Ex Parte Ueda et al

Patent Trial and Appeal Board

Sep 27, 2016

12671002 (P.T.A.B. Sep. 27, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/671,002 01127/2010 Hiroshi Ueda
22428 7590 09/29/2016
Foley & Lardner LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
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.
106301-0105 7008
EXAMINER
OGUNBIYI, OLUW ATOSIN A
ART UNIT PAPER NUMBER
1645
NOTIFICATION DATE DELIVERY MODE
09/29/2016 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):
ipdocketing@foley.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HIROSHI UEDA and MIKI KOJIMA
Appeal2014-007910
Application 12/671,002
Technology Center 1600
Before DEMETRA J. MILLS, ERIC B. GRIMES, and JOHN G.
NEW, Administrative Patent Judges.
MILLS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF CASE
Appellants' Specification is directed to, "an antibody-enzyme fusion
protein and a method for detecting an antigen using the antibody-enzyme
fusion protein." Spec. 1. The Specification states that by tethering a fusion
protein comprising a VH domain polypeptide and one part of an enzyme
protein and a fusion protein comprising a VL domain polypeptide and the
remaining part of the enzyme protein with a linker peptide, the drawbacks
associated with detecting a low molecular weight antigen are overcome.
Spec. 1, 3. Figure 1 of the Specification is reproduced below.
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Appeal2014-007910
Application No. 12/671,002
SLAcp168
•
~:: Produ.;1
~ ~Subttram
0
00
Figure 1 shows a schematic diagram of a conformational change of
a fusion protein of the invention depending on the presence or absence of the
binding of the V H domain polypeptide and the V L domain polypeptide to an
antigen. Spec. 5.
The following claim is representative.
1. A fusion protein comprising a polypeptide containing a
VH domain of an antibody, a given protein, a linker peptide, a
partner protein, and a polypeptide containing a V L domain of
the antibody, in this order or in reverse order,
wherein the given protein is the C-terminal fragment of
B-lactamase and consists essentially of the amino acid sequence
of SEQ ID NO: 7 and the partner protein is the N-terminal
fragment of B-lactamase and consists essentially of the amino
acid sequence of SEQ ID NO: 5,
wherein binding of the polypeptide containing a V H
domain and the polypeptide containing a V L domain to an
antigen is capable of inducing binding of the given protein to
the partner protein, and wherein presence of binding of the
given protein to the partner protein is detectable.
Cited References
Ostermeier et al. W0/2005/072392 A2 Aug. 11, 2005
Yokozeki et al., A Homogeneous Noncompetitive Immunoassay for the
Detection of Small Haptens, 74 Anal. Chem. 2600-2504 (2002).
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Application No. 12/671,002
Grounds of Rejection
Claims 1, 5, 6, and 11 are rejected under 35 U.S.C. §103(a) as being
unpatentable over Ostermeier, alone or in combination with Y okozeki.
FINDINGS OF FACT
The Examiner's findings of fact are set forth in the Answer at pages
4-8. The following facts are highlighted.
1. Ostermeier discloses molecular switches which couple external signals
to functionality. Abstract. Preferred switches are fusion molecules
comprising an insertion sequence and an acceptor sequence for
receiving the insertion sequence, wherein the state of the insertion
sequence is coupled to the state of the acceptor sequence. P. 5.
Ostermeier discloses inserting a circularly permutated B-lactamase
( cpBLA) into an "acceptor sequence" by, for example, site specific
insertion by ligating cpBLA in between a gap (generated by
restriction) between two domains of maltose binding protein (MBP)
(Seep. 52 lines 15-31 and see figure 4). Thus, in this case the cpBLA
is not inserted into a single polypeptide like random insertion. Ans.
10.
2. Ostermeier, Figure 4 and p. 52 lines 15-31 and p. 53, under the
section entitled "ligation of inserts into target DNA," shows that a
fusion protein of an acceptor sequence is needed to make the
molecular switch and shows that the cpBLA can be ligated between
two separate portions of MBP or a ligand binding domain which
forms the binding domain in the presence of ligand. Ans. 12.
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Application No. 12/671,002
3. Ostermeier discloses that the state of the insertion sequence is coupled
to the state of the acceptor sequence upon fusion, such that a change
in state in either the insertion sequence or acceptor sequence will
result in a change of state of the respective other portion of the
fusion. See p. 32 lines 3-7. Ostermeier discloses that a "state" can be
a conformation ... which can be triggered by a signal to which the
fusion molecule is exposed. Seep. 32 lines 3-28. Ans. 12-13.
4. Ostermeier discloses on p. 34 lines 8-14 that "in one aspect, an
acceptor sequence is a polypeptide whose state resides in a
discontinuous domain of a protein (e.g. the amino acids involved in
conferring the state/activity of the acceptor sequence are not
necessarily contiguous in the primary polypeptide sequence)". Ans.
