Ex Parte Davis

Board of Patent Appeals and Interferences

Feb 28, 2007

10057629 (B.P.A.I. Feb. 28, 2007)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HARRY R. DAVIS
__________

Appeal No. 2006-3204
Application No. 10/057,629
__________

ON BRIEF
__________

Before GRIMES, GREEN, and LEBOVITZ, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the examiner’s
final rejection of claims 1, 8-11, 13-24, 32-45 and 53-56.1 Claim 1 is
representative of the claims on appeal, and reads as follows:
1. A method of treating sitosterolemia, comprising administering to a
mammal in need of such treatment an effective amount of at least one
sterol absorption inhibitor, or pharmaceutically acceptable salt or solvate
of the least one sterol absorption inhibitor, or prodrug of the at least one
sterol absorption inhibitor or pharmaceutically acceptable salt or solvate of
the least one sterol absorption inhibitor, or mixture thereof.

1 Claims 2-7, 12, 25-31, 46, 57 and 58 are also pending, but stand withdrawn from consideration
as being drawn to a non-elected invention. See Appeal Brief, page 1. In addition, appellant
elected the species of ezetimibe as the sterol adsorption inhibitor, cholestyramine as the lipid
lowering agent, and simvastatin as the third therapeutic agent. See id. at 4-5

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Application No. 10/057,629

Claims 1, 8, 9, 10, 11, 13-24, 32-45 and 53-56 stand rejected under 35
U.S.C. § 103(a) as being obvious over the combination of Rosenblum2 and
Belamarich.3 After careful review of the record and consideration of the issues
before us, we reverse.
BACKGROUND
According to the specification:
Sitosterolemia is a genetic lipid storage disorder
characterized by increased levels of sitosterol and other plant
sterols in the plasma and other tissues due to increased non-
selective intestinal absorption of sterols and decreased hepatic
removal. Individuals having sitosterolemia can exhibit one or more
of the following conditions: tendon and tuberous xanthomas,
arthritis, hemolytic episodes, accelerated atherosclerosis and
myocardial infarctions, and can die at an early age due to extensive
coronary atherosclerosis.

Id. at 1.
DISCUSSION
Claims 1, 8, 9, 10, 11, 13-24, 32-45 and 53-56 stand rejected under
35 U.S.C. § 103(a) as being obvious over the combination of Rosenblum and
Belamarich.
Rosenblum is cited for teaching the use of ezetimibe, a sterol adsorption
inhibitor, with an HMG-CoA reductase inhibitor, such as simvastatin, in lowering
cholesterol and reducing the risk of atherosclerosis. See Examiner’s Answer,
page 3. The examiner acknowledges that Rosenblum “does not expressly teach

2 Rosenblum et al. (Rosenblum), U.S. Patent No. 5,846,966, issued December 8, 1998.
3 Belamarich et al. (Belamarich), “Response to Diet and Cholestyramine in a Patient with
Sitosterolemia,” Pediatrics, Vol. 86, No. 6, pp. 977-81 (1990).

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Application No. 10/057,629

. . . employing . . . ezetimibe with simvastatin, a HMG-CoA reductase inhibitor
and/or cholestyramine, . . . to treat sitosterolemia.” Id. at 4.
Belamarich is cited for teaching that “hypercholesterolemia is one of the
manifestation[s, sic] of sitosterolemia,” and that a low-sterol diet, as well as
cholestyramine, are effective in lowering sterol and cholesterol levels in
sitosterolemic patients. Id.
The examiner concludes:
It would have been obvious to one of ordinary skill in the art
at the time the invention was made to employ ezetimibe with
simvastatin and/or cholestyramine, . . . to treat sitosterolemia.
One of ordinary skill in the art would have been motivated to
employ ezetimibe with simvastatin and/or cholestyramine, . . . to
treat sitosterolemia. [Rosenblum] teaches the combination of
simvastatin and ezetimibe as useful in reducing cholesterol level.
Employing the combination of simvastatin and ezetimibe in a
method to reduce cholesterol level and thereby treating
sitosterolemia, a condition known to have elevated cholesterol
level, would have been reasonably expected to be effective, absent
evidence to the contrary. Moreover, cholestyramine is known to be
effective in lowering cholesterol in sitosterolemic patient.
Therefore, administering all three compounds concomitantly for the
very same purpose would have been obvious to one of ordinary
skill in the art (See In re Kerkhoven, 205 USPQ 1069).

Id. at 4-5.
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the initial
burden of presenting a prima facie case of obviousness. Only if that burden is
met, does the burden of coming forward with evidence or argument shift to the
applicant.” In re Rijckaert, 9 F.3d 1531, 1532, 28 USPQ2d 1955, 1956 (Fed. Cir.
1993) (citations omitted). The test of obviousness is “whether the teachings of
the prior art, taken as a whole, would have made obvious the claimed invention.”

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Application No. 10/057,629

In re Gorman, 933 F.2d 982, 986, 18 USPQ2d 1885, 1888 (Fed. Cir. 1991).
Appellant argues that the examiner has failed to establish a prima facie case of
obviousness. See Appeal Brief, page 10. We agree, and the rejection is
reversed.
As noted by appellant, Rosenblum, while teaching that ezetimibe,
optionally in combination with an HMG-CoA reductase inhibitor such as
simvastatin, may be used for reducing the cholesterol and the risk of
atherosclerosis, does not teach or suggest the use ezetimibe in the treatment of
sitosterolemia. See id. at 11.
Belamarich teaches that patients with sitosterolemia “are frequently
hypercholesterolemic with elevated levels of low-density lipoprotein (LDL)
cholesterol.” Belamarich, page 977, second column. While Belamarich teaches
that sitosterolemia may be treated with cholestyramine, a bile sequestering resin,
it does not teach or suggest the use of ezetimibe.
The examiner’s rationale for the combination appears to be that since
patients with sitosterolemia are frequently hypercholesterolemic, and Rosenblum
teaches that ezetimibe optionally in combination with an HMG-CoA reductase
inhibitor is used to lower cholesterol, it would have been obvious to the ordinary
artisan to use ezetimibe optionally in combination with an HMG-CoA reductase
inhibitor to treat sitosterolemia.
We find that the examiner’s reasoning to be flawed, however, as the art
established that compounds that are used to treat hypercholesterolemia may not
be useful in the treatment of sitosterolemia. See Appeal Brief, pages 12-14.

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Application No. 10/057,629

Appellant cites Hidaka,4 Nguyen5 and Salen,6 all of which teach that HMG-CoA
reductase inhibitors such as lovastatin and pravastatin are ineffective in the
treatment of sitosterolemia.
Thus, Hidaka teaches that “[p]ravastatin had little effect in a sitosterolemic
patient on plasma levels of sterols, where cholestyramine decreased the plasma
levels of both cholesterol and cholestanol.” Hidaka, abstract. Salen teaches that
“[l]ovastatin, a competitive inhibitor of cholesterol biosynthesis that is widely used
in the treatment of hypercholesterolemia has been tried but has not been an
effective treatment in sitosterolemia.” Salen, page 952, paragraph bridging the
two columns. Nguyen also teaches that lovastatin is “ineffective” in the treatment
in sitosterolemia. Nguyen, page 1942, first column. Moreover, Nguyen suggests
that differences in responses may be used diagnostically. Specifically, Nguyen
teaches that “[t]he therapies with cholestyramine and lovastatin not only support
our contention of the fundamental abnormality in the regulation of cholesterol
biosynthesis that underlies sitosterolemia, but the response to these therapies
can also be used to detect sitosterolemia. . . . Therefore, the failure to respond
to lovastatin and a substantial response to cholestyramine may suggest
sitosterolemia . . . .” Id. at page 1946, second column.

4 Hidaka et al. (Hidaka), “Effects of an HMG-CoA Reductase Inhibitor, Prevastatin, and Bile
Sequestering Resin, Cholestyramine, on Plasma Plant Sterol Levels in Hypercholesterolemic
Subjects,” Journal of Atherosclerosis and Thrombosis, Vol. 2, No. 1, pp. 60-65 (1995).
5 Nguyen et al. (Nguyen), “Regulation of cholesterol biosynthesis in sitosterolemia: effects of
lovastatin, cholestyramine, and dietary sterol restriction,” Journal of Lipid Research, Vol. 32,
pp. 1941-48 (1991).
6 Salen et al. (Salen), “Sitosterolemia,” Journal of Lipid Research, Vol. 33, pp. 945-55 (1992).

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Therefore, the references as combined do not teach or suggest that
known cholesterol lowering agents may be used in the treatment of
sitosterolemia, but in fact teach that patients with sitosterolemia respond
differently to known cholesterol-lowering agents than hypercholesterolemic
patients, and we find that the examiner has not set forth a prima facie case of
obviousness. Moreover, even if we were to assume for the sake of argument
that the combination suggests the use of ezetimibe in the treatment of
sitosterolemia, at most, it merely would have obvious to try its use, “[b]ut,
‘obvious to try’ is not the standard,” and the rejection of the claims must be
reversed. Ecolochem, Inc. v. Southern California Edison Co., 227 F.3d 1361,
1374, 56 USPQ2d 1065, 1075 (Fed. Cir. 2000).
The dissent bases its conclusion that it would have been obvious to use
ezetimibe to treat sitosterolemia “[b]ased on the similar mechanisms of action of
cholestyramine and ezetimibe.”
Rosenblum, however, discloses that ezetimibe exerts its therapeutic effect
“by virtue of [its] ability to inhibit absorption and/or esterification of cholesterol.”
Rosenblum, col. 20, lines 44-46. In contrast, cholestyramine is a bile-
sequestering resin. See Hikada, abstract. That is, cholestyramine is a
quaternary ammonium exchange resin with a polystyrene polymer skeleton, and,
as the chloride salt, it binds to bile acids. See Casdorph,7 page 293, column 1.
With the increased loss of bile acids in stool, there is also a reduction in serum

7 Casdorph, “Hypercholesteremia: Treatment with Cholestyramine, a Bile Sequestering Resin,”
California Medicine, Vol. 106, pp. 293-95 (1967).

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Application No. 10/057,629

cholesterol. Id. Therefore, the only similarity that ezetimibe and cholestyramine
is that both have been shown to lower cholesterol in hypocholestermic patients.
But, by the dissent’s reasoning, all classes of cholesterol lowering drugs would
have “similar mechanisms of action.”
As indicated by the evidence submitted by appellants, not all cholesterol
lowering agents are effective in treating sitosterolemia. The physiological defect
in sitosterolemia is the increase in intestinal absorption of dietary plant sterols,
not the metabolism of cholesterol. The assumption that all cholesterol lowering
agents would be effective in the treatment of sitosterolemia was demonstrated to
be incorrect as statins were shown to be ineffective in treating sitosterolemia.
Thus, once the assumption was proven wrong, there would have been no
expectation of using other cholesterol lowering agents in the treatment of
sitosterolemia.

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Application No. 10/057,629

CONCLUSION
Because the examiner has failed to set forth a prima facie case of
obviousness, the rejection over the combination of Rosenblum and Belamarich is
reversed.
REVERSED

)
)
Lora M. Green )
Administrative Patent Judge ) BOARD OF PATENT
)
) APPEALS AND
)
Richard M. Lebovitz ) INTERFERENCES
Administrative Patent Judge )
)
)

LMG/jlb

GRIMES, Administrative Patent Judge, dissenting in part.
I agree that the cited references would not have led those skilled in the art
to administer an HMG-CoA reductase inhibitor to patients having sitosterolemia.
In my opinion, however, the evidence of record would have suggested using
ezetimibe to treat sitosterolemia to those skilled in the art. I would reverse the
rejection of the claims that require administering an HMG-CoA reductase inhibitor
but affirm the rejection of the remaining claims.
The claims are directed to a method of treating sitosterolemia by
administering a sterol absorption inhibitor, ezetimibe being the elected species.
The examiner rejected the claims as obvious in view of Rosenblum and
Belamarich. Belamarich discloses that
[t]he metabolic defect [underlying sitosterolemia] is related to a five-
fold or greater increase in intestinal absorption of dietary plant
sterols compared with subjects who do not have sitosterolemia.
Failure to excrete plant sterols in the bile has also been implicated
as a contributing factor.

Page 977, right-hand column. Belamarich also teaches that
[p]atients with sitosterolemia are frequently hypercholesterolemic
. . . , however, the hypercholesterolemia of sitosterolemia is
responsive to cholesterol-lowering diets, bile acid binding resins,
and ileal bypass surgery.

Id.
Belamarich reports that treating a patient with a combination of a low-
sterol diet and cholestyramine, a bile acid binding resin, “evoked a 40% decrease
in plasma cholesterol and a 42% reduction of plasma sitosterol concentration.
These findings confirm previous observations of the effectiveness of
cholestyramine in sitosterolemia.” Page 980, left-hand column.

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Application No. 10/057,629

Salen, cited by Appellant (Appeal Brief, page 14), shows how Belamarich
would have been understood by those of skill in the art. Salen teaches that
cholestyramine produces “bile acid malabsorption.” Page 951, left-hand column.
That is, cholestyramine interferes with absorption of sterol-containing bile acids in
the digestive tract, with the result that the bile acids and their component sterols
are excreted in the stool and eliminated from the patient’s body.
Rosenblum teaches that “[w]hen intestinal cholesterol absorption is
reduced, by whatever means, less cholesterol is delivered to the liver. . . . Thus,
the net effect of inhibiting intestinal cholesterol absorption is a decrease in plasma
cholesterol levels.” Column 2, lines 6-12. Rosenblum also teaches that
“[c]ombination therapy of an HMG CoA reductase inhibitor and a bile acid
sequestrant [a.k.a. bile acid binding resin] has been demonstrated to be more
effective in human hyperlipidemic patients than either agent in monotherapy.”
Column 2, lines 17-21.
Rosenblum teaches that compounds like ezetimibe “have been found to
inhibit the intestinal absorption of cholesterol and to significantly reduce the
formation of liver cholesteryl esters in animal models.” Column 20, lines 41-44.8
Rosenblum teaches that ezetimibe can be administered to reduce serum
cholesterol levels either alone (column 3, lines 44-49) or in combination with a
“cholesterol biosynthesis inhibitor” (column 3, lines 54-67) such as an HMG-CoA
reductase inhibitor (column 6, lines 37-40)

8 Appellant does not dispute that Rosenblum’s genus encompasses ezetimibe. See the Appeal
Brief, page 11 (“Rosenblum et al. disclose that ezetimibe, optionally in combination with an HMB-
CoA reductase inhibitor . . . , is useful for reducing cholesterol.”).

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Application No. 10/057,629

I agree with the examiner that these teachings would have made it
obvious to administer the ezetimibe taught by Rosenblum to a patient having
sitosterolemia. Motivation to do so is provided by the cited references:
Belamarich teaches that cholestyramine, a bile-acid binding resin, is an effective
treatment for sitosterolemia. Those skilled in the art recognized that bile acid
binding resins act by inhibiting absorption of sterol-containing bile acids. See
Salen. Rosenblum teaches that ezetimibe inhibits intestinal absorption of
cholesterol. Based on the similar mechanisms of action of cholestyramine and
ezetimibe, and the known effectiveness of cholestyramine in treating
sitosterolemia, those of skill in the art would have been led to administer
ezetimibe with a reasonable expectation that it would be an effective treatment of
sitosterolemia.
The majority focuses on the reasoning that the examiner provided for
combining the references: that it would have been obvious to use a combination
of simvastatin, ezetimibe, and cholestyramine to treat patients having
sitosterolemia because those patients also suffer from high serum cholesterol
(hypercholesterolemia) and Rosenblum teaches that the combination of
simvastatin and ezetimibe is effective in lowering serum cholesterol. The
majority finds this reasoning flawed because the evidence of record shows that
HMG-CoA reductase inhibitors (i.e., statins such as simvastatin) are ineffective in
lowering cholesterol levels in sitosterolemic patients.
I agree with my colleagues that the prior art of record would not have led
those skilled in the art to expect a statin to lower cholesterol levels in a patient

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Application No. 10/057,629

with sitosterolemia. Therefore, I agree that the rejection of claims 16-18, 22-24,
33, 41, 42 should be reversed.
The remaining claims, however, do not require administering a statin.
Statins act in a completely different way than cholestyramine and ezetimibe.
Statins inhibit cholesterol biosynthesis (Rosenblum; column 6, lines 37-39), while
cholestyramine and ezetimibe inhibit sterol absorption. The defect underlying
sitosterolemia was known to involve sterol absorption (Belamarich; page 977,
right-hand column). Therefore, the ineffectiveness of statins would not, in my
opinion, have led those skilled in the art to doubt the effectiveness of treating
sitosterolemia with ezetimibe. For the reasons discussed above, I conclude that
claims 1, 8-11, 13-15, 19-21, 32, 34-40, 43-45 and 53-56 would have been
obvious to those of ordinary skill in the art. I would affirm the rejection of those
claims.
Appellant argues that the references would not have suggested that
ezetimibe would be useful for treating sitosterolemia. Appeal Brief, pages 11-13.
This argument is adequately addressed above. In addition, Appellant argues that
the claimed method solved a long-felt need in the art. Appellant cites Hidaka and
Nguyen as evidence that “those of ordinary skill in the art were working on the
problem of treating sitosterolemia without the deleterious side effects associated
with cholestyramine.” Id., page 14. Appellant cites Steiner as evidence that “this
long-felt need has been successfully satisfied by Zetia® ezetimibe formulation.”
Id., page 16. Appellant concludes that the claimed method “has successfully
met” the “need for a treatment for sitosterolemia with less likelihood of

