using such antibodies in a sandwich assay, the Frankel article does not compensate for the substantial difference between the Oi/Herzenberg work and the claimed subject matter, and therefore those references in combination cannot support a holding of obviousness.4. Objective Evidence of Nonobviousness 91 In one part of its opinion the court found that the commercial success of the kits may well be attributed to the business expertise and acumen of the plaintiff's personnel, together with its capital base and marketing abilities (emphasis ours) and later that [w]here commercial success is based on the sudden availability of starting materials, in this instance the availability of monoclonal antibodies as a result of the Kohler and Milstein discovery, business acumen, marketing ability, and capital sources, no causal relationship is proven. (Citation omitted.) 92
93 a Substantial Market Share 94 The undisputed evidence is that Hybritech's diagnostic kits had a substantial market impact. The first diagnostic kit sales occurring in mid-1981, sales increased seven million dollars in just over one year, from $6.9 million in 1983 to an estimated $14.5 million in 1984; sales in 1980 were nonexistent. Competing with products from industry giants such as Abbott Labs, Hoffman LaRoche, Becton-Dickinson, and Baxter-Travenol, Hybritech's HCG kit became the market leader with roughly twenty-five percent of the market at the expense of market shares of the other companies. Its PAP kit ranks second only to a product sold by Dupont's New England Nuclear, surpassing products from Baxter-Travenol, Abbott, and others. Hybritech's other kits, indisputably embodying the invention claimed in the '110 patent, obtained similar substantial market positions. 95 Although the district court did not provide its insights into why commercial success was due to business acumen and not to the merits of the claimed invention, Monoclonal urges in support that it was due to Hybritech's spending disproportionate sums on marketing, 25-30% of income. The undisputed evidence was that expenditures of mature companies in this field are between 17 and 32%. Furthermore, the record shows that advertising makes those in the industry--hospitals, doctors, and clinical laboratories--aware of the diagnostic kits but does not make these potential users buy them; the products have to work, and there is no evidence that that is not the case here or that the success was not due to the merits of the claimed sandwich assays--clearly contrary to the district court's finding. 96 The trial court's finding that the sudden availability of monoclonals was the reason for the commercial success of Hybritech's diagnostic kits (Finding 11) is unsupported by the record and clearly erroneous. Monoclonal admits that monoclonal antibodies were available in the United States in 1978, and the evidence clearly reflects that. Thus, at least three years passed between the time monoclonal antibodies were available in adequate supply and the time Hybritech began selling its kits. Especially in the fast-moving biotechnology field, as the evidence shows, that is anything but sudden availability. 97
98 Hybritech points to the testimony of three witnesses skilled in the diagnostic field who state that, based on tests done in their laboratories as a result of real-world comparisons in the normal course of research, the diagnostic kits that embody the '110 invention unexpectedly solved longstanding problems. Dr. Hussa, the head of a large referral laboratory and a world-wide consultant, testified that until Hybritech introduced its kits, he and others were very skeptical and had almost exclusively used competitive assays with a radioactive tracer (RIAs). 5 In relation to an HCG Hybritech kit, he testified that he had first thought that the Hybritech HCG kit would not give accurate results for low antigen concentrations because that condition is indicated in the Hybritech kit by a low radioactivity reading, a reading difficult to differentiate from control samples containing no antigen. He also stated that in the past, RIA kits falsely detected HCG in nonpregnant women, a condition which would indicate cancer and surgery. He stated that when he employed the Hybritech HCG kit in such instances it demonstrated, correctly and absent any difficulty interpreting the data, that no HCG was present. 99 Dr. Blethen, an M.D. holding a Ph.D. in biochemistry, testified that she did not think that the Hybritech HGH kit, for detecting growth hormone in children, would offer any advantage, but she determined that it detected HGH deficiencies in children where conventional RIAs failed to do so. She also stated that the kit does not give false positive readings as do conventional RIA kits, an opinion shared by Dr. Hussa. A third witness, Dr. Herschman, who holds a master's degree in chemistry, testified that he spent years working on the development of an assay that would determine the presence of TSH (thyroid stimulating hormone) with greater sensitivity. He succeeded but discovered that the Hybritech TSH kit had the same sensitivity, the test being performed in four hours rather than the three days his kit required. 100 Having considered the evidence of nonobviousness required by Sec. 103 and Graham, supra, we hold, as a matter of law, that the claimed subject matter of the '110 patent would not have been obvious to one of ordinary skill in the art at the time the invention was made and therefore reverse the court's judgment to the contrary. The large number of references, as a whole, relied upon by the district court to show obviousness, about twenty in number, skirt all around but do not as a whole suggest the claimed invention, which they must, to overcome the presumed validity, Lindemann, 730 F.2d at 1462, 221 USPQ at 488, as a whole. See 35 U.S.C. Sec. 103; Jones v. Hardy, 727 F.2d 1524, 1529, 220 USPQ 1021, 1024 (Fed.Cir.1984). Focusing on the obviousness of substitutions and differences instead of on the invention as a whole, as the district court did in frequently describing the claimed invention as the mere substitution of monoclonal for polyclonal antibodies in a sandwich assay, was a legally improper way to simplify the difficult determination of obviousness. See generally Hodosh v. Block Drug Co., 786 F.2d 1136, 229 USPQ 182 (Fed.Cir.1986). 6 101 With respect to the objective indicia of nonobviousness, while there is evidence that marketing and financing played a role in the success of Hybritech's kits, as they do with any product, it is clear to us on the entire record that the commercial success here was due to the merits of the claimed invention. It cannot be argued on this record that Hybritech's success would have been as great and as prolonged as admittedly it has been if that success were not due to the merits of the invention. The evidence is that these kits compete successfully with numerous others for the trust of persons who have to make fast, accurate, and safe diagnoses. This is not the kind of merchandise that can be sold by advertising hyperbole. 102