Ex Parte Chang et al

Patent Trial and Appeal Board

Mar 17, 2017

13483761 (P.T.A.B. Mar. 17, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
IBC118US10 2268
EXAMINER
HUYNH, PHUONG N
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
13/483,761 05/30/2012
63322 7590 03/17/2017
IMMUNOMEDICS, INC.
300 AMERICAN ROAD
MORRIS PLAINS, NJ 07950
Chien-Hsing Chang
03/17/2017 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte CHIEN-HSING CHANG,
DAVID M. GOLDENBERG, and EDMUND A. ROSSI
Appeal 2014-002802
Application 13/483,761
Technology Center 1600
Before DEBORAH KATZ, ULRIKE W. JENKS, and JOHN G. NEW,
Administrative Patent Judges.
KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appeal 2014-002802
Application 13/528,077
Appellants1 seeks our review, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 1 and 3-6. (App. Br. 1.) We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
Appellants indicate that the appeal in application 13/528,077 (Appeal
2014-002239) is related to the current appeal. (See App. Br. 2.) Appellants
also indicate that the appeal in application 13/295,647 is related (id.),
although it appears a subsequent request for continued examination was
made in that application.
Introduction
Claims 1 and 3-6 are currently pending in this application, in light of
the cancellation of claims 2, 7-8, and 17 and the withdrawal of claims 9-16
and 18-23. (App. Br. 2.) We consider the rejections of claims 1 and 3-6.
Appellants claim fusion proteins comprising an antibody or a
fragment of an antibody and a dimerization and docking domain (“DDD”).
(App. Br. 2.) Figure 3 of Appellants’ Specification is reproduced below.
1 The real party in interest are said to be IBC Pharmaceuticals, Inc. (App.
Br. 1.)
2
Appeal 2014-002802
Application 13/528,077
N-DM)2-Fab-hMN44
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hMN-14-YH
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Figure 3
Figure 3 depicts a schematic diagram of a DDD domain fused to an antigen­
binding antibody fragment (N-DDD2-Fab-hMN-14) in panel A, and the
putative structure formed by DDD2-mediated dimerization of two of these
N-DDD2-Fab fusion proteins in panel B. (Spec., 141.)
Claim 1 recites:2
A fusion protein comprising:
(i) an antibody or an antigen-binding antibody fragment;
and
(ii) a dimerization and docking domain (DDD) moiety of
human protein kinase A regulatory subunit, wherein the amino
acid sequence of the DDD moiety is selected from the group
consisting of residues 1 to 44 of human PKA Rlla and residues
1 to 44 of human PKA RIip.
(App. Br. 10, Appendix A.)
Although Appellants’ Specification explains that hexameric
complexes may be formed using the claimed fusion proteins along with
others comprising an antibody fragment and an anchor domain (“AD”), to
2 Indentations added for clarity.
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Appeal 2014-002802
Application 13/528,077
which the DDD domain binds (see, e.g. Spec., 122), Appellants’ claim 1
recites only the antibody or antigen-binding antibody fragment and a DDD
moiety.
The Examiner rejected claims 1 and 4-6 under 35 U.S.C. § 103 as
being obvious over Makowski,3 Braun4, and either Banky5 or Newlon.6
(Ans. 2-5.) Appellants do not argue for the separate patentability of these
claims. Accordingly, we designate claim 1 as the representative claim. See
37C.F.R. §41.37(c)(l)(iv).
The Examiner also rejected claims 3 and 4 under 35 U.S.C. § 103 as
being obvious over Makowski, Braun, and either Banky or Newlon, as well
as Hansen.7 (Ans. 5-6.) Appellants state that the rejection of claims 3 and 4
is not argued separately from the rejection of claim 1. (App. Br. 4.)
Accordingly, we focus on the rejection of claim 1 in our analysis.
Findings of Fact
1. Makowski teaches fusion proteins comprising antibodies and
antigen-binding antibody fragments fused to the dimerization sequence of
the protein GCN4, which is a leucine zipper. (Makowski, || 222 and 239.)
3 U.S. Patent Application Publication No. 2003/0198956 Al, published
October 23, 2003.
4 U.S. Patent Application Publication No. 2003/0232420 Al, published
December 18, 2003.
5 Banky et al., 273 J. Biol. Chem. 35048-55 (1998).
6 Newlon et al., 6 Nature Structural Biology 222-27 (1999).
7 U.S. Patent Application Publication US 2002/0018750 Al, published
February 14, 2002.
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Application 13/528,077
2. Figure 11 of Makowski is reproduced below.
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Figure 11 depicts dimerization motifs such as leucine zipper motifs
(depicted as elongated ovals in panels A and B) or four-helix bundle motifs
(depicted as rectangles in panels C and D) that are fused to antigen-binding
multimers. (Makowski, | 83.)
