Ex Parte Arai

Patent Trial and Appeal Board

Feb 24, 2017

12599962 (P.T.A.B. Feb. 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.
12/599,962 08/03/2010 Heii Arai 05273.0122 4885
22852 7590 02/28/2017
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON, DC 20001-4413
EXAMINER
CARTER, KENDRA D
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
02/28/2017 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):
regional-desk @ finnegan. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HEII ARAI
Appeal 2016-000806
Application 12/599,9621
Technology Center 1600
Before JEFFREY N. FREDMAN, RYAN H. FLAX, and DAVID COTTA,
Administrative Patent Judges.
COTTA, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for treating Alzheimer’s disease. The Examiner rejected the claims on
appeal as obvious under 35 U.S.C. § 103(a) and on the ground of
obviousness-type double patenting.
We affirm.
1 According to Appellant, the real party in interest is Otsuka Pharmaceutical
Co. Ltd. App. Br. 3.
Appeal 2016-000806
Application 12/599,962
STATEMENT OF THE CASE
Claims 6—9 are on appeal. Claim 6 is illustrative and reads as follows:
wherein A is a lower alkylene group, R is a
cycloalkyl group, and the bonding between 3- and
4-positions of the carbostyril skeleton is a single
bond or a double bond, and donepezil or a salt
thereof to a patient in need of such treatment.
The claims stand rejected as follows:
Claims 6—9 under 35 U.S.C. § 103(a) as unpatentable over the
combination of Hong,2 Schmitt3 and Sugimoto.4
Claims 6—9 on the grounds of obviousness-type double patenting over
claims 1—4 of US Patent No. 8,329,731 (Hong).
FINDINGS OF FACT
1. The Examiner finds, and Appellant does not dispute, that Hong
discloses a compound of Appellant’s formula (1), specifically cilosstazol.
Final Act. 7; App. Br. 5.
2 Hong, US Patent No. 8,329,731 B2, issued Dec. 11, 2012 (“Hong”).
3 Schmitt et al., Combination Therapy in Alzheimer’s Disease, 18(13) CNS
Drugs, 827-A4 (2004) (“Schmitt”).
4 Sugimoto, Donepezil Hydrochloride: A Treatment Drug for Alzheimer’s
Disease, 1(1) The Chemical Record, 63-73 (2000) (“Sugimoto”).
6. A method for treating Alzheimer’s disease
which comprises administering an effective
amount of a carbostyril derivative or a salt thereof
of the general formula:
2
Appeal 2016-000806
Application 12/599,962
2. The Examiner finds, and Appellant does not dispute that “it is
well known and taught in the cited art that [] donepezil and the compounds
of Formula I work through a different mechanism to treat AD.” Ans. 4.
3. Hong discloses: “Cilostazol has an anti-platelet and vaso­
dilating action, which has an indication for ASO and prevention of
secondary brain infarction. These actions of Cilostazol may contribute to
reduce the deposition of amyloid-beta protein, and improve a behavior of
Alzheimer’s dementia.” Id. at col. 8,11. 32—37.
4. Sugimoto discloses:
Donepezil hydrochloride (E2020) is the second drug
approved by the US FDA for the treatment of mild to
moderate AD. It is a new class of AChE inhibitor having
an N-benzylpiperidine and an indanone moiety, which
shows longer and more selective action. It is now
marketed in the US and in some European and Asian
countries under the trade name Aricept®.
Sugimoto 65.
5. Sugimoto discloses:
The role of the cholinergic system with respect to
cognitive deficits characteristic of Alzheimer’s disease
(AD) has led to a number of studies focusing on the
development of acetylcholinesterase (AChE) inhibitors as
a drug for treating this disease. The earliest known AChE
inhibitors, namely, physostigmine and tacrine, performed
poorly in clinical trials (e.g., poor oral activity, brain
penetration, and hepatotoxic liability). Studies were then
focused on finding a new type of acetylcholinesterase
inhibitor that would overcome the disadvantages of these
two compounds. Donepezil hydrochloride inaugurates a
new class of AChE inhibitors with longer and more
selective action and with manageable adverse effects.
Id. at Abstract.
