Ex Parte Nishibori et al

Patent Trial and Appeal Board

Jul 18, 2017

13498413 (P.T.A.B. Jul. 18, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/498,413 03/27/2012 Masahiro Nishibori 20120478A 3409
513 7590 07/20/2017
WENDEROTH, LIND & PONACK, L.L.P.
1030 15th Street, N.W.,
Suite 400 East
Washington, DC 20005-1503
EXAMINER
GAMBEL, PHILLIP
ART UNIT PAPER NUMBER
1644
NOTIFICATION DATE DELIVERY MODE
07/20/2017 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):
ddalecki@wenderoth.com
eoa@ wenderoth. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MASAHIRO NISHIBORI, HIDEO TAKAHASHI, SHUJI MORI,
KEYUE LIU, and YASUKO TOMONO
Appeal 2015-003663
Application 13/498,4131
Technology Center 1600
Before DEMETRA J. MILLS, ERIC B. GRIMES, 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 suppressing or treating atherosclerosis, which have been rejected as
obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
“Atherosclerosis is a disease in which deposition called a[n]
atherosclerosis plaque develops in the intimal layer of arterial blood vessel
to decrease or block blood flow.” (Spec. 12.) “[Pjrogress of atherosclerosis
1 Appellants identify the Real Party in Interest as National University
Corporation Okayama University and Sowakai Medical Foundation.
(Appeal Br. 2.)
Appeal 2015-003663
Application 13/498,413
causes thrombosis or organ ischemia, and leads to cerebral infarction,
myocardial infarction, renal failure and the like.” (Id. ) It is believed that
“atherosclerosis begins by activation of monocytes in blood and invasion of
the activated monocytes under vascular endothelial cells,” which then invade
arterial blood vessels and activate macrophages. (Id. 1 5.) “In general, the
activation of monocytes and macrophages is observed in inflammation
reaction[s].” (Id.) “Therefore, treatment of atherosclerosis using a factor
suppressing an inflammation reaction has been investigated” in the prior art.
(Id.) Appellants’ invention is directed at using an anti-HMGBl monoclonal
antibody that binds to C-tail of HMGB1 for suppressing or treating
artherosclerosis. (Id. || 14—15.)
Claims 5, 7, 8, and 13—15 are on appeal. Claims 5 and 15 are
representative and read as follows:
5. A method for suppressing atherosclerosis, comprising the
step of administering an anti-HMGBl monoclonal antibody
binding to C-tail of HMGB 1 as an active component so that
atherosclerosis is suppressed by one or more functions selected
from the group consisting of:
(a) suppressing vascular permeability;
(b) reducing fatty degeneration of a blood vessel;
(c) suppressing an invasion of a macrophage, a dendritic
cell, or a CD4 positive T-lymphocyte into a vascular
endothelial cell;
(d) suppressing activation of a vascular endothelial cell;
(e) suppressing migration of a monocyte, a macrophage,
or a dendritic cell; and
(f) decreasing the number of PCNA-positive cells; and
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Application 13/498,413
wherein the anti-HMGB 1 monoclonal antibody specifically
recognizes the amino acid sequence, EEEDDDDE (SEQ ID
NO: 1), in the C-tail of HMGB1.
15. A method for treating atherosclerosis, comprising the step
of administering an anti-HMGB 1 monoclonal antibody binding
to C-tail of HMGB1 as an active component.
(Appeal Br. 27—28.)
The following ground of rejection by the Examiner is before us on
review:
Claims 5, 7, 8, and 13—15 under 35 U.S.C. § 103(a) as unpatentable
over Nishibori I,2 Nishibori II,3 Traversa,4 Barone,5 Fumero,6 and Li.7
DISCUSSION
The Examiner finds that Nishibori I teaches anti-HMGB 1 antibodies
to neutralize HMGB 1 in the treatment of cerebral infarction, where the
infarction “is caused by blood vessel [that is] occluded or narrowed due to
various factors, including artherosclerosis” and where the thrombus formed
in the extracerebral blood vessel is transferred into the brain. (Ans. 3.) The
2 Nishibori et al., WO 2007/049468, published May 3, 2007. WO’468 is in
Japanese, and the Examiner relied on the English language equivalent of
WO ‘468, US 2009/0252739, published Oct. 8, 2009 (Ans. 3) (“Nishibori
I”), as will we.
3 Nishibori et al., WO 2007/135992, published Nov. 29, 2007. WO ’992 is
in Japanese, and the Examiner relied on the English language equivalent of
WO ’992, US 2009/0175878, published July 9, 2009 (Ans. 3) (“Nishibori
II”), as will we.
