Ex Parte BURTON et al

Board of Patent Appeals and Interferences

Apr 23, 2003

09231642 (B.P.A.I. Apr. 23, 2003)

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for publication and is not binding precedent of the Board.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. 31
UNITED STATES PATENT AND TRADEMARK OFFICE
__________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________
Ex parte JACK D. BURTON and
DAVID M. GOLDENBERG
___________
Appeal No. 2003-0177
Application No. 09/231,642
__________
HEARD: April 15, 2003
__________
Before WILLIAM F. SMITH, SCHEINER, and LORIN, Administrative Patent Judges.
WILLIAM F. SMITH, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the examiner's final rejection of
claims 1 through 6, 8, 9, and 13 through 22. Claims 7 and 10 through 12 are pending
but have been withdrawn from consideration by the examiner. Claims 1, 4, 5, 6, and 9
are representative of the subject matter on appeal and read as follows:
1. A targeting moiety comprising a conjugate of an antibody linked to a ligand-
binding region of interleukin-13 receptor
subunit (IL-12R
), which antibody is specific
for a cellular antigen specific to a targeted cell.
4. A targeting moiety as claimed in claim 1, comprising a bispecific antibody that
has a first specificity for a cellular antigen specific to a targeted cell and a second
specificity for IL-13R
receptor subunit.
Appeal No. 2003-0177
Application No. 09/231,642
Page 2
5. A targeting moiety as claimed in claim 1, wherein the antibody is specific to
an antigen expressed by solid tumors and is linked to the ligand-binding region of IL-
12R
.
6. A targeting moiety as claimed in claim 5, wherein the antibody is specific to
carcinoembryonic antigen.
9. A kit comprising a conjugate of interleukin-12 (IL-13) linked to a drug,
radionuclide or toxin, and a targeting moiety comprising an antibody specific for a
cellular antigen specific to a targeted cell, linked to the ligand-binding region of
interleukin-13 receptor
subunit (IL-13R
).
The references relied upon by the examiner are:
Hansen et al. (Hansen) 5,874,540 Feb. 23, 1999
PCT Application (Eshhar) WO 93/19163 Sep. 30, 1993
PCT Application (Willson) WO 97/15663 May 1, 1997
MacLean et al. (MacLean), "Anti-CD3:Anti-IL-2 Receptor-Bispecific mAb-Mediated
Immunomodulation," Journal of Immunology, Vol. 155, pp. 3674-3682 (1995)
Claims 1 through 3, 5, 6, 8, 9, and 13 through 21 stand rejected under 35 U.S.C.
§ 103(a). As evidence of obviousness, the examiner relies upon Eshhar, Willson, and
Hansen. Claims 1, 4, and 22 also stand rejected under 35 U.S.C. § 103(a) with the
examiner relying upon MacLean in addition to Eshhar, Willson, and Hansen. We
reverse.
Discussion
Initially, we need to clarify what subject matter has been examined and thus
before us for review. As seen, claim 1 is directed to a targeting moiety which comprises
a conjugate having two portions. The first portion is an antibody and the second portion
is a ligand-binding region of interleukin-13 receptor
subunit (IL-13R
). The antibody
is specific for a cellular antigen specific to a targeted cell. However, as a result of a
Appeal No. 2003-0177
Application No. 09/231,642
Page 3
restriction requirement, claim 1 has only been examined to the extent that the antibody
is specific to carcinoembryonic antigen (CEA). See Paper No. 8, page 3 ("The claims
encompass non-elected embodiments. These claims will be examined only to the
extent they read on a targeting moiety comprising an antibody specific to CEA linked to
a ligand binding region of IL-13R
."). Thus, it appears that claim 6 reflects the subject
matter which has been examined by the examiner on the merits and thus before us for
review in this appeal.
