Ex Parte Weidanz et al

Patent Trial and Appeal Board

May 18, 2016

09874907 (P.T.A.B. May. 18, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
09/874,907 06/05/2001 Jon A. Weidanz
100807 7590 05/20/2016
Mintz Levin/Special Group
One Financial Center
Boston, MA 02111
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
48277-510001US 3602
EXAMINER
SCHWADRON, RONALD B
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
05/20/2016 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
IPDocketingBOS@mintz.com
IPFileroombos@mintz.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JON A. WEIDANZ, KIMBERLYN F. CARD,
and HING C. WONG 1
Appeal2013-009639
Application 09/874,907
Technology Center 1600
Before JEFFREY N. FREDMAN, JOHN G. NEW, and
ROBERT A. POLLOCK, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants state the real party-in-interest is Altor BioScience Corp. App.
Br. 4.
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Application 09/874,907
STATEMENT OF THE CASE
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 81, 82, 85, 86, 102, 124, and 147-
153.2 Specifically, the claims stand rejected as unpatentable under 35
U.S.C. § 112, first paragraph, for lack of written description support.
Claims 81, 82, 85, 86, 102, 124, and 147-153 also stand rejected as
unpatentable under 35 U.S.C. § 103(a) being obvious over the combination
ofWeidanz et al. (WO 99/18129; April 15, 1999) ("Weidanz '129") and
Bonneville (US 5,723,309; March 3, 1998) ("Bonneville").
We have jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to T cell receptor complexes
designed to redirect the immune system against various diseases. The T cell
receptor complexes of the invention have been engineered to recognize a
target antigen in a functionally bispecific nature. Fusion protein complexes
and protein conjugate complexes are comprised of high affinity antigen-
specific TCR and biologically active proteins and/or effector molecules.
Also featured are methods of production of T cell receptor fusion and
conjugate complexes as well as therapeutic compositions for use of the
complexes. Abstract.
2 Claims 1-80, 83, 101, and 124--146 are canceled. Claims 84, 87-100,
103-123, 125, and 154--156 are withdrawn. App. Br. 16-23.
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REPRESENTATIVE CLAIM
Claim 81 is representative of the claims on appeal, and recites:
81. A soluble single-chain T cell receptor fusion molecule
comprising a T cell receptor and a cytokine or fragment thereof
connected by a first peptide linker, wherein the soluble single-
chain T cell receptor has one recognition binding site and the
cytokine or fragment thereof has a different recognition binding
site, wherein the soluble single-chain T cell receptor comprises
a and B variable chain TCR covalently linked together by a
second peptide linker.
App. Br. 22.
ISSUES AND ANALYSES
We do not agree with the Examiner's written description analysis.
We agree with, and adopt, the Examiner's findings and conclusion that the
appealed claims are prima facie obvious over the cited prior art references.
We address the arguments raised by Appellants below.
A. Rejection under 35 U.S.C. § 112, first paragraph
Issue 1
Appellants argue the Examiner erred in finding Appellants'
Specification discloses only constructs having a Va chain linked to a VB
chain, which in tum is linked to a CB chain, and that there is therefore no
written descriptive support for constructs having only Va and VB chains.
App. Br. 4.
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Analysis
Appellants point to page 8, 11. 9-25 of their Specification, which, they
argue, incorporates by reference Weidanz et al. (US 6,534,633; March 18,
2003) ("Weidanz '633") for its description of the single-chain T-Cell
Receptor ("scTCR") portion of the claimed fusion proteins. App. Br. 8-9.
Appellants remind us that 37 C.F.R. § 1.57(c) states that "'essential matter'
may be incorporated by reference, but only by way of an incorporation by
reference to a U.S. patent or U.S. patent application publication."' Id. at 5.
Appellants contend Weidanz '633 provides detailed description of an
embodiment of an scTCR "having only a Va and VB chain". Id. at 5---6
(citing, e.g., Weidanz '633 Fig. 2A, cols. 14--15, 11. 53---60). Appellants also
argue Weidanz '633 teaches that the inclusion of the CB domain is optional,
rather than required. Id. (quoting Weidanz '633 15, 11. 12-14, 17-21, and
56---60).
