The Standard of Reviewing Obviousness Determinations from the USPTO
By Kevin E. Noonan --
The Federal Circuit vacated and remanded a Board of Patent Appeals and Interferences determination that the claims in U.S. Application No. 09/719,045 were obvious on Thursday, in deciding In re Chapman. The CAFC's decision addressed not only the proper obviousness standard that the Board must apply, but also revisited the proper standard of review the Federal Circuit applies regarding factual determinations by the Office according to the Supreme Court's instructions in Dickinson v. Zurko.
The Chapman application is a U.S. national phase of an International Application first filed in Great Britain. The following claim is representative:
1. A divalent antibody fragment comprising
(a) two antibody heavy chains and
(b) at least one polymer molecule effective for increasing the circulating half-life of said fragment in covalent linkage,
(c) each heavy chain being covalently linked to the other by at least one non-disulphide interchain bridge linking the sulphur atom of a cysteine residue in one chain to the sulphur atom of a cysteine residue in the other chain, said cysteine residues being located outside of the variable region domain of each chain, characterized in that the at least one non-disulphide interchain bridge contains the at least one covalently linked polymer molecule.
As the CAFC explained, the invention was directed towards making a derivative of an antibody comprising two heavy chains linked to one another using a polymer attached at each end to a sulfur atom comprising a cysteine residue in each of the different heavy chain molecules, and that the cysteine residues in each heavy chain came from outside the variable region domain (i.e., where the specificity of antibody binding is structurally determined).
Importantly for the Court's understanding of the underlying technology, the government explained that there was a need in the art for antibody fragments, since antibodies were frequently too large and had extended half-lives that could be deleterious to a patient. Advantages of antibody fragments, according to the Court, were that they had better serum clearance rates and more rapid distribution throughout the body. The Court noted that enzymatic digestion was known to produce antibody fragments effectively. The Court also noted that one species (F(ab')2) produced by digestion (with pepsin) was "dumbbell shaped" and that it was divalent (having two antigen binding sites) as required by the claims.
With regard to the teachings of the specification supporting the Chapman claims, the Court said that Chapman's specification taught combining two separate Fab' fragments (having removed the light claims) "using an interchain bridge that contains at least one covalently linked polymer." Thus, the linkage between two heavy chain molecules is mediated by the polymer rather than the disulfide bridges used in the native molecule. One of the advantages of using a polymer rather than a disulfide bridge is that it increases the circulating half-life of the antibody fragment, according to the Court, to a half-life "that is intermediate between that of an individual fragment and a whole antibody."
The prior art asserted by the Office included U.S. Patent No. 6,025,158 (the Gonzales reference), which the Court said "describes linking antibody fragments to a polymer to increase an antibody's circulating half-life for therapeutic purposes." One polymer known in the art, polyethylene glycol (PEG), when attached to the sulfur atom in the cysteine residue in the hinge region of the molecule "reduced clearance compared to the parental Fab' molecule"; the reference also describes dumbbell-shaped embodiments "made up of two antibody fragments linked by a polymer and the preparation of such conjugates," including Fab, Fab', Fab'-SH, F(ab')2, scFv, and Fv as choice for the antibody portion of the conjugate and PEG as the polymer linking them. Included in the description of the '158 patent were methods for linking antibody fragments and the polymer without using a disulphilde bond in some embodiments (albeit using sulfur atoms in cysteine residues as the point of PEG attachment, specifically cysteine residues in the hinge region).
The Examiner applied the Gonzales reference for anticipation under 35 U.S.C. § 102(e), or in the alternative, combined Gonzales with U.S. Patent No. 5,436,154 to Barbanti (teaching antibody therapy) in rejecting the claims under 35 U.S.C. § 103. The Board affirmed as to the obviousness rejection, reversing the anticipation rejection on the ground that "too much in the way of mental gymnastics would have been necessary for persons of ordinary skill to have 'at once envisage[d]' the claimed antibody structure among the different structures described in the Gonzalez patent. . . . [P]icking and choosing would have been necessary to have arrived at the antibody structure of claim 1." The Federal Circuit noted several findings of fact made by the Board in affirming the Examiner's rejections. These included:
• Antibody fragments disclosed in the Gonzales reference include monovalent Fab fragments, monovalent Fab' fragments having one or more cysteine residues in the constant region, or F(ab')2 fragments having a disulfide bond between cysteine residues in the hinge region.
• The Gonzales reference disclosed conjugates wherein the F(ab')2 fragment is conjugated to the polymer at a cysteine that would otherwise comprise the disulfide bond between the two fragments. However, Gonzales describes the polymer as being linked to a cysteine in the light chain or the heavy chain, and that the cysteine in the other chain that would otherwise for a disulfide bond with the cysteine bonded to the polymer is changed to prevent a disulfide bond from forming.
• Gonzales in other embodiments describes a polymer that links two antibody fragments in a "dumbbell-shaped structure," using a polymer having multiple functional groups "permitting the direct attachment . . . of two or more antibody fragments to the polymer backbone."
