Ex Parte Bubnis et al

Patent Trial and Appeal Board

Nov 21, 2012

11487120 (P.T.A.B. Nov. 21, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE PATENT TRIAL AND APPEAL BOARD
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Ex parte WILLIAM BUBNIS, STEPHANIE SHIELD, and
GAYLE P. HOSKOVEC
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Appeal 2012-000294
Application 11/487,120
Technology Center 1600
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Before ERIC GRIMES, FRANCISCO C. PRATS, and STEPHEN WALSH,
Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
pharmaceutical composition. The Examiner has rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
The Specification discloses “that many ‘high purity’ polyethylene
glycols (e.g. ‘PEG’), have a significant amount of aldehyde impurity.… [I]f
this PEG with significant aldehyde content is used in a phenylephrine
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composition, degradation of the phenylephrine is facilitated” (id. at 2:12-17).
The Specification discloses that “phenylephrine stability compatible with
commercial product requirements can be obtained by using substantially
aldehyde-free polyethylene glycol (i.e. ‘SAF-PEG’)” (id. at 2:19-21). “SAF-
PEG may be obtained commercially from Sasol Germany GmbH….
Alternatively, SAF-PEG may be obtained by purification of commercial
PEG with higher levels of aldehyde.” (Id. at 2:25-28.)
Claims 1, 2, 6-17, 21-33, and 37 are on appeal. Claims 2, 6-17, 21-33,
and 37 have not been argued separately and therefore stand or fall with claim
1. 37 C.F.R. § 41.37(c)(1)(vii). Claim 1 reads as follows:
1. An oral liquid pharmaceutical composition comprising:
(a) phenylephrine or a pharmaceutically acceptable salt thereof; and
(b) substantially aldehyde-free polyethylene glycol, wherein the
substantially aldehyde-free polyethylene glycol has less than 20 ppm total
aldehyde content and maintains said level of aldehyde content for at least six
months.

Issue
The Examiner has rejected claims 1, 2, 6-17, 21-33, and 37 under 35
U.S.C. § 103(a) as obvious in view of Santos1 and Fukuta.2 The Examiner
finds that Santos discloses an “oral liquid composition of a bitter tasting
drug such as phenylephrine” (Answer 5), and an embodiment that includes
polyethylene glycol (PEG) (id.), but does not “disclose the aldehyde content
of the composition” (id.).

1 Santos et al., US 2003/0118654 A1, June 26, 2003.
2 Fukuta et al., US 6,187,340 B1, Feb. 13, 2002.
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The Examiner finds that Fukuta discloses that “decomposition
products of … PEG, which include aldehydes” are caused by free radicals
and that the aldehydes cause drug decomposition (id. at 6). The Examiner
concludes that it “would have been obvious to the person of ordinary skill in
the art … to decrease or eliminate aldehydes from the liquid phenylephrine
compositions taught by Santos … because Fukuta et al. discloses that
aldehydes, the result of decomposition of alcohols like PEG, can …
decompose drugs present in the formulation” (id.).
Appellants contend that Fukuta discloses coated tablets and does not
suggest using a substantially aldehyde-free polyethylene glycol liquid
formulation (Appeal Br. 6-7).
The issue presented is: Does the evidence of record support the
Examiner’s conclusion that a liquid pharmaceutical composition comprising
phenylephrine and a substantially aldehyde-free polyethylene glycol would
have been obvious in view of the cited references?
Findings of Fact
1. Santos discloses “a taste masked oral liquid composition
comprising … a bitter-tasting drug” (Santos 1, ¶ 0010).
2. Santos discloses that “unpleasant tasting drugs include but are not
limited to … phenylephrine hydrochloride” (id. at 2, ¶ 0015).
3. Santos discloses that the “drug is dissolved or dispersed in an
aqueous taste masking excipient base comprising a high molecular weight
(MW) polyethylene glycol, a polyvinyl pyrrolidone and/or copolyvidone”
(id.).
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4. Fukuta discloses that “O6-benzylguanine is decomposed in an
aqueous solution of polyethylene glycol 400 … by the reaction of
formaldehyde (present as an impurity of polyethylene glycol 400 and
probably produced by air oxidation of polyethylene glycol 400) with O6-
benzylguanine” (Fukuta, col. 1, ll. 12-18).
5. Fukuta discloses that a study of film-coated tablets showed that
1) titanium oxide in a coating agent produces free radicals when
exposed to ultraviolet rays, 2) free radicals decompose an
alcohol such as polyethylene glycol, etc., in a coating agent, or
a drug, 3) decomposition products of an alcohol such as
polyethylene glycol in a coating agent, for instance, an
aldehyde such as formaldehyde, acetaldehyde, etc., an acid such
as formic acid, etc., or a peroxide, also decomposes a drug.
(Id. at col. 1, ll. 56-65.)
6. Fukuta discloses that the drug included in the pharmaceutical
preparation is “a drug decomposed when exposed to light …; a drug
decomposed by free radicals; or a drug decomposed by an aldehyde …, an
acid (e.g. formic acid) or a peroxide, which are produced as a consequence
of decomposition of a preparation ingredient by free radicals” (id. at col. 6,
ll. 44-49).
7. Fukuta discloses that the drug may be phenylephrine (id. at col. 8,
ll. 30-32).
Analysis
Claim 1 is directed to an oral liquid pharmaceutical composition
comprising phenylephrine and polyethylene glycol that is substantially
aldehyde-free (less than 20 ppm).
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Santos discloses a taste-masked oral liquid composition comprising a
bitter-tasting drug, such as phenylephrine, and polyethylene glycol (PEG),
among other things. Fukuta discloses that formaldehyde is an impurity of
PEG 400 and decomposes the drug O6-benzylguanine in aqueous solution.
Fukuta also discloses that drugs can be decomposed by aldehydes produced
from PEG by the action of free radicals. In view of these disclosures, it
would have been obvious to one of skill in the art to modify Santos’
phenylephrine/PEG formulation to contain substantially aldehyde-free PEG
in order to minimize the decomposition of phenylephrine caused by
aldehyde contaminants of PEG.
Appellants argue that “Fukuta teaches coating the drug with a coating
agent comprising an agent capable of producing free radicals, a free radical
scavenger, and optionally polyethylene glycol to protect it from light.
However a liquid cannot be coated in this way.” (Appeal Br. 6.) Appellants
argue that the “Examiner has failed to provide any rationale to support a
conclusion that one [of] ordinary skill in the art would be motivated to
modify Santos with Fukuta … to prepare improved and stable … liquid
compositions comprising phenylephrine and substantially aldehyde-free
polyethylene glycol” (id. at 7).
This argument is not persuasive. Although Fukuta discloses solid,
rather than liquid, dosage forms, Fukuta’s description of drug decomposition
caused by aldehydes resulting from PEG decomposition or oxidation would
have led a skilled worker to expect that minimizing the amount of aldehyde
impurities in the PEG used in a liquid formulation would reduce
decomposition of the active agent. Thus, one of skill in the art would have
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found it obvious to modify Santos’ phenylephrine/PEG formulation by using
substantially aldehyde-free PEG in order to obtain enhanced stability of the
phenylephrine.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that a
liquid pharmaceutical composition comprising phenylephrine and a
substantially aldehyde-free PEG would have been obvious in view of the
cited references.
SUMMARY
We affirm the rejection claims 1, 2, 6-17, 21-33, and 37 under 35
U.S.C. § 103(a).
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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