Ex Parte Ziegelmaier

Board of Patent Appeals and Interferences

Sep 13, 2002

08445584 (B.P.A.I. Sep. 13, 2002)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

Paper No. 68

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ROBERT ZIEGELMAIER
__________

Appeal No. 2001-1654
Application No. 08/445,584
__________

ON BRIEF
__________

Before SCHEINER, MILLS and GRIMES, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL

This is a decision on appeal under 35 U.S.C. § 134 from the examiner’s
final rejection of claims 4-8, 13, 14, and 16-24, all of the claims remaining.
Claims 16, 17, and 8 are representative and read as follows:
16. An immunological method for the detection of an antigen specific
antibody comprising one or more of the immunoglobulin classes A, M,
D or E in a fluid, comprising the simultaneous incubation of:

a. A solid phase having bonded thereto antibody specific for said
immunoglobulin classes A, M, D, or E;

b. A fluid containing an immunoglobulin of class A, M, D, or E;

c. A labeled antigen immunologically reactive to the fluid phase
immunoglobulin; and
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Application No. 08/445,584

d. A substance which inhibits the binding of immunoglobulin G
to the solid phase and which inhibits the binding of said labeled
antigen to immunoglobulin G.

17. An immunological method for the detection of an antigen specific
antibody comprising one or more of the immunoglobulin classes A, M, D,
or E in a fluid, comprising the simultaneous incubation of:

a. A solid phase having bonded thereto antibody specific for said
immunoglobulin classes A, M, D, or E;

b. A fluid containing an immunoglobulin of class A, M, D, or E;

c. An unlabeled antigen immunologically reactive to the fluid phase
immunoglobulin;

d. A labeled antibody, immunologically reactive with said unlabeled
antigen; and

e. A substance which inhibits the binding of immunoglobulin G to
the solid phase and which inhibits the binding of said unlabeled
antigen to immunoglobulin G.

8. The method as claimed in claim 16, wherein the labeling means are
erythrocytes.

The examiner relies on the following references:
Molinaro et al. (Molinaro) 4,130,634 Dec. 19, 1978
Duermeyer 4,292,403 Sept. 29, 1981
Unger 4,434,227 Feb. 28, 1984
David et al. (David) 4,486,530 Dec. 04, 1984

Schmitz et al. (Schmitz), “Detection of IgM Antibodies to Cytomegalovirus (CMV)
Using an Enzyme-labelled Antigen (ELA)”, Journal of General Virology, Vol. 50
pp. 59-68 (1980)

Claims 4-7, 13, 14, 16-21, 23, and 24 stand rejected under 35 U.S.C.
§ 103 as obvious in view of Duermeyer, Unger, David, and Schmitz.
Appeal No. 2001-1654 Page 3
Application No. 08/445,584

Claims 8 and 22 stand rejected under 35 U.S.C. § 103 as obvious in view
of Duermeyer, Unger, David, Schmitz, and Molinaro.
We reverse.
Background
The specification discloses a method of detecting antigen-specific
antibodies belonging to classes other than IgG, i.e., IgA, IgM, IgD, or IgE.
Detection of these classes of antibodies is important for a variety of reasons.
Immunoglobulins of the IgM class appear very soon after an
infection, for which reason their determination is important for the
early diagnosis of an infectious disease or for the diagnosis of an
acute infection.

The second most abundant immunoglobulins are of the
immunoglobulin class IgA and are the most important secretory
antibodies.

Immunoglobulins of classes IgD and IgE can be found in elevated
concentration in certain pathological processes; for example IgE
has properties which sensitize mast cells and it plays a significant
part in the pathogenesis of a number of allergic reactions. IgD
antibodies are found in autoimmune diseases.

Specification, page 2.
The specification discloses that methods were known for detecting
antigen-specific antibodies of a particular class but that these methods suffered
from the disadvantage that “the non-antigen-specific immunoglobulin fraction of
any particular immunoglobulin class enters into competition with the antigen-
specific fraction.” Page 3. The specification discloses a detection method that
eliminates this competition and also shortens the time required to perform the
assay.
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Application No. 08/445,584

This “one-step method” has become possible after successful
elimination of two possible interferences:

In the first place, the effect of antigen-specific IgG antibodies must
be eliminated. . . .

In the second place, the activity of rheumatoid factors (RF), that is
to say antibodies against IgG which belong to various
immunoglobulin classes, has to be suppressed because it can lead
to falsification of the result. This falsification is possible because
RF are bound to the antibody on the solid phase, and bound over
the antigen-specific IgG antigen which is bound by the RF in turn,
and thus a false-positive detection reaction is obtained.

It has been possible to eliminate both possibilities of interference
by, for example, addition of anti-human IgG, gamma chain (“RF
adsorbent” of Behringwerke AG) to the sample (for example
serum).

