Ex Parte Kangawa et al

Patent Trial and Appeal Board

Mar 24, 2016

10554875 (P.T.A.B. Mar. 24, 2016)

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.
10/554,875 09/19/2006 Kenji Kangawa 69740.000004 9887
21967 7590 03/24/2016
HUNTON & WILLIAMS LLP
INTELLECTUAL PROPERTY DEPARTMENT
2200 Pennsylvania Avenue, N.W.
WASHINGTON, DC 20037
EXAMINER
HEARD, THOMAS SWEENEY
ART UNIT PAPER NUMBER
1675
MAIL DATE DELIVERY MODE
03/24/2016 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 KENJI KANGAWA and HIROSHI HOSODA1
____________

Appeal 2013-006829
Application 10/554,875
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
JOHN G. NEW, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to a method of treating hepatopathy comprising the administration of a
ghrelin polypeptide derivative. The Examiner rejects the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 According to Appellants, the Real Party in Interest is Kenji Kangawa.
(App. Br. 3.)
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STATEMENT OF THE CASE
The Specification discloses that “ghrelin is a peptide consisting of 28
amino acids residues which were found in the stomach, and the serine
residue at position 3 is modified with an octanoyl group . . . . It is shown
that ghrelin acts on Growth Hormone Secretagogue-Receptor (GHS-R) . . . ,
and is an endogenous brain-gut hormone which stimulates GH secretion
from pituitary gland. (Spec. 3: 16–20.) “[A] polypeptide derivative having
an activity of binding to GHS-R . . . have an activity of promoting
hepatocyte proliferation.” (Spec. 5: 11–15.)
Claims 20, 27–30, 32 and 48–53 are on appeal,2 and can be found in
the Claims Appendix of the Appeal Brief. Claim 20 is representative of the
claims on appeal, and reads as follows:
20. A method for treating hepatopathy comprising
administering to a mammal a polypeptide derivative consisting
of an amino acid sequence selected from the amino acid
sequences of SEQ ID NOS: 1 to 16, 19 to 22, or combinations
thereof,
wherein the second or third amino acid residue from the
amino-terminus of said amino acid sequence comprises a serine
or a group represented by the formula (2):

wherein R3 represents -T2-P2-Q2 or P2-Q2,
wherein T2 represents methylene; P2 represents -CO-O-;
and Q2 represents an optionally substituted C1-20 alkyl group,

2 Appellants acknowledge that claims 26 and 31 are pending but presently
withdrawn from consideration. (App. Br. 3.)
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and
wherein said polypeptide derivative has growth hormone
secretagogue receptor binding and elevating intracellular
calcium ion concentration activities,
or a pharmacologically acceptable salt thereof, and
further wherein said polypeptide promotes hepatic regeneration
and/or recovery of hepatic function.
(App. Br. Claims Appendix.)
Appellants request review of the Examiner’s rejection of claims 20,
27–30, 32, and 48–53 under 35 U.S.C. § 103(a) over Bednarek3 and/or
Kangawa4 in view of Matsumoto5, Tacke-I,6 Skakkebræk 7,8and Wonke.9
As Appellants do not argue the claims separately, we focus our
analysis on claim 20, and claims 27–30, 32 and 48–53 stand or fall with that
claim. 37 C.F.R. § 41.37 (c)(1)(iv).
The Examiner takes the position that ghrelin “is known in the art to
induce GH [growth hormone], and GH is known to increase IGF-1 [(insulin-
like growth factor-1)], which is beneficial to those in need of treatment for