13.
Ostermeier discloses that the domain sequence can be minimal
sequences, such as are known in the art, which are associated with a
particular known state or can be an entire protein comprising the
domain or a functional fragment thereof. Seep. 34 lines 29-30 top.
35lines1-2. Ans. 13.
5. Ostermeier discloses that a domain sequence includes ligand
binding domains of ligand binding proteins (for example, an
immunoglobulin.) See, p. 41lines21to24. Ans. 13.
7. Ostermeier discloses:
1. A given protein consisting of residues 168-286 of TEM B-
lactamase (corresponding to instant SEQ ID NO: 7);
2. A DKS linker peptide;
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Application No. 12/671,002
3. A partner protein consisting of residues 24-170 of TEM 13-
lactamase (corresponding to instant SEQ ID NO: 5). See p. 56 table
4, Switch IFD-5-15. Ans. 5.
8. The difference between the fusion protein of Ostermeier, for
example, MBP[l-165](BLA[l68-286]-DKS-BLA[24-l 70])-
MBP[l64-370] and the instant claims is that Ostermeier does not
specifically disclose ipsis verbis that the cpBLA (insertion sequence)
(BLA[l68-286]-DKS-BLA[24-l 70]) is flanked by a VH domain of an
antibody at one terminus and a VL domain of an antibody at the other
terminus i.e. Ostermeier does not disclose ipis verbis disclose the
fusion protein:
VH(BLA[l68-286]-DKS-BLA[24-l 70])-VL, this order or reverse
order. Ans. 6.
9. Y okozeki discloses a homogeneous noncompetitive immunoassay
for the detection of small haptens. P. 2500. Figure 1 b of Y okozeki is
reproduced below.
(b)
Figure 1 (b) shows the principles of the assay for the detection of
small haptens. Without antigen, the two fusion proteins remain
monomeric. The j3-gal activity of each chimeric protein is low. The
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Application No. 12/671,002
addition of antigen induces heterodimerization of the two chains,
accompanied by the recreated B-gal activity tethered with the V H and
VL domains. P. 2501, col. 2.
PRINCIPLES OF LAW
In making our determination, we apply the preponderance of the
evidence standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427
(Fed. Cir. 1988) (explaining the general evidentiary standard for proceedings
before the Office).
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Obviousness - Ostermeier and Yokozeki
We agree with the Examiner's fact finding, statement of the rejection
and responses to Appellants' arguments as set forth in the Answer. We find
that the Examiner has provided evidence to support a prima facie case of
obviousness based on Ostermeier and Y okozeki. 1 Since Appellants have not
argued the claims separately, we select claim 1 as representative claim. We
provide the following additional comment to the Examiner's argument set
forth in the Final Rejection and Answer.
The Examiner concludes from the facts listed above, and of record,
that in Ostermeier' s molecular switches, the ligand binding domain of an
1 In view of the discussion in the Final Rejection, Answer, and below, we
need not address the alternative basis of the rejection; i.e., obviousness based
on Ostermeier alone.
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Application No. 12/671,002
immunoglobulin can be an acceptor sequence (the ligand binding domain of
an immunoglobulin being on two different polypeptides i.e. VH and VL
domains). Ans. 14. The Examiner concludes from Ostermeier, that B-
lactamase can be placed in between the two discontinuous domains and the
molecular switch can work when the VH and VL domains both form the
ligand binding domain of an immunoglobulin and bind an antigen and thus
reconstituting the enzymatic activity of B-lactamase. Ans. 14. The
Examiner further concludes that, it would have been prima facie obvious to a
person of ordinary skill in the art at the time the instant invention was made
from reading Ostermeier, that a ligand binding domain of an
immunoglobulin may be discontinuous and formed by both the V H and V L
domains. Ans. 14.
Appellants contend that
The Examiner's interpretation of both the antibody heavy chain
variable domain ("V H domain") and antibody light chain
variable domain ("V L domain") together as constituting the
"acceptor sequence" taught in Ostermeier is not supported by
the plain disclosure of the reference. The Examiner also erred
by improperly ignoring Y okozeki' s discovery of the
considerable background noise caused by V H- V L association,
even when the V H domain and the V L domain are present in two
separate proteins instead of one fusion protein. See Y okozeki at
Figure 2.
Appeal Br. 4-5.
Appellants further argue that
Ostermeier . . . never teaches flanking circularly permutated B-
lactamase with two different domains of two different
polypeptides to yield a fusion protein, much less specifically a
VH domain of an antibody heavy chain polypeptide and a VL
domain of an antibody light chain polypeptide. Indeed, flanking
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Application No. 12/671,002
circularly pennutated 13-lactamase with two different
polypeptides contravenes Ostermeier' s core concept of
"insertional fusion," where the insertion sequence must be
inserted into a single polypeptide to yield a fusion protein. See
Ostermeier, page 4, lines 1-4; page 5, lines 24-28; and page 34,
lines 8-14 ...
