Ex Parte Chen et al

Patent Trial and Appeal Board

Jul 19, 2013

11355335 (P.T.A.B. Jul. 19, 2013)

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.
11/355,335 02/16/2006 Chih-Ming Chen 141-594 C 3876
96056 7590 07/19/2013
Florek & Endres PLLC
1156 Avenue of the Americas
Suite 600
New York, NY 10036
EXAMINER
CHANNAVAJJALA, LAKSHMI SARADA
ART UNIT PAPER NUMBER
1611
MAIL DATE DELIVERY MODE
07/19/2013 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte CHIH-MING CHEN, JOSEPH CHOU, and DAVID WONG

____________

Appeal 2011-011665
1

Application 11/355,335
2

Technology Center 1600
____________

Before LORA M. GREEN, JACQUELINE WRIGHT BONILLA, and
JOHN A. EVANS, Administrative Patent Judges.

EVANS, Administrative Patent Judge.
DECISION ON APPEAL

This is an appeal under 35 U.S.C. § 134(a) involving claims to
methods for reducing serum cholesterol levels in humans. The Examiner has
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

1
A transcript of the oral hearing held July 11, 2013 will be entered into the
record in due time.
2
The real party in interest is Andrx Labs, LLC, a wholly-owned subsidiary
of Watson Pharmaceuticals, Inc. This application has been licensed to
Shionogi Pharma, Inc. (App. Br. 4).
Appeal 2011-011665
Application 11/355,335

2
Rather than reiterate the arguments of Appellants and the Examiner,
we refer to the Appeal Brief (filed Jan. 31, 2011) and the Answer (mailed
Apr. 14, 2011.

STATEMENT OF THE CASE
The claims relate to methods and controlled release oral solid dosage
forms for the reduction of serum cholesterol levels in humans include a drug
comprising an alkyl ester of hydroxy substituted naphthalenes (e.g.,
lovastatin) and a controlled release carrier, such that the dosage form
provides a mean time to maximum plasma concentration (Tmax) of the drug
which occurs at about 10 to about 32 hours after oral administration on a
once-a-day basis to human patients. (See Abstract.)
Claims 121, 125, 127-129, 132, 134 are on appeal. Claims 121 and
128 are independent. Claims 1-120, 122-124, 126, 130, 131, 133, and 135
are canceled. (App. Br. 29-31.) An understanding of the invention can be
derived from a reading of exemplary claim 121, which is reproduced below
with disputed limitations italicized and some paragraphing and formatting
supplied:
121. A method for reducing serum cholesterol levels in
humans comprising

orally administering to a human on a once a day basis a
controlled release lovastatin tablet comprising 10 to 80 mg of
lovastatin and formulated with a core comprising the lovastatin
Appeal 2011-011665
Application 11/355,335

3
and a water swellable polymer and a coating surrounding the
core

wherein the coating comprises a water insoluble polymer and a
pH sensitive polymer that dissolves at a pH above 3 to release
less than 20% of the lovastatin after 2 hours of in vitro testing
and between 20% and 70% of the lovastatin after 5 hours of in
vitro testing wherein the in vitro testing is conducted using a
USP XXII, Type II dissolution apparatus in 2% sodium lauryl
sulfate, pH 7.0 NaH2PO4 buffer at 37°C and 50 rpms,

so that a mean time to maximum plasma concentration of
lovastatin after a single dose administration in the morning
without food is at least about 12 hours and the ratio of AUC0-
48hr of lovastatin for the controlled release dosage form to
AUC0-48hr of lovastatin for an immediate release oral lovastatin
tablet is greater than unity following the single dose
administration of the controlled release tablet and immediate
release tablet.

The claims stand rejected as follows:
1. Claims 121, 127-129, and 134 under 35 U.S.C. § 103(a) as obvious
over Alberts,
3
Gould,
4
and Edgren.
5
(Ans. 4-8).
2. Claims 121, 123-125, 127-132, and 134 under 35 U.S.C. § 103(a) as
obvious over Rork,
6
Edgren, and any of Alberts or Gould. (Ans. 8-10).