4 Traversa et al., US 2009/0324677, published Dec. 31, 2009.
5 Barone et al., US 2008/0305073, published Dec. 11, 2008.
6 Fumero et al., US 2008/0317809, published Dec. 25, 2008.
7 Li et al, Role of HMGB1 in cardiovascular diseases, 8 Current Opinion in
Pharmacology, 130—135 (2006).
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Application 13/498,413
Examiner notes that the antibody taught for use in Nishibori [I] is not
particularly described as having “specificity to the C-tail / EEEDDDDE of
HMGBI.” (Id.) The Examiner notes, however, that Nishibori II teaches
such an antibody and that it is used in the treatment of prevention of cerebral
vasospasm. (Ans. 3—4.)
The Examiner further finds that Traversa, Barone, and Fumero teach
that it was known in the art that that “the interaction of the C-terminal of
HMGB1 and RAGE triggers a sustained period of cellular activation . . . and
atherosclerosis (as well as myocardial infarction, ischemia), belong to the
inflammatory conditions associated with cellular activation. . . (Ans. 4
citing Traversa 9, 58; Barone Tflf 12, 30, 53, and 58; Fumero 6, 34, 35,
39, and 36-44.) In addition, the Examiner finds that Li teaches that
cardiovascular disease
encompass[es] the binding of HMGBI to RAGE, wherein
engagement of RAGE induces production of various
proinflammatory cytokines, as well as inhibition of RAGE-
HMGB1 induction of proinflammatory cytokines, including the
role of HMGB 1 stimulation of endothelial cells and, in turn,
adhesion molecules, proinflammatory cytokines and
chemokines as well as mucosal permeability.
(Id.) In light of the foregoing teachings, the Examiner contends that one of
ordinary skill in the art
would have been motivated to provide anti-HMGB 1 antibodies
that bind the C-terminus of HMGBI (EEEDDDDE), to treat
various vascular, thrombotic and occlusive diseases and
conditions, including atherosclerosis, as clearly taught by
Nishibori I and II.
(Id.)
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Application 13/498,413
We disagree with the Examiner’s conclusion that it would have been
obvious from the teachings of the relied upon references to treat (or
suppress) atherosclerosis with the claimed monoclonal antibody that is
specific for the C-tail/ EEEDDDDE of HMGB1.8
While we agree with the Examiner that Nishibori I and II are
concerned with occlusive diseases and conditions, we disagree that the
secondary references would have suggested to one of ordinary skill in the art
that inhibiting the binding of HMGB1 with RAGE at the C-tail would be
reasonably expected to treat a different occlusive disease, atherosclerosis, or
to suppress it by one or more functions recited in the claims.
We agree with the Examiner that Traversa, Barone, and Fumero teach
that the C-terminal HMGB 1 binds to RAGE triggering cellular activation.
(Ans. 4.) However, we do not understand these references to teach that
artherosclersosis is an inflammatory condition associated with cellular
activation. Nevertheless, these references do teach that atherosclerosis is a
cardiovascular disease that is an HMGB-1 associated disease mediated by
activation of the inflammatory cytokine cascade. (See, e.g., Traversa 57—
58.)
8 There is no indication in either Nishibori I or II that the patient population
being treated for cerebral infarction or cerebral vasospasm also necessarily
has atherosclerosis. Thus, carrying out the method in Nishibori I or II would
not necessarily result in the method of treating atherosclerosis. Perricone v.
Medicis Pharm. Corp., 432 F.3d 1368, 1378 (Fed. Cir. 2005) (“If Pereira
discloses the very same methods, then the particular benefits must naturally
flow from those methods even if not recognized as benefits at the time of
Pereira's disclosure.”) Here, the claims recite a new use of the composition
disclosed in Nishibori II.
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It is the case that each of Traversa, Fumero, and Barone broadly
indicate that the inventions described therein “are used as active agents for
the prevention, alleviation and/or treatment of RAGE-related pathologies”
and can include using an antibody to RAGE or an agent that is a “small
synthetic molecule antagonist of the interaction of HMGB1 with RAGE.”
{Id. 1 59; Fumero 141, Barone 1 55.) However, as Appellants point out, not
one of those references suggests blocking binding of HMGB1 to RAGE with
an antibody to the C-terminal of HMGB 1 for such treatment. (Appeal Br.
12-13.)
Barone is directed at using “synthetic double-stranded nucleic acid or
nucleic acid analogue molecules with a bent shape structure, comprising at
least one structural bend, capable of binding to the HMGB1 protein,
particularly to an extracellular HMGB 1 protein “in order to inhibit in
patients the broad spectrum of pathological effects induced by the
chemokine itself and/or by the cascade of inflammatory cytokines caused by
the extracellular release of the HMGB1 protein.” (Barone Tflf 22—23.)
