Ex Parte Chang et al

Patent Trial and Appeal Board

Mar 17, 2017

13528077 (P.T.A.B. Mar. 17, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
IMM321US2 5430
EXAMINER
HUYNH, PHUONG N
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
13/528,077 06/20/2012
63322 7590 03/20/2017
IMMUNOMEDICS, INC.
300 AMERICAN ROAD
MORRIS PLAINS, NJ 07950
Chien-Hsing Chang
03/20/2017 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 2014-002239
Application 13/528,077
Technology Center 1600
Before DEBORAH KATZ, ULRIKE W. JENKS, and JOHN G. NEW,
Administrative Patent Judges.
KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appeal 2014-002239
Application 13/528,077
Appellants1 seeks our review, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claim 28. (App. Br. 1.) We have jurisdiction
under 35 U.S.C. § 6(b). We affirm.
Appellants cite the appeal in application 13/483,761 (Appeal 2014-
002802) as a being related to this appeal. (App. Br. 2.) Appellants also
indicate that the appeal of application 13/295,647 is related {id.), although it
appears that a subsequent request for continued examination was made in
that application.
Introduction
Claim 28 is currently pending in this application, in light of the
cancellation of claims 29 and 30 and the withdrawal of claims 1—27. (App.
Br. 2 ; see Amendment filed February 28, 2013.) We consider the rejection
of claim 28.2
Appellants’ invention is in the field of compositions of toxins,
preferably the toxin ranpimase (“Rap”). (Spec. 14.) These toxins can be
used for the treatment of cancers and other therapeutic uses by targeting and
killing specific cells. (Spec. 1 5.) Appellants’ Specification provides for
1 The real party in interest are said to be Immunomedics, Inc. and IBC
Pharmaceuticals, Inc. (App. Br. 1.)
2 Appellants state that claims 1-28 are the subject of the instant appeal, but
the Examiner has only rejected claim 28, following withdrawal of claims 1-
27. (App. Br. 2; see also App. Br. 9-10 (arguments regarding claim 1).)
Because the only rejection before us is of claim 28 {see Final Office Action
of March 8, 2013), we do not consider claims 1-27. See 37 C.F.R.
§ 41.31(a) (“Who may appeal. ... (1) Every applicant, any of whose claims
has been twice rejected, may appeal from the decision of the examiner to the
Board . . . .” (emphasis added).)
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Application 13/528,077
embodiments of these toxins that are immunotoxins, that is, toxins fused to
antibodies or antibody fragments in order to target such cells. (Id.)
In certain embodiments, these immunotoxins are part of “dock-and-
lock” (“DNL”) constructs, wherein the antibody or antibody fragment entity
is a fusion protein comprising two “anchoring domain” (“AD”) moieties and
the ranpimase entities are fusion proteins comprising a “dimerization and
docking domain” (“DDD”) moieties. (Spec. 1 5.) According to Appellants’
specification, “[t]he DDD moieties spontaneously form dimers which bind
to an AD moiety, producing a DNL construct comprising four copies of the
cytotoxin conjugated to one antibody or antibody fragment.” (Id.)
Figure 15 of Appellants’ specification depicts a Rap DNL construct
and is reproduced below.
FIG. 15
Part A of Figure 15 depicts an antibody fused to two ADs. (Spec. 140.)
Part B of Figure 15 depicts a Rap-DDD2 module. (Id.) Part C of Figure 15
depicts the interaction of the AD and DDD components to form a Rap
immunotoxin (“IgG-Rap”) construct with four copies of the Rap toxin. (Id.)
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Application 13/528,077
Appellants’ specification states that immunotoxins in a DNL construct
“show greater potency against target cells than the parent antibody alone, the
cytotoxin alone, a non-conjugated combination of antibody and cytotoxin or
cytotoxin conjugated to a control antibody.” (Spec., 1 5.)
Appellants’ current claim recites only the Rap and DDD portions of
an IgG-Rap DNL construct as depicted in part B of Figure 15. Claim 28
recites:3
A fusion protein comprising
[1] ranpimase attached to
[2] a DDD (dimerization and docking domain) moiety
from human protein kinase A (PKA) Rlla or RIip,
wherein the amino acid sequence of the DDD moiety is
selected from the group consisting of residues 1-44 of human
PKA Rlla and residues 1-44 of human PKA RIip.