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deleterious side effects such as those associated with treatment with
cholestyramine.” Id., page 18.
The majority reverses for lack of a prima facie case and thus has no need
to address this argument. I would reach it, but I find it unpersuasive for the
following reasons. First, although Hidaka states that cholestyramine can have
side effects,9 it does not disclose a specific problem and provide evidence that
those in the art were attempting to solve that problem. “[L]ong-felt need is
analyzed as of the date of an articulated identified problem and evidence of
efforts to solve that problem.” Texas Instruments, Inc. v. International Trade
Comm., 988 F.2d 1165, 1178, 26 USPQ2d 1018, 1029 (Fed. Cir. 1993). Neither
Hidaka nor any other reference identified by Appellant articulates a specific,
identified problem with existing sitosterolemia treatments and provides evidence
of efforts to solve that problem.
Second, Appellant defines the need allegedly met by ezetimibe as a “need
for a treatment for sitosterolemia with less likelihood of deleterious side effects
such as those associated with treatment with cholestyramine.” Appeal Brief,
page 18. This definition of the “long-felt need”, in addition to lacking support in
the evidence, sets the bar too low to be useful in an obviousness analysis.
Under Appellant’s standard, any incremental improvement in a method of
treatment would satisfy a “long-felt need” if it is more effective, or effective in
more patients, than pre-existing treatments. Thus, for example, substituting

9 “The patient had been treated with cholestyramine, but unfortunately could not tolerate the
treatment because of her associated hemorrhoids.” Page 61, right-hand column.

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ibuprofen for aspirin or acetaminophen, in a formulation containing
pseudoephedrine, would be considered nonobvious if the new composition did
the same thing as the old ones but had fewer side-effects. This is not the
appropriate standard. Cf. Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476,
1483-84, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997).
Finally, whether an invention satisfied a long-felt need, and what relevance
that has to obviousness, must be considered in light of the state of the art at the
time the invention was made: that an invention satisfied a long-felt need has little
relevance to obviousness if the means for satisfying that need became available
in the art only recently. See, e.g., Graham vs. John Deere Co., 383 U.S. 1, 36,
148 USPQ 459, 474 (1966) (“At the latest, those differences [between the
claimed and prior art products] were rendered apparent in 1953 by the
appearance of the Livingstone patent, and unsuccessful attempts to reach a
solution to the problems confronting [the inventor] made before that time became
wholly irrelevant.”); In re Sabatino, 387 F.2d 981, 986, 156 USPQ 212, 216
(CCPA 1968) (“[T]he evidentiary value of the many apparently unsuccessful
attempts to [solve the problem addressed by the invention] appears to be well-
tempered by the fact that those attempts occurred before Rigsby, the most
pertinent reference, became available to those in the art.”).
Therefore, any need that existed before ezetimibe was known to those
skilled in the art is irrelevant to the question at hand – whether it would have
been obvious to use ezetimibe to treat sitosterolemia.

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Application No. 10/057,629

Here, the evidence appears to show that ezetimibe became known to
those skilled in the art as of December 8, 1998 (the issue date of Rosenblum).
The instant application claims an effective filing date of January 6, 2001.
Therefore, it appears that there was a time period of only two years and one
month between the time ezetimibe became known in the art and the time
Appellant filed an application claiming its use to treat sitosterolemia.
Appellant’s position – that the evidence shows nonobviousness because
there was a long-felt need for alternative sitosterolemia treatments and no one
else thought to use ezetimibe before he did – is undercut by the short time period
between the time ezetimibe became known to those skilled in the art and the
time Appellant filed his application. In sum, Appellant’s evidence of long-felt
need is at best weak evidence of nonobviousness and does not overcome the
prima facie case.
)
) BOARD OF PATENT
)
Eric Grimes ) APPEALS AND
Administrative Patent Judge )
) INTERFERENCES
)

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