Appeal Br. 5-6.
We are not persuaded by Appellants arguments. Ostermeier teaches a
13-lactamase (BLA) and Maltose binding protein (MBP) molecular switch
(fusion protein) designated IFD-5-15 (p. 56) having the following structure:
MBP[l-165]-BLA[l68-286]-DKS-BLA[24-l 70]-MBP[l64-370].
This structure differs from that claimed in that the claimed structure includes
a split VHIVL immunoglobulin in place of the split MBP portions.
Ostermeier suggests that either the insertion sequence or acceptor sequence
of its molecular switch (fusion protein) may be split or discontinuous (p. 34)
and may be an immunoglobulin. P. 3 9, 41. Y okozeki discloses a functional
structure (FF9) having split VH and VL portions linked to 13-galactosidase
enzyme (instead of 13-lactamase enzyme). This structure has no linker
between the 13-galactosidase enzyme portions.
We agree with the Examiner that, in view of the disclosures of
Ostermeier and Y okozeki,
It would have been prima facie obvious to a person of ordinary
skill in the art at the time the instant invention was made to have
inserted or ligated the cpBLA (circularly permutated 13-lactamase in
between a VH and VL domain) which constitute the ligand binding
domain of an immunoglobulin which are discontinuous and are not
necessarily contiguous in the immunoglobulin, and in any order, thus
resulting in the instant invention with a reasonable expectation of
success.
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The motivation to do so is that Ostermeier et al disclose that
circularly permutated insertion sequences can be inserted or ligated
between two domains of an acceptor sequence, such as a ligand
binding domain of an immunoglobulin whose state resides in a
discontinuous domain of a protein e.g. the amino acids involved in
conferring the state/activity of the acceptor sequence, are not
necessarily contiguous in the primary polypeptide.
Ans. 6-7. We further agree with the Examiner that in view of the
disclosures of Ostermeier and Y okozeki
one of ordinary skill in the art would have a reasonable
expectation of success in inserting or ligating the circularly
permutated B-lactamase in between V H and V L domains of an
antibody as the use of V H domains fused to one fragment of an
enzyme and fusion of another V L domain to an enzyme
fragment complementing to the first fragment of an enzyme to
detect antigen via binding of the V H and V L domain to antigen
and thus reconstitution of enzyme activity is known. See
Y okozeki et al cited previously, title, abstract and figure 1 b.
Ans. 7-8.
Appellants argue that the claimed fusion protein when used in a
method for detecting a low molecular weight antigen using the antibody-
enzyme fusion protein, unexpectedly achieved a desirable signal-to-noise
ratio even if the V H and V L domains are joined in a single fusion protein and
in close spatial proximity that is even better than Y okozeki's two-protein
approach. Appeal Br. 10-11; Reply Br. 3--4. Appellants argue that
Y okozeki would have led one of ordinary skill in the art away from
covalently conjugating the V H and V L domains in a single molecule. Reply
Br. 4.
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Application No. 12/671,002
"[W]hen unexpected results are used as evidence of nonobviousness,
the results must be shown to be unexpected compared with the closest prior
art." In re Baxter-Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991). The
burden of demonstrating unexpected results rests on the party asserting
them, and "it is not enough to show that results are obtained which differ
from those obtained in the prior art; that difference must be shown to be an
unexpected difference." In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972).
Appellants have come forth with no comparative evidence comparing
the activity of the claimed fusion protein with that of either Y okozeki or
Ostermeier, alone or in combination, under similar culture and/or testing
conditions. Therefore we are not persuaded by Appellants' allegation of
unexpected results.
Furthermore, while Y okozeki reported a background signal using a
previous assay format due to the V H-V L interaction in the absence of antigen
(p. 2501, col. 1.), Yokozeki provided an additional disclosure on how to
optimize the assay to improve results and reduce non-specific V w V L
interaction. P. 2502-2503; Ans. 17-18. In addition, the linked fusion
proteins of Ostermeier evidence functionality. Ostermeier, p. 56.
Appellants have presented no evidence to show that one of ordinary skill in
the art would have doubted the functionality of Ostermeier' s molecular
switches. Attorney argument cannot take the place of evidence. Other
arguments of Appellants have been addressed fully in the Examiner's
Answer.
The obviousness rejection over Ostermeier and Yokozeki is affirmed
for the reasons of record.
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CONCLUSION OF LAW
The cited references support the Examiner's obviousness rejection of
claim 1. The rejection is affirmed for the reasons of record. Remaining
claims fall with claim 1.
AFFIRMED
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