Panagiota Iliopoulou et al.

Patent Trials and Appeals Board

Apr 15, 2020

15287365 - (D) (P.T.A.B. Apr. 15, 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.
15/287,365 10/06/2016 Panagiota Iliopoulou STAN-1230 3548
77974 7590 04/15/2020
STANFORD UNIVERSITY OFFICE OF TECHNOLOGY LICENSING
BOZICEVIC, FIELD & FRANCIS LLP
201 REDWOOD SHORES PARKWAY
SUITE 200
REDWOOD CITY, CA 94065
EXAMINER
JUEDES, AMY E
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
04/15/2020 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):
docket@bozpat.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte PANAGIOTA ILIOPOULOU, ROSEMARIE H. DEKRUYFF, and
EVERETT HURTEAU MEYER
__________

Appeal 2019-004369
Application 15/287,3651
Technology Center 1600
__________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, 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 graft versus host disease in a transplant recipient, which have
been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
Graft versus Host Disease (GVHD) is a debilitating side effect of
bone marrow transplantation. (Spec. ¶ 3) “It occurs when lymphocytes from
the donor present in the bone marrow inoculums attack and destroy healthy

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 The Board of
Trustees of the Leland Stanford Junior University. (Appeal Br. 1.)
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tissues of the recipient.” (Id.) Appellant’s invention is concerned with
treating donor cells to be transplanted.
Claims 1 and 4 are on appeal. Claim 1 is representative and reads as
follows:
1. A method for treating a graft versus host disease in a
transplant recipient, comprising:
contacting donor graft cells with a therapeutically effective
amount of a blocking antibody specific for TIM-1 binding to
phosphatidylserine prior to transplantation in said recipient.
(Appeal Br. 9.)

The prior art relied upon by the Examiner is:
Name Reference Date
Bailly WO 2013/078089 A1 May 30, 2013
Rennert US 2006/0222648 A1 Oct. 5, 2006
Noelle US 5,869,049 Feb. 9, 1999
Presta US 2009/0181015 A1 July 16, 2009

The following ground of rejection by the Examiner is before us on
review:
Claims 1 and 4 under 35 U.S.C. § 103(a) as unpatentable over WO
2013/078089, US 2006/0222648, US 5,869,049, and US 2009/0181015.2
DISCUSSION
The Examiner finds that WO ’089 teaches a method of treating
GVHD that includes administering an anti TM-1 antibody that inhibits TIM-
1 binding to phosphatidylserine and to dendritic cells. (Final Action 3–4;

2 The rejection by the Examiner of the claims under 35 U.S.C. § 112,
second paragraph was withdrawn in the Examiner’s Answer. (Ans. 5)
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Ans. 5.) The Examiner further finds that WO ’089 “teaches GVHD is
initiated when donor T cells recognize host antigen” (Final Action 4) and
provides “mechanistic details” regarding mediation of GVHD “by activated
T cell responses as well as antibody responses” (Ans. 5). The Examiner
further explains that WO ’089 teaches that in addition to blocking
phosphatidylserine, the TIM-1 antagonist antibodies described “eliminate
TIM-1 interaction with antigen presenting cells (dendritic cells).” (Ans. 5.)
Furthermore, explains the Examiner, WO ’089 “teaches administration of
the TIM-1 antibody at periodic intervals over a period of time as well as
administration of the antibody before the onset of the immunological
disorder as a preventative measure.” (Id. at 7)
The Examiner further finds that US ’648 teaches that GVHD can be
treated with antagonist antibodies to TIM-1 (also known as KIM-1), a
protein that is expressed by T cells, where the antagonist antibodies inhibit
the interaction of T-cells with antigen presenting cells. (Final Action 4; Ans.
6.) The Examiner further explains that US ’648 teaches “in vitro assays
involving T cell allorecognition where it is shown that anti-KIM-1
antibodies reduce T cell cytokine production (see page 16).” (Ans. 6.) The
Examiner explains that US ’648 teaches that “an antagonist[] which blocks
the interaction of TIM-1 with APCs/dendritic cells (which is a function of
the antibodies disclosed by WO 2013078089) can reduce cytokine secretion,
inhibit signaling between an activated T cell and APCs, and inhibit
activation of B cells and production of antibodies (see page 1, in
particular).” (Id.) In addition, the Examiner finds that US ’648 teaches
“administration to a subject preparing to receive a graft and teaches
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administering before the immune system of the subject first recognizes one
or more alloantigens (see page 1, paragraph 6-11, in particular).” (Id.)
The Examiner notes that these two references do not explicitly
disclose the claim limitation of contacting the graft cells with the TIM-1
antibody prior to transplantation of the graft into the subject. (Final Action
4; Ans. 7.) However, the Examiner finds that such a step would have been
obvious to one having ordinary skill in the art in light of the teachings of the
’049 and ’015 references. (Id.) The Examiner explains that these references
teach a number of alternative treatments of GVHD prior to transfer of bone
marrow graft, which include (1) administering antagonist antibodies that
inhibit the interaction of T cells with APCs to the subject prior to transfer
with continued administration after as well as alternatively, (2) incubating
the cells in the bone marrow graft ex vivo with antagonist antibodies that
inhibit the interaction of T cells with APCs prior to transfer of the graft, with
continued treatment with the antagonist in vivo after transfer. (Id.)
The Examiner explains that “[s]electing from the know[n] methods of
administrating T cell/APC inhibitor antibodies for treatment of GVHD
would involve choosing among a finite number of predictable options which
could be pursued with a reasonable expectation of success” and that “a
person of ordinary skill has good reason to pursue the known options within
his or her technical grasp.” (Final Action 4.) Furthermore, the Examiner
determined that one of ordinary skill would have been motivated to treat the
cells “before transfer with the anti-TIM-1 antibodies, in addition to
administering the antibodies directly to the subject, to enhance the
therapeutic efficacy in treatment of GVHD.” (Id.)
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The Examiner provided adequate evidence to establish prima facie
obviousness of the claimed subject. We address Appellant’s arguments
below.