Eshhar describes a conjugate which also comprises an antibody and a ligand-
binding region of a cellular receptor. Specifically, the antibody portion of the Eshhar
conjugate is a single-chain Fv domain (scFv) of a specific antibody. Eshhar, page 7,
lines 9-16. A preferred embodiment of Eshhar is that the conjugate is to target tumor
cells and the scFv domain is derived from an antibody specific to an epitope expressed
on the tumor cell. Id., page 19, lines 7-9. There is no dispute on this record that CEA
would have been an obvious choice to one of ordinary skill in the art in designing the
conjugate of Eshhar to target tumor cells. As set forth by appellants:
CEA is a glycosylated cell surface protein of approximately 180 kDa,
and is a solid tumor antigen that has been extensively studied clinically,
both as a circulating tumor marker and as an antigenic target for
radiolabeled mAbs for imaging and therapy. A number of anti-CEA
antibodies have been under study in phase I-III clinical diagnostic and
therapeutic trials. Exemplary of an anti-CEA mAb is the MN-14mAb. A
humanized version of this mAb, hMN-14, in which human constant and
framework regions replace the corresponding mouse sequences, has
been constructed and expressed and is the mAb and used in these
clinical trials. A 99mTc-labeled Fab' fragment of another, related anti-CEA
mAb, Immu-4, has received FDA approval for the detection and staging of
colon cancer.
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Application No. 09/231,642
Page 4
1 The examiner relies upon Hansen to establish the obviousness of this aspect of the claimed
conjugate. In view of appellants’ admissions, we need not dwell on Hansen.
Specification, page 19, lines 9-24.1 Thus, for the purposes of this appeal, the issue
becomes whether it would have been obvious to one of ordinary skill in the art to use IL-
13R
as the receptor portion of the Eshhar conjugate. We agree with appellants that it
would not have been obvious to do so from the references relied upon by the examiner.
We initially note that the examiner's position is difficult to review due to the
manner in which the Examiner's Answer was crafted. The examiner refers the reader
of the Answer to Paper Nos. 8 and 13 for a statement of the two rejections pending in
this appeal. This is manifestly improper. As set forth in the Manual of Patent
Examining Procedure § 1208, “[o]nly those statements of grounds of rejection
appearing in a single prior action may be incorporated by reference. An examiner’s
answer should not refer, either directly or indirectly, to more than one prior Office
action.” The examiner's error is exacerbated in this appeal because Paper No. 13
refers the reader to Paper No. 8. In reviewing Paper 8, we believe we understand the
examiner's position on the merits
sufficiently to conclude that the references relied upon by the examiner, at least in the
manner applied by the examiner, do not support a prima facie case of obviousness.
The receptor portion of the Eshhar conjugate must function as a "lymphocyte-
triggering molecule." Eshhar, page 7, lines 27-35. To this end, a chimeric gene
encoding the Eshhar conjugate is used to transfect T-cells or other lymphocytes so that
the "scFv linked to receptor subunits [will] serve to transduce the signal from the scFv
and confer antibody specificity to T cells as well as other lymphocytes." Eshhar, page
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Application No. 09/231,642
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16, lines 27-31. Candidate molecules for the receptor portion of the Eshhar conjugate
are "receptor molecules which take part in signal transduction as an essential
component of a receptor complex, such as receptors which trigger T cells and NK
activation and/or proliferation." Eshhar, page 17, lines 5-8.
Given this disclosure in Eshhar, it was the examiner's responsibility to establish
by factual evidence that IL-13R
is a receptor which meets the signal transducing
requirements of Eshhar. The statement of the rejection in Paper No. 8 does not
discuss this issue in any manner. Rather, this issue was developed through appellants'
arguments over the course of the prosecution of this application. This points out the
danger in the examiner referring to a statement of rejection appearing earlier in the
prosecution instead of ensuring that the statement of rejection appearing in the
Examiner's Answer is up to date and complete and reflects the amendments to the
claims and arguments presented by applicant in the course of the prosecution.
The examiner belatedly attempted to recapture this lost ground by responding to
the arguments set forth in applicants' Appeal Brief. The examiner states at page 5 of
the Examiner's Answer that Willson teaches that IL-13R
is a "high affinity receptor
capable of signal transduction," citing to page 27, lines 8-10 of the reference. The
phrase "signal transduction" does in fact appear at that portion of Willson. However,
appellants responded to the examiner's belated position stating:
[T]he examiner has identified no teaching in Eshhar or elsewhere that IL-
13R
is involved in signal transduction to any of the cells identified by
Eshhar, i.e., in signalling the cell bearing the chimera to generate a
cellular response directed toward the specific antigen encoded by the
chimera in a MHC nonrestricted manner (see Eshhar at page 8. lines 21-
24). To the contrary, Willson teaches that IL-13R is produced by
activated T-cells, but acts on macrophages to induce differentiation and
suppress the production of inflammatory cytokines. In other words, the
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Application No. 09/231,642
Page 6
signal transduction production of inflammatory cytokines. In other words,
the signal transduction mentioned on page 27 of Willson entails the
signalling of cells such as macrophages, and does not involved signalling
of the T-cells themselves as in Eshhar. Thus, there is no basis for
substituting the ligand binding region of IL-13R
for the ligand binding
region of IL-2R
in Eshhar.
Reply Brief, paragraph bridging pages 2-3.
The examiner did not file a substantive response to the Reply Brief. Thus, we
have no basis to disagree with appellants' position that the "signal transduction" of
Willson differs from the "signal transduction" required by Eshhar. Absent a fact -based
explanation from the examiner establishing that the "signal transduction" of Willson is in
fact the "signal transduction" envisioned by Eshhar, the rejection cannot be sustained.
As we understand the examiner's rejection of claims 1, 4, and 22, MacLean is
relied upon only to show the bispecific antibody required by claim 4 on appeal and is
not relied upon to show the overall conjugate required by claim 1. We do not find that
MacLean makes up for the shortcomings of the examiner's rejection premised upon
Eshhar and Willson. Thus, we also reverse this rejection.
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Application No. 09/231,642
Page 7
2 We note as did the examiner that the nomenclature "NR4" appearing at this portion of Willson
is stated at page 1 of the reference to be interchangeable with IL-13R
.
Other Issues
As explained above, the conjugate of claim 1 is broadly directed in part to an
antibody specific for a cellular antigen specific to a targeted cell. However, claim 1 has
only been examined to the extent that the antibody is specific to CEA. As result of the
action we have taken today, the claims on appeal are free of rejection. Upon return of
the application to the examiner, the examiner and appellants should carefully consider
the broad scope of claim 1 on appeal in light of the disclosure at page 7 of Willson
describing conjugates of IL-13R
and immunoglobulins which allow targeting of the
conjugate to particular cells.2 These conjugates may anticipate claim 1 in its broadest
sense.
Also upon return of the application, the examiner and appellants should review
all of the claims pending to ensure that they are in proper form. For example, claims 16
and 14 may be considered duplicates. Also, the examiner rejected claim 4 and claim
22 which depends from claim 4 separately, presumably because of the requirement of
claim 4 for a bispecific antibody. However, claims 16 and 19 also appear to be directed
to bispecific antibodies yet were not separately rejected by the examiner. It is not clear
from this record whether this was an oversight on the part of the examiner or whether
the examiner is reading claims 16 and 19 in a manner different from claim 4. Further,
the examiner and appellants should focus on the specific language used in the
dependent claims to make sure it is appropriate. For example, it is not clear from claim
4 as presently drafted whether the bispecific antibody is a third portion of the conjugate
Appeal No. 2003-0177
Application No. 09/231,642
Page 8
of claim 1 or whether the bispecific antibody of claim 4 is a further limitation on the
antibody required by claim 1. If the latter is intended by appellants, claim 4 should be
redrafted using language such as "wherein the antibody is a bispecific antibody . . .."
See, e.g., claim 5 on appeal.
The decision of the examiner is reversed.
REVERSED
)
William F. Smith )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
Toni R. Scheiner )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
Hubert C. Lorin )
Administrative Patent Judge )
Appeal No. 2003-0177
Application No. 09/231,642
Page 9
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