3. Makowski teaches that the dimerized antigen-binding
multimers depicted in Figure 11 may be utilized as the structural and joining
elements in assembly unit fabrication. (Makowski, | 83.)
4. Braun teaches that particular isoforms of Protein Kinase A
(“PKA”), e.g., PKA-RIa or PKA-RIIa, bind to its target protein AKAP.
(Braun 113.)
5. Braun teaches fusion proteins comprising the
“dimerization/docking (D/D) domain” of the regulatory subunit of PKA, for
example mouse Rlla, fused to green fluorescence protein (GFP). (Braun,
1269; see also 1254.)
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Appeal 2014-002802
Application 13/528,077
6. Braun does not teach human DDDs.
7. Newlon teaches that amino acids 1-44 of the PKA Rlla protein
are responsible for AKPA binding and for dimerization. (Newlon at 222,
Fig. 1A, and abstract.)
8. Banky et al teach dimerization docking domains from various
protein kinase A regulatory subunits such as human PKA Rlla (residues 1-
44) and human PKA RIip (residues 1-44). (Banky at 35054, Fig. 8.)
Analysis
“[W]hen a patent claims a structure already known in the prior art that
is altered by the mere substitution of one element for another known in the
field, the combination must do more than yield a predictable result.” KSR
Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
The Examiner concludes that it would have been obvious for one of
ordinary skill in the art at the time to have modified the antibody fusion
protein of Makowski (FFs 1-3) by substituting the GCN4 leucine zipper
dimerization domain taught with a PKA-RIa or PKA-RIIa DDD taught in
Braun (FFs 4 and 5) and also to use the human Rlla and RIip DDDs taught
in Newlon (FF 7) and Banky (FF 8). (Ans. 4.) Alternatively, the Examiner
determines that it would have been obvious to modify the DDD-GFP fusion
proteins of Braun by fusing an antibody or antigen-binding antibody
fragment as taught in Makowski to a DDD of Braun, using a human Rlla or
RIip domain of Banky or Newlon. (Ans. 4.)
The Examiner finds that one of ordinary skill in the art would have
had reason to make these modifications because the DDD moiety is a known
dimerization domain having the same function as the GCN4 leucine zipper
dimerization domains of Makowski. (Ans. 5 and 9.) The Examiner also
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Application 13/528,077
finds that the human proteins of Banky and Newlon were known to be less
immunogenic than the murine DDDs of Braun and, thus, those of ordinary
skill in the art would have had reason to use them. (Ans. 5.) In addition, the
Examiner finds that there would have been reason to dimerize antibody or
antibody fragments in order to increase antigen binding as taught in
Makowski. (Ans. 5.)
The Examiner finds, further, that there would have been a reasonable
expectation that combing the teachings of the cited references would be
successful because the GCN4 leucine zipper domains taught by Makowski
have similar secondary structure helices as the DDD moieties of Banky.
(Ans. 8.)
Appellants present several arguments that each of the prior art
references cited by the Examiner do not alone render the claimed fusion
proteins obvious. For example, Appellants argue that Makowski does not
teach or suggest a fusion protein comprising a DDD moiety from PKA-RIIa
or -RIip. (App. Br. 4.) Appellants also argue that Braun focuses on
screening for AKAP polymorphisms, but does not teach or suggest using
AD or DDD moieties to construct synthetic complexes for delivery of
antibodies, antibody fragments, or other therapeutic proteins. (App. Br. 4-
5.) Appellants argue further that neither Newlon nor Banky teach using
PKA DDD moieties to assemble synthetic complexes comprising antibody
or antibody fragment moieties and that Hansen does not teach or suggest
fusion proteins comprising DDD moieties. (App. Br. 5.)
We are not persuaded by these arguments because “[n]on-obviousness
cannot be established by attacking references individually where the
rejection is based upon the teachings of a combination of references.” In re
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Appeal 2014-002802
Application 13/528,077
Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). These arguments
do not provide a reason why the combination of references cited by the
Examiner do not teach the elements of the fusion proteins claimed by
Appellants.