3
Appeal 2016-000806
Application 12/599,962
6. Schmitt discloses:
any combination regimen will need to consider AChE
inhibitors, either as part of the treatment combination or as
a comparison, because they are the gold standard in AD.
Thus, it is highly likely that AChE inhibitors will be part
of any combination regimen; this approach has in fact been
followed by all except one of the presently available
combination therapy studies in AD patients.
Id. at 839-840.
7. Schmitt discloses:
Considering the complexity of AD, and that multiple
aetiologies may contribute to the disease, a combination of
therapeutic agents may result in more effective strategies
for treatment than one drug alone. Since the extent and
topography of the neurochemical and molecular pathology
of AD changes over the course of the disease, which
results in a shift of symptoms over time, the efficacy of
drugs may change over time as well. This might affect the
choice of a rational combination of drugs. Thus, the
development of an effective therapy for AD remains a
great challenge for drug research.
Schmitt 828 (emphasized as in App. Br. at 6—7).
8. Schmitt discloses:
Altogether, empirical evidence for the efficacy of
combining antidementia drugs is far too limited to draw
firm conclusions. The practice of augmenting AChE
inhibitors with other potentially neuroprotective drugs has
little empirical or theoretical support. The risks of add-on
therapy strategies have not been studied systematically.
No study has examined the economic impact of
combination treatment. Thus, further trials of
antidementia combination therapies are needed before this
currently unsupported practice can be recommended.
4
Appeal 2016-000806
Application 12/599,962
Id. at 841 (emphasized as in App. Br. at 8).
OBVIOUSNESS
Appellant argues claims 6—9 together as a group. We designate claim
6 as representative for the group.
The Examiner found that Hong taught that compounds of formula (1)
of claim 6 are “useful as medicament for the treatment of cognitive disorders
and Alzheimer’s disease.” Final Act. 7. The Examiner acknowledged,
however, that Hong did not teach combination therapy with donepezil or
donepezil hydrochloride. Id.
The Examiner found that Schmitt taught the use of combination
therapy to treat Alzheimer’s and suggested that “[a]ny combination regimen
will need to consider AChE inhibitors, either as part of the treatment
combination or as a comparison, because they are the gold standard in AD
[Alzheimer’s disease].” Id. The Examiner further found that Schmitt
disclosed that AChE inhibitors include donepezil. Id.
The Examiner found that Sugimoto taught that donepezil
hydrochloride is “a treatment drug for Alzheimer’s disease and [has]
overcome the disadvantages of other AChE inhibitors physostigmine and
tacrine.” Id. at 8.
Based on the combined teachings of Hong, Schmitt and Sugimoto, the
Examiner concluded:
one skilled in the art would have found it obvious to
combine the compounds of Hong and donepezil or
donepezil hydrochloride because of the following:
1) both compounds treat Alzheimer’s disease;
2) combination therapy for the treatment of AD is
known; 3) Schmitt et al. teach that any combination
5
Appeal 2016-000806
Application 12/599,962
regimen will need to consider AChE inhibitors, either as
part of the treatment combination or as a comparison,
because they are the gold standard in AD; 4) Schmitt et
al. also teaches that it is highly likely that AChE
inhibitors will be part of any combination regimen; this
approach has in fact been followed by all except one []
presently available combination therapy studies in AD
patients (see page 839, last paragraph to page 840, first
paragraph); and 5) “It isprima facie obvious to combine
two compositions each of which is taught by the prior art
to be useful for the same purpose, in order to form a third
composition to be used for the very same purpose ....
[T]he idea of combining them flows logically from their
having been individually taught in the prior art.”
Id. at 8.
Appellant argues that neither Hong nor Sugimoto teaches combination
therapy for Alzheimer’s disease and Schmitt does not remedy this deficiency
because Schmitt teaches the unpredictability of combination therapy in the
treatment of Alzheimer’s disease. App. Br. 5. Appellant contends that
Schmitt discloses only a “potential” for combination therapy and does not
create a reasonable expectation that combination therapy will be successful.
Id. at 6—7 (quoting FF7). Appellant notes that Schmitt teaches that
administering drugs in combination may have adverse and/or antagonistic
effects and points out that fewer than all of the nine studies of combination
therapy reported in Schmitt favored combination therapy over monotherapy.
