Jean Wang et al.

Patent Trials and Appeals Board

Jun 29, 2020

2019006491 (P.T.A.B. Jun. 29, 2020)

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.
13/320,629 04/02/2012 Jean C.Y. Wang 32820/52302 7929
4743 7590 06/29/2020
MARSHALL, GERSTEIN & BORUN LLP
233 SOUTH WACKER DRIVE
6300 WILLIS TOWER
CHICAGO, IL 60606-6357
EXAMINER
DENT, ALANA HARRIS
ART UNIT PAPER NUMBER
1643
NOTIFICATION DATE DELIVERY MODE
06/29/2020 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):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JEAN C.Y. WANG, JOHN DICK, JAYNE DANSKA,
LIQING JIN, ALEXANDRE
THEOCHARIDES, and SUJEETHA RAJAKUMAR
__________

Appeal 2019-006491
Application1 13/320,629
Technology Center 1600
__________

Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for treating a patient having cancer cells or tumours that are CD47+, which
have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as University
Health Network, The Hospital for Sick Children, and Trillium Therapeutics,
Inc. (Appeal Br. 2.)
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STATEMENT OF THE CASE
According to Appellant’s Specification it is known that “CD47 is
expressed in most human AML [(acute myeloid leukemia)] samples.”
(Spec. 2.) “CD47 is [also] present on most hematopoietic cells.” (Id. at 1.)
“CD47 expression is higher on human AML LSCs [(human leukemia
initiating cells)] compared to normal HSCs [(hematopoietic stem cells)].”
(Id. at 2.) However, “little is known about molecular regulators that govern
AML-LSC fate.” (Id.)
Appellant’s Specification states that “[t]reatment of immune-deficient
mice engrafted with human AML with a monoclonal antibody directed
against CD47 results in reduction of leukemic engraftment in the murine
bone marrow.” (Id.)
“In mouse and human, Sirpa encodes for the SIRPα protein which
interacts with its ligand CD47. In the hematopoietic system, SIRPα is
mainly found on macrophages, dendritic cells, and granulocytes.” (Spec. 1.)
Appellant’s “invention relates to targeting the SIRPα–CD47 interaction in
order to treat hematological cancer, particularly human acute myeloid
leukemia.” (Id.)
Claims 1, 3, 4, 7, 9–12, 32, and 54–86 are on appeal. Claim 1 is
representative and reads as follows:
1. A method for treating a patient having cancer cells or
tumours that are CD47+, comprising administering to the
patient a therapeutically effective amount of a fusion protein
capable of binding to the extracellular domain of human CD47
to interrupt signaling between human Sirpα and human CD47,
wherein the fusion protein comprises a first polypeptide
comprising soluble human Sirpα, or a CD47 binding fragment
thereof, fused to a second polypeptide comprising the Fc
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portion of IgG, and wherein the method results in a
desuppression of macrophages.
(Appeal Br. 34.)

The prior art relied upon by the Examiner is:
Name Reference Date
Jamieson et al. US 2009/0191202 A1 July 30, 2009
Smith et al. US 2010/0239579 A1 Sept. 23, 2010
Danska et al. US 2010/0239578 A1 Sept. 23, 2010
Yuan Liu et al., Functional Elements on SIRPα IgV domain Mediate Cell
Surface Binding to CD47, 365(3) J. Mol. Biol. 680–93 (2007)

The following ground of rejection by the Examiner is before us on
review:
Claims 1, 3, 4, 7, 9–12, 32, and 54–86 under 35 U.S.C. § 103(a) as
unpatentable over Liu,2 Smith, Jamieson, and Danska.
DISCUSSION
The Examiner finds that “Liu teaches contacting promyelocytic
leukemic cell line, HL-60 with wild-type and mutant soluble SIRPα1.IgV-Fc
fusion proteins,” as well as contacting CD47 expressing epithelial cells with
SIRPα-IgV-Fc fusion proteins. (Ans. 3; Final Action 7.) The Examiner
additionally finds that “HL-60 promyelocytic leukemic cells are art known
to express CD47.” (Id.)
The Examiner finds that Smith teaches a fusion polypeptide that
includes the CD47 extracellular domain fused to an Fc polypeptide that is
used to treat proliferative orders such as B-cell chronic lymphocytic