Appellants also assert that Makowski teaches away from the invention
of claim 1 because an ordinarily skilled artisan would have believed that
Makowski teaches self-assembled structures to be unsuitable for the
complexes it teaches. (App. Br. 5.) Appellants cite to paragraph 21 of
Makowski, which states that “[t]he drawback of the method disclosed in WO
00/68248 is that fusion protein units are assembled into nanostructures by
self-assembly and cannot spontaneously recognize where they belong within
a larger framework.” Appellants also cite to paragraph 23 of Makowski,
which states that “[t]he major drawback the method disclosed in WO
01/121646 [cited as background art]... is that fusion proteins are assembled
into nanostructures by self-assembly, the formation of which is not readily
controllable.” Appellants note that the abstract of Makowski explains:
The present invention provides methods and assembly units for
the construction of nanostructures. Assembly of nanostructures
proceeds by sequential, non-covalent, vectorial addition of an
assembly unit to an initiator or nanostructure intermediate
during an assembly cycle, a process termed “staged assembly.”
Attachment of each assembly unit is mediated by specific, non-
covalent binding of a single pre-determined joining element of
one assembly unit to a complementary joining element on a
target initiator or nanostructure intermediate. Each interaction
of a joining element is designed such that the joining element
does not interact with any other joining element of the assembly
unit. Self-association of the assembly unit is therefore obviated:
only one assembly unit can be added at a time to a target
initiator or nanostructure intermediate.
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Application 13/528,077
According to Appellants, these statements demonstrate that Makowski
teaches the skilled artisan to avoid use of components that will self-
assemble. (App. Br. 6.)
Appellants contrast this asserted intended function for Makowski with
the description in paragraph 958 of Appellants’ specification, which states:
In some embodiments, A, consisting of two identical subunits
(a2), is combined with B, consisting of one subunit (b), to form
an assembly in the configuration of a2b. The association of A
and B is site-specific and spontaneous, due to the strong
binding interaction between the DDD and AD sequences that
are built into A and B, respectively. Both A and B can be any
entity and the precursor of A to which the DDD is linked may
be different from or the same as the precursor of B to which the
AD is linked. In the latter case, the resulting a2b complex,
referred to as a3, is composed of three subunits, each containing
the same precursor but linked to both DDD and AD.
Appellants also cite to paragraph 96, which states that “[w]here A and B are
produced in the same host cell, they may spontaneously assemble into an a2b
complex.” (App. Br. 6.)
We are not persuaded by Appellants’ argument because, as explained
in their Specification, self-assembly occurs between components “A” and
“B” of Appellants’ specification, wherein component “A” is linked to a
DDD moiety and component B is linked to an AD moiety. (See Spec., 95
8 Appellants cite to paragraph 91, but that paragraph of the specification as
filed does not include the quoted text recited by Appellants. Instead,
paragraph 95 does.
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Appeal 2014-002802
Application 13/528,077
and 96.) In contrast, Appellants’ claimed fusion proteins include antibodies
or fragments fused to DDD moieties only.
Appellants argue that antibody-DDD fusion proteins as claimed,
exhibit self-assembly, citing to Figure 3 (reproduced above) and Figure 5 of
their Specification as evidence. (App. Br. 7-8.) The fusion proteins
depicted in Figures 3 and 5 are similar, having the same DDD and Fab
components, except that the two figures depict the components in different
orders.
That is, whereas Figure 5 depicts the DDD moiety in the carboxy terminus
of the fusion proteins, Figure 3 depicts a fusion protein with the DDD
domain in the amino-terminus. Both Figures 3 and 5 show the two fusion
proteins dimerized through the DDD moieties.
We are not persuaded that Figures 3 and 5 depict self-assembly as
discouraged by Makowski. We note that Figure 11 of Makowski also
depicts dimerized fusion proteins. (See FF 2.) Appellants have not
explained why the depicted dimerized fusion proteins in Figures 3 and 5 of
its Specification are self-assembled when the depicted dimerized fusion
proteins in Figure 11 of Makowski are not. Thus, we are not persuaded that
Appellants’ claimed fusion protein self-assembles as discouraged by
Makowski.
Appellants also argue that paragraphs 96 and 100 of their
Specification discuss other structures, such as tetrameric structures that can
be formed by DDD fusion proteins. (See App. Br. 7.) For the same reasons
as discussed above, we are not persuaded that these structures self-assemble
as discouraged by Makowski.
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Application 13/528,077
Appellants argue further that the only use of their claimed antibody-
DDD fusion proteins is as a component in the formation of a “dock-and-
lock” complex, which is described to self-assemble in paragraphs 95 and 96
of their Specification. (App. Br. 7-8.) We are not persuaded by this
argument because Appellants’ claimed fusion proteins require only an
antibody or antibody fragment and a DDD. A DNL complex is not required
in Appellants’ claims. Appellants do not direct us to evidence that their
claimed fusion proteins would have no utility without the other components
of a “dock-and-lock” complex. Accordingly, Appellants’ argument about
the uses of the currently claimed fusion protein do not persuade us that they
necessarily self- assemble as discouraged by Makowski. We note that the
evidence of unexpected results presented by Appellants, discussed in more
detail below, include a reference reporting results obtained with antibody-
DDD fusion proteins in the absence of an AD moiety. (See App. Br. 8-9,
citing Rossi (2008)9.) Contrary to Appellants’ argument, this reference
tends to demonstrates that there are uses of Appellants’ claimed fusion
proteins without an AD moiety.