The Examiner responds that Appellants' Specification, as filed, fails
to disclose constructs containing only Va and a VB chains and, further, fails
to disclose such constructs linked by a peptide linker. Ans. 6-7. The
Examiner finds the Specification discloses a Va chain linked to VB and CB
chains, but does not disclose a construct that lacks the CB chain. Id. at 7.
The Examiner finds the claims under consideration encompass scTCR
constructs without a CB chain and finds such constructs are not disclosed in
Appellants' Specification, as originally filed. Id.
The Examiner also finds that the material Appellants incorporate by
reference, including Weidanz '633, constitutes new matter under 35 U.S.C. §
132(a). Ans. 7 (citing Final Act. 2). The Examiner further notes that the
reference to WO 99/18129 refers only to "methods for production and use of
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scTCRs," and not particular constructs. Id. Finally, the Examiner finds
Weidanz '633 discloses scTCR constructs that are used for the production of
conjugates that contain an scTCR and an antibody-derived binding
molecule, which is not, the Examiner finds, the invention claimed by
Appellants but are rather used only as intermediates for producing
scTCR/antibody chimeric molecules. Id. at 7-8 (citing Weidanz '633 col.
14, 11. 40-52).
We are persuaded by Appellants' arguments. As an initial matter, we
are not persuaded by the Examiner's finding that the Specification fails to
provide written description support for the limitation reciting "wherein the
soluble single-chain T cell receptor comprises a and B variable chain TCR
covalently linked together by a second peptide linker," as recited in claim
81. The claim term "comprising" signals this is an open limitation, i.e., one
which leaves the claim open for the inclusion of unspecified ingredients
even in major amounts. See, e.g., Mars Inc. v. HJ. Heinz Co., 377 F.3d
1369, 1376 (Fed. Cir. 2004); see also MPEP § 2111.03 ("The transitional
term 'comprising,' which is synonymous with 'including,' 'containing,' or
'characterized by,' is inclusive or open-ended and does not exclude
additional, unrecited elements or method steps"). The Examiner finds that,
because the Specification does not disclose a construct that has Va and VB
chains only, i.e., a construct which lacks the CB chain, the disputed
limitation lacks written description support. We do not agree, because we
find the Specification explicitly discloses Va and VB chains joined by a
peptide linker and the open language of the claim does not, explicitly or
implicitly, also preclude a CB chain linked to the VB chain.
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Furthermore, we disagree with the Examiner's finding that W eidanz
'633 constitutes new matter. The September 14, 2009 amendment added the
following language to Appellants' Specification: "WO 99/18129 discloses
scTCR proteins include covalently linked TCR Va and VB chain fused to an
immunoglobulin light chain constant region (i[.]e.[,] lg-CL) or a suitable Ig-
CL fragment. WO 99/18129 discloses that in another aspect, the scTCR is
provided without a fused lg-CL chain or fragment." Amend. Spec. 2.
(emphasis omitted). We agree with the Examiner that Appellants may not
rely upon this new matter for written description support of the claims.
However, the Specification, as originally submitted, states:
Technology has been developed previously to produce highly
specific T cell receptors (TCR) which recognize particular
antigen. For example, the pending U. S. patent applications
U.S.S.N. 08/813,781 and U.S.S.N. 09/422,375, incorporated
herein by reference; and International publications PCT
/US98/04274 and PCT/US99/24645, and references discussed
therein disclose methods of preparing and using specific TCRs.
Spec. 8, 11. 9--14. Appellants' US Application Ser. No. 09/422,375 cited in
this passage subsequently issued as the Weidanz '633 patent. Therefore
Appellants' incorporation by reference ofWeidanz '633 is not new matter,
as the Examiner finds, and Appellants may rely upon the incorporated
teachings of Weidanz for written description support of the claims. See 37
C.F.R. § 1.57(c).
The Weidanz '633 discloses:
As mentioned previously, the sc-TCR includes TCR V-a
and V-B chains covalently linked through a suitable peptide
linker sequence. For example, the V-a chain can be covalently
linked to the V-fJ chain through a suitable peptide linker
sequence fused to the C-terminus of the V-a chain and the N-
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terminus of the V-jJ chain. The V-a and V-B chains of the sc-
TCR fusion protein are encoded by nucleic acids generally about
200 to 400 nucleates in length, preferably about 300 to 350
nucleotides in length, and will be at least 90% indentical [sic],
and preferably 100% indentical to the V-a and V-B chains of a
naturally-occuring [sic] TCR. By the term "indentical" is meant
that the amino acids of the V-a or V-B chain are 100%
homologous to the corresponding naturally occurring TCR V-B
or V-a chains. See Examples 1-3 below and the pending U.S.
application Ser. Nos. 08/813,781 and 08/943,086 for more
specific disclosure relating to sc-TCR V chains.