Id. at 7. Appellant also argues that Schmitt’s conclusion (quoted at FF8)
“establishes the lack of reasonable predictability in using a combination
therapy.” Id. at 8. We are not persuaded.
“It is prima facie obvious to combine two compositions each of which
is taught by the prior art to be useful for the same purpose, in order to form a
6
Appeal 2016-000806
Application 12/599,962
third composition which is to be used for the very same purpose.” In re
Kerkhoven, 626 F.2d 846, 850 (CCPA 1980); Merck & Co., Inc. v. Biocraft
Labs, Inc., 874 F.2d 804, 808 (Fed. Cir. 1989) (“Given the prior art teaching
that both amiloride and hydrochlorothiazide are natriuretic, it is to be
expected that their co-administration would induce more sodium excretion
than would either diuretic alone”); In re Gee, 614 Fed. Appx. 495, 497—98
(Fed. Cir. 2015) (finding it obvious to combine two treatments because both
were known to be useful in treating viral infections, rejecting arguments that
the sole reason for combining treatments was that both have been used in the
past to treat viral infections and that there was no indication in the prior art
as to which of many possible combination treatments was likely to be
successful); In re Crockett, 279 F.2d 274, 276 (CCPA 1960) (The “joint use
[of magnesium oxide and calcium carbide] is not patentable” where the prior
art teaches “that both magnesium oxide and calcium carbide, individually,
promote the formation of a nodular structure in cast iron, and it would be
natural to suppose that, in combination, they would produce the same effect
and would supplement each other.”).
Here, the record evidences that cilostazol and donepezil hydrochloride
were both known to treat Alzheimer’s disease and that they work through
different mechanisms of action. FF2—FF4. In addition Schmitt teaches that
combination therapy for Alzheimer’s disease was known (FF7) and that it
was considered “highly likely that AChE inhibitors will be part of any
combination regimen.” FF6. Further, Sugimoto teaches that donepezil
hydrochloride is part of a new class of AChE inhibitors that is superior to
physostigmine and tacrine, providing “longer and more selective action and
with manageable adverse effects.” FF5.
7
Appeal 2016-000806
Application 12/599,962
We acknowledge that Schmitt teaches some degree of unpredictability
with respect to the use of combination therapy to treat Alzheimer’s (see FF7
and FF8), but the law does not require absolute predictability. In re
O’Farrell, 853 F.2d 894, 903—04 (Fed. Cir. 1988) (“Obviousness does not
require absolute predictability of success. ... For obviousness under § 103,
all that is required is a reasonable expectation of success.”). Moreover,
when teachings of the prior art are considered together, we find that a person
of ordinary skill would reasonably have expected that donepezil
hydrochloride and cilostazol, both of which were known to be effective
individually in treating Alzheimer’s (see FF3 and FF4), would be successful
in treating Alzheimer’s when administered in combination.
Appellant argues that the Examiner did not properly consider
evidence of unexpected results. App. Br. 10. The Specification teaches that
“the administration of cilostazol [in] combination with donepezil
hydrochloride can recover the effect of donepezil hydrochloride which
tended to descend due to long-term administration of donepezil
hydrochloride.” Specification p. 13,11.6—8. The recovered effect of
donepezil hydrochloride is reflected in Table 1 (reproduced below):
Table 1
Patient
No,
Age Sex
MMSE Score [
-12 Ms — 9 Ms — 6 Ms -3 Ms 0 M 1 M 3 Ms |
1 63 F — 17 17 16 13 IS 17 1
2 52 F 16 13 12 10 6 11 — I
M(s) denotes "month(s)”.
The administration of cilostazol in the combination started at 0 M«
Id. at 13. Appellant asserts that the recovery of the effect of donepezil
hydrochloride reflected in Table 1 was surprising and unexpected. App. Br.
10.
8
Appeal 2016-000806
Application 12/599,962
Appellant also contends that Ihara5 supports a finding of unexpected
results. Ihara is a post-filing date study reporting the results of clinical
studies evaluating the combination therapy of donepezil and cilostazol.
App. Br. 11. Ihara’s Figure 1, reflecting the results of its study is
reproduced below:
A AfvIMSE/year
o -ss -s .vr> .j .as •:»
Donepazi!
Donepezif/cifostazo!