Barone suggests that a possible relevant way to block the extracellular
HMGB 1 chemokine-protein involved in the development of the pathogenic
sequence of systemic inflammation could be by “administering] mono- or
oligo-clonal antibodies against the HMGB 1 B-box, or its 20 amino acid
relevant core which signals through RAGE.” (Barone 119.) Barone teaches
that HMGB1 “has a tripartite structure composed of three distinct domains:
two DNA binding domains called HMG Box A and Box B, and an acid
carboxyl terminus.” {Id. 5.) Thus, even if we were to consider Barone to
suggest an antibody to HMGB1 as a possible active agent for use in RAGE-
related pathologies, we find Barone does not teach the use of an antibody
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against the C-terminal of HMGB1.9 And it certainly does not teach an
antibody that specifically recognizes the sequence EEEDDDDE in the C-tail
of HMGB1, as required by claim 5.10
Traversa is focused on a compound that is a conjugate of HMGB1
Box-A polypeptide. (Traversa Tflf 68—69, 72.) And Fumero teaches using a
kinase inhibitor blocking the cascade triggered by HMGB1 binding (Fumero
125), and the use of a RAGE inhibitor, “e.g. an antibody directed to RAGE,
a nucleic acid or nucleic acid analogue capable of inhibiting RAGE
expression, e.g. an antisense molecule, a ribozyme or a RNA interference
molecule, or a small synthetic molecule antagonist of the interaction of
HMGB1 with RAGE,” (id. 14), or “an HMGB1 antagonist/inhibitor, e.g. an
antibody against HMGB1, particularly against the HMGB1 Box-B or a
fragment of HMGB 1 which has antagonistic activity” (id. 142). Thus, we
do not find Traversa or Fumero to suggest that one look to an antibody that
binds the C-tail of HMGB 1 for use in RAGE-related pathologies.
Unlike Traversa, Barone, and Fumero, which teach that
artherosclerosis is a RAGE-related cardiovascular disease, Li indicates that
atherosclerosis is a “chronic inflammatory disease of the arterial system.”
(Li 132.) Li indicates that HMGB1 binding to RAGE might play a role in
atherosclerosis in light of its cytokine activities. (Li 132 (“Potential role of
9 Li teaches that the B box contains a cytokine functional motif at amino
acids 106—123, and that this is different from the C-terminus, which has a
RAGE-binding motif at amino acids 150-183. (Li 131 and Fig. 1.) Thus,
there appears to be conflicting information in the art regarding HMGB 1 and
RAGE interaction.
10 Li teaches that this portion of the C-tail is distinct from the RAGE-binding
site. (Li Fig. 1 at 131.)
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Application 13/498,413
HMGB1 in cardiovascular disease”), 133 (Figure 2 legend: “Hypothetical
roles of HMGB1 in the pathogenesis of atherosclerosis.”).) Li further notes
that “the expression levels for a HMGB1 receptor, RAGE, are significantly
upregulated in macrophages of the atherosclerotic lesions, and competitive
inhibition of RAGE activity using a soluble RAGE prevents the progression
of atherosclerotic injury.” (Li 133, reference citations omitted.) However,
Li does not indicate that an interaction of the C-terminal of HMGB1 and
RAGE is known to be involved in atherosclerosis or that interrupting such
an interaction is known to interrupt the pathogenesis. What Li does indicate
at the conclusion of the article, after proposing “[hypothetical roles of
HMGB1 in the pathogenesis of atherosclerosis” from various observations
(Li 133), is that “[i]t is currently unknown if the HMGB 1-mediated
inflammatory response contributes to the pathogenesis of cardiovascular
diseases” {Id.).
Thus, the Examiner has not shown, and the cited secondary references
do not suggest that if one were to block the binding to RAGE at the C-
terminal end of HMGB 1 that atherosclerosis is reasonably likely to be
treated or suppressed. At most the references might pique a scientist’s
curiosity or suggest one might “explore a new technology or general
approach that seemed to be a promising field of experimentation.” In re
Kubin, 561 F.3d 1351, 1359 (Fed. Cir. 2009). However, such an obvious to
try situation does not provide a proper basis to establish obviousness. Id.
For the foregoing reasons, we find the Examiner fails to establish a
prima facie case that the subject matter of independent claims 5 or 15 and
their dependent claims 7, 8, 13, and 14 would have been obvious at the time
of Appellants’ invention. Thus, we do not sustain the Examiner’s rejections.
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SUMMARY
We reverse the rejection of claims 5, 7, 8, and 13—15 under 35 U.S.C.
§ 103(a) as unpatentable over Nishibori I, Nishibori II, Traversa, Barone,
Fumero, and Li.
REVERSED
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