Specification, pages 4-5.
Thus, the disclosed method involves simultaneous incubation of all the
components of the immunoassay: a solid phase that will bind antibodies of a
particular class (IgA, IgM, IgD, or IgE), a sample, an antigen-specific label,1 and
“a substance which inhibits binding of immunoglobulin G to the solid phase and
inhibits binding of [the] . . . antigen to immunoglobulin G.”
Discussion
The examiner rejected claims 4-7, 13, 14, 16-21, 23, and 24 as obvious in
view of Duermeyer, Unger, David, and Schmitz. The examiner also rejected
claims 8 and 22 over these same references, combined with Molinaro.

1 The antigen-specific label can be supplied in the form of labeled antigen or in the form of
unlabeled antigen combined with a labeled, antigen-specific antibody. The first embodiment is
disclosed in the specification at page 6, lines 14-15, and recited in claim 16; the second
embodiment is disclosed in the specification at page 6, lines 17-19, and recited in claim 17.
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Application No. 08/445,584

The examiner characterized Duermeyer as teaching a method of detecting
an antigen-specific antibody of class IgM, IgA, IgD, or IgE. According to the
examiner, Duermeyer differs from instant claim 17 only “in failing to exemplify the
use of an additional substance to inhibit the binding of IgG to the antigen and to
the antibody on the solid phase.” Examiner’s Answer, page 4. The examiner
states that Duermeyer teaches “an immunological reagent composition”
comprising three components, and teaches that “the immunological reagent
composition may be combined to form a single reagent.” Examiner’s Answer,
page 4.
We agree with Appellants that this characterization of Duermeyer
somewhat overstates the relevance of the reference. Specifically, we agree with
Appellants that Duermeyer also fails to teach the “simultaneous incubation”
limitation of the claims. Duermeyer states that the assay is performed in at least
two steps: first, “serum . . . is brought into contact with an insolubilized antibody
against the antigen specific IgX concerned,” then “[a]n incubation is subsequently
performed with an antigen . . ., after which a further incubation takes place with a
labelled antigen binding fragment of an antibody” against the antigen. Column 2,
lines 28-39. Duermeyer’s working example makes clear that these steps are
separated by washings. See column 4, line 51 to column 5, line 30. Although
Duermeyer states that the antigen and labeled antibody fragment can be
complexed beforehand (see column 2, lines 61-66), this embodiment would still
involve two incubation steps separated by a wash. Therefore, we do not agree
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Application No. 08/445,584

that Duermeyer discloses the claim limitation requiring simultaneous incubation
of all reaction components.
Thus, the method disclosed by Duermeyer differs in two respects from the
method recited in claim 17: first, it includes a washing step between binding of
the sample and addition of a labeled reagent, and second, it does not include an
IgG-binding inhibitor in the incubation. The examiner cited Unger, David, and
Schmitz to make up these deficiencies.
Like Duermeyer, Unger discloses a method for detecting an antigen-
specific antibody of class IgA, IgM, IgD, or IgE. Unger discloses the problem of
false-positives resulting from RF interacting with antigen-specific IgG in the
sample, giving the appearance of an antigen-specific IgM. See column 2, lines
22-33. Unger discloses that this problem can be avoided by pretreating the
sample with anti-IgG, which prevents RF from binding to IgG in the sample. See
column 3, lines 5-11. Thus, Unger’s assay comprises the steps of (1) treating the
sample with anti-IgG, (2) contacting the treated sample with a solid support
having antigen bound to it, (3) washing to remove unbound sample, and (4)
treating the sample bound to the solid support with labeled anti-IgX antibody to
detect bound (antigen-specific) antibody of the IgX class. Column 3, lines 11-26.
Unger does not disclose incubating all the reactants simultaneously. The
examiner cited David as disclosing this limitation. See the Examiner’s Answer,
page 5: “David teaches a simultaneous assay involving a single incubation step
as the antibody bound to the solid support and the labeled antibody are both
added to the sample being tested at the same time.” Finally, apparently in
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Application No. 08/445,584