(App. Br. 15, Appendix A.) Thus, claim 28 is not limited to a fusion protein
including antibody or antibody fragment portions or to fusion proteins
including an AD moiety.
The Examiner rejected claim 28 under 35 U.S.C. § 103 as being
obvious over Braun,4 Rybak,5 and either Newlon6 or Banky.7
The Examiner also rejected claim 28 as under 35 U.S.C. § 103 as
being obvious over Pliickthun,8 Rybak, and either Newlon or Banky.
3 Indentations and bracketed numbers add for clarity.
4 U.S. Patent Application Publication No. 2003/0232420 Al, published
December 18, 2003.
5 U.S. Patent No. 6,045,793, issued April 4, 2000.
6 Newlon et al., 6 Nature Structural Biology 222-27 (1999).
7 Banky et al., 237 J Biol. Chem. 35048-55 (1998).
8 U.S. Patent No. 5,910,573 issued June 8, 1999.
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Application 13/528,077
Findings of Fact
1. Braun teaches that particular isoforms of the regulatory subunit
(“R”) of Protein Kinase A (“PKA”), e.g., PKA-RIa or PKA-RIIa, bind to
their target protein, AKAP. (Braun 113.)
2. Braun teaches that mouse PKA regulatory subunits, such as
Rlla, include a “dimerization/docking (D/D) domain,” which can be fused to
other proteins, such as green fluorescence protein (GFP), to form fusion
proteins such as a PKA-RIIa-GFP fusion protein. (Braun, 1269; see also
1254.)
3. Braun teaches that PKA-RIIa-GFP has higher affinity for an
AKAP-derived peptide than does PKA-RIa. (Braun 1279.)
4. Braun does not teach human DDDs.
5. 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.)
6. Banky teaches dimerization docking domains from various
protein kinase A regulatory subunits, including human PKA Rlla (residues
lto44) and human PKA RIip (residues 1^44). (Banky at 35054, Fig. 8.)
7. Rybak teaches the toxin ranpimase (“Rap”) also called
Onconase®or nOnc. (Rybak at 2:22-35.)
8. Rybak teaches that
rOnc molecules may be used alone or conveniently used to
form chemical conjugates, as well as to form targeted
recombinant immunofusions. These rOnc molecules can be
used to decrease tumor cell growth. An effective recombinant
form of nOnc advantageously permits the recombinant
molecule to be fused to other therapeutic or targeting molecules
of interest recombinantly.
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Application 13/528,077
(Rybak at 2:29-35.)
9. Rybak teaches:
The rOnc molecules are uniquely adapted for gene therapy
applications. They can be fused to other therapeutic agents, for
example, they could be fused to an anti-B cell lymphoma
antibody. For example, as will be explained in more detail
below, rOnc molecules recombinantly fused to an anti­
transferrin receptor antibody or an anti-colon cancer antibody
were active.
(Rybak at 13:23-29.)
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 prior art cited by the Examiner shows that PKA-RIIa and -RIip
DDDs and Rap have been successfully fused to other proteins to achieve
their intended effects of dimerization and docking. For example, Braun
teaches that mouse PKA-RIIa DDD has been used to achieve dimerization
and docking to AKAP, even when fused to GFP. (FFs 1-3.) Rybak teaches
that the Rap protein had been fused to antibodies to target its toxic effects to
specific cells. (FFs 7-9.) The Examiner’s rejection of claim 28 relies on
modifications of these prior art fusion proteins by substituting different
domains.
Specifically, the Examiner concludes that it would have been obvious
for one of ordinary skill in the art to have modified the mouse PKA-RIIa-
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Application 13/528,077
GFP protein of Braun (FF 2) by substituting human PKA-RIIa of Newlon
(FF 5) or the human PKA-RIip of Banky (FF 6) for the mouse PKA-RIIa
protein of Braun. (Ans. 4.) The Examiner also concludes that it would have
been obvious to substitute Rap as taught in Rybak (FFs 8-10) for the GFP
protein of Braun. (Ans. 4.)