The Board agreed with the examiner that the Gonzales reference had disclosed "linking two antibody fragments with a polymer to form a 'dumbbell-shaped' structure," and had expressly taught "a Fab molecule with a PEG linked to the hinge cysteine of the heavy chain." "The only issue," according to the Board, was "whether persons of skill in the art would have had reason to join the [Fab'] fragments together using a polymer linked to the hinge cysteine residue." The Board concluded that the preference disclosed in the Gonzales reference for linking the polymer to the hinge region would have "led the skilled artisan to utilize the claimed hinge cysteine," based in part on the advantages disclosed in the Gonzales reference regarding such linkages (i.e., producing "reduced clearance" from the bloodstream). Especially important for the Board's decision was that, in its view, the Gonzales reference taught "a complete working example" of attaching a polymer to a hinge region cysteine residue. The combination of this teaching, and the "dumbbell" structure disclosed in the Gonzales reference, "would have suggested to the ordinary skilled person that such Fab' fragments could be readily linked polymer to polymer using a bifunctional linker, as explicitly stated by Gonzalez when characterizing the dumbbell-shaped antibody structure."
In the Federal Circuit opinion, by Judge Dyk joined by Judges Gajarsa and Clevenger, the Court began with the standard of review: no deference for legal conclusions, and substantial evidence for factual findings. The opinion notes that both parties agree that whether the obviousness rejection was correctly maintained depends on whether the Office had correctly interpreted the teachings of the Gonzales reference. In this regard, the Court refused to reverse the Board's determination as a matter of law, instead remanding to the Board "to correct certain errors in the Board's decision." The Court rejected applicants' argument that the Gonzales reference teaches away from the claimed invention, based on the multiplicity of positions for polymer attachment, in view of the express preference for attachment at the hinge region. The Court also noted that the reference was directed towards solving the same problem as the claimed invention -- increasing the half-life of the antibody in circulation.
Applicants' most persuasive argument was directed to three of the Board's factual findings, which both applicants and the government agreed were erroneous. The difference in the parties position was that the Office argued that the errors were harmless, and the opinion hinged on the Court's assessment of the harm caused by these errors, applying the same "harmless error" rule that it applies to factual determinations from district courts, citing In re Watts, 354 F.3d 1362 (Fed. Cir. 2004) (citing In re McDaniel, 293 F.3d 1379 (Fed. Cir. 2002) and Gechter v. Davidson, 116 F.3d 1454 (Fed. Cir. 1997)), an approach the opinion asserted was affirmed by the Supreme Court in Shinseki v. Sanders, 129 S. Ct. 1696, 1706 (2009).
Specifically, the Board erred in finding that:
• Gonzales taught a "dumbbell-shaped" structure comprising two monovalent Fab' fragments lined via a polymer. The government agreed that the Board "conflated" two correct statements on the record from the Examiner to arrive at an incorrect conclusion. The Court found that this error was harmless, because the Board did not rely on "any such explicit disclosure" in the Gonzales reference
• "Gonzalez describes a divalent antibody in which the polymer is linked between light and heavy chains and only one cysteine residue is present." The Examiner stated that "Gonzalez describes conjugates containing an 'F(ab')2 antibody fragment in which the polymer is attached between the disulphide bridge that would ordinarily link the light and heavy chains.'" The government conceded at oral argument that applicants were correct, that the Gonzales reference in fact disclosed that:
[T]he conjugate contains a F(ab')2 antibody fragment attached to no more than about 2 polymer molecules, wherein every polymer molecule is attached to a cysteine residue in the light or heavy chain of the antibody fragment that would ordinarily form the disulfide bridge linking the light and heavy chains, wherein the disulfide bridge is avoided by substituting another amino acid, such a serine, for the corresponding cysteine residue in the opposite chain.
• Finally, applicants argued (and the government agreed) that Gonzales taught that there were up to six antibody fragments that could be conjugated to a polymer (F(ab), F(ab'), F(ab')-SH, F(ab')2, scFv, and Fv) and not just Fab, Fab' or F(ab')2 fragments.
The Court found that both of the latter references were not harmless because "they increased the likelihood that [applicants were] denied a patent on grounds of obviousness." The Board's obviousness finding being based on "a misunderstanding" of the Gonzales reference "called into question" its legal determination of obviousness, according to the Federal Circuit. Specifically, if the Board misinterpreted the Gonzales reference regarding whether it contained a teaching of using a polymer to link the light and heavy chains in an F(ab')2 fragment, then applicants' invention of using a polymer to link two F(ab')2 fragments together "may be less obvious" in the Court's opinion. Similarly, with regard to the number of possible fragments that could be conjugated, "if the Board did not appreciate the full scope of antibody fragments disclosed in Gonzalez, we cannot be confident about its ultimate conclusion that the selection of one of them to form Chapman's molecule is obvious, as it appears that there are more possibilities from which to choose." Thus, "[b]ecause we cannot say with confidence that the Board would have reached the same conclusion in the absence of these errors, we are persuaded they are indeed harmful."
Interestingly, despite the Court's clear understanding that the Board had made several prejudicial errors in making its obviousness determination, rather than reversing the Board outright the Court remanded to permit the Board to "revisit" its obviousness assessment, in view of a correct understanding of the Gonzales reference. "The Board is in no way precluded from, and indeed may be correct in, finding the claims to be obvious, particularly in the light of Gonzalez's disclosure of joining two antibody fragments together with a polymer to make a dumbbell-shaped structure," wherein the Court thus exhibited a high level of deference to how the Board makes its factual findings.
In re Chapman (Fed. Cir. 2010)
Panel: Circuit Judges Gajarsa, Clevenger, and Dyk
Opinion by Circuit Judge Dyk