8 AOrssniation € ^Orientation D ADelsyed
for Jime/y-sar for pfoca/year recaii/year
Figure 1. Ccl«Sta2c}8 add-on th«fapy suppressed CognitJve decline In parents with mild dementis receiving cJtmepeziL ;A) OtKU«2e?
UioriipY S‘y:wK.;v>hy i-yppiKii-tid score 'A* wk: MM.SE subseascur-M> "A tXi-KivXKv'- for urruc \b\, (Xie:;toi:o» for aWa
ft), find dc'ioyo'd ft: >rt paiter.rs with miid dementi* receiving dcmepoYsi.''' CrOS versus dotNjjX'iijgroyp, Error bars show iterxiattf error of rho
Ihara. 3. According to Appellant, Ihara shows that “the addition of
cilostazol delays cognitive decline in the elderly receiving donepezil.” App.
Br. 11. Appellant contends that these results are surprising and unexpected.
Id. We are not persuaded.
“[T]he burden of showing unexpected results rests on he who asserts
them. Thus it is not enough to show that results are obtained which differ
from those obtained in the prior art: that difference must be shown to be an
unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972).
Here, Ihara indicates that treatment with a combination of donepezil and
cilostazol showed superior results as compared to treatment with just
donepezil. There is, however, no evidence that this result was unexpected.
5 Ihara et al., Cilostazol Add-On Therapy in Patients with Mild Dementia
Receiving Donepezil: A Retrospective Study, 9(2) PLOS ONE 1—5 (2014)
(“Ihara”). Ihara was submitted by Appellant as evidence of unexpected
results. App. Br. 11.
9
Appeal 2016-000806
Application 12/599,962
See, Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989)
(“Attorneys’ argument is no substitute for evidence.”); In re Pearson, 494
F.2d 1399, 1405 (CCPA 1974). As the Federal Circuit explained:
[B]y definition, any superior property must be unexpected
to be considered evidence of non-obviousness. Thus, in
order to properly evaluate whether a superior property was
unexpected, the [fact-finder] should have considered what
properties were expected. Here, Pfizer’s evidence must
fail because the record is devoid of any evidence of what
the skilled artisan would have expected. We will not
simply presume that the skilled artisan would have
expected that amlodipine besylate would have the same
characteristics as amlodipine maleate, because as Pfizer
asserts, its properties are not absolutely predictable.
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007); see also,
In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985) (“There is nothing to show
that the results attested in the declaration were unexpected. The fact that
some titanium compounds function more effectively, and that the exact
magnitude of the increased catalytic activity might not be predictable, does
not preclude a conclusion of obviousness. Only a reasonable expectation of
success, not absolute predictability, is necessary for a conclusion of
obviousness.”).
As the Federal Circuit explained in Pfizer, we cannot simply presume
that the person of ordinary skill would have expected the claimed
combination have the same characteristics as its individual components.
Indeed, as donepezil and cilostazol were known to be effective and utilized
different mechanisms of actions, “it would be natural to suppose that, in
combination, they would produce the same effect and would supplement
each other.” In re Crockett, 279 F.2d at 276. Absent declaratory or other
10
Appeal 2016-000806
Application 12/599,962
evidence reflecting that the superior properties of combined therapy with
donepezil and cilostazol exceed what the person of ordinary skill would have
expected at the time of the invention, the record cannot support a finding of
unexpected results. Accordingly, we affirm the Examiner’s rejection of
claim 6 as obvious over Hong, Schmitt, and Sugimoto. Because they were
not argued separately, claims 7—9 fall with claim 6.
DOUBLE PATENTING
The patent relied upon as the basis for the Examiner’s double
patenting rejection is the Hong reference that the Examiner relied upon in
the obviousness rejection. Appellant’s arguments with respect to the double
patenting rejection are substantially the same as their arguments with respect
to obviousness. See, App. Br. 12—13. Accordingly we affirm the
Examiner’s rejection of claims 6—9 on the ground of obviousness-type
double patenting for the reasons discussed in connection with the
Examiner’s obviousness rejection.
SUMMARY
For these reasons and those set forth in the Examiner's Answer, and
the Final Office Action, we affirm the Examiner’s decision to reject claims
6-9.
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)(1).
AFFIRMED
11