Ex Parte Widmann

Patent Trial and Appeal Board

Jun 23, 2016

12809927 (P.T.A.B. Jun. 23, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/809,927 08/19/2010
32425 7590 06/27/2016
NORTON ROSE FULBRIGHT US LLP
98 SAN JACINTO BOULEVARD
SUITE 1100
AUSTIN, TX 78701-4255
FIRST NAMED INVENTOR
Rudolf Stefan Widmann
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
REDL.P0008US/l 1006246 1008
EXAMINER
CORNET, JEAN P
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
06/27/2016 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):
aoipdocket@nortonrosefulbright.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte RUDOLF STEP AN WIDMANN
Appeal2014-004105
Application 12/809,927 1
Technology Center 1600
Before LORA M. GREEN, FRANCISCO C. PRATS, and RYAN H. FLAX,
Administrative Patent Judges.
FLAX, Administrative Patent Judge.
DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) involving
claims directed to a composition comprising an ultrashort-effective B-
adrenoreceptor antagonist or a pharmaceutically acceptable salt thereof,
water, and a cyclodextrin or functional cyclodextrin derivative. Claims 13-
16 and 19-26 are on appeal as rejected under 35 U.S.C. § 112, fourth
paragraph, and§ 103(a). We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 The Real Party in Interest is AOP Orphan Pharmaceuticals AG. App.
Br. 1.
Appeal2014-004105
Application 12/809,927
STATEMENT OF THE CASE
The appealed claims can be found in the Claims Appendix of the
Appeal Brief. Claim 13 is the sole independent claim and reads as follows:
13. A pharmaceutical composition comprising:
a) an ultrashort-effective B-adrenoreceptor antagonist or a
pharmaceutically acceptable salt thereof;
b) water; and
c) a cyclodextrin or a functional cyclodextrin derivative m
concentration of 0.5 to 4%.
App. Br. 8 (Claims Appendix).
The following grounds of rejection are on appeal:
A. Claim 16 rejected under 35 U.S.C. § 112, fourth paragraph, for
failing to further limit the scope of the claimed subject matter with respect to
that of the claim from which it depends.
B. Claims 13-16 and 19-24 [and 25]2 rejected under 35 U.S.C.
§ 103(a) as unpatentable over Escobar, 3 Tiwari, 4 Loftsson, 5 and Rajewski. 6
2 The Examiner indicates that Appellant and the Examiner agreed in an
interview conducted Nov. 12, 2012, that claim 25 was included in this
obviousness rejection. Ans. 17.
3 U.S. Patent 5,017,609 to Escobar et al. (issued May 21, 1991) (hereinafter
"Escobar").
4 U.S. Patent Application Pub. No. US 2008/0293810 Al (published Nov.
27, 2008) (hereinafter "Tiwari").
5 Loftsson et al., Expert Opinion - Cyclodextrins in Drug Delivery, 2 EXPERT
OPINION ON DRUG DELIVERY 335-351 (2005) (hereinafter "Loftsson").
6 Roger A. Rajewski and Valentino J. Stella, Pharmaceutical Applications of
Cyclodextrins. 2. In Vivo Drug Delivery, 85 J. PHARMA SCI. 1142-1169
(Nov. 1996) (hereinafter "Rajewski").
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Application 12/809,927
C. Claim 26 rejected under 35 U.S.C. § 103(a) as unpatentable over
Escobar, Tiwari, Loftsson, Rajewski, and Masui. 7
FINDINGS OF FACT
FFl. Escobar disclosed B-blockers/compounds with B-adrenergic
blocking activity, e.g., esmolol, and "pharmaceutically acceptable acid
addition salt[s]" thereof, where "[t]he ester groups in these compounds have,
however, been found to be somewhat unstable in aqueous environments,
such as intravenous infusion solutions." Escobar col. 1, 11. 30-38, col. 4, 11.
37--40, col. 10, 11. 15-23; see also Final Action 4 (discussing Escobar).
FF2. Escobar disclosed providing ethanol with a B-blocker
compound because "[ e ]thanol has been found to be important in the
stabilization of the B-blocking compound." Escobar col. 4, 11. 57-59.
FF3. Escobar disclosed "[a] particularly preferred liquid polyhydric
compound is propylene glycol. Liquid polyhydric compounds, in
conjunction with ethanol are useful stabilizing components of the B-blocking
compounds." Escobar col. 5, 11. 7-12.
FF 4. Escobar disclosed an Example VII where 1 OOmg/ml of methyl
3-(p-Phenoxypropanolamine) Propionate