3 Bednarek, WO 01/92292 A2, published Dec. 6, 2001.
4 Kangawa et al., US 7,385,026 B1, issued June 10, 2008.
5 Matsumoto et al., Structure-Activity Relationship of Ghrelin:
Pharmacological Study of Ghrelin Peptides, 287 Biochem. and Biophys.
Res. Comm. 142–146 (2001).
6 Tacke et al, Ghrelin is a parameter of catabolism in patients with chronic
liver disease, Hepatology 530A (October 2002)(hereinafter “Tacke-I”).
7 Skakkebræk et al., US 5,492,891, issued Feb. 20, 1996.
8 We note that the prosecution history refers to the Skakkebræk patent as
“Anderson.” (See App. Br. 6 and Ans. 4.) We will refer to the reference as
“Skakkebræk.”
9 Wonke et al, New Approaches to the Management of Hepatitis and
Endocrine Disorders in Cooley's Anemia, 850 Annals New York Academy
of Sciences 232–241 (1998).
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liver diseases (hepatopathy).” (Ans. 21.) The Examiner finds that Bednarek
and Kangawa each teach the claimed ghrelin analogs (see Ans. 7). Kangawa
“teach the Ghrelin peptides instantly claimed as a potent ligand for the
growth hormone (GH) secretagogue receptor in vitro and in vivo, Kangawa .
. . does not teach the use of Ghrelin for the treatment of hepatopathy.” (Ans.
7.) The Examiner relies on the other references to establish a nexus
between Ghrelin and IGF-1 [levels], and this was demonstrated
in both mouse and, more importantly, [in] humans suffering
from hepatitis (a form of hepatopathy). . . . There is more than a
reasonable expectation of success and ample motivation to
administer Ghrelin to increase GH, which in turn, increases
IGF-1 which is beneficial to those patients with liver diseases
(hepatopathy).
(Ans. 21.)
Appellants contend that the Examiner has not established a prima
facie case (see App. Br. 6–10), that there would be no reasonable
expectation of success (see App. Br. 10–12), that Tacke-II10 teaches away
from the use of ghrelin in treating hepatopathy (see App. Br. 12), and that
the Examiner did not consider the Hayashi’s Declaration (see App. Br. 12).
The issue is: Does the preponderance of evidence of record support
the Examiner’s conclusion that the combination of references renders the
claimed treatment method obvious?
Findings of Fact
We adopt the Examiner’s findings and analysis concerning the scope
and content of the prior art. The following facts are repeated for reference
convenience.

10 Frank Tacke et al., Ghrelin in chronic liver disease, 38 J. Hepatology
447–454 (2003).
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FF1. Bednarek teaches “truncated ghrelin analogs active at the GHS
receptor. Ghrelin is a naturally occurring modified peptide. The
analogs can bind to the GHS [(growth hormone secretagogue)]
receptor and, preferably, bring about signal transduction.”
(Bednarek3: 6–8.) The structure of human ghrelin is as follows:

(Id. at 3.)
FF2. Bednarek teaches “[g]hrelin analogs can be administered to a subject”
including humans. (Bednarek 5: 23.) Bednarek teaches administering
an effective amount of the ghrelin analog to subjects for “achieving a
beneficial effect.” (Id. at 28: 6–8 (claim 15).) In addition, Bednarek
teaches “[a] method for stimulating growth hormone secretion
comprising the step of administering to a subject an effective amount
of” ghrelin analog. (Id. at 29: 1–3 (claim 17).)
FF3. Kangawa teaches a “peptide-type compound which induces secretion
of growth hormone provides a peptide-type compound which induces
secretion of growth hormone and which has the activity of increasing
the intracellular calcium ion concentration.” (Kangawa, Abstract.)
Kangawa teaches SEQ ID NO: 3 which is identified as an “[a]mino
acid sequence for human endogenous peptides of growth hormone
secretagogue.” (Id. at col. 93.)
FF4. Matsumoto teaches the minimal structural requirements that maintains
ghrelin activity (see Matsumoto Table 1) and also teaches the
production of ghrelin analogs. “To compare the effect of bonding
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structures on ghrelin activity, we altered the ester bond between
octanoic acid and the Ser3 side chain to a more chemically stable
thioether and ether.” (Id. at 144, see also Table 2.)
FF5. Matsumoto teaches the administration of the ghrelin and ghrelin
analogs to subjects, in this case rat, and monitors the secretion of
growth hormone. “The level or GH in plasma, stimulated by the
intravenous injection of compound 23 (5 µg/head, iv), is equivalent to
that produced by treatment with native rat ghrelin (5 µg/head, iv)”
(Matsumoto 144, see also Fig. 1.)
FF6. Tacke-I teaches that
[g]hrelin was significantly elevated and IGF-1 reduced in CLD
[chronic liver disease] patients compared with healthy controls.
IGF-1 levels inversely correlate with Child's classification. . . .
[However,] ghrelin levels did not correlate with liver
function. . . . Our results suggest a central role of ghrelin in the
pathophysiology of metabolic disturbances in patients with end-
stage cirrhosis. Further studies should evaluate ghrelin as a
prognostic parameter and as a potential treatment option.
(Tacke-I.)
FF7. Skakkebræk teaches the administration of human growth hormone to
patients with chronic liver disease. (Skakkebræk, Abstract.)
[I]n patients with liver cirrhosis the concentration of
IGF-1 in the blood is very low, while GH, which stimulates the
synthesis and release of IGF-1 from the liver, is present in a
very high concentration. Therefore it seems that GH is present
in relative excess, however an excess that cannot be used and
which consequently is excreted in the urine.
. . . it is possible by administration of GH to the already
existing surplus to increase the also above mentioned very low
IGF-1 concentration considerably.
(Id. at 2: 29–44; see also 3: 4–25.)
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FF8. Wonke discloses the administration of “rhGH (0.1 unit/kg body
weight/day s.c for four days) followed by measurements of IGF1, and
insulin-like growth factor and their binding protein (IGFBP3) levels in
the serum.” (Wonke 237.)
Principle of Law
“Obviousness does not require absolute predictability of success . . .
all that is required is a reasonable expectation of success.”’ In re Kubin, 561
F.3d 1351, 1360 (Fed. Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 903-
904 (Fed. Cir. 1988)).
Analysis
The Examiner finds, and Appellants do not contest, that Bednarek
and/or Kangawa teach the claimed ghrelin analogs. (See App. Br. 7; Ans. 7;
see FF1 and FF2.) Appellants, however, contend that the secondary
references “do not remedy the deficiencies of either Bednarek and/or
Kangawa because none of these secondary references specifically teaches or
suggests administering ghrelin for the purposes of a treating hepatopathy,
much less provide a reasonable expectation of success that such
administration would be successful even if one of ordinary skill in the art
had effected the proposed combination.” (App. Br. 7.)
After considering the evidence and the arguments, we conclude the
evidence favors the Examiner’s conclusion of obviousness. Accordingly, we
adopt the Examiner’s reasoning (see Grounds of Rejection, Ans. 5–10), and
agree that the Examiner properly found Appellants’ arguments unpersuasive
(see Response to Argument, Ans. 10–22). We address Appellants’
arguments below.
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We are not persuaded by Appellants’ contention that the Examiner has
not presented a prima facie case of obviousness based on the combination of
the disclosed references (see App. Br. 6–10).
Bednarek and Kangawa each teach the claimed ghrelin analogs (FF1
and FF2). In addition, Bednarek teaches that these analogs are administered
to subjects for the purpose of achieving a beneficial effect (FF2). In other
words, Bednarek instructs the administration of ghrelin analogs. Although,
Bednarek does not disclose what condition or patient population should be
treated with the ghrelin analogs, the reference does disclose that these
analogs will stimulate growth hormone secretion (FF2). Matsumoto teaches
the administration of ghrelin peptides to rats and observes the increase of
plasma growth hormone levels (FF4 and FF5; see also Ans. 7–8).
Skakkebræk teaches the administration of growth hormone to patients
with chronic liver disease in order to increase the low IGF-1 levels in this