reference to claim 16, the examiner also cited Schmitz as teaching an
immunoassay using “an enzyme-labelled antigen.” Examiner’s Answer, page 5.
The examiner concluded that it would have been obvious to add the
anti-IgG taught by Unger to the assay method disclosed by Duermeyer, in order
to prevent RF-induced false positives. The examiner also concluded that “[i]t
would have been obvious to one of ordinary skill in the art at the time the
invention was made to optimize the assay by simultaneously adding all
necessary reagents because such optimization procedure involves a single
incubation step and eliminates washing steps which serve to shorten the length
of time required for an assay,” Examiner’s Answer, page 6, and that it would
have been obvious to use a labeled antigen for detection, as disclosed by
Schmitz.
“In proceedings before the Patent and Trademark Office, the Examiner
bears the burden of establishing a prima facie case of obviousness based upon
the prior art. ‘[The Examiner] can satisfy this burden only by showing some
objective teaching in the prior art or that knowledge generally available to one of
ordinary skill in the art would lead that individual to combine the relevant
teachings of the references.’” In re Fritch, 972 F.2d 1260, 1265, 23 USPQ2d
1780, 1783 (Fed. Cir. 1992) (citations omitted). An adequate showing of
motivation to combine requires “evidence that ‘a skilled artisan, confronted with
the same problems as the inventor and with no knowledge of the claimed
invention, would select the elements from the cited prior art references for
Appeal No. 2001-1654 Page 8
Application No. 08/445,584

combination in the manner claimed.’” Ecolochem, Inc. v. Southern Calif. Edison
Co., 227 F.3d 1361, 1375, 56 USPQ2d 1065, 1075 (Fed. Cir. 2000) (quoting
In re Rouffet, 149 F.3d 1350, 1357, 47 USPQ2d 1453, 1456 (Fed. Cir. 1998)).
In this case, although the references suggest most of the limitations of the
claims, they are not adequate to support a prima facie case under § 103. On the
one hand, the combination of Duermeyer and Unger appears to be reasonable.
Both references disclose assays to detect an antigen-specific antibody of class
IgA, IgM, IgD, or IgE, and both refer to the problem of RF-induced false positives.
See Duermeyer, column 2, lines 10-19, and Unger, column 2, lines
22-33. Duermeyer discloses avoiding false positives by using “a labelled antigen
binding fragment of an antibody” for detection (column 2, lines 56-61), while
Unger addresses the same problem by pretreating the sample with anti-IgG
(column 3, lines 5-11). Thus, Unger and Duermeyer teach complementary
methods of addressing the problem of RF-induced false positives. A person
skilled in the art would have found it obvious to include Unger’s anti-IgG
pretreatment step in Duermeyer’s assay, in order to further reduce the incidence
of RF-induced false positives. We agree with this much of the examiner’s
analysis.
However, we do not agree that the references would have suggested
conducting the claimed assay in a “simultaneous incubation” of all the recited
components, as required by both claims 16 and 17. The examiner relies on
David to meet this limitation, but we find David’s disclosure to be more limited
than the examiner characterizes it.
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Application No. 08/445,584

David teaches that a sandwich immunoassay can be conducted by
simultaneously incubating an immobilized antibody, the antigen, and a labeled
antibody. See column 4, lines 50-61. David’s assay comprised only these three
components. See column 8, lines 6-25. David teaches that simultaneous
incubation is possible if both the immobilized antibody and the labeled antibody
are monoclonal antibodies, directed to different epitopes of the same antigen.
See id.
David does not provide guidance with respect to immunoassays in
general, nor does it suggest that all immunoassays can or should be conducted
by simultaneously incubating all the components in a single incubation. In
particular, David does not suggest converting Unger’s pretreatment with anti-IgG
into a simultaneous incubation of anti-IgG with the other assay components.
Schmitz also fails to suggest this limitation of the claimed method. The
examiner cited Schmitz simply to meet the limitation requiring use of a labeled
antigen. See the Examiner’s Answer, page 6 (“It would have been obvious . . . to
use the labeled antigen of Schmitz in the assay of Duermeyer.”). Schmitz does
not suggest simultaneous incubation of all the recited reagents.
We therefore conclude that the references cited by the examiner do not
teach or suggest all of the limitations of the instant claims. In particular, the
references do not suggest the limitation requiring simultaneous incubation of “a
substance which inhibits binding of immunoglobulin G to the solid phase and
inhibits binding of [the] . . . antigen to immunoglobulin G” with an immobilized
anti-IgX antibody, a sample, and an antigen-specific label.
Appeal No. 2001-1654 Page 10
Application No. 08/445,584

With respect to the rejection of claims 8 and 22, the examiner additionally
cited Molinaro for teaching the limitation that “the labeling means are
erythrocytes.” Molinaro does not remedy the deficiency discussed above. The
rejection of claims 8 and 22 is also reversed.
Summary
The cited references do not teach or suggest simultaneous incubation of
all the reagents recited in claims 16 and 17, and therefore do not render the
claimed methods prima facie obvious. The rejections under 35 U.S.C. § 103 are
reversed.
REVERSED

Toni R. Scheiner
Administrative Patent Judge )
)
)
) BOARD OF PATENT
Demetra J. Mills )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
Eric Grimes )
Administrative Patent Judge )

EG/dym

Appeal No. 2001-1654 Page 11
Application No. 08/445,584

Finnegan Henderson Farabow
Garrett and Dunner
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