Stanko Skrtic et al.

Patent Trials and Appeals Board

Jul 18, 2019

14255332 - (D) (P.T.A.B. Jul. 18, 2019)

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.
14/255,332 04/17/2014 Stanko SKRTIC 2006685-0964 1046
119393 7590 07/18/2019
Choate/Shire, Inc.
Two International Place
Boston, MA 02110
EXAMINER
MILLIGAN, ADAM C
ART UNIT PAPER NUMBER
1612
NOTIFICATION DATE DELIVERY MODE
07/18/2019 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
jnease@choate.com
patentdocket@choate.com
shireip@shire.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte STANKO SKRTIC, JÖRGEN JOHNSSON,
HANS LENNERNÄS, THOMAS HEDNER, and
GUDMUNDUR JOHANNSSON
__________

Appeal 2018-004379
Application 14/255,3321
Technology Center 1600
__________

Before RYAN H. FLAX, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for a once daily treatment of a glucocorticoid deficiency disorder, which
have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
Appellant’s Specification discloses that “[g]lucocorticoids are
important steroids for intermediary metabolism, immune, musculosceletal,
connective tissue and brain function.” (Spec. 1.) Cortisol is a

1 Appellant is Shire ViroPharma Inc., which identifies itself as the real party
in interest. (Appeal Br. 3.)
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glucocorticoid. (Id.) “[I]n healthy persons, the cortisol secretion has a 24-
hour circadian pattern with peak serum levels in the early morning, 3–6
hours after onset of sleep, and nadir levels around midnight.” (Id.)
Replacement therapy is used to treat glucocorticoid deficiency. (Id.)
“The aim of glucocorticoid replacement therapy is to mimic the circadian
serum cortisol profile, respond to the increased cortisol need during physical
and psychological stimuli and obtain normal well-being, metabolism and
long-term outcome.” (Id. at 3.) Appellant’s “invention relates to
glucocorticoid replacement therapy.” (Id. at 1.)
Claims 112, 114–116, 118–120, 122–128, 130, 132, and 134–140 are
on appeal. Claim 112 is representative and reads as follows:
112. A method for once daily treatment of a glucocorticoid
deficiency disorder in a patient in need thereof, comprising
administering to said patient a therapeutically effective amount
of a coated tablet dosage form once daily in the morning, said
coated tablet dosage form comprising:
(a) an extended release tablet core and an immediate
release coating surrounding said extended release tablet core;
and
(b) a total dose of about 1 mg to about 80 mg of
hydrocortisone;
wherein said extended release tablet core comprises
hydrocortisone, the amount of hydrocortisone present in said
extended release tablet core is about 60% to 80% of the total
amount of hydrocortisone present in said coated tablet dosage
form and is released over an extended period of time of at least
8 hours,
wherein said immediate release coating comprises
hydrocortisone and the amount of hydrocortisone present in
said immediate release coating is about 20% to 40% of the total
amount of hydrocortisone in said coated tablet dosage form.
(Appeal Br. 17.)
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The following ground of rejection by the Examiner is before us on
review:
Claims 112, 114–116, 118–120, 122–128, 130, 132, and 134–140
under 35 U.S.C. § 103 as unpatentable over Ross2 and Faour.3
DISCUSSION
The Examiner finds that Ross teaches a method of treating the
glucocorticoid deficiency disorder Addison’s disease by administering
hydrocortisone in a sustained and delayed release tablet form to mimic the
circadian cortisol profile, a profile which spikes to its highest level in the
morning then tapers off throughout the day. (Non-Final Action4 3.) The
Examiner notes that Ross teaches a multilayered tablet for differential
release times of drug from an outer layer and an inner core. (Id. at 3–4.)
The Examiner also finds that Ross teaches treatment regimens involving
administration of medication two to three times per day. (Ans. 4.)
The Examiner recognizes that Ross does not teach administration of a
tablet only once a day for treatment of Addison’s disease. The Examiner
contends that once daily administration “in order to replicate the circadian
rhythm over a full 24 hours” for treating Addison’s disease is rendered
obvious, however, by the teachings of tablet formulations of Faour. (Non-
Final Action 4–5.)
The Examiner finds that Faour teaches a composition that comprises
an immediate release coating and a controlled release core. (Id. at 4 (citing

2 Ross et al., WO 03/015793 A1, published Feb. 27, 2003.
3 Faour et al., US 2005/0008702 A1, published Jan. 13, 2005.
4 The referenced Non-Final Action is dated May 5, 2017.
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Faour ¶¶ 20, 73, and 180).) The Examiner further finds that Faour teaches
that immediate release means that the active is released within 45 minutes
and that controlled release means the active is released over the course of a
day or more. (Id. (citing Faour ¶¶ 37, 39).) The Examiner also finds that
Faour teaches that “[c]ontrolled release generally effects at least a two-fold
reduction in dosing frequency.” (Ans. 4 (citing Faour ¶ 39).) The Examiner
further finds that Faour teaches that the active may be hydrocortisone in a
pharmaceutically effective amount and that the core may contain about 65%
of the active and the immediate release coating may contain about 35% of
the active ingredient. (Non-Final Action 4–5 (citing Faour ¶¶ 116, 155,
180).) In addition, the Examiner finds that Faour teaches that the
formulation may be made so as “to release over 50% of the active ingredient
in the first 10 hours and over 80% in the first 24 hours (fig.3)” and that
“[t]he release rate may be maintained between 3% and 7.5% per hour from 1
to 12 hours after administration (fig. 3).” (Id. at 4.) According to the
Examiner, therefore, “the dosage of Faour is designed to enable once-a-day
administration.” (Non-Final Action 6.)
According to the Examiner, it would have been obvious to use a
formulation such as described in Faour of an immediate and controlled
release tablet of hydrocortisone “first thing in the morning in order to
correlate the immediate release portion of the dosage with the morning spike
in the natural circadian cortisol level.” (Id. at 5.) The Examiner contends
that “[o]ne of ordinary skill in the art would not expect such a dosage to
perfectly replicate natural cortisol levels, but rather to approximate such
levels.” (Id. at 6.) The Examiner further contends that Ross contemplates a
morning dosage, though it is a non-preferred embodiment. (Id. at 7.) The
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Examiner explains that “Ross teaches administration in the morning, but
acknowledges that such a method does not reflect normal cortisol levels
because patients will wake with undetectable levels of cortisol.” (Id. at 7.)
We do not agree with the Examiner’s conclusion that the claimed
method of treating a glucocorticoid deficiency disorder such as Addison’s
disease would have been obvious from the teachings of Ross and Faour. As
the Appellant correctly observes (Appeal Br. 11), Ross teaches a dosing
regimen to treat primary adrenal failure such as in Addison’s disease in a
manner to mimic circadian serum cortisol that depends upon administration
of a tablet at night, which tablet is a delayed sustained release formulation.
(Ross 2 (“In treating patients with adrenal failure, an attempt is made to
mimic the cortisol circadian rhythm”), 4 (“the problem addressed by the
present invention is how to provide a treatment regime which combines both
the delayed and sustained release of a therapeutic agent to provide an
optimal treatment regime”), 5–6.)
Ross provides in Figure 2, reproduced below, a representation of the
normal circadian rhythm of cortisol in an animal.
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Figure 2 above is a depiction of the normal twenty four hour cycle of
cortisol levels in an animal. As can be seen, normally, cortisol is at a low of
near zero in the middle of the night (about midnight or 1 am), and that
amount rises over several hours to a peak in the morning at around 7 am, and
then the amount slowly decreases for the remaining 17 hours of the day.
Ross explains that the combination of a delayed and sustained release
formulation administered at night combined with administration of a
sustained release preparation in the morning is said to be able to “reproduce
the normal circadian rhythm of, for example, cortisol production.” (Ross 6,
15, and Figure 4.) The delayed sustained release formula taken in the
evening allows for controlled release of hydrocortisone that may begin in the
middle of the night while a patient is sleeping and thus provides a release
profile that mimics the normal circadian rhythm. As Ross explains, where
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administration is provided in the morning, the patient will not have the
benefit of hydrocortisone levels prior to when he wakes up and is able to
take his medication, and will “only get a peak an hour after taking [his]
hydrocortisone.” (Id. at 2.) In light of the foregoing, we agree with
Appellant, that “Ross emphasizes the importance of [achieving an] early
morning rise in cortisol levels prior to waking” in efforts to mimic the
normal circadian rhythm when providing a method for treating primary
adrenal failure such as in Addison’s disease. (Appeal Br. 14.)
We agree with the Examiner that Faour teaches a drug formulation
that can include hydrocortisone. (Faour ¶ 116.) And it may also reasonably
be concluded that Faour discloses a formulation that would be capable of
being used as a once a day administration. (Non-Final Action 6; Faour
¶ 39.) It is also true that Faour discloses that the formulation can have a
controlled release core and can have an immediate release coating over the
core. (Id. ¶¶ 20, 73.) Even though one of ordinary skill in the art may have
been able to make a formulation of hydrocortisone with an extended release
core and an immediate release coating that would have the percent active
claimed in each layer based on the teachings in Faour, that is not the
obviousness question we are presented with. Rather, in view of the
Examiner’s rejection, we must consider whether there is sufficient evidence
of record to establish that one of ordinary skill in the art, (a) in an effort to
mimic the normal circadian rhythm of serum cortisol levels taught in Ross,
(b) would have made a controlled release formulation as disclosed in Faour
that also had an immediate release coating where hydrocortisone was the
active and (c) would have administered that formulation to a patient when he
wakes in the morning, with a reasonable expectation of achieving the
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claimed method and claimed coated tablet dosage form. We conclude that
there is not sufficient evidence to support the Examiner’s conclusion of
obviousness.
The Examiner relies on Figure 3 of Faour for the assessment of
specific drug release parameters taught by Faour. We reproduce Figure 3
below.

Faour states that Figure 3 “depicts the maximum and the minimum
percentage of nifedipine released from several samples of the osmotic device
according to Example 1.” (Id. ¶ 32.) As can be seen, the formulation
provides for near 100% release of drug in 24 hours or 60% release. (Id. at
Figure 3.) We agree with the Examiner that Figure 3 shows that, where the
maximum percent of drug is released, about 80% of the drug is released over
10 hours. (Id.) We also agree with the Examiner that Faour demonstrates a
drug formulation where 65% of the active (carisoprodol) is in the core and
35% of the same active is in a coating surrounding the core for immediate
release. (Id. ¶ 180.) However, the fact that some formulations may be made
with an about 80% drug release within 10 hours and 20% within 4 hours and
that a formulation can be made with an immediate release coating over a
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controlled release core, does not establish that such a formulation when
administered as a wake-up morning dose would reasonably be expected to
achieve a release that approximates the circadian rhythm of serum cortisol
where there is a slow but steady rise of cortisol levels in the middle of the
night and also a tapering of cortisol levels from a peak time in the morning
until the slow rise again in the middle of the night. Stated differently, the
Examiner has not established that a person of ordinary skill in the art who
sought to mimic the circadian rhythm of serum cortisol taught in Ross would
have had reason to create a formulation with an about 80% drug release
within 10 hours and 20% drug release within 4 hours, using an immediate
release coating over a controlled release core, because there is no indication
that such a formulation would result in mimicking the normal circadian
rhythm of cortisol.
“[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting a prima facie case of unpatentability.” In
re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). We conclude that the
Examiner has not met his burden to establish that Ross in combination with
Faour would have rendered obvious a once daily morning administration of
a hydrocortisone formulation that falls within Appellant’s claims without the
benefit of hindsight. Therefore, we do not sustain the Examiner’s rejection
of the method of treatment claims on appeal as being obvious over Ross and
Faour.
SUMMARY
We reverse the rejection of claims 112, 114–116, 118–120, 122–128,
130, 132, and 134–140 under 35 U.S.C. § 103 as unpatentable over Ross
and Faour.
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REVERSED