3
Alberts et al., US 5,376,383, issued Dec. 27, 1994.
4
Gould et al., US 6,251,852 B1, issued Jun. 26, 2001.
5
Edgren, US 4,522,625, issued Jun. 11, 1985.
6
Rork et al., US 5,543,154, issued Aug. 6, 1996.
Appeal 2011-011665
Application 11/355,335

4
REJECTION I
ISSUE
Appellants’ contentions frame as dispositive the issue of whether the
cited art teaches or suggests a controlled-release dosage form of lovastatin
having the claimed release profile. (App. Br. 14.)
FINDINGS OF FACT
The following enumerated Findings of Fact (FF) are supported by a
preponderance of the evidence.
1. The Specifications defines an “immediate release reference
standard” as Mevacor®. (Spec. 12.)
ANALYSIS
The Examiner finds that Alberts teaches a method of lowering plasma
cholesterol by administering lovastatin, that controlled-release formulations
yield improved effects compared to rapid-release formulations, and that
controlled-release may be achieved through a variety of controlled-release
matrices. (Ans. 4.) The Examiner finds that Alberts fails to teach the claimed
lovastatin dosage and a combination of a water-insoluble polymer and a pH-
sensitive polymer. (Ans. 6.) The Examiner finds that Alberts fails to teach
the claimed AUC and Tmax release profiles. (Id. at 7.) The Examiner finds
that Gould teaches the claimed lovastatin dosage. (Id. at 6.) The Examiner
finds that Edgren teaches the claimed water-insoluble and pH-sensitive
polymers. (Id. at 6-7.)
Appeal 2011-011665
Application 11/355,335

5
The Examiner gives no patentable weight to the AUC0-48hr limitation
by finding that whereas:
applicants claim the ratio of AUC0-48 hrs of instant versus that
of an immediate release, such a ratio is arbitrary because
applicants have not specified what constitutes the immediate
release composition that is being compared to a controlled
release dosage form, because each of the delivery forms is
different and a skilled artisan would expect different release
rates from the different forms.

(Id. at 8.)
Appellants contend, contrary to art of record, that an increased
bioavailability of lovastatin can be obtained with a controlled release
lovastatin tablet that exhibits the recited in vitro and in vivo profiles recited
in the appealed claims. In support, Appellants refer to data reported in the
present Specification in Example 5 and summarized in the Declaration of
Keith Gallicano.
7
(App. Br. 14.)
Appellants contend that:
Controlled release lovastatin tablets exhibiting the unique
release profile recited in the appealed claims, i.e., a slow initial
release followed by a more rapid release between 2 and 6 hours,
are not disclosed or suggested by the cited prior art references.
Based upon the in vivo data provided by the prior art of record,
a skilled artisan would not be able to predict or remotely
suspect that a controlled release lovastatin tablet exhibiting the
claimed in vitro profile would produce a greater AUC for

7
Declaration of Keith Gallicano, submitted Sept. 30, 2009.
Appeal 2011-011665
Application 11/355,335

6
lovastatin and lovastatin acid compared to the oral
administration of an immediate release lovastatin tablet.

(App. Br. 15, 17.)
Appellants contend that Rork teaches osmotic tablets comprising
lovastatin, but that Rork does not provide any pharmacokinetic data. (Id. at
18.) Appellants contend that Alberts teaches a percentage reduction in serum
cholesterol, but not the Tmax or AUC values. Appellants contend, contrary to
the claimed invention, that Alberts teaches that controlled-release dosage
forms reduce the amount of drug in a patient’s blood stream compared to
conventional intermediate release tablets. (Id. at 19-20.) Appellants contend
that Gould teaches rapid-release and controlled-release formulations, but
does not provide any information relating to in vivo or in vitro properties of
HMG-CoA inhibitor dose forms. (Id. at 20.) Appellants contend that Edgren
teaches controlled-release dosage forms, but Edgren relates to the kinetics of
release at acid pH, which is not relevant to the claimed release at pH 7.0.
Moreover, Appellants contend that Edgren’s in vitro release profile does not
teach the claimed in vitro release profile. (Id. at 20-21.)
Appellants contend that the combination of Edgren, Rork, Alberts
and/or Gould does not teach the claimed in vivo or in vitro release profiles.
(App. Br. 21.)
The Examiner finds Appellants’ arguments regarding release kinetics
not persuasive because the instant claims do not specify the immediate
release form. (Ans. 13-14.)
Appeal 2011-011665
Application 11/355,335

7
Appellants contend that the Examiner’s Answer asserts for the first
time that “applicants have not specified what constitutes the immediate
release composition.” (Reply Br. 4-5.) Appellants state that:
a skilled artisan reading the present specification would
understand the terms “immediate release oral lovastatin tablet”
and “immediate release tablet” to mean a solid tablet containing
lovastatin and conventional pharmaceutical excipients wherein
the tablet dissolves and thereby releases at least 80% of the
lovastatin within 30 minutes. This understanding is in
accordance with the definition of the term “immediate release
dosage form” as described in the United States Pharmacopeia
23 (1995) and the United States Pharmacopeia 24 (2000). More
importantly, this understanding is consistent with the
description and example of the immediate release tablet,
MEVACOR®, described on page 12, lines 6-9 of the present
specification.

(Id. at 8.)
We agree with Appellants that the person of skill in the
pharmaceutical formulary arts would have been apprised of the definition of
an immediate release tablet either in view of the Specification’s definition
(MEVACOR
®
), or the definition as provided in the United States
Pharmacopeia. Consistent with the United States Pharmacopeia definition
(Reply 8), the Specification indicates that the phrase “AUC0-48hr of lovastatin
for an immediate release oral lovastatin tablet” recited in the independent
claims refers to the AUC0-48hr of the immediate release lovastatin tablet
Mevacor® (FF 1). Thus, contrary to the Examiner’s position, the claimed
pharmacokinetic limitations are entitled to patentable weight.
Appeal 2011-011665
Application 11/355,335

8
Appellants contend that the Examiner initially relied upon Cheng
8
as
the basis of the obviousness analysis, but that Cheng was withdrawn as an
applied reference. Appellants contend that Cheng, while not invalidating
prior art, is representative of knowledge a person of ordinary skill in the art
would have had at the time the present invention and is the only reference, of
record, with detailed pharmacokinetic data regarding controlled release
lovastatin dosage forms. (App. Br. 12.) Appellants contend that Cheng’s
data demonstrate that sustaining the release of lovastatin results in a
substantial decrease in the bioavailability of lovastatin and lovastatin acid.
Appellants contend that this assumption is further confirmed by Cheng’s
simvastatin data, which also shows a substantial decrease in Cmax and AUC
of the total inhibitors for modified release simvastatin products. This
decrease in AUC is contrary to the increased value as claimed in their
present invention. Appellants contend that the observed decrease in the AUC
would not have motivated the formulary chemist to make the claimed
invention, which claims an increased AUC (App. Br. 17). We agree that
sustained-release formulations having increased AUC properties as recited
in the independent claims were not taught or suggested by prior art
sustained-release formulations having decreased AUC properties, as

8
Haiyung Cheng, et al., Evaluation of Sustained/Controlled-Release Dosage
Forms of 3-Hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) Reductase
Inhibitors in Dogs and Humans, 10 PHARMACEUTICAL RESEARCH 1683-87
(1993).

Appeal 2011-011665
Application 11/355,335

9
described in Cheng and a Declaration by Keith Gallicano dated September
30, 2009.
Independent claim 128 recites similar pharmacokinetic limitations
relating to lovastatin release as recited in claim 121. Because the Examiner
has not established by a preponderance of the evidence that the prior art
teaches or suggests these claimed limitations, we cannot sustain the rejection
of claims 121, 127-129, and 134 over the combination of Alberts, Gould,
and Edgren.

REJECTION 2
ISSUES AND ANALYSIS
The Examiner has not found that the prior art teaches or suggests the
claimed pharmacokinetic limitations. Therefore, in view of the foregoing
discussion, we cannot sustain the rejection of claims 121, 123-125, 127-132,
and 134 over the combination of Rork, Edgren, and any of Alberts or Gould.

SUMMARY
We reverse the rejection of claims 121, 123-125, 127-132, and 134
under 35 U.S.C. § 103.

REVERSED

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