Weidanz '633 cols. 14--15, 11. 62-11 (emphasis added). We therefore find
Weidanz '633 provides adequate written description support for the
limitation of claim 81 reciting "wherein the soluble single-chain T cell
receptor comprises a and B variable chain TCR covalently linked together by
a second peptide linker." We therefore reverse the Examiner's rejection on
this ground.
Issue 2
Appellants next argue the Examiner erred in finding the Specification
fails to provide written support for peptide linkers between the Va and VB
domains of the claimed scTCR fusion proteins. App. Br. 7.
Analysis
Appellants argue that, contrary to the Examiner's findings,
Appellants' Specification provides written description support for scTCRs
having a peptide linker between the Va and VB domains. App Br. 7.
Appellants point to Figure 1 of the Specification which, they assert, depicts a
linker having the amino acid sequence (Glycine4 Serine )4 between the Va
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and VB domains of the 264 scTCR. Id. Appellants also point to pages 19--
20 of the Specification, which, they allege, explicitly provides a description
of a polypeptide linker joining both Va and VB chains of a scTCR. Id. at 7-
8. Appellants contend the only way a linear polypeptide linker sequence
may be linked to both Va and VB chains is if the linker sequence links the
two chains, i.e., via a Va-linker sequence-VB. Id.
Appellants also argue that Weidanz '633 provides written description
support for the peptide linker between the Va and VB chains. App. Br. 8-9
(citing Weidanz '633 col. 14, 11. 62----67; col. 20, 11. 23-31, col. 4, 11. 16-21).
The Examiner finds the Specification discloses said linkers between a
TCR and a biologically active molecule, but does not disclose said linkers as
used between the Va and VB chains of a scTCR. Ans. 8. With respect to
Figure 1, the Examiner finds the Specification discloses only the
(Glycine4Serine )4 linker which is 20 amino acids, but does not provide
support for the limitations of claim 147 (which requires about 7 to 20 amino
acids). Id. The Examiner finds the Specification similarly does not provide
support for the linker of claim 148 (requiring 8 to 16 amino acids) or claim
149 (which requires at least one of the first and second peptide linkers
consist of alanine, serine and glycine to provide for flexibility). Id.
With respect to Appellants' reliance upon the passage of pages 19-20
of the Specification, the Examiner finds the cited passage does not disclose
the linkers recited in the claims as used between the Va and VB chains of an
scTCR, but rather refers to linkers between the TCR and the effector peptide
(i.e., IL-2). Ans. 10.
We agree with Appellants that Figure 1 of the Specification explicitly
discloses the Va and VB chains of a scTCR linked by a (Glycine4 Serine )4
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linker. However, we are not persuaded by Appellants' argument with
respect to the disclosure of pages 19-20 of the Specification. That passage
recites, in relevant part:
Preferred fusion and conjugate complexes in accord with the
present invention typically include operatively linked in
sequence (N to C terminus): 1) a TCR/one or more linker
molecules I and a biologically active molecule; 2) TCR/linker
molecules/and a biologically active molecule; and 3) TCR/ a first
linker molecule /a first biologically active molecule subunit/ a
second linker molecule I and a second biologically active
molecule subunit.
The linker sequence is preferably a nucleotide sequence that
codes for a peptide that can effectively position the binding
groove of the TCR molecule for recognition of a presenting
antigen.
Preferably the linker sequence comprises from about 7 to 20
amino acids, more preferably from about 8 to 16 amino acids.
The linker sequence is preferably flexible so as not hold the
biologically active peptide in a single undesired conformation.
The linker sequence can be used, e.g., to space the recognition
site from the fused molecule. Specifically, the peptide linker
sequence can be positioned between the TCR chain and the
effector peptide, e.g., to chemically cross-link same and to
provide molecular flexibility. The linker is preferably
predominantly comprises amino acids with small side chains,
such as glycine, alanine and serine, to provide for flexibility.
