Ex Parte Davis et al

Board of Patent Appeals and Interferences

Apr 11, 2008

10057534 (B.P.A.I. Apr. 11, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte HARRY R. DAVIS
and
TEDDY KOSOGLOU
____________________

Appeal 2007-4484
Application 10/057,5341
Technology Center 1600
____________________

Decided: April 11, 2008
____________________

Before TEDDY S. GRON, CAROL A. SPIEGEL, and DEMETRA MILLS,
Administrative Patent Judges.

SPIEGEL, Administrative Patent Judge.

DECISION ON APPEAL

1 Application 10/057,534 ("the 534 application") filed 25 January 2002, said
to claim priority benefit of the 26 January 2001 filing date of provisional
application 60/264,600 and the 21 September 2001 filing date of provisional
application 60/323,842. The real party-in-interest is said to be Schering
Corporation (Appellant's Brief Under 37 C.F.R. § 1.192 filed 2 August 2005
("Br."), 1).
Appeal 2007-4484
Application 10/057,534

I. Statement of the Case
Harry R. Davis and Teddy Kosoglou ("Appellants") appeal under 35
U.S.C. § 134 from a final rejection of claims 1-3, 5, 6, 8-11, 28, 31-33, 35,
36, 70-72, 74-77, 79, and 80 (Ans.2 2). Claim 7 has been cancelled (Br. 1;
Ans. 2). Claims 4, 12-27, 29, 30, 34, 37-69, 73, 78, and 81, the only other
pending claims, have been withdrawn from consideration (Ans. 2). We have
jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.
The subject matter on appeal relates to compositions and therapeutic
combinations comprising at least one bile acid sequestrant, about 10 mg of at
least one structurally identified sterol absorption inhibitor, and, optionally, at
least one cholesterol biosynthesis inhibitor, as well as methods of use thereof
for treating hyperlipidemic conditions.
Claims 1 and 8 are illustrative and read:
1. A composition comprising:
(a) at least one bile acid sequestrant; and
(b) about 10 milligrams of at least one sterol
absorption inhibitor represented by Formula (I):

or isomers thereof, or pharmaceutically acceptable
salts or solvates of the compounds of Formula (I)

2 Examiner's Answer mailed 24 October 2005 ("Ans.").
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Application 10/057,534

or of the isomers thereof, or prodrugs of the
compounds of Formula (I) or of the isomers, salts
or solvates thereof, wherein in Formula (I) above:
Ar1 and Ar2 are independently selected from
the group consisting of aryl and R4-substituted
aryl;
Ar3 is aryl or R5-substituted aryl;
X, Y and Z are independently selected from
the group consisting of -CH2-, -CH (lower alkyl)-
and -C(dilower alkyl)-;
R and R2 are independently selected from
the group consisting of -OR6, -O(CO)R6,
-O(CO)OR9 and -O(CO)NR6R7;
R1 and R3 are independently selected from
the group consisting of hydrogen, lower alkyl and
aryl;
q is 0 or 1;
r is 0 or 1;
m, n and p are independently selected from 0, 1, 2,
3 or 4; provided that at least one of q and r is 1,
and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6;
and provided that when p is 0 and r is 1, the sum of
m, q and n is 1, 2, 3, 4 or 5;
R4 is 1-5 substituents independently selected
from the group consisting of lower alkyl, -OR6, -
O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -
O(CO)NR6R7, -NR6R7, -NR6(CO)R7,
-NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9,
-COOR6, -CONR6R7, -COR6, -SO2NR6R7,
S(O)0-2R9, -O(CH2)1-10-COOR6,
-O(CH2)1-10CONR6R7, -(lower alkylene)COOR6,
-CH=CH-COOR6, -CF3, -CN, -NO2 and halogen;
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Application 10/057,534

R5 is 1-5 substituents independently selected
from the group consisting of -OR6, -O(CO)R6, -
O(CO)OR9, -O(CH2)1-5OR6, -
O(CO)NR6R7, -NR6R7, -NR6(CO)R7,
-NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9,
-COOR6, -CONR6R7, -COR6, -SO2NR6R7,
S(O)0-2R9, -O(CH2)1-10-COOR6,
-O(CH2)1-10CONR6R7, -(lower alkylene)COOR6
and -CH=CH-COOR6;
R6, R7 and R8 are independently selected
from the group consisting of hydrogen, lower
alkyl, aryl and aryl-substituted lower alkyl; and
R9 is lower alkyl, aryl or aryl-substituted
lower alkyl.
8. The composition according to claim 1,
further comprising at least one cholesterol
biosynthesis inhibitor.
Claim 3 ultimately depends from claim 1 and recites a composition
"wherein the at least one bile acid sequestrant comprises cholestyramine."
Claim 11 ultimately depends from claim 8 and recites a composition
"wherein the at least one cholesterol biosynthesis inhibitor comprises at least
one HMG CoA reductase inhibitor" which is simvastatin. [Br. 21-23,
"CLAIM APPENDIX."]
In response to an election of species requirement in the Office Action
of July 16, 2003, Appellants elected cholestyramine as the bile acid
sequestrant, ezetimibe as the sterol absorption inhibitor, and simvastatin as
the cholesterol biosynthesis inhibitor for examination (Br. 7-8). Thus,
compositions, combinations, and methods including these three species are
before us.
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Appeal 2007-4484
Application 10/057,534

The Examiner relies on the following references3 as evidence of
unpatentability:
Dechow US 4,837,255 Jun. 6, 1989
Albright US 5,300,288 Apr. 5, 1994
Davis US 5,661,145 Aug. 26, 1997
Rosenblum US 5,846,966 Dec. 8, 1998

The Examiner has rejected claims 1-3, 5, 6, 8-11, 28, 31-33, 35, 36,
70-72, 74-77, 79, and 80 under 35 U.S.C. § 103(a) as unpatentable over
Rosenblum in view of Albright, Dechow, and Davis (Ans. 2-3).
II. Findings of Fact ("FF")
The following findings of fact and any set out in the Discussion are
supported by a preponderance of the evidence of record.
A. The 534 Application
[1] In one embodiment, the 534 specification describes compositions,
pharmaceutical compositions, therapeutic combinations, kits and
methods of treatment using the same comprising at least one bile acid
sequestrant and at least one substituted azetidinone sterol absorption
inhibitor or substituted ß-lactam sterol absorption inhibitor (Spec.
23:21-26).
[2] In a preferred embodiment, the sterol inhibitor is ezetimibe, i.e., 1-(4-
fluorophenyl)-3(R)-[3(R)-(4-fluorophenyl)-3-hydroxypropyl)]-4(s)-
(4-hydroxyphenyl)-2-azetidinone (Spec. 30:9-17).
[3] According to the 534 specification,
[t]he daily dose of the sterol absorption inhibitor(s)
preferably ranges from about 0.1 to about 1000 mg
per day, and more preferably about 0.25 to about

3 No references to et al. are made in this opinion.
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50 mg/day, given in a single dose or 2-4 divided
doses. The exact dose, however, is determined by
the attending clinician and is dependent on the
potency of the compound administered, the age,
weight, condition and response of the patient.
[Spec., 65:23-27.]
[4] In another embodiment, the composition or treatment further
comprises one or more cholesterol biosynthesis inhibitors co-
administered, or in combination, with the bile acid sequestrant(s) and
sterol absorption inhibitor(s) (Spec. 66:4-6).
[5] Suitable cholesterol biosynthesis inhibitors include competitive
inhibitors of HMG CoA reductase such as simvastatin (Spec. 66:7-
15).
[6] The compositions and combinations of the 534 application are said to
be useful "for treating hyperlipidemic conditions . . . associated with
atherosclerosis, hypercholesterolemia and other vascular conditions
in mammals" (Spec. 1:12-15).
B. Rosenblum
[7] Rosenblum discloses using a combination of a hydroxy substituted
azetidinone and cholesterol biosynthesis inhibitor for treating and
preventing atherosclerosis (Rosenblum 1:19-24).
[8] Suitable cholesterol biosynthesis inhibitors include HMG CoA
reductase inhibitors such as simvastatin (Rosenblum 6:37-41; claim
3).
[9] Suitable hydroxy substituted azetidinones include ezetimibe
(Rosenblum 32:45-58 (product "6B"); claim 5).
[10] According to Rosenblum, the daily hypocholesteremic dose of a
hydroxy-substituted azetidinone cholesterol absorption inhibitor
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is about 0.1 to about 30 mg/kg of body weight per
day, preferably about 0.1 to about 15 mg/kg. For
an average body weight of 70 kg, the dosage level
is therefore from about 5 mg to about 1000 mg of
drug per day, given in a single dose or 2-4 divided
doses. The exact dose, however, is determined by
the attending clinician and is dependent on the
potency of the compound administered, the age,
weight, condition and response of the patient.
[Rosenblum 21:17-26.]
[11] Rosenblum claim 5 recites a pharmaceutical composition for the
treatment or prevention of atherosclerosis, or for the reduction of
plasma cholesterol levels, comprising a combination of ezetimibe and
one of lovastatin, pravastatin, fluvastatin, simvastatin or atorvastatin.
C. Albright
[12] According to Albright, "[t]wo materials which are known to be
effective in lowering blood cholesterol levels by acting on bile acids
in the digestive tract are cholestyramine and cholestipol" (Albright
2:2-5).
D. Dechow
[13] Dechow discloses improving the palatability of cholestyramine by
providing it in a hypocholesterolemic gel formulation for oral
administration (Dechow 1:8 through 2:9).
E. Davis
[14] Davis discloses using a combination of a cholesterol biosynthesis
inhibitor, e.g., the HMG CoA reductase inhibitor simvastatin, and a
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Application 10/057,534

ß-lactam cholesterol absorption inhibitor4 for reducing plasma
cholesterol levels in a mammal in need thereof (Davis 2:2-55).
III. Discussion
A claimed invention is not patentable if the subject matter of the
invention would have been obvious to a person having ordinary skill in the
art at the time the invention was made. 35 U.S.C. § 103(a); KSR Int'l Co. v.
Teleflex Inc., 127 S.Ct. 1727 (2007); Graham v. John Deere Co., 383 U.S. 1
(1966). Facts relevant to a determination of obviousness include (1) the
scope and content of the prior art, (2) any differences between the claimed
invention and the prior art, (3) the level of ordinary skill in the art, and (4)
any relevant objective evidence of obviousness or nonobviousness. KSR,
127 S.Ct. at 1734; Graham, 383 U.S. at 17-18.
The question under 35 U.S.C. § 103 is not merely what the prior art
references expressly teach, but what the combined teachings of the
references would have suggested to those of ordinary skill in the art. In re
Keller, 642 F.2d 413, 425 (CCPA 1981). A combination of known elements
with no change in their respective functions is likely to be obvious when it
does no more than yield predictable results. KSR, 127 S.Ct. at 1739-41.
"[A] reasonable expectation of success, not absolute predictability", supports
a conclusion of obviousness. In re Longi, 759 F.2d 887, 897 (Fed. Cir.
1985).
One of ordinary skill in the art is presumed to have skills apart from
what the prior art references expressly disclose. In re Sovish, 769 F.2d 738,

4 Ezetimibe is a ß-lactam containing fluorine in the side chain. See e.g.,
Konev et al., "A simple route to side-chain fluorinated ß-lactams from ring-
fluorinated aziridines," Journal of Fluorine Chemistry, Vol. 128 (2007):114-
119.
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Application 10/057,534

743 (Fed. Cir. 1985). A person of ordinary skill is also a person of ordinary
creativity, not an automaton. KSR, 127 S.Ct. at 1742.
The subject matter on appeal before us is directed to compositions and
combinations comprising cholestyramine and about 10 mg of ezetimibe, and
optionally simvastatin, and methods of use thereof for treating or preventing
hyperlipidemic conditions, e.g., atherosclerosis, hypercholesterolemia and
other vascular conditions.
The Examiner found that Rosenblum teaches the combination of
ezetimibe and simvastatin, but not the combination of either cholestyramine
and ezetimibe or cholestyramine, ezetimibe and simvastatin, for use in
treating hypercholesterolemia. The Examiner found that Rosenblum teaches
that the daily dosage of the ezetimibe is about 5 mg to about 1000 mg, given
in a single dose or 2-4 divided doses, and that the exact dosage depends on
various conditions. The Examiner also found that Albright and Dechow
teach using cholestyramine for treating hypercholesterolemia and that Davis
teaches the combination of a ß-lactam cholesterol absorption inhibitor and
simvastatin for use in treating hypercholesterolemia. [Ans. 4-5.]
The Examiner concluded that it would have been obvious to one of
ordinary skill in the art to make a blood cholesterol lowering composition
comprising a combination of (a) ezetimibe and cholestyramine or (b)
ezetimibe, cholestyramine, and simvastatin since each agent individually is
taught in the prior art for use in lowering cholesterol and the prior art would
have taught persons having ordinary skill in the art to combine different
cholesterol lowering agents for treating hypercholesterolemia (Ans. 5-6).
The Examiner further concluded that use of about 10 mg of ezetimibe in the
modified composition of Rosenblum would have been a matter of routine
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optimization and prima facie obvious to a person having ordinary skill in the
art (Ans. 5-6).
Appellants argue that the cited prior art does not suggest combining
about 10 mg of ezetimibe with cholestyramine as recited in claim 1 (Br. 14)
or about 10 mg of ezetimibe with cholestyramine and simvastatin as recited
in claim 8 (Br. 18) and each of these three agents have a different
mechanism of action (Br. 15 and 18).5 Appellants further argue that there
would have been no motivation to use the claimed amount of about 10 mg of
ezetimibe (Br. 16 and 20).
Here, the cited prior art teaches that each of cholestyramine (Albright
and Dechow), ezetimibe (Rosenblum and Davis), and simvastatin
(Rosenblum and Davis) are known lipid lowering agents. The prior art also
teaches that ezetimibe and simvastatin are combinable in a single
composition for lowering blood lipid (cholesterol) concentrations
(Rosenblum and Davis). Therefore, we agree with the Examiner, that based
on the teachings of the applied prior art, it would have been prima facie
obvious to one of ordinary skill in the art to combine two or all three of the
three known lipid lowering agents in a single composition useful for treating
hyperlipidemia and diseases associated with hyperlipidemia. In re
Kerkhoven, 626 F.2d 846, 850 (CCPA 1980) ("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 third composition which is to

5 Appellants' arguments directed to combinations of other lipid management
components are immaterial since only combinations comprising ezetimibe,
cholestyramine, and simvastatin are before us on appeal. Similarly,
Appellants' arguments specifically directed to the subject matter of claims
23, 24, and 27 (Br. 19) are immaterial since none of claims 23, 24, and 27
are on appeal before us.
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be used for the very same purpose. * * * As this court explained in [In re]
Crocket [279 F.2d 274, 276-77 (CCPA 1960], the idea of combining them
flows logically from their having been individually taught in the prior art. In
the case at bar, appealed claims 2-4, 9 and 14 require no more than the
mixing together of two conventional spray-dried detergents. Thus, the
claims set forth a prima facie obvious subject matter."). The fact that one,
two or three of these lipid lowering agents act by different mechanisms is
not persuasive of nonobviousness since one of ordinary skill in the art would
have reasonably expected the combinations of ezetimibe and cholestyramine
and ezetimibe, cholestyramine, and simvastatin to reduce or lower lipids.
Indeed, we find that one of ordinary skill in the art should have known that
agents having different mechanisms for the same action would, in
combination, often require lower doses than when administered individually
for that action.6
We also agree with the Examiner that it would have been prima facie
obvious to optimize the daily hypocholesteremic dose disclosed by
Rosenblum. Optimization flows from the "normal desire of scientists or
artisans to improve upon what is already generally known." In re Peterson,
315 F.3d 1325, 1330 (Fed. Cir. 2003); In re Aller, 220 F.2d 454, 456 (CCPA
1955). "[D]iscovery of an optimum value of a result effective variable in a
known process is ordinarily within the skill of the art." In re Boesch, 617
F.2d 272, 276 (CCPA 1980). Appellants have not directed us to evidence
showing that more than routine experimentation would be required to
optimize the amount of ezetimibe in the claimed compositions/combinations,

6 See e.g., the discussion of drug combinations in In re Diamond, 360 F.2d
214, 217 (CCPA 1966).
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especially given the range of the daily hypocholesteremic dose disclosed by
Rosenblum. Rohm and Haas Co. v. Brotech Corp., 127 F.3d 1089, 1092
(Fed. Cir. 1997) (nothing in the rules or in jurisprudence requires the fact
finder to credit unsupported or conclusory assertions); In re Schulze, 346
F.2d 600, 602 (CCPA 1965) (argument in the brief does not take the place of
evidence of record).
Accordingly, based on the foregoing, we AFFIRM the rejection of
claims 1-3, 5, 6, 8-11, 28, 31-33, 35, 36, 70-72, 74-77, 79, and 80 under 35
U.S.C. § 103(a) as unpatentable over Rosenblum in view of Albright,
Dechow, and Davis.
IV. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the decision of the Examiner rejecting claims 1-3, 5,
6, 8-11, 28, 31-33, 35, 36, 70-72, 74-77, 79, and 80 under 35 U.S.C. §103(a)
as obvious over Rosenblum in view of Albright, Dechow, and Davis is
AFFIRMED; and,
FURTHER ORDERED that no time period for taking any subsequent
action in connection with this appeal may be extended under 35 U.S.C.
§ 1.136(a) (2006).
AFFIRMED

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MAT

SCHERING-PLOUGH CORPORATION
Patent Department (K-6-1, 1990)
2000 Galloping Hill Road
Kenilworth, NJ 07033-0530

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