patient population (FF7). Wonke teaches the administration of growth
hormone and tracking IGF-1 levels in patients (FF8; see Ans. 9 (“the
administrating of GH correlates to serum IGF-I levels are a measure of the
level of resistance upon administration of GH as a treatment, demonstrating
a connection between GH and IGF-1”)). Tacke-I teaches that although
ghrelin levels do not correlate with liver function, the reference never the
less suggests that further studies should be conducted to evaluate the use of
ghrelin in treatment options (FF6).
The claims are directed to treating hepatopathy, i.e., any disease of the
liver, by administering of ghrelin analogs having the recited structure as
disclosed in claim 20. There appears to be no dispute that the structures
taught in Bednarek and Kangawa each meet the limitations the claimed
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ghrelin analogs (FF1 and FF3). Additionally, Bednarek also teaches
administration of these ghrelin analogs to patients in order to stimulate a
beneficial effect or to stimulate growth hormone secretion (FF2).
The art suggests administering growth hormone to a patient
population that has chronic liver disease, for the purpose of increasing the
IGF-1 levels produced by the liver (see FF7 and FF8). Skakkebræk teaches
that it would be beneficial to increase GH in patients with chronic liver
disease, even though that patient population already has high GH levels in
the blood (FF7). Skakkebræk explains that the administration of GH
increases the available GH in the patient and allows for an increase the
production of IGF-1 from the liver (FF7). Thus, the art suggests that in
patients with chronic liver disease it would be beneficial to increase the
levels of GH even further in order to increase IGF-1 production from the
liver.
The art teaches that increasing GH levels in the plasma can also be
achieved by administering ghrelin and ghrelin analogs (FF5, see also FF2).
We agree with the Examiner’s conclusion that it would have been obvious to
administer ghrelin or ghrelin analogs to patient with chronic liver disease in
order to increase the GH level in the plasma and thereby increase IGF-1
production from the liver (Ans. 9–10) as suggested by the teachings of
Skakkebræk and Matsumoto.
The limitation that the “polypeptide promotes hepatic regeneration
and/or recovery of hepatic function” is a property that is associated with the
structure of the ghrelin analog compound. “Newly discovered results of
known processes directed to the same purpose are not patentable because
such results are inherent.” Bristol-Myers Squibb Co. v. Ben Venue Labs.,
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Inc., 246 F.3d 1368, 1376 (Fed. Cir. 2001). The combination of Bednarek
and Matsumoto suggests that administration of ghrelin analogs to patients
necessarily results in increasing growth hormone levels in plasma (see FF1,
FF2, FF4, and FF5). Here, the art suggests that increasing in GH levels
would also inherently increase IGF-1 levels (see FF2, FF3, FF5, and FF7).
Appellants contend that there is no reasonable expectation of success
in combining the teachings of the references. Specifically, Appellants
contend that the teachings of Tacke-I and Tacke-II “demonstrating a lack of
reasonable expectation of success.” (App. Br. 11.)
We are not persuaded by Appellants’ contention that there is no
expectation of success that increasing growth hormone levels using ghrelin
in a subject would not also result an increase in IGF-1 production. Tacke-II
teaches that “[g]hrelin showed significant but relatively weak correlation
with various parameters in patients with CLD [chronic liver disease].”
(Tacke-II, 450; see also FF6.) Tacke-II discloses that Child C. cirrhosis
shows increased serum ghrelin concentrations. (Tacke-II, 450.) As
recognized by the Examiner “[i]n both Tacke I and Tacke II, a lack of
correlation between liver function and GH levels are admitted, but benefits
are still envisioned and stated despite an unproven assumption (hypothesis)
that GH would not increase IGF-1.” (Ans. 12.) Furthermore, Tacke-II
suggests that “ghrelin could potentially counteract these challenges in Child
C, cirrhosis by its various metabolic function besides GH release, like
induction of hyperglycemia, modulation of energy balance, stimulation of
appetite and food intake . . . . Given the wide-spread presence of GH
secretagogue binding sites in numerous human tissues . . . , probably not all
of the peripheral ghrelin effects have been discovered yet.” (Tacke-II, 450.)
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In other words, Tacke-II says that even if we do not know the actual
mechanism of action for ghrelin in a patient with liver disease it would still
be beneficial to administer ghrelin because there are numerous ghrelin
binding sites throughout the body.
Appellants contend that Tacke-II teaches away from the use of ghrelin
in treating hepatopathy (see App. Br. 12). Specifically, Appellants contend
that “one of ordinary skill in the art, reading Tacke[-]I and [Tacke-]II in their
entireties, would conclude that these references direct the skilled person to
consider targeting ghrelin for treatment-not to use ghrelin as a therapeutic
agent.” (Reply Br. 4.)
We are not persuaded by Appellants’ contention that the references
would suggest targeting ghrelin as the therapeutic rather than using ghrelin
as a therapeutic agent. Even though both Tacke-I and Tacke-II state the