2 The Examiner relies on the “Author Manuscript” of Liu which is
paginated 1–27. We likewise refer to this Author Manuscript.
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leukemia and lymphoma where the Fc portion can include IgG1 or IgG4.
(Ans. 3–4; Final Action 8.)
The Examiner finds that Jamieson teaches CD47 expression is present
in acute myeloid leukemia (AML) and diffuse large B-cell lymphoma
(DLBCL), known as a B-cell non-Hodgkin’s lymphoma, and that using
molecules that disrupt the CD47-SIRPα interaction, represses CD47 on the
tumor cells, allows for phagocytosis of them by macrophages and clearing of
those cells. (Ans. 4; Final Action 8.)
The Examiner finds that Danska teaches 3 particular polypeptides that
are “capable of interrupting signaling between SIRPα and CD47” and
explains that those polypeptides are the same as Appellant’s SEQ ID NOs: 4,
6, and 7. (Ans. 4; Final Action 8.)
The Examiner concludes that in view of Jamieson’s teaching that
SIRPα1.IgV-Fc fusion proteins are able to mediate cell surface
binding to CD47 and with the implementation of molecules
able to disrupt the CD47-SIRPα interaction there is consequent
repression of CD47, phagocytosis and clearing of tumor cells
by macrophages
it would have been obvious to one having ordinary skill in the art “to treat
additional CD47 expressing cells [beyond those described in Liu] with
fusion polypeptides that comprise SIRPα extracellular domain or variant
thereof that is fused to a Fc polypeptide and/or a CD47-binding fragment.”
(Ans. 4.)
We agree with the Examiner that the cited prior art renders the
claimed invention prima facie obvious. In particular, Appellant does not
dispute that Jamieson teaches targeting tumor cells or leukemia cells for
phagocytosis using CD47 monoclonal antibodies. (Appeal Br. 19.)
Although Jamieson exemplifies the use of CD47 monoclonal antibodies,
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Jamieson’s teachings suggest extension to other compounds that prevent
interaction between CD47 on the cancer cell and SIRPα.
Jamieson explains “tumor cells, e.g. solid tumor cells, leukemia cells,
etc. are targeted for phagocytosis by blocking CD47 on the cell surface.”
(Jamieson ¶ 13.) Jamieson indicates that they tested “the model that CD47
overexpression on AML LSC prevents phagocytosis of these cells through
its interaction with SIRPα on effector cells” with a “monoclonal antibody
directed against CD47 known to disrupt the CD47-SIRPα interaction.” (Id.
¶ 131.) “[S]ignificant phagocytosis was detected with the addition of the
anti-CD47 antibody (FIG. 9). Thus, blockage of human CD47 with a
monoclonal antibody is capable of stimulating the phagocytosis of these
cells by mouse macrophages.” (Id.) Jamieson further states that “[f]inding
methods to disrupt CD47-SIRPα interaction may thus prove broadly useful
in developing novel therapies for cancer.” (Id. ¶ 146.) Thus, we conclude
that Jamieson suggests that “agents that mask the CD47 protein” by binding
to CD47 so as to “prevent interaction between CD47 and SIRPα” will likely
increase the clearance of AML cells via phagocytosis, which cells are
otherwise able to “evade macrophage surveillance by upregulation of CD47
expression.” (See, e.g., id. ¶ 13.)
As Appellant acknowledges, Liu teaches SIRPα constructs. (Appeal
Br. 8.) Liu’s teachings go beyond that simple fact, however. Liu identifies
seven amino acids on SIRPα that are “unique” compared to SIRPβ, a protein
that is “commonly co-expressed on the same cell surfaces of neutrophils and
mononuclear cells” as SIRPα and shares a “strikingly similar extracellular
domain structure[] with highly homologous amino acid sequences” but does
not bind to CD47, which amino acids “likely form a functional motif on
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SIRPα protein surface that mediates specific binding interaction with
CD47.” (Liu 1, 6–7.) Liu states that: “Our results thus revealed the
molecular basis by which SIRPα selectively binds to CD47.” (Id. at 1.)
Liu “generated SIRPαl.IgV-Fc and Bit.IgV-Fc fusion proteins3” that
were “tested for binding to CD47 using CD47 extracellular domain fusion
protein, CD47-AP.”4 (Liu 3.) Both fusion proteins “directly bound to
CD47-AP and exhibited equivalent binding capability.” (Id.) In addition, as
the Examiner noted, these fusion proteins were determined to bind to HL-60
cells. (Id. at 5.) Appellant does not dispute the Examiner’s finding that
“HL-60 promyelocytic leukemic cells are art known to express CD47.”
(Ans. 3; Final Action 7.)
Furthermore, although we agree with Appellant that Smith “teaches a
different molecule than the present inventors, to treat a different class of
disease” (Appeal Br. 14), Smith, nevertheless, teaches uses of “[a]n Fc
polypeptide or portion thereof (such as at least one immunogloblulin
constant region domain, for example, the CH2 domain or CH3 domain)
when fused to a peptide or polypeptide of interest” for in vivo therapeutic
use. (Smith ¶ 48.) In particular, Smith states the Fc portion of the fusion
peptide
acts, at least in part, as a vehicle or carrier moiety that prevents
degradation and/or increases half-life, reduces toxicity, reduces
immunogenicity, and/or increases biological activity of the
peptide such as by forming dimers or other multimers