Claim 1
Appellant argues that WO ’089 does not provide a reasonable
expectation of success for treatment of GVHD because it provides evidence
only of “reducing symptoms of acute allergic asthma in a humanized animal
model” and that anti-TIM-1 antibodies affect antigen-specific IgE
production. (Appeal Br. 4.)3 Appellant explains that IgE is known to play a
causative role in allergic asthma but that GVHD “is not known to include an
IgE component.” (Id. at 4–5.) Furthermore, argues Appellant, WO ’089
recites a “vast number of conditions” that are treatable with the anti-TIM-1
antibodies described. (Id. at 5.) According to Appellant “there is no
explanation in WO2013078089 as to why an antibody that reduces
expression of IgE antibody would also be expected to be successful in
treating hundreds of different immune-related diseases, which involve
different cells and causative factors.” (Id. at 6) Thus, argues Appellant, WO
’089 “does not provide one of skill in the art for a reasonable belief that any
particular condition in the list could be treated.” (Id.)
We do not find this argument persuasive. First, the Examiner’s
rejection relied on a combination of references for its prima facie case.
“Non-obviousness cannot be established by attacking references individually
where the rejection is based upon the teachings of a combination of

3 Appellant did not file a Reply Brief.
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references. . . . [The reference] must be read, not in isolation, but for what it
fairly teaches in combination with the prior art as a whole.” In re Merck &
Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Here, as the Examiner
explained, both WO ’089 and US ’648 together provide a reasonable
expectation of success in treating GVHD with an anti-TIM-1 antagonist
antibody. Both references specifically identify GVHD as being treatable
with an anti-TIM-1 antagonist antibody, not simply identifying those as
conditions that could possibly be treated in a long list of conditions. (WO
’089 43–44, US ’648 ¶ 15, 52.)
Moreover, as the Examiner also noted, WO ’089 teaches the
autoimmune condition GVHD and inflammatory diseases such as asthma,
have a similar mechanism in that they both involve an aberrant inflammatory
T cell immune response. (Ans. 6) Furthermore, US ’648 teaches that
“[r]eagents which interfere with T cell interactions with antigen presenting
cells (e.g., dendritic cells, macrophages, B cells: APC) effectively block both
acute and chronic GVHD.” (US ’648 ¶ 139.) And US ’648 teaches that an
antagonist that blocks TIM-1 interaction with APCs, such as an antagonist
anti-TIM-1 antibody, can reduce cytokine secretion, inhibit signaling
between an activated T cell and APCs, and inhibit activation of B cells and
production of antibodies. (See, e.g., id. at 1 and ¶¶ 49–50, 139.) Thus, we
disagree with Appellant that there is no explanation as to why the antagonist
antibody described in WO ’089 reasonably would be expected to be
successful in treating GVHD.
As the Examiner explained, regarding the asthma point with respect to
WO ’089, not only does that reference provide evidence that anti-TIM-1
antagonist antibody has an effect on IgE, it also provided evidence that the
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anti-TIM-1 antagonist antibody reduces immune cell cytokine production.
(Ans. 5; WO ’089 72.)
Appellant argues that the prophetic example and assertions of efficacy
in US ’648 would not provide one of skill in the art with a “reasonable
expectation of success in treating actual disease based on these teachings.”
(Appeal Br. 7.) Appellant has not provided evidence why the specific
teachings in the prior art discussed above would not provide one of ordinary
skill in the art with a reasonable expectation of success in view of the
express teaching in US ’648 to treat GVHD. For example, Appellant has not
provided any reason related to technical unfeasibility. “That the inventors
were ultimately successful is irrelevant to whether one of ordinary skill in
the art, at the time the invention was made, would have reasonably expected
success.” Life Techs. Inc. v. Clontech Labs. Inc., 224 F.3d 1320, 1326 (Fed.
Cir. 2000).
We also do not find persuasive Appellant’s contention that the prior
art does not teach the “use of a blocking antibody specific for TIM-1 binding
to phosphatidylserine.” (Appeal Br. 7.) According to Appellant WO ’089