Preferably about 80 or 90 percent or greater of the linker
sequence comprises glycine, alanine or serine residues,
particularly glycine and serine residues. For a TCR fusion
complex that contains a heterodimer TCR, the linker sequence is
suitably linked to the B chain of the TCR molecule, although the
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linker sequence also could be attached to the a chain of the TCR
molecule. Alternatively, linker sequence may be linked to both
a and B chains of the TCR molecule. For covalently linking an
effector molecule peptide to a TCR B chain molecule, the amino
sequence of the linker should be capable of spanning suitable
distance from the N-terminal residue of the TCR B chain to the
C terminal residue of the effector molecule peptide. When such
a B+peptide chain is expressed along with the Cf. chain, the
linked TCR-effector peptide should fold resulting in a functional
TCR molecule as generally depicted in Figure 1.
Spec. 18-20. We find that a plain reading of this passage requires the
conclusion that the peptide linker molecule discussed constitutes the link
between the Va and/or VB chains of an scTCR and the effector molecule.
Appellants place particular emphasis on the sentence "Alternatively, linker
sequence may be linked to both a and B chains of the TCR molecule," but
we find that this sentence, when taken in context with the rest of the quoted
passage, states that a linker peptide sequence can link the effector protein to
either or both the Va and VB chains of the scTCR and not, instead, the
linking of just the Va and VB chains to each other. Amend. Spec. 5.
Nevertheless, we agree with Appellants that Weidanz '633 provides
written description support for a peptide linker between the Va and VB
chains that meets the requirements of the claims. Wiedanz '633 explicitly
discloses:
As mentioned previously, the sc-TCR includes TCR V-a and V-
B chains covalently linked through a suitable peptide linker
sequence. For example, the V-a chain can be covalently linked
to the V-B chain through a suitable peptide linker sequence fused
to the C-terminus of the V-a chain and the N-terminus of the V-
B chain.
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Weidanz '633 col. 14, 11. 62----67. Furthermore, Weidanz '633 also discloses:
More particularly, the peptide linker sequence separating
the Va,B chains of the sc-TCR preferably flexibly positions the
V-chains in a pocket that is capable of specifically binding
ligand.
In a more specific embodiment, the polypeptide linker sequence
comprises from about 7 to 25 amino acids, more preferably from
about 10 to 20 amino acids, still more preferably from about 12
to amino acids. The linker sequence is typically flexibly
disposed in the fusion protein so as to position the V-a and V- B
chains in a configuration which provides for specific binding of
a desired ligand such as a peptide antigen. The linker preferably
predominantly comprises amino acids with small side chains,
such as glycine, alanine and serine, to provide optimal flexibility.
Preferably, about 80 or 90 percent or greater of the linker
sequence comprises glycine, alanine or serine residues,
particularly glycine and serine residues.
Weidanz '633 col. 18, 11. 37-64. Weidanz '633 thus explicitly discloses
peptide linkers between the Va and VB chains that are between 7 to 25
amino acids in sequence and which preferably comprise glycine, alanine or
serine residues. We therefore conclude Appellants' Specification, which
explicitly incorporates the disclosures ofWeidanz '633, provides written
description support of the claims on appeal, and we consequently reverse the
Examiner's rejection of claims 81, 82, 85, 86, 102, 124, and 147-153 on
these grounds.
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A. Rejection under 35 U.S.C. § 103(a)
Issue 1
Appellants argue the Examiner erred because, at the time of invention,
a person of ordinary skill in the art would expect that fusion of a peptide to
either the C-terminus or the N-terminus of IL-2 with a peptide linker would
disrupt the function of the IL-2 cytokine. App. Br. 10.
Analysis
Appellants contend that, at the time of invention, the art indicated that
the N-terminal domain of IL-2 was critical for IL-2's biological activity.
App. Br. 10. As indicative of the state of the art, Appellants point to G. Ju et
al., Structure-Function Analysis of Human Interleukin-2, Identification of
Amino Acid Residues Required for Biological Activity, 262(12) J. BIOL.
CHEM. 5723-31 (1987) ("Ju"). Id. According to Appellants, Ju teaches that
amino acid substitutions in the N-terminal's 20 amino acid residues result in
the IL-2 protein retaining less than 1 % of its activity. Therefore, Appellants
argue, a person of skill in the art would have expected that fusion of a large
peptide, e.g., an scTCR, to the N-terminus of IL-2 would result in the
inactivation or at least substantial loss of activity of IL-2. Id. Accordingly,
argue Appellants, a skilled artisan would likely expect that the fusion of a
large polypeptide, e.g., an scTCR domain, to the N-terminus of IL-2 would
result in the inactivation or at least substantial loss of activity of IL-2. Id.
We do not agree. Appellants cite Ju as representative of the state of
the art at the time of invention, but we are not persuaded by Appellants'
characterization of the teachings of this reference. Ju teaches:
The primary structure of this lymphokine has been
deduced from nucleotide sequence analysis of cDNA clones and
confirmed by amino acid sequencing of the Jurkat-derived
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material. However, the secondary and tertiary structures of
human IL-2 remain undetermined, and little information is
available on which amino acid residues are important for the
biological effects induced by IL-2. We have approached this
problem by site-specific mutagenesis of a biologically active IL-
2 cDNA clone.
Ju 5731 (internal references omitted). Ju further teaches, inter alia:
Results from the structure-function studies indicated that the
integrity of at least three regions of the IL-2 molecule must be
maintained for substantial activity: the NHP-terminal 20 amino
acids (region I), the COOR-terminal 13 amino acids (region IV),
and 2 of the 3 cysteine residues (region 111 ).
Ju 5728. However, Ju also teaches:
In region I [amino acids 1-20 at the N-terminus], a mutation of
Thr7 to valine or isoleucine caused slight reductions in
bioactivity. It does not seem likely that this residue is required
for IL-2 activity because the deletion which encompasses Thr7
(deletion of first 10 amino acids) did not significantly decrease
the bioactivity. It is possible that the amino acid substitutions
chosen for this residue were responsible for changing the
conformation of the protein such that a slight decrease in activity
resulted.
Ju 5726. Finally, Ju concludes:
The importance of the NH2-terminal residues 10 to 20 have been
confirmed using an immunological approach. Monoclonal
antibodies generated to the rIL-2 protein were analyzed to
identify clones which could inhibit IL-2 bioactivity in a
neutralization assay .... The importance of residues 10 to 20 has
also been indicated in an independent study using immunological
means.
Ju 5728-29 (internal references omitted); see also Ju Table II. Ju thus
teaches amino acids 10-20 are critical for IL-2 binding, but amino acids 1-
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10 are much less so. Nevertheless, Ju teaches the deletion of amino acid
sequences 10-20 is responsible for a profound loss ofIL-2 activity, but
teaches nothing whatever with respect to the effect upon IL-2 activity of
binding polypeptides to the IL-2 N-terminus.
Furthermore, the Examiner cites Bonneville as prior art to Appellants'
invention. Bonneville teaches:
The subject of the invention is also a fusion protein formed
between a soluble T [cell] receptor and a peptide sequence. the
peptide sequence being constitutive of a peptide or of a protein,
the fusion protein being obtained by fusing the DNA sequence
encoding the peptide or the protein to one of the chains or to the
two chains of DNA encoding the submits of a T [cell] receptor
from which their transmembrane portion has been deleted,
followed by a co-transfection of the DNA sequences thus fused
into a host cell. Advantageously in this case, the peptide
sequence is that of interleukin-2 (IL-2).
Bonneville col 3, 11. 42-52. Bonneville thus teaches a fusion protein in
\vhich IL-2 is fhsed \vith the Va or VB chains of an scTCR. Therefore, and
contrary to Appellants' arguments, enabled fusion proteins including IL-2
itself were known in the art at the time of invention, and were believed to be
functional. We therefore disagree with Appellants' assertion that a person of
ordinary skill in the art would expect that fusion of a peptide to either the C-
terminus or the N-terminus of IL-2 with a peptide linker would disrupt the
function of the IL-2 cytokine. Appellants provide no evidence supporting
this position. See In re Antor Media Corp., 689 F.3d 1282, 1289 (Fed. Cir.
2012) ("[D]uring patent prosecution, an examiner is entitled to reject claims
... by a prior art publication or patent without conducting an inquiry into
whether or not that prior art reference is enabling. As long as an examiner
makes a proper prima facie case ... by giving adequate notice under§ 132,
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the burden shifts to the applicant to submit rebuttal evidence of
nonenab lement. ")
Issue 2
Appellants argue the claimed fusion proteins have a number of
beneficial characteristics that are unexpected and that are not taught or
suggested by the cited references. App. Br. 11.
Analysis
Appellants point to the Declaration of Dr. Hing Wong (the "Wong
Declaration") in support of their assertion of unexpected results. App. Br.
11. Appellants contend the Wong Declaration describes a number of
experiments that demonstrate that the claimed fusion molecules have highly
enhanced efficacy when compared to IL-2 activity alone. Id. (citing Wong
Deel. Figs. 1-5. Specifically, Appellants contend the Declaration presents
data demonstrating that the claimed fusion molecules exhibit longer cell
surface residency time and bind more stably to the IL-2 receptor than does
IL-2 itself. Id. (citing Wong Deel. 2, 3; Fig. 1). Furthermore, argue
Appellants, the Wong Declaration also demonstrates the claimed fusion
proteins demonstrate equivalent IL-2 biological activity in vitro and similar
pharmacokinetics in vivo. Id. at 11-12 (citing Wong Deel. 3, 4, 7; Figs. 2, 3,
5).
Finally, Appellants argue, the Wong Declaration also describes
experiments demonstrating scTCR-IL-2 fusion proteins have an
unexpectedly much longer serum half-life and higher serum recovery than
IL-2 alone. Id. (citing Wong Deel. 5, 6; Fig. 4). According to Appellants,
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the longer half-life, modest tissue distribution, slow clearance and stable
bifunctionality of the sc TCR-IL-2 fusion proteins provide significantly more
favorable pharmacokinetic properties than are observed for IL-2-only-based
therapeutic agents.
The Examiner responds that, although the Wong Declaration teaches
the claimed fusion protein has certain properties that are superior to IL-2
alone, it does not compare the claimed invention to the closest prior art (viz.,
the TCR-IL-2 fusion proteins taught by Bonneville. Ans. 12. The Examiner
points to Section 716.02(b) of the MPEP, which states, with respect to direct
and indirect comparative tests are probative of nonobviousness, that:
"Evidence of unexpected properties may be in the form of a direct or indirect
comparison of the claimed invention with the closest prior art which is
commensurate in scope with the claims." Id. (citing, inter alia, In re
Boesch, 617 F.2d 272, 276 (C.C.P.A. 1980).
We are not persuaded by Appellants' arguments. The Wong
Declaration states that, with respect to the in vivo and in vitro testing results,
the activity and pharmacokinetics of the fusion protein is approximately
equivalent to that ofIL-2 alone. See Wong Deel. 4--6. We agree with
Appellants that, with respect to other properties, the claimed scTCR-IL2
fusion proteins exhibit superior properties to IL-2 alone. However, we find
Appellants have not established what makes these superior outcomes
"unexpected" because they do not compare the properties of their claimed
fusion proteins with other fusion proteins, such as the TCR-IL-2 fusion of
Bonneville, that were well-known in the art at the time of invention, but only
to IL-2 alone. Moreover, we find that, although the properties of the fusion
proteins are superior to IL-2 alone, the improved properties do not represent
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the "difforen[ ce] in kind and not merely in degree from the results of the
prior art" that is probative of unexpected results. Appellants' results,
therefore, do not overcome the Examiner's prima facie conclusion that the
claims are obvious over the combined cited prior art. Iron Grip Barbell Co.
v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (citation omitted).
Furthermore, unexpected results must be "commensurate in scope
with the degree of protection sought by the claimed subject matter." In re
Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). The claims on appeal do not
limit the effector protein to IL-2, but rather to the very large genus of
cytokines. We find that Appellants' proffer of proof of unexpected results
with respect to the scTCR-IL-2 fusion protein is not commensurate with the
scope of protection sought for the claims that encompasses any effector
protein whatsoever.
"Although secondary considerations must be taken into account, they
do not necessarily control the obviousness conclusion." Pfizer, Inc. v.
Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007). In this instance we find
the evidence presented in the Wong Declaration with respect to the claimed
scTCR-IL-2 fusion proteins' allegedly improved properties do not represent
the "difference in kind" required to overcome the Examiner's prima facie
case of obviousness, particularly in light of the lack of comparison between
the claimed fusion proteins and fusion proteins known in the art. We
therefore affirm the Examiner's rejection on this ground.
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Issue 3
Appellants argue the Examiner erred in finding a person of ordinary
skill would be motivated to combine the teachings of Bonneville and
Weidanz '129 to arrive at the claimed invention. App. Br. 12.
Analysis
Appellants argue that Weidanz '129 teaches an scTCR comprising an
effector molecule linked to the single chain TCR via an lg-CL chain. App.
Br. 12. According to Appellants, Weidanz teaches the effector molecule can
be a cell toxin or biologically active fragment thereof, a chemotherapeutic
drug or a detectably-labeled radionuclide suitable for diagnosis or imaging.
Id. (citing Weidanz 32-33). Appellants assert Weidanz neither teaches nor
suggests a cytokine effector molecule and argue that the effector molecules
taught by W eidanz are structurally and functionally very different from a
cytokine molecule. Id. at 12-13. Nor, argue Appellants, is it predictable
that a cytokine domain will fold correctly as part of a TCR fusion molecule
such that it retains receptor binding capability. Id. at 13.
Furthermore, Appellants argue, Weidanz '129 teaches an lg-CL chain
linker of about 70 to 150 amino acids in length, whereas Appellants' claimed
invention comprises a peptide linker of about 7-20 amino acids between the
single-chain TCR and the cytokine. App. Br. 13 (citing Weidanz '129 18;
Spec. 19).
Appellants contend Bonneville teaches soluble heterodimeric (two
chain) TCRs comprising VaCa and VBCB subunits or other combinations of
Vy-Cy and V8-Cc8 subunits. App. Br. 13 (citing Bonneville cols. 2-3, 11.
39-6). According to Appellants, Bonneville does not teach a single-chain T-
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cell receptor. Id. Appellants also contend Bonneville teaches a fusion
protein between a soluble TCT and a peptide sequence. Id. Appellants
further argue that Bonneville presents no data demonstrating that the TCR-
IL-2 fusion protein complexes were ever made or tested to determine if the
expressed constructs folded properly or had any of the desired activities. Id.
Appellants therefore contend that combining the teachings of W eidanz
'129 with Bonneville would not lead to the claimed invention. App. Br. 13.
Appellants argue the structure of the TCR fusion proteins of Weidanz and
Bonneville are different from each other and from the TCR fusions of the
invention: neither W eidanz '129 nor Bonneville teach a peptide linker
between a single-chain T cell receptor and a cytokine. Id. Furthermore,
argue Appellants, there is no teaching by either Weidanz '129 or Bonneville
with respect to the functional activity of the cytokine domain of the TCR
fusion molecule. Id. at 13-14.
The Examiner responds that a person of ordinary skill in the art would
have been motivated to combine the references because Weidanz '129
teaches a TCR in a fusion protein containing an effector molecule, whereas
Bonneville teaches soluble TCR fusion proteins in which a TCR is linked to
a cytokine (IL-2) and can be used to treat disease. Ans. 13.
We are not persuaded by Appellants' argument. "[O]ne cannot show
non-obviousness by attacking references individually where ... the
rejections are based on combinations of references." In re Keller, 642 F.2d
413, 426 (C.C.P.A. 1981). Rather, the test of obviousness is "what the
combined teachings of the references would have suggested to those of
ordinary skill in the art." Id. at 425.
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We agree with the Examiner's findings, and further agree that a
person of ordinary skill would be motivated to combine the teachings of
Weidanz '129, which teaches a scTCR fusion protein linked to an effector,
with teachings of Bonneville, which teaches a peptide-linked cytokine (IL-2)
as an effector molecule that can be linked to a fusion protein, with the
resultant molecule being effective as a means of treating disease. We
therefore find the Examiner has articulated a rational underpinning as to why
a person of ordinary skill would be motivated to combine the references, and
we consequently affirm the Examiner's rejection of claims 81, 82, 85, 86,
102, 124, and 147-153. SeeKSRint'l. Co. v. Teleflex Inc., 550U.S. 398,
418 (2007).
CONCLUSION
We conclude that the Examiner has established a prima facie case of
obviousness on the evidence before us which has not been rebutted by
Appellants.
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Application 09/874,907
DECISION
The Examiner's rejection of claims 81, 82, 85, 86, 102, 124, and 147-
153 as unpatentable under 35 U.S.C. § 112, first paragraph, as lacking
written description support is reversed.
The Examiner's rejection of claims 81, 82, 85, 86, 102, 124, and 147-
153 as unpatentable under 35 U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l ). See 37 C.F.R.
§ 1.136(a)(l )(iv).
AFFIRMED
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