Ex Parte Chang et al

Patent Trial and Appeal Board

Mar 24, 2017

12869823 (P.T.A.B. Mar. 24, 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.
IBC128US1 8577
EXAMINER
HUYNH, PHUONG N
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
12/869,823 08/27/2010
63322 7590 03/24/2017
IMMUNOMEDICS, INC.
300 AMERICAN ROAD
MORRIS PLAINS, NJ 07950
Chien-Hsing Chang
03/24/2017 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 and
DAVID M. GOLDENBERG
Appeal 2014-008773
Application 12/869,823
Technology Center 1600
Before DEBORAH KATZ, ULRIKE W. JENKS, and JOHN G. NEW,
Administrative Patent Judges.
KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appeal 2014-008773
Application 12/869,823
Appellants1 seek our review, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 1 and 5—13.2 (App. Br. 1.) We have
jurisdiction under 35 U.S.C. § 6(b). We affirm.
Appellants cite to the following applications and appeals as being
related to this appeal: Application 13/528,077 (Appeal 2014-002239);
Application 13/483,761 (Appeal 2014-002802); and Application 13/567,226
(Appeal 2014-008841). (See App. Br. 2)
Introduction
Appellants claim a construct of several proteins that includes effector
moieties (antibodies, or fragments of antibodies, and cytokines) and
components to bind the effector moieties into a “DNL (dock and lock)”
construct. (See Spec. 3.)
Claims 1 and 5—13 are currently pending and rejected3 under 35
1 The real party in interest is said to be IBC Pharmaceuticals, Inc. (App. Br.
1.)
2 Claims 1 and 5—13 are currently pending in this application, following
cancelation of claims 2-4 and 14-25. (App. Br. 2.)
3 Appellants state that claim 9 was not rejected on any grounds. (App. Br. at
5). We disagree because we accept the Examiner’s explanation that the
omission of claim 9 in the Final Office Action was due to an oversight. The
Examiner notes that the Final Office Action includes discussion of the
disclosure of sequences of the humanized L243 antibody, as recited in
claim 9, in Goldenberg. (See Final Office Action of Nov. 21, 2013 at p. 10,
citing Goldenberg at Figs. 1 and 2; see Ans. 9.) Appellants do not contest
this explanation in their Reply Brief and the explanation indicates that
Appellants were on notice of the substance of the rejection of claim 9.
Accordingly, we consider claim 9 to have been rejected under 35 U.S.C.
§103.
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Application 12/869,823
U.S.C. § 103 as being obvious over Chang l,4 Chang 2,5 Chang 3,6 and
Goldenberg.7 (Ans. 2-9.)
Appellants assert that claim 1 is representative of claims 1 and 5-7 and
that claim 8 is representative of claims 8-13. (App. Br. 5.) Appellants state
that “[cjlaims 1 and 8 are argued separately for appeal” {id.), but the only
separate argument that they provide regarding claim 8 is to note that in
regard to the evidence of unexpected results, claim 8 is narrower in scope
than claim 1. Accordingly, we focus on claim 1 in our analysis below, and
address Appellants’ arguments about claim 8 in our discussion of
unexpected results. See 37 C.F.R. § 41.37(c)(l)(iv).
Claim 1 recites:8
A trimeric DNL (dock and lock) construct comprising
three different effector moieties, wherein the effector moieties
are attached to either
[1] a DDD (dimerization and docking domain) moiety
from human protein kinase A (PKA) RIa, Rip, Rlla or RIip or
[2] an AD (anchoring domain) moiety from an AKAP
protein, and
wherein two copies of the DDD moiety form a dimer and
bind to the AD moiety to form the DNL construct,
wherein the effector moieties comprise
[a] a first antibody or antigen-binding antibody fragment
thereof,
4 US Patent Application Publication 2009/0202487 Al, published August
13,2009.
5 US Patent Application Publication 2006/0228357 Al, published October
12, 2006.
6 Clinical Cancer Research 13(18 Suppl) 5586s-5591s.
7 US Patent Application Publication 2006/0210475 Al, published September
21,2006.
8 Indentations and bracketed numbers and letters added for clarity.
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Application 12/869,823
[b] a second antibody or antigen-binding antibody
fragment thereof, and
[c] a cytokine and
the first antibody or antigen-binding antibody fragment
thereof binds to a different antigen than the second antibody or
antigen-binding antibody fragment thereof.
(App. Br. 12, Appendix A (formatting added).)
Accordingly, Appellants’ claimed construct has three parts, each
attached to either a “DDD (dimerization and docking domain)” moiety from
human protein kinase A (“PKA”) or to an “AD (anchoring domain)” from
the AKAP protein, to which the DDD moiety binds. (See Spec., 13.) The
claimed constructs include three different effector moieties attached to either
the DDD or AD moieties. The effector moieties include two different
antibodies or antigen-binding antibody fragments and a cytokine. (See Spec.