3 Liu explains that “SIRPα subfamily contains multiple members, such as
Bit, SIRP αl and α2, which vary mainly in the membrane-distal IgV
domains.” (Liu at 3.)
4 AP is alkaline phosphatase. (Id. at 14.)
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(Id.)
In light of these teachings, we agree with the Examiner that it would
have been prima facie obvious to use the fusion protein described by Liu in
targeting tumor cells or leukemia cells for phagocytosis as taught in
Jamieson with a reasonable expectation of success. We do not find
Appellant’s argument to the contrary (Appeal Br. 10, 26) persuasive. That
“most of the cited prior art - including all of the cited art relating to fusion
constructs - demonstrated or hypothesized that interference with the
S1RPα/CD47 signalling pathway had a suppressive effect on various
components of the immune system” (id.) does not negate Jamieson’s clear
suggestion that a compound that specifically binds to the external cellular
domain of CD47 and prevents the interaction between CD47 and SIRPα will
be reasonably likely to at least increase the clearance of AML cells via
phagocytosis, which cells would have otherwise evaded macrophage
surveillance by upregulation of CD47 suppression. That Jamieson’s
experimental evidence employed an antibody that was specific for the
extracellular domain of CD47 and not to a SIRPα-Fc construct (see, e.g.,
Appeal Br. 26 (emphasis omitted) (“No direct evidence in the cited prior art
that soluble Sirpα-Fc has anti-cancer activity”)) is immaterial, as such
evidence is not necessary to establish a reasonable expectation of success
where the art indicates other compounds that can prevent the interaction
between CD47 and SIRPα would be expected to achieve the same result.
(Jamieson ¶¶ 13, 145–146.)
That the treatment “was not yet established in the field” (Appeal Br.
10) does not defeat obviousness. “Only a reasonable expectation of success,
not absolute predictability, is necessary for a conclusion of obviousness.” In
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re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985). Appellant’s claim requires
that the method of treatment results in desuppression of macrophages.
Jamieson’s teachings combined with the fact that Liu teaches a fusion
protein construct of SIRPα that specifically binds to CD47 on the cell
surface of a leukemic cell line provides the reasonable expectation of
success.
We have considered the Declaration of Dr. Uger5 (Appeal Br. 25) in
arriving at our conclusion. We appreciate the following statements by Dr.
Uger
First, at the time of the patent application in 2009, a number of
lines of evidence had been reported implicating macrophages in
tumor progression. In view of this evidence, there was a basis
for concluding that suppression or depletion of tumor
associated macrophages was the proper approach to enhancing
cancer therapy. Stated differently, there was no consensus that
de-suppression of macrophages was the desirable approach to
cancer therapy.
Second, the evidence relating to macrophages and cancers was
focused on a number of signaling molecules and cellular
functions other than the CD47-Sirpα “do not eat” signaling that
is the focus of the patent application.
A potential complication of therapies designed to target CD47
on cancer cells to suppress a “do not eat” signal is the fact that
CD47 also is expressed on many healthy cells throughout the
body, including on the surface of red blood cells (RBCs).
(Uger Declaration ¶¶ 3.8–3.9, 4.1 (emphasis omitted).) However, Dr. Uger
does not address Jamieson and its teachings, which strongly implicate that
other compounds besides antibodies that specifically bind to the external
cellular domain of CD47 and prevent the interaction between CD47 and