The Examiner finds that one of ordinary skill in the art would have
had a reason to make these modifications of the fusion protein taught in
Braun because it was known that the DDD of PKA RII moieties allow for
more than one toxin protein and, therefore, enhanced cytotoxicity. (Ans. 5,
9-10, and 11.) The Examiner also finds that one of ordinary skill in the art
would have had a reason to use a human DDD PKA Rlla moiety because it
was known to be less immunogenic when administered to a human subject
as a therapeutic agent. (Ans. 10 and 11.)
The Examiner finds that those of ordinary skill in the art would have
had a reasonable expectation that the resulting fusion protein would be
successful because Braun teaches that fusion proteins between mouse Rlla
DDD and GFP are active (FF 2). (Ans. 4.) Additionally, the Examiner finds
that one of ordinary skill in the art would have had a reasonable expectation
of success because Rybak teaches that Rap is useful as a therapeutic
treatment when fused to other proteins (FFs 9 and 10). (Ans. 4-5.)
Appellants present several arguments that each of the prior art
references cited by the Examiner do not individually render the claimed
fusion protein obvious. For example, Appellants argue that Braun does not
teach or disclose using the AD and DDD moieties of PKA Rlla to construct
synthetic complexes for delivery of antibodies, antibody fragments or
therapeutic proteins, peptides, or toxins. (App. Br. 5; Reply Br. 2.)
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Similarly, Appellants argue that although Rybak teaches the Rap toxin, it has
no disclosure of DDD moieties from human PKA. (App. Br. 5.) Appellants
argue further that, although Newlon and Banky teach structure-function
relationships in DDD moiety sequences, they do not teach or suggest using
PKA DDD moieties to assemble synthetic complexes comprising toxins
such as ranpimase. (Ans. 6.) 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 Merck & Co., Inc., 800 F.2d 1091, 1097
(Fed. Cir. 1986).
Appellants also argue that one of skill in the art would not have had
any motivation to make the substitution of the Examiner’s rejection because
substituting the DDD moiety of Braun, Newlon, or Banky for the antibody
moiety of Rybak, would result in a fusion protein with an untargeted Rap,
which would be equally likely to kill non-targeted, normal tissue as it is to
kill tumor cells or other desired tissue. According to Appellants, an
untargeted fusion protein resulting from the substitution of a DDD moiety of
Braun, Newlon, or Banky for the antibody targeting domain of Rybak would
result in a dimer that is more toxic to non-targeted normal tissues and less
toxic to tumor or other diseased tissues. We are not persuaded by this
argument because Appellants do not claim a fusion protein limited by
targeting to any specific tissue. Thus, even if a fusion protein comprising an
untargeted Rap toxin kills cells indiscriminately, it falls within the scope of
Appellants’ claim.
We are also not persuaded by Appellants’ argument that one of
ordinary skill in the art would not have been motivated to substitute the Rap
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Application 13/528,077
moiety of Rybak for the GFP moiety of Braun because the resulting protein
would no longer work for the purpose intended in Braun. (App. Br. 7.)
Appellants argue that the GFP-DDD fusion protein of Braun was intended to
determine binding and subcellular localization of AKAP muteins, but if Rap
were substituted for GFP the cells would be killed and no localization
studies could be performed. (Id.; see also Reply Br. 2-3.)
This argument is not persuasive because the intended purpose of the
DDD domain of Braun was to demonstrate association of the PKA subunit
with its target AKAP through the interaction of the DDD moiety and the AD
moiety. (See Braun, 1269: “In addition, the minimal sequence required for
regulatory subunit binding was also assessed using N- and C-terminal
truncations of the 27-residue human D-AKAP2 sequence. . . . Binding was
evaluated by incubating each membrane with GFP-RIa D/D and GFP-RIIa
D/D as indicated below.”) Thus, the DDD taught in Braun was intended to
associate with an AD, with the GFP serving only as a way to visualize this
interaction. Appellants have not directed us to evidence that the interaction
between the DDD and AD moieties would be any different if the DDD
moiety were fused to Rap. Instead, we are persuaded that the DDD taught in
Braun would have the same dimerization and AD-binding function in a Rap-
DDD fusion protein as claimed.