3.)
Findings of Fact
1. Chang 1 teaches constructs, called dock and lock (“DNL”)
constructs. (Chang 1, abstract.)
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Application 12/869,823
2. Figure 1 of Chang 1 is reproduced below.
FKZ 1
CH3~AD2~igG~v-mab + IFNa2b-DDD2 —>4 20~2b
Figure 1 depicts the gene structures (A and B) for expression of cytokine
(IFNa2b)-DDD2, and antibody (IgG-v-Mab)-AD2 DNL modules. The
modules are combined to form DNL structures consisting of four cytokines
fused to an antibody (C).9 (Chang 1,126.)
3. Chang 1 teaches a DNL construct comprising four IFNa2b
cytokines attached to a humanized anti-CD20 antibody (hA20) that can be
used to treat lymphomas, leukemias, myelomas and related conditions.
(Chang 1,120.)
4. Chang 1 teaches that “other types of DNL complexes with
different structures and different ratios of cytokine to antibody or antibody
9 Paragraph 26 of Chang 1 refers to panels (D) and (E) of Figure 1. These
panels are not shown, but the description of panel (E) seems to be of the
panel (C) present in Figure 1, which is consistent with the Examiner’s
understanding on page 3 of the Answer.
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Application 12/869,823
fragment may be constructed and used within the scope of the claimed
methods and compositions.” (Chang 1, |11.)
5. Chang 1 teaches that an antibody fusion protein may comprise a
single antibody component, a multivalent or multispecific10 combination of
different antibody components or multiple copies of the same antibody
component. (Chang 1,125.)
6. Chang 2 teaches a “tyPe 5 category” construct that has a
bispecific tetravalent binding protein composed of two different a2 subunits,
for example, an a2a'2 product composed of two Fab fragments of
trastuzumab and two Fab fragments of pertuzumab. (Chang 2,120.)
7. Chang 2 teaches that complexes comprising two antibody
fragments may be more efficacious than treatments with only one antigen
specificity. (Chang 2,120.)
8. Chang 2 provides Table 5, with selected examples of “type 5”
products that allow for binding domains of two different immunoglobulins.
(Chang 2, at pp. 2-3.)
9. Chang 2 teaches stably tethered structures that comprise
combinations of structures having binding specificities including an anti-
CD20 antibody or fragment combined with an anti-HLA-DR antibody or
fragment. (Chang 2,133.)
10. Chang 3 teaches multispecific complexes of different antibody
fragments fused to either AD or DDD moieties. (Chang 3, at 5587s.)
10 Chang 1 explains that a natural antibody is bivalent because it has two
binding arms but is monospecific because it binds to one epitope. (Chang 1,
125.)
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Application 12/869,823
11. Chang 3 teaches that DNL is a modular system, where “[t]here
is essentially no limit on the types of precursors that can be derived into a
DDD or AD module, so long as the resulting modules do not interfere with
the dimerization of DDD or the binding of DDD to AD.” (Chang 3, 5590s.)
12. Goldenberg teaches the humanized anti-HLA-DR antibody,
L243. (Goldenberg, | 87 and Figs. 1 and 2.)
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 rejected claims 1 and 5-13 as being obvious under 35
U.S.C. § 103 because Chang 1 teaches trimeric DNL (dock and lock)
constructs that include antibodies to cytokines and cytokines. Specifically,
Chang 1 teaches complexes that include an antibody (IgG) attached to two
AD moieties, wherein each IgG-AD fusion binds to two cytokine-DDD
fusion proteins by docking of the DDD moieties to the AD moieties. (See
FFs 1-2.) Chang 1 provides the specific example of a complex of a CH3-
AD2-IgG, which has an antibody that binds to CD20, complexed with two
homodimers of the cytokine IFN-a2b fused to DDD moieties. (See FF 3.)
The resulting complex has two CD20 binding proteins and four IFN-a2b
molecules. (Ans. 3 and 7.)
Chang 1 also teaches that in addition to monospecific antibody fusion
proteins, the fusion proteins of the complex may be a combination of
different antibody components that are multispecific because they bind
different antigens. (Ans. 3; see FFs 4 and 5.)
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Application 12/869,823
The Examiner finds that, like the claimed invention, Chang 2 teaches
constructs that are bispecific because they include fragments from different
antibodies. (Ans. 6; see FFs 6 and 8.) Chang 2 specifically discloses a
stably-tethered complex of an anti-CD20 protein combined with an anti-
HFA-DR protein that can be used to create bispecific antigen-binding
structures. (Ans. 6; see FF 9.)
The Examiner also cites to Chang 3 for its teaching of multivalent,
bispecific antibody complexes and for explaining that the advantage of the
DNF system is its modularity, wherein each DDD and AD containing
moiety can be paired with any other. (Ans. 7; see FFs 10-11.)