5 Declaration of Robert Uger, PhD. dated January 15, 2018.
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SIRPα will be reasonably likely to at least increase the clearance of AML
cells via phagocytosis, in the Declaration. Thus, we do not find Appellant’s
argument that
The Rule 132 Declaration of Dr. Uger explains that it was
uncertain, at the time of the invention, that therapies targeted at
potentiating macrophages would be successful for the treatment
of cancer because substantial scientific literature existed which
had reported that macrophages appear to play a role in cancer
progression
(Appeal Br. 25) (emphasis omitted), persuasive that the Examiner’s evidence
does not establish a prima facie case of obviousness.
Appellant’s argument that “a person of ordinary skill would not and
could not have extrapolated, with a reasonable expectation of success, that
results reportedly obtained with CD47 antibodies would be predictive of
results with soluble Sirpα-Fc” given “[t]he complexity of CD47 biology”
and because the CD47 antibodies of Jamieson “are a different size than
Sirpα-Fc, potentially bind to different CD47 epitopes than Sirpα-Fc, and do
not necessarily bind with the same affinity” (Appeal Br. 29) is not
persuasive. First, we note this argument is not supported by any declaration
testimony. “Attorneys’ argument is no substitute for evidence.” Johnston v.
IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989). Second, Liu teaches
specific binding of soluble Sirpα-Fc to cell bound CD47 on a leukemic cell
line and determines the seven amino acids that are important for such
binding. It is true as Appellant notes that Liu teaches “soluble Sirpα
‘demonstrated remarkable binding/adhesion’ to healthy PBMC and RBC”
(Appeal Br. 29). However, Liu teaches that differentiated HL-60 cells
“demonstrated remarkable binding/ adhesion” as well. (Liu 4.) In addition,
Liu teaches that the greater the number of CD47 on the cell surface of the
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leukemic cells (differentiated v. undifferentiated HL60 cells), the better the
adhesion of Bit IgV. (Id.) The fact of greater binding to RBC than to other
tested cell types (Appeal Br. 29) is of little significance for non-obviousness
given that the experimental setting was not one in which a multiplicity of
cell types was provided in the same well and contacted with the SIRPα-Fc
fusion peptide. Appellant suggests that Dr. Uger’s Declaration concluded
that “the adhesion to healthy cells would have suggested that the treatment
could have unacceptable side effects and/or could fail to reach the target
cells due to the plentiful RBC population acting as an ‘antigen sink.’”
(Appeal Br. 29 (citing Uger Declaration ¶¶ 4.1 - 4.3.).) However, Dr. Uger
made no such conclusion when also considering the teachings of Jamieson.
“Attorney’s argument in a brief cannot take the place of evidence.” In re
Pearson, 494 F.2d 1399, 1405 (CCPA 1974).
Moreover, even considering that CD47 is expressed on the surface of
RBCs, Dr. Uger only notes that for “therapies designed to target CD47 on
cancer cells to suppress a ‘do not eat’ signal” this is “[a] potential
complication,” not that a SIRPα-Fc fusion peptide would fail to reach its
cancer target cell and be incapable of desuppressing macrophages.
Notwithstanding the foregoing, we conclude that Appellant has
provided evidence of unexpected results in the record that when weighed
together with the Examiner’s evidence of obviousness is sufficient for us to
conclude that the Examiner’s ultimate holding of obviousness should not
stand. In re Huai-Hung Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011)
(citations omitted) (“Once the examiner establishes a prima facie case of
obviousness, the burden shifts to the applicant to rebut that case. . . .
However, once the applicant has come forward with rebuttal evidence, the
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examiner must consider the totality of the evidence to determine whether the
obviousness rejection should stand.”)
In particular, Appellant presented unrebutted evidence that a Sirpα-Fc
fusion construct “displays markedly reduced RBC binding and agglutination
compared to anti-CD47 antibodies,” including the antibody described in
Jamieson, B6H12 (Appeal Br. 11; Jamieson ¶ 23). Dr. Uger discusses the
experiments and resultant data in his declaration. (Uger Declaration ¶¶ 5.1–
5.6.) Dr. Uger explains that the SIRPα-Fc fusion protein (TTl-621)
exhibited only minimal binding to human erythrocytes, compared with high
binding of five different anti-CD47 antibody clones. (Id. ¶ 5.3 (referring to
Figures 1A and 1B).) Figure 1B demonstrating the difference in binding is
reproduced below.