In making a determination on the Examiner’s rejection, we consider
the evidence of unexpected results presented by Appellants. Appellants
argue that Examples 16 and 17 of their specification demonstrate the
unexpected results achieved with the claimed fusion proteins. (App. Br. 9.)
According to Appellants, the results obtained with cells exposed to anti-
CD2-Rap conjugates and anti-EGP-l-Rap complexes were unexpectedly
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Appeal 2014-002239
Application 13/528,077
superior to those reported in the prior art because the EC50 values reported
with these fusion proteins were significantly lower than the antibody
conjugates reported in Rybak. (Id. )
We are not persuaded that these results are unexpected because
Appellants do not direct us to evidence that one of skill in the art would have
considered them to be unexpected. Appellants do not direct us to a
discussion in the Specification of what was unexpected or to testimony of
what a ordinarily skilled artisan would have considered to be unexpected at
the time. “Argument of counsel cannot take the place of evidence lacking in
the record.” Meitzner v. Mindick, 549 F.2d 775, 782 (CCPA 1977).
In addition, we agree with the Examiner that the results discussed in
Examples 16 and 17 are not commensurate in scope with Appellants’
currently claimed invention because the fusion proteins of the examples are
targeted to specific cells. (Ans. 16-17.) In contrast, Appellants’ claimed
fusion proteins do not require a complex with an antibody fusion protein to
target the Rap fusion protein.
Appellants argue further that their claimed fusion proteins can only be
used in a complex with a targeting moiety and, thus, the results reported in
Examples 16 and 17 are commensurate in scope with their claims. (Reply
Br. 5.) Appellants point to a paragraph of their Specification, which
describes an embodiment of the invention that includes a targeting moiety.
(Reply Br. 5, citing Spec., 14.) We are not persuaded by this argument
because although we look to the Specification to interpret claims, we give
them the broadest reasonable interpretation consistent with the Specification,
without importing limitations that are not expressly defined in the
Specification or expressly provided in the claims. See In re Am. Acad, of
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Appeal 2014-002239
Application 13/528,077
Sci. Tech. Or., 367 F.3d 1359, 1364 (Fed. Cir. 2004) (“ During examination,
‘claims ... are to be given their broadest reasonable interpretation consistent
with the specification, and ... claim language should be read in light of the
specification as it would be interpreted by one of ordinary skill in the art.’”
(quoting In re Bond, 910 F.2d 831, 833 (Fed. Cir. 1990)); see In re Prater,
415 F.2d 1393, 1395 (CCPA 1969) (‘“reading a claim in the light of the
specification, ’ to thereby interpret limitations explicitly recited in the claim,
is a quite different thing from ‘reading limitations of the specification into a
claim, ’ to thereby narrow the scope of the claim by implicitly adding
disclosed limitations which have no express basis in the claim.”). Thus,
even if Appellants provided for a preferable embodiment in their
Specification, we have not been directed to language that would necessarily
limit the entire scope of the current claims to inclusion of a targeting moiety.
We note, but are not persuaded by, Appellants’ argument regarding a
lack of motivation to make an untargeted fusion protein because it would be
more toxic to normal tissue and less toxic to tumor or other diseased tissues
(see App. Br. 6-7). The argument is not persuasive because there is no
evidence that an untargeted fusion protein comprising Rap-DDD has
different toxicities on the different cell types. The evidence to which we
have been directed by Appellants does not persuade us that EC50 values
reported in Examples 16 and 17 would have been unexpected or would be
applicable to untargeted fusion proteins that fall within the scope of
Appellants’ claims. Accordingly, Appellants have not directed us to
evidence that a Rap-DDD fusion protein is not obvious.
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Application 13/528,077
After consideration of Appellants’ arguments and evidence, we are
not persuaded that the Examiner erred in rejecting claim 28 as being obvious
over Braun, Raybak, and either Banky or Newlon.
Having affirmed the rejection of claim 28 on appeal, we see no need
to address the alternative grounds of rejection set out in the Answer and
Final Action, and do not reach the rejection of claim 28 as being obvious
over Pluckthun, Rybak, and either Newlon or Banky.
Conclusion
Upon consideration of the record and for the reasons given, the
rejection of claim 28 under 35 U.S.C. § 103(a) over Braun, Rybak, and
either Newlon or Banky 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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