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