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Figure 1B depicts binding of erythrocytes from 43 healthy donors to
controls, 5 CD47 monoclonal antibodies included B6H12, and the SIRPα-Fc
fusion protein (TTl-621) with mean fluorescence intensity. The difference
in intensity is several orders of magnitude between the TTI-621 and all the
CD47 monoclonal antibodies tested. Dr. Uger states that the experiments,
which included testing of different FC isotypes and different domain
structures, which data is not shown, “indicate that SIRPα-Fc fusion proteins
bind poorly to human RBCs regardless of Fc isotype . . . and regardless of
whether a one-or three-domain structure . . . from the Sirpα extracellular
region is used to make the further protein.” (Id. ¶ 5.4.) Dr. Uger further
explains that the difference in erythrocyte binding “does not simply reflect a
difference in overall activity: both classes of proteins trigger similar levels of
tumor cell phagocytosis.” (Id. ¶ 5.6.) Although this phagocytic activity was
observed using monoclonal antibody 5F9, and not B6H12, we note that, as
can be seen in the figure above, the erythrocyte binding of 5F9 and B6H12
were both at least two orders of magnitude higher than TTI-621.
In response to this data, the Examiner states that the “declaration and
Exhibits have been carefully considered, but fail to persuade.” (Final Action
4; see also Ans. 10 (“Appellant[] ha[s] not produced sufficient evidence
showing that the determinations herein on obviousness are incorrect or
misplaced”).) According to the Examiner, “the specific properties achieved
are merely inherent properties of the combination” and there is an “absence
of adequate evidence of unexpectedly superior results.” (Final Action 5.)
We do not find the Examiner’s response sufficient to discount Appellant’s
evidence. That evidence demonstrates a substantial difference in a particular
property between the prior art compound established in Jamieson to
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desuppress macrophages which would necessarily result in lower side effects
when the claimed fusion protein is used to treat cancer by desuppressing
macrophages. “Given a presumption of similar properties for similar
compositions, substantially improved properties are ipso facto unexpected.”
In re Soni, 54 F.3d 746, 751 (Fed. Cir. 1995). The Examiner established a
prima facie case, the Appellant responded to it with a showing of data, and
the Examiner made an inadequate challenge to the adequacy of that
showing. Id.
The foregoing applies to each of the independent claims in appeal,
i.e., claims 1, 9, and 75. For this reason, we do not affirm the Examiner’s
rejection of claims 1, 3, 4, 7, 9–12, 32, and 54–86 under 35 U.S.C. § 103(a)
as unpatentable over Liu, Smith, Jamieson, and Danska.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 3, 4, 7, 9–
12, 32, 54–
86
103 Liu, Smith,
Jamieson, Danska
1, 3, 4, 7, 9–
12, 32, 54–
86

REVERSED