ghrelin levels are not correlated with liver function, both articles still suggest
ghrelin as a potential therapeutic. (See Ans. 13.) Tacke-II discloses that
“[s]erum ghrelin levels were significantly elevated in Child C liver cirrhosis
compared with CLD patients. . . . In contrast, IGF-1 levels significantly
decreased with every stage of cirrhosis according to Child’s criteria.”
(Tacke-II, 448–449.) Just because ghrelin levels are high does not mean that
the ordinary artisan would not be motivated in increase the levels ghrelin
even further in order to direct a downstream effect. Here, the teachings of
Skakkebræk are informative because they suggest that it would still be
beneficial to increase GH in patients with chronic liver disease, a population
that already has high GH in the blood, in order to make sufficient GH
available to the liver in order to increase the production of IGF-1 from the
liver (FF7). We are not persuaded by Appellants’ contention that a
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disclosure of high ghrelin level in patients with liver disease would teach
away from using ghrelin as a therapeutic agent, especially since Tacke-I and
more importantly Tacke-II teaches that not all “peripheral ghrelin effects
have been discovered yet.” (Tacke-II, 451.) We agree with the Examiner
conclusion that the references do not teach away from the combination (see
Ans. 10–15.)
Appellants contend that the Examiner did not consider the Hayashi's
Declaration (see App. Br. 12.) “The treatment of hepatopathy operates
through a GH-independent pathway” (Reply Br. 6, citing Hayashi
Declaration; see also App. Br. 13–14.)
We are not persuaded by Appellants contention that the Examiner did
not consider the Hayashi Declaration. The Hayashi Declaration attempts to
establish that ghrelin acts by a pathway that is independent of growth
hormone. (Hayashi Declaration 10 (“effects of ghrelin on DMN-induced
hepatopathy model are exerted by GH-independent actions of ghrelin”).) As
explained by the Examiner that “[d]espite the apparent finding in the
Declaration in dwarf mice, a finding that GH is not involved in the pathway
for Dwarf mice, cannot negate what is found in humans. The finding that it
can work in a genetically odd mouse line, does not render the findings of
Ghrelin in humans, and [furthermore,] contradicts what Appellants have
already asserted in the patents.” (Ans. 19–20 (emphasis omitted).) We
agree with the Examiner’s position that teaching the mechanism of action of
ghrelin is not persuasive to overcome the obviousness rejection that is based
on the combination of references. To confirm something that was already
suggested in the art – in this case that not all peripheral effects of ghrelin
have been discovered yet (Tacke-II, 451) – is not inventive. “Scientific
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confirmation of what was already believed to be true may be a valuable
contribution, but it does not give rise to a patentable invention.” Pharma
Stem Therpeutic, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (2007)
While Appellants do present arguments directed to evidence that the
administration of ghrelin “cannot sustain levels of GH secretion necessary to
elicit IGF-1 production” (Reply Br. 7, citing Exhibits A–E), we note that
absent a showing of good cause, the Board is not required to address
arguments in the Reply Brief that could have been presented in the principal
Brief and lack opportunity for an informative response by the Examiner. See
Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (“informative”).
(“Properly interpreted, the Rules do not require the Board to take up a
belated argument that has not been addressed by the Examiner, absent a
showing of good cause.”).
Additionally, we note that Appellants contend that Office Action of
Dec. 16, 2001 contains a new rejection and, therefore, the Final Rejection
was made prematurely (App. Br. 14). We direct the Appellants’ attention to
MPEP § 1201, which states:
The line of demarcation between appealable matters for the
Board and petitionable matters for the Director of the U.S.
Patent and Trademark Office (Director) should be carefully
observed. The Board will not ordinarily hear a question that
should be decided by the Director on petition, and the Director
will not ordinarily entertain a petition where the question
presented is a matter appealable to the Board.
(MPEP § 1201, 9th ed.)
In the present case, Appellants have not filed a petition to resolve the
Examiner’s premature holding of finality. Any question as to prematurity of
a Final Rejection should be raised, if at all, while the application is still
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pending before the primary Examiner. It is reviewable by petition under
37 C.F.R. § 1.181 and thus not within the jurisdiction of the Board.
We conclude that the evidence cited by the Examiner supports a prima
facie case of obviousness with respect to claim 20, and Appellants have not
provided sufficient rebuttal evidence or secondary considerations that
outweighs the evidence supporting the prima facie case. As Appellants do
not argue the claims separately, claims 27–30, 32, and 48–53 fall with
claim 20. 37 C.F.R. § 41.37 (c)(1)(iv).

SUMMARY
We affirm the rejection of claim 20 under 35 U.S.C. § 103(a) over
Bednarek and/or Kangawa in view of Matsumoto, Tacke, Skakkebræk, and
Wonke. Claims 27–30, 32 and 48–53 fall with claim 20.

TIME PERIOD FOR RESPONSE
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