Appellants also argue that the fusion proteins taught in Makowski
differ from the claimed fusion proteins in a fundamental way because the
claimed fusion proteins are designed to form a three-part complex that
inherently includes an AD moiety, while the fusion proteins of Makowski
form only a two-part complex. (Reply Br. 2-4.) We are not persuaded by
this argument because regardless of how Appellants’ claimed antibody-DDD
component could be used, the required elements do not include any
68 Cancer Res 8384-92 (2008).
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Appeal 2014-002802
Application 13/528,077
components other than an antibody or antigen-binding antibody fragment
and a DDD. A “third” part allowing for self-assembly, such as an AD
moiety, is not required in Appellants’ current claims. Thus, we are not
persuaded that the fusion proteins Appellants claim differ fundamentally
from those taught in Makowski.
We consider the evidence presented by Appellants of unexpected
results in our determination of whether the Examiner erred in rejecting
Appellants’ current claims as being obvious. (See App. Br. 8-9; Reply Br. 5-
6.) Appellants cite to the following references:
Rossi (2012),10 which provides results of anti-CD 19 Fab2-DDD
fusion proteins attached to an anti-CD3-AD scFv fusion protein;
Chang,* 11 which provides results of anti-IGF-IRhRl IgG-AD fusion
protein attached to hRl Fab-DDD fusion protein (Hex-hRl);
Gupta,12 which provides results of anti-CD20 or anti-CD74 IgG-AD
fusion proteins with anti-CD74 or anti-CD20 FabDDD fusion proteins; and
Rossi (2008), which provides results of anti-CD20 IgG-AD or anti-
CD20 Fab-AD fusion proteins attached to anti-CD20 Fab-DDD fusion
proteins.
We are not persuaded by this evidence that Appellants’ claimed fusion
proteins would not have been obvious because the results noted by
Appellants are of antibody-DDD fusion proteins complexed with antibody-
AD fusion proteins. Because the claimed fusion protein does not include a
10 Abstract No. 2762, 54th ASH Annual Meeting (2012).
11 PFoS One 7:e44235 (2012).
12 119 Blood 3767-78 (2012).
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Application 13/528,077
component fused to an AD moiety, this evidence is not commensurate in
scope with Appellants’ claimed subject matter. See In re Grasselli, 713 F.2d
731, 743 (Fed. Cir. 1983) (“It is well settled ‘that objective evidence or non­
obviousness must be commensurate in scope with the claims which the
evidence is offered to support.’” (quoting In re Tiffin, 448 F.2d 791 (CCPA
1971)). The results noted by Appellants relate only to the claimed fusion
proteins in complex with an additional protein, but non-complexed fusion
proteins are encompassed by Appellants’ claims because they are the only
proteins expressly recited.
Appellants also argue that Rossi (2008) also reports potent
antiproliferative activity against cancer cells with a tetrameric Fab that
includes four copies of antibody Ifagment-DDD fusion protein without an
antibody-AD or antibody fragment-AD fusion protein. (App. Br. 8-9, citing
Rossi (2008) at abstract, pg. 8386, col. 1, 3rd paragraph; pg. 8387, col. 1, 1st
paragraph; and Figures 1, 4b and 5a.) We are not persuaded by the reported
results of this antibody-DDD fusion protein because even if it demonstrates
potent antiproliferative activity, Appellants do not direct us to evidence that
such activity was unexpected. Appellants do not direct us to a comparison
of this activity with the closest prior art or to evidence showing what those
of ordinary skill in the art would have considered about the level of reported
activity. Accordingly, we are not persuaded that the results obtained with
the antibody-DDD fusion protein of Rossi 2008 would have been considered
to be unexpected by an ordinarily skilled artisan.
After reviewing Appellants’ arguments and evidence, we are not
persuaded that the Examiner erred in rejecting Appellants’ current claims.
Conclusion
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Application 13/528,077
Upon consideration of the record and for the reasons given by the
Examiner, the rejection of claims 1 and 4-6 under 35 U.S.C. § 103(a) over
Makowski, Braun, and either Banky or Newlon is sustained and the rejection
of claim 3 under 35 U.S.C. § 103(a) over Makowski, Braun, and either
Banky or Newlon, as well as Hansen, is sustained.
Therefore, we affirm the decision of the Examiner.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136.
AFFIRMED
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