The Examiner concludes that it would have been obvious to use the
technique of Chang 1 to create DNF structures with antibodies or fragments
and cytokines, as modified by the teaching in Chang 2, to use bispecific
antigen-binding proteins. (Ans. 7.) Specifically, the Examiner finds that it
would have been obvious to substitute one of the two cytokine IFNa2b-
DDD moieties of Chang 1 with the antibody fragment-DDD that binds to
HFA-DR, taught in Chang 2, to create a trimeric complex having two
antibody proteins — an anti-CD20 (present as the AD fusion protein) an anti-
HFA-DR (present as one of the DDD fusion proteins), in addition to an
IFNa2b fused to the other DDD moiety. (Ans. 7.)
The Examiner finds, further, that one of ordinary skill in the art would
have had reason to make the substitution because Chang 2 teaches that two
different antigen-binding fragments may be more efficacious for treating
cancers. (Ans. 7; see FF 7.)
The Examiner also finds that there would have been a reasonable
expectation of success in making this substitution because the two DDD
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Application 12/869,823
fusion proteins were known to spontaneously form a dimer and then
complex with the AD fusion protein to form a2b structure. (Ans. 9.) The
Examiner finds that Chang 3 provides an expectation of success by teaching
that the DNL system is modular, wherein any DDD module can be paired
with any AD module. (Ans. 9; see FF 11.)
Appellants argue that the Examiner erred because Chang 1 teaches a
complex of two different types of subunits (an antibody or fragment
conjugated to an AD moiety and an interferon attached to a DDD moiety)
represented by the designation “a2b”, while the claimed fusion protein has
three different types of subunits (a first antibody or fragment, a second
antibody or fragment, and a cytokine) represented by the designation “abc.”
(App. Br. 6-8.) We are not persuaded by this argument because the
Examiner’s rejection does not rely solely on Chang 1.11 Instead, the
rejection is based on the modification of the express complexes disclosed in
Chang 1 in view of the other references cited: Chang 2, and Chang 3.
Appellants’ argument about the differences between the claimed fusion
proteins and Chang 1 are not persuasive because “[n]on-obviousness cannot
be established by attacking references individually where the rejection is
11 In the Reply Brief, Appellants argue that because the Examiner
determined that the Appellants’ instant application cannot claim priority to
the filing date of the application (12/418,877) published as Chang 1, which
is recited in Appellants’ claim for priority, the Examiner erred in rejecting
over the current claims over Chang 1. (Reply Br. 2-3.) Appellants have not
argued there is good cause to consider this argument, which was not raised
in their Appeal Brief. (See 37 C.F.R. § 41.41(b)(2).) We note the
Examiner’s rejection was based on the combined teachings of several
references, not on the disclosures in Chang 1 alone.
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Application 12/869,823
based upon the teachings of a combination of references.” In re Merck &
Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). To the extent that
Appellants argue that neither Chang 2 nor Chang 3 teaches or suggests
producing, purifying, and using an abc type complex as claimed (see App.
Br. 9-10), we are similarly not persuaded.
Appellants also argue that the prior art teaches away from the claimed
fusion proteins because it teaches using only two different subunits, which
Appellants argue would avoid the extensive purification protocols that cause
a decreased yield and increased time and expense. (App. Br. 8-9.)
Appellants cite to paragraphs three and four of Chang 2, which discuss the
need for methods of manufacturing that are low cost and produce high yields
without extensive purification steps. (Id.)
Under the proper legal standard, a reference teaches away when it
suggests that the developments flowing from its disclosures are unlikely to
produce the objective of the applicant's invention. Syntex LLC v. Apotex,
Inc. 407 F.3d 1371, 1380, (Fed. Cir. 2005). The objective of Appellants’
claimed invention is the presentation of three different entities joined by a
DNL system into one complex. Appellants do not direct us to teachings in
any of the cited prior art that indicates this objective could not be achieved
by modifying the complexes taught by substituting elements. Even if the
purification scheme for a three component complex is necessarily more
extensive than for a two component complex, we are not persuaded that the
cited prior art teaches away from the objective of Appellants’ claimed
invention. Accordingly, Appellants’ argument is not persuasive.
In its Reply Brief, Appellants argue that Chang 1 also teaches away
from the claimed fusion proteins because it teaches that having four
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Application 12/869,823
cytokines contributes to enhanced potency. (Reply Br. 5.) Appellants have
not argued there is good cause to consider this argument, which was not
raised in their Appeal Brief. See 37 C.F.R. § 41.41(b)(2). Therefore, we
need not consider this argument. Even if we did, we note that Appellants
fail to direct us to any specific teaching in Chang 1 that would have been
understood by one of ordinary skill in the art to discourage the use of two
cytokines. “A reference may be said to teach away when a person of
ordinary skill, upon reading the reference, would be discouraged from
following the path set out in the reference, or would be led in a direction
divergent from the path that was taken by the applicant.” In re Gurley, 27
F.3d 551, 553 (Fed. Cir. 1994).