“specifically notes that the antibody disclosed in that reference ‘binds the
receptor at an epitope located on a face of the IgV domain that is opposite
that of the phosphatidylserine-interacting FG/CC cleft’, and US
2006/0222648 is generally drawn to the use of various antagonists.” (Id.)
However, as the Examiner explained (Ans. 7), that the antagonist antibody
taught in WO ’089 does not bind to the phosphatidylserine-interacting cleft
is immaterial because the claim only requires that the antibody is one that is
a “blocking antibody specific for TIM-1 binding to phosphatidylserine.”
And, as the Examiner notes, and Appellant does not refute, WO ’089 teaches
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antibodies that function to inhibit TIM-1 binding to phosphatidylserine,
“even though they bind to an epitope opposite the phosphatidylserine
interacting cleft.” (Id.) WO ’089 states: “The invention is based, at least in
part, on the identification and characterization of an antibody that binds to
human TIM-1 on the BED face of the protein and inhibits TIM-1 binding to
phosphatidylserine.” (WO ’089 1:24–26; see also id. 58:5–28 (“Example 2:
ARD5 Disrupts TIM-1 Binding to Phosphatidylserine”).) Thus, WO ’089
describes a blocking antibody as claimed.
Claim 4
Appellant argues that ex vivo treatment of the graft prior to
transplantation is not suggested by the prior art. (Appeal Br. 7.) Appellant
further argues that because “there are many signaling pathways utilized by T
cells” that “[o]ne cannot extrapolate” the effects of the markers from the
’049 patent and US ’015 to TIM-1. (Appeal Br. 8.)
We do not find these arguments persuasive. That the specific
mechanisms by which the antibodies of the ’049 patent and US ’015 work to
treat GVHD may be different is not telling as to whether treating transplant
cells ex vivo prior to transplantation would be considered by one of ordinary
skill in the art to be obvious. That is because the ’049 patent and US ’015
teach that antibodies with mechanistically similar activity to that of the WO
’089 antibody (inhibit interaction between T cells and APCs) that are also
used for the treatment of GVHD may be administered equivalently to the
patient before transplant, or can be used to treat cells to be transplanted ex
vivo prior to transplant. (See Ans. 7.) In particular, the ’049 patent states
that to induce antigen-specific T cell tolerance one can administer a gp39
antagonist to a patient prior to administering the cells, or:
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wherein inhibition of graft-versus-host disease is desired, the
donor T cells in the bone marrow can be tolerized before
transfer to the recipient host by incubating the donor bone
marrow with B cells from the host and a gp39 antagonist in
vitro. gp39 treatment can be continued in vivo during and after
bone marrow transfer if necessary.
(’049 patent at 9:32–48.) Similarly, US ’015 states that “[t]he humanized
anti-CD40 antibody or agent may be administered by “perfusing or
otherwise contacting the graft with the antibody before transplantation.”
(US ’015 ¶ 210.) Both antibodies therefore treat GVHD. It is obvious to
those skilled in the art to substitute one known equivalent for another for the
purpose of treating GVHD. See In re Omeprazole Patent Litigation, 483
F.3d 1364, 1374 (Fed. Cir. 2007) (“[T]his court finds no . . . error in [the]
conclusion that it would have been obvious to one skilled in the art to
substitute one ARC [alkaline reactive compound] for another.”). Moreover,
“[i]f a person of ordinary skill can implement a predictable variation [of a
known work], § 103 likely bars its patentability.” KSR Int’l Co. v. Teleflex
Inc., 550 U.S. 398, 417 (2007). The prior art indicates that the ex vivo
treatment of the graft cells is a predictable variation to treating those cells in
vivo with an antibody that is to prevent interaction of T cells with antigen
presenting cells, and Appellant has not provided any contrary evidence.
Thus, for the foregoing reasons we affirm the Examiner’s rejection of
claims 1 and 4 as being obvious over WO 2013/078089, US 2006/0222648,
US 5,869,049, and US 2009/0181015.
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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 4 103 Bailly, Rennert,
Noelle, Presta
1, 4

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED