Ex Parte Kao et al

Board of Patent Appeals and Interferences

Aug 9, 2012

11680432 (B.P.A.I. Aug. 9, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HUAI-HUNG KAO, ANAND R. BAICHWAL,
TROY MCCALL, and DAVID LEE
__________

Appeal 2009-013710
Application 11/680,432
Technology Center 1600
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Before DONALD E. ADAMS, ERIC GRIMES, and RICHARD M.
LEBOVITZ, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to controlled
release formulations of oxymorphone. The claims stand rejected under 35
U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We reverse.
STATEMENT OF THE CASE
Claims 1-3 and 5-20 are pending and on appeal. Claim 1 is
representative and reads as follows:
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1. An analgesically effective controlled release pharmaceutical
composition with a twelve hour dosing interval in the form of a tablet,
comprising oxymorphone or a pharmaceutically acceptable salt thereof as
the sole active ingredient in the tablet, and a controlled release delivery
system comprising at least one pharmaceutical excipient, wherein upon
placement of the composition in an in vitro dissolution test comprising USP
Paddle Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at
37 ºC, about 15% to about 50%, by weight, of the oxymorphone or salt
thereof is released from the tablet at about 1 hour in the test.

The claims stand rejected under 35 U.S.C. § 103(a) as follows:
• Claims 1-3, 5, 17, 19, and 20 based on Maloney,1 by itself or
combined with Calanchi2 (Ans. 3);
• Claims 11 and 12 based on Maloney, by itself or combined with
Calanchi, and further in view of Oshlack3 (Ans. 6);
• Claims 6-10 and 16 based on Maloney, by itself or combined with
Calanchi, and further in view of Baichwal ‘1434 (Ans. 8); and
• Claims 13-16 and 18 based on Maloney, by itself or combined with
Calanchi, and further in view of Baichwal ‘143 and Baichwal ‘4205 (Ans. 9).
This appeal returns to us following a remand by the U.S. Court of
Appeals for the Federal Circuit. Our initial decision, mailed Jan. 13, 2010
(“Decision”), affirmed the Examiner’s rejections. Based on a comparison of
the Paddle and Basket methods of measuring dissolution rates presented in
the Second Chang Declaration, we concluded that substituting oxymorphone

1 Maloney, WO 01/08661 A2, Feb. 8, 2001
2 Calanchi et al., US 5,047,248, Sept. 10, 1991
3 Oshlack et al., US 5,266,331, Nov. 30, 1993
4 Baichwal et al., US 5,128,143, July 7, 1992
5 Baichwal et al., US 6,093,420, July 25, 2000
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for the oxycodone in Maloney’s Formula 6 composition would yield a
formulation with a dissolution rate encompassed by claim 1 (Decision 6-7).
The Court of Appeals concluded that this finding was not supported by
substantial evidence, because the same declaration on which we depended
“expressly stated that there is no general correlation between the Basket and
Paddle Methods and cited prior art literature that supported this conclusion.”
In re Huai-Hung Kao, 639 F.3d 1057, 1067 (Fed. Cir. 2010). The court
vacated our decision and remanded “so that the Board can consider whether,
under the proper analysis, the evidence of record is sufficient to maintain an
obviousness rejection.” Id.
The application was remanded to the Examiner so that five questions
could be addressed (Remand Order, Jan. 3, 2012). The Examiner provided a
response to the questions (mailed April 16, 2012), as did Appellants
(received May 16, 2012).
After considering the evidence of record anew, in light of the
guidance provided by the Court of Appeals, we conclude that the Examiner
has not provided evidence sufficient to support a prima facie case of
obviousness. Claim 1 is directed to a controlled release formulation of
oxymorphone and a pharmaceutical excipient, “wherein upon placement of
the composition in an in vitro dissolution test comprising USP Paddle
Method at 50 rpm in 500 ml media having a pH of 1.2 to 6.8 at 37°C, about
15% to about 50%, by weight, of the oxymorphone or salt thereof is released
from the tablet at about 1 hour in the test” (claim 1). Claim 20, the only
other independent claim, requires the same dissolution rate.
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As discussed in our previous Decision (page 6), it would have been
obvious to modify Maloney’s controlled release Formula 6 composition to
comprise oxymorphone instead of oxycodone. Maloney, however, only
describes the dissolution rate of its Formula 6 composition as measured in
the USP Basket Method, not the USP Paddle Method as recited in the claims
(Decision 7).
The Examiner finds that “there is generally no correlation between the
methods other than the fact that Basket methods generally afford[ ] a faster
release rate than the Paddle method” (Examiner’s Remand Response, page
12). Thus, Maloney’s disclosure that “the Formula 6 tablets had a release
rate of 24.3% after one hour when measured by the USP Basket Method”
(Decision 7) supports a conclusion that the release rate would be something
less than 24.3% if measured by the USP Paddle Method, but it does not
support a conclusion that the same tablets, modified to include oxymorphone
rather than oxycodone, would inherently have a dissolution rate within the
range required by the claims on appeal. That is, since there is insufficient
evidence to establish how much less than 24.3% the one-hour release rate
would be if the Paddle Method was used, it cannot be concluded that the
value would be at least 15%, as claimed. The Examiner’s assertion to the
contrary (Examiner’s Remand Response, page 12) is unsupported by any
citation to evidence or by sound technical reasoning, and therefore is
unpersuasive.
The Examiner also concludes that “one of an ordinary skill would
have recognized that the same controlled release systems can be modified to
produce different dissolution rates and also different release rates that are
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therapeutically effective in treating pain” (Examiner’s Remand Response,
page 14). The Examiner notes that prior art will support a prima facie case
of obviousness when it suggests “choosing from a finite number of
identified, predictable solutions, with a reasonable expectation of success”
(id., citing KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007)).
Appellants argue that “neither Maloney nor Calanchi provide the
skilled artisan with any guidance for achieving an analgesically effective
oxymorphone controlled release dosage form having the claimed dissolution
profile suitable for a 12 hour dosing interval” (Appellants’ Remand
Response, page 26). Appellants argue that
[t]he release rate dictates the amount of drug that reaches the
circulation. Thus, this release rate “is a critical variable in
attempting to control the blood plasma levels of oxymorphone
and 6-hydroxyoxymorphone in a patient.” ([Specification] at
19). However, prior to the work of Kao et al. no one knew of
any release rate for oxymorphone that would work in vivo in an
extended release formulation and still correlate to analgesic
patient blood levels.
(Id. at 28.)
The evidence of record supports Appellants’ position that the
dissolution rate, or release rate, specifically required by the claims on appeal
is critical to the effectiveness of the claimed formulation in allowing for a
twelve-hour dosing interval. As Appellants have noted, the Specification
expressly states that “[r]elease rate is a critical variable in attempting to
control the blood plasma levels of oxymorphone” (Spec. 19, ¶ 60). The
Specification describes the invention as including a “release rate . . . such
that a sufficient plasma level of oxymorphone and/or 6-OH oxymorphone is
maintained to allow the controlled release dosage to be used to treat patients
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suffering moderate to severe pain with once or twice daily dosing” (id. at 5,
¶ 20). That release rate is “a dissolution rate in vitro, when measured by
USP Paddle Method at 50 rpm in 500 ml media having a pH between 1.2
and 6.8 at 37°C, of about 15% to about 50% by weight oxymorphone
released after 1 hour” (id. at 5, ¶ 22), the same dissolution rate required by
the claims on appeal.
The Specification is supported in this regard by Appellants’
Declarations. Dr. Chang declared that, although formulating a given drug to
have a desired dissolution profile is routine, “[i]t is the determination of
exactly what the dissolution profile should be for a given drug to provide
safe yet therapeutic blood levels that requires inventive effort and substantial
experimentation” (First Chang Declaration, signed April 7, 2008, ¶ 10).
Dr. Fiske declared that “[i]n [his] view, one skilled in the art would
not have any meaningful guidance from Maloney in determining what
release rate, if any, would yield a safe and effective therapeutic
concentration of oxymorphone (as opposed to oxycodone) administered in a
controlled release formulation” (Fiske Declaration, ¶ 5). Dr. Fiske explained
that oxymorphone is substantially metabolized in the liver before reaching
the systemic circulation (id. at ¶¶ 7, 14), and that
one skilled in the art would be concerned that decreasing the
release rate of oxymorphone enough to achieve the desired
extended effect would significantly lower the resulting liver
concentration, causing an increase in the amount of
oxymorphone metabolism and/or extraction on its first pass
through the liver and thus preventing achievement of a
sustainable systemic therapeutic concentration.
(Id. at ¶ 13.)
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Thus, the evidence of record supports Appellants’ position that the
dissolution rate recited in the claims on appeal is critical to providing “a
twelve hour dosing interval,” as claimed. The evidence also shows that
those skilled in the art could formulate a drug to provide a desired
dissolution profile through routine experimentation, but the evidence does
not show that a person of ordinary skill in the art would have reasonably
expected to achieve a controlled release formulation of oxymorphone by
making a formulation having a dissolution rate within the the specific range
required by the claims.
In summary, the evidence of record does not support a conclusion that
the dissolution rate required by the claims on appeal would be an inherent
property of the formulation suggested by the prior art. The evidence shows
that the dissolution rate is a critical parameter for effective functioning of the
claimed composition, and the Examiner has not provided evidence or sound
technical reasoning sufficient to show that the prior art would have directed
those skilled in the art to a composition having the claimed dissolution rate.
We therefore conclude that the evidence of record does not support a prima
facie case of obviousness.
SUMMARY
Each of the Examiner’s rejections relies on the conclusion that
Maloney, alone or combined with Calanchi, would have made obvious the
composition recited in independent claims 1 and 20. Because this
conclusion is not supported by a preponderance of the evidence of record,
we reverse all of the rejections on appeal.

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REVERSED

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