In making a determination on the merits of the Examiner’s rejection,
we consider the evidence of unexpected results presented by Appellants.
Appellants argue that the results reported in Example 23 of their
Specification would have been considered to be unexpected by those of
ordinary skill in the art. (App. Br. 10-11.) Specifically, Appellants argue
that the effectiveness of a three-component complex compared to a two
component complex in sensitive versus resistant cells would have been
unexpected. Example 23 reports that the three-component complex (“20-
C2-2b”) demonstrated an EC50 of 8 x 10'5 M in the sensitive Daudi
lymphoma cells, compared to an EC50 of 4 x 10'4 nM for the two-component
complex (“20-2b-2b”).12 (See Spec. 1264.) Appellants compare these
12 Appellants argue that the difference between the EC50 value of the two-
component complex compared to the three-component systems is “an order
of magnitude” (App. Br. 10), but the difference is characterized in their
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Application 12/869,823
results with the EC50 values reported for the more resistant cell line, Raji, of
0.3 nM for the three-component complex 20-C2-2b and 15.56 nM for two-
component complex 20-2b-2b. According to Appellants, the 50-fold
difference in Raji cells was surprising. (App. Br. 10-11, citing Spec., Fig.
13, Table 3.) Appellants also argue that 10 out of the 12 cell lines tested
demonstrated a potency difference between the three- and two-component
complexes of an order of magnitude. (Id.) According to Appellants, these
results could not have been predicted from the prior art.
We are not persuaded that these results would have been unexpected
by those of ordinary skill in the art. Appellants do not direct us to evidence
that one of skill in the art would have found them surprising, but instead
provide only an unsupported attorney statement to this effect. We note that
Appellants’ Specification explains that the resistant Raji cells have a “much
greater HLA-DR antigen density than CD20.” (Spec., 1266.) Appellants do
not explain whether the greater antigen density would have been expected to
lead to greater targeting. In the absence of evidence, such as a statement by
one of ordinary skill in the art regarding whether the results would have been
unexpected, we are not persuaded that the results to which Appellants direct
us demonstrate the nonobviousness of the claimed construct. “Argument of
counsel cannot take the place of evidence lacking in the record.” Meitzner v.
Mindick, 549 F.2d 775, 782 (CCPA 1977).
Appellants argue that claim 8 is narrower than claim 1 and, therefore,
would be commensurate with the scope of the unexpected results reported.
specification as being only a “5-fold” (i.e., a half-magnitude) difference
(Spec., 1264).
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(App. Br. 11.) Because Appellants have not persuaded us that these results
would have been unexpected by one of ordinary skill in the art, we are not
persuaded that they demonstrate the Examiner erred in rejecting either claim
1 or claim 8.
We note that in their Reply Brief, Appellants raise an issue of the
determination of a priority date for their pending claims. (See Reply Br. 2-
3.) According to Appellants, the Examiner indicated in the Answer that
Chang 1 exemplifies a trimeric DNL construct having three different
effector moieties as in Appellants’ claim 8. (See Ans. 6.) Appellants argue
that this assertion is without merit because Chang 1 discloses constructs with
only two different effector moieties. (Reply Br. 2.) But, Appellants also
argue that because the Examiner refused to award the filing date of Chang 1
(which is recited in the claim to priority in Appellants’ current application),
the Examiner cannot assert that Chang 1 discloses a three-component
construct for the purposes of asserting obviousness under 35 U.S.C. § 103.
(Reply Br. 3.) According to Appellants, if Chang 1 discloses a three-
component construct, the current claims are entitled to priority of the date of
its filing and Chang 1 is not prior art. (App. Br. 3.)
Appellants do not argue in the Appeal Brief that its claims should
have been accorded the benefit of the filing date of Chang 1 because it meets
all the requirements of 35 U.S.C. §§ 119, 120, or 121. Nor do Appellants
indicate that there was good cause why they could not have done so.
Accordingly, we do not consider the issue of whether the Examiner properly
denied benefit of the filing date of Chang 1. See 37 C.F.R. § 41.41(b)(2).
We note that because a reference was cited as the basis, in part, for a
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Application 12/869,823
rejection under 35 U.S.C. § 103 does not necessarily indicate that it discloses
all of the elements of a specific claim.
After reviewing Appellants’ arguments and evidence, we are not
persuaded that the Examiner erred in rejecting claims 1 and 5-13.
Conclusion
Upon consideration of the record and for the reasons given, the
rejection of claims 1 and 5-13 under 35 U.S.C. § 103(a) over Chang 1,
Chang 2, Chang 3 an Goldenberg 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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