Ex Parte Davis et al

Board of Patent Appeals and Interferences

Apr 21, 2010

10154106 (B.P.A.I. Apr. 21, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HARRY R. DAVIS, ERIC McFEE PARKER,
MARGARET VAN HEEK,
GWENDOLYN T. WONG and LAURA B. MERKEL
__________

Appeal 2009-010891
Application 10/154,106
Technology Center 1600
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Decided: April 21, 2010
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Before ERIC GRIMES, TONI R. SCHEINER, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to methods
of treating Alzheimer’s disease. The Examiner has rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

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STATEMENT OF THE CASE
Claims 1-25, 27-46 and 65 are on appeal.1 Claim 1 is representative
and read as follows:
Claim 1: A method of treating or ameliorating symptoms of
Alzheimer's Disease comprising the step of administering to a subject in
need of such treatment an effective amount of a composition comprising at
least one compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof or solvate thereof,
wherein [the various substituents are defined]
to treat or ameliorate symptoms of Alzheimer's Disease in the subject.
OBVIOUSNESS
Issue
The Examiner has rejected claims 1-25, 27-46 and 65 under 35 U.S.C.
§ 103(a) as being obvious in view of Rosenblum,2 Kosoglou,3

1 The claims in the Claims Appendix to the Appeal Brief are numbered
consecutively 1-46. However, claims 26 and 47-64 have been withdrawn
from consideration (Appeal Br. 5). Thus, the claims numbered 26-45 in the
Claims Appendix correspond to claims 27-46, and the claim numbered 46
corresponds to claim 65.
2 Rosenblum et al., US 5,767,115, Jun. 16, 1998
3 Kosoglou et al., XIIth International Symposium on Atherosclerosis,
Stockholm, Sweden, Poster Abstract No. TuP24:W16 (2000).
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Simons,4 Scolnick5 and Sugimoto.6 The claims have been argued in six
groups: claims 2-4, 6-25, 27, 32-41, 44 and 65 stand or fall with claim 1;
claims 29-31 stand or fall with claim 28; claim 43 stands or falls with claim
42; claims 5, 45 and 46 were each argued separately. 37 C.F.R.
§ 41.37(c)(1)(vii).
The Examiner finds that Rosenblum discloses “a method of reducing
plasma cholesterol levels and treating atherosclerosis comprising
administering a combination of a[] hydroxy-substituted azetidinone
cholesterol absorption inhibitor of formula I [of instant claim 1]… and a
cholesterol biosynthesis inhibitor” (Answer 4-5; citing compound 6a in
particular as the compound ezetimibe). The Examiner relies on Kosoglou as
disclosing “that co-administration of ezetimibe (EZE) and simvastatin (SIM-
10mg) was safe and well tolerated and showed a dose dependent reduction
in LDL-C” (id. at 5).
The Examiner finds that Simons discloses that “lovastatin (an HMG-
CoA reductase inhibitor) and methyl-β-cyclodextrin reduced the cellular
cholesterol level of hippocampal neurons by 70% and completely inhibited
the formation of β-amyloid [Aβ] … and implies a link between cholesterol,
Aβ and Alzheimer’s disease” (id.). The Examiner finds that Scolnick
discloses “treating … and preventing Alzheimer’s disease by regulating the
amount of ApoE isoform 4 circulating in the bloodstream and in the brain by
administration of an HMG-CoA reductase inhibitor such as simvastatin” (id.

4 Simons et al., Cholesterol depletion inhibits the generation of β-amyloid
in hippocampal neurons, 95 Proc. Natl. Acad. Sci. USA 6460-6464 (1998).
5 Scolnick, WO 95/06470, Mar. 9, 1995
6 Sugimoto et al., US 4,895,841, Jan. 23, 1990
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at 6), and that Sugimoto discloses using donepezil hydrochloride to treat
Alzheimer’s disease (id. at 6-7). The Examiner concludes that it “would
have been obvious … to use ezetimibe, simvastatin and/or donepezil
hydrochloride (singly or in combination) in a method of treating or
ameliorating symptoms of Alzheimer’s disease, as simvastatin and ezetimibe
are cholesterol lowering agents and Simons … show[s] a link between
cholesterol levels, Aβ and Alzheimer’s disease” (id. at 7).
Appellants contend that one of skill in the art would not have had a
reasonable expectation of successfully treating Alzheimer’s disease with
Rosenblum’s compound 6A because Simons discloses that lovastatin alone
was not effective in reducing cellular β amyloid and thus would not be
effective in treating Alzheimer’s disease (Appeal Br. 11-15).
The principal issue presented in this appeal is: Does the evidence of
record support the Examiner’s conclusion that one of skill in the art would
have a reasonable expectation of success in treating the symptoms of
Alzheimer’s disease by administering a composition comprising a
compound recited in claim 1?
Findings of Fact
1. Rosenblum discloses “[h]ydroxy-substituted azetidinone
hypocholesterolemic agents … as well as a method of lowering serum
cholesterol by administering said compounds, alone or in combination with a
cholesterol biosynthesis inhibitor” (Rosenblum, Abstract).
2. Rosenblum discloses “a method of treating or preventing
atherosclerosis, comprising administering to a mammal in need of such
treatment an effective amount of a combination of a hydroxy-substituted
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azetidinone cholesterol absorption inhibitor of formula I and a cholesterol
biosynthesis inhibitor” (id. at col. 3, ll. 48-53)
3. Rosenblum discloses that the “inhibition of cholesterol
biosynthesis by 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
reductase … inhibitors has been shown to … reduce plasma cholesterol …
and reduce atherosclerosis. Combination therapy of an HMG CoA reductase
inhibitor and a bile acid sequestrant has been demonstrated to be more
effective in human hyperlipidemic patients than either agent in
monotherapy” (id. at col. 2, ll. 8-16).
4. The Examiner finds that Rosenblum’s compound 6A (id. at col. 31,
ll. 1-12) is within the scope of claim 1’s Formula I (Answer 4-5).
5. The Examiner finds, and Appellants do not dispute, that
Rosenblum’s compound 6A is known in the art as “ezetimibe” (Answer 5).
6. Appellants agree that “[e]zetimibe [is] an example of Formula (I)”
(Appeal Br. 18).
7. Kosoglou discloses that the “coadministration of EZE and SIM
[simvastatin] 10 mg was safe and well tolerated. EZE combined with SIM
10 mg caused a dose-dependent reduction in LDL-C” (Kosoglou, Abstract).
8. Kosoglou discloses that the “coadministration of EZE 10 mg and
low dose SIM has the potential to produce clinically significant reductions in
LDL-C, comparable to maximum doses of sim alone, with a favorable safety
profile” (id.).
9. Simons discloses that the “amyloid precursor protein (APP) plays a
crucial role in the pathogenesis of Alzheimer’s disease” and that proteolytic
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cleavage of APP can lead to the release of β-amyloid (Aβ) fragment
(Simons, Abstract).
10. Simons discloses that “[i]t is Aβ that accumulates in the brain
lesions that are thought to cause [Alzheimer’s] disease” (id.).
11. Simons discloses that “[b]y reducing the cellular cholesterol level
of living hippocampal neurons by 70% with lovastatin and methyl-β-
cyclodextrin, we show that the formation of Aβ is completely inhibited.…
Our results show that cholesterol is required for Aβ formation to occur and
imply a link between cholesterol, Aβ, and Alzheimer’s disease” (id.).
12. Simons discloses that the “lovastatin treatment protocol alone did
not cause a significant difference in Aβ secretion, suggesting that fairly large
amounts of cholesterol need to be removed before effects on Aβ secretion
can be observed” (id. at 6462).
13. Scolnick discloses “a method of preventing and treating
Alzheimer’s disease by treating a patient in need of such treatment with an
HMG-CoA reductase inhibitor … to lower Apolipoprotein E isoform 4
(ApoE isoform 4) levels in the central nervous system” (Scolnick, 4: 34 to 5:
6).
14. The Examiner finds, and Appellants do not dispute, that Sugimoto
discloses that donepazil hydrochloride is useful for treating Alzheimer’s
disease (Answer 6-7).
Principles of Law
“Obviousness does not require absolute predictability of success…
For obviousness under § 103, all that is required is a reasonable expectation
of success.” In re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988).
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“In the patent claim context, the term ‘comprising’ is well understood
to mean ‘including but not limited to’.” CIAS, Inc. v. Alliance Gaming
Corp., 504 F.3d 1356, 1360.
Analysis
Claim 1 is directed to a method of treating symptoms of Alzheimer's
disease by administering to a subject a composition comprising a compound
of the recited formula.
Rosenblum discloses a compound (compound 6A, or ezetimibe)
within the scope of claim 1’s formula, and discloses that its compounds are
cholesterol absorption inhibitors that can be used in combination with a
cholesterol biosynthesis inhibitor for the treatment of atherosclerosis.
Kosoglou discloses that the combination of ezetimibe and simvastatin has a
favorable safety profile. Simons discloses that cholesterol is required for
formation of the β-amyloid fragment that accumulates in Alzheimer’s
disease lesions, and Scolnick discloses treating Alzheimer’s disease with an
HMG CoA reductase inhibitor. In view of these disclosures, it would have
been obvious to one of skill in the art to administer ezetimibe, especially in
combination with an HMG CoA reductase inhibitor, to lower cholesterol
levels and thereby treat Alzheimer’s disease.
Appellants argue that one of skill in the art would not have reasonably
expected administration of a compound of Formula I to effectively treat
Alzheimer’s disease because Simon discloses that lovastatin alone was
ineffective in reducing Aβ generation, and thus one of skill in the art would
not expect a compound of Formula I to be any more effective (Appeal Br.
11-14). Appellants argue that one of skill in the art would not have a
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reasonable expectation of success in arriving at the invention of claims 45 or
46 for the same reason (Appeal Br. 15-16).
This argument is not persuasive. As recognized by the Examiner,
claim 1 is not limited to the administration of a compound of Formula I
alone but uses the open language “comprising” and thus encompasses the
administration of the compound of Formula I together with other cholesterol
lowering agents. Additionally, Rosenblum discloses that using two
cholesterol lowering agents in combination is more effective than either
agent alone, and Kosoglou discloses using ezetimibe in combination with
simvastatin. Thus, given that the art discloses a link between lowering
cholesterol and treating Alzheimer’s disease and discloses ezetimibe is used
for the treatment of cholesterol levels in atherosclerosis, one of skill in the
art would have a reasonable expectation that ezetimibe, either alone or in
combination with other cholesterol lowering agents, would effectively treat
Alzheimer’s disease by lowering a patient’s cholesterol level.
With regard to claim 28, Appellants argue that In re Kerkhoven
“cannot be relied upon to support a per se reason or motivation to combine a
biosynthesis inhibitor” with the compound of claim 1, because two different
mechanisms of action in cholesterol inhibition are involved (Appeal Br. 17-
18). Thus, Appellants argue that the Examiner has not provided a
motivation to combine the agents (id. at 18).
This argument is not persuasive. Claim 28 depends from claim 1 and
requires that the composition also comprises a cholesterol biosynthesis
inhibitor. As discussed above, Rosenblum expressly suggests combining a
cholesterol absorption inhibitor with a cholesterol biosynthesis inhibitor.
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Kosoglou discloses that the combination of a cholesterol absorption inhibitor
(ezetimibe) and a cholesterol biosynthesis inhibitor (simvastatin) is safe and
effective to lower cholesterol levels. Thus, it would have been obvious to
one of ordinary skill in the art to administer ezetimibe in conjunction with
simvastatin to treat Alzheimer’s disease by lowering cholesterol levels. See
KSR Int’l v. Teleflex Inc., 550 U.S. 398, 416 (2007) (The “combination of
familiar elements according to known methods is likely to be obvious when
it does no more than yield predictable results.”)
With regard to claim 42, Appellants argue that the compound recited
in the claims “operates on a different biopathway from other Alzheimer’s
Disease treatments.… Therefore, applying the correct interpretation of
Kerkhoven, there is no per se motivation to combine Formula (I) and a
different Alzheimer’s treatment” (Appeal Br. 19).
Claim 42 depends from claim 1 and requires that the “composition
further comprises at least one Alzheimer’s treatment different from
compound I above.” The Examiner finds that Sugimoto discloses certain
compounds, including donepazil hydrochloride, as “being useful in the
treatment of diseases such as senile dementia and Alzheimer’s disease”
(Answer 6). The Examiner concludes that it “would have been obvious … to
use ezetimibe, simvastatin and/or donepezil hydrochloride (singly or in
combination) in a method of treating or ameliorating symptoms of
Alzheimer’s disease, as simvastatin and ezetimibe are cholesterol lowering
agents and Simons … show[s] a link between cholesterol levels, Aβ and
Alzheimer’s disease” (id. at 7). We agree with the Examiner’s reasoning –
since cholesterol-lowering agents and donepazil hydrochloride were known
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for use in treating Alzheimer’s disease, it would have been obvious to use
them in combination with a reasonable expectation that the combination
would be more effective than the individual agents administered alone.
Appellants argue that the Examiner has not adequately explained
“why one of ordinary skill in the art would expect that the recited method
would be useful in a human subject having trisomy 21,” as recited in claim 5
(Appeal Br. 19).
This argument is not persuasive. Appellants have pointed to no
evidence showing that subjects with Alzheimer’s disease and trisomy 21
would be treated differently from other subjects with Alzheimer’s disease.
We therefore conclude that the Examiner has provided a reasonable basis to
establish that cited references would have suggested treating the trisomy 21
population the same way as the general population.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that one
of skill in the art would have a reasonable expectation of success in treating
the symptoms of Alzheimer’s disease by administering a composition
comprising a compound recited in claim 1.
SUMMARY
We affirm the rejection of claims 1-25, 27-46 and 65 under 35 U.S.C.
§ 103(a).
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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

alw

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PATENT DEPARTMENT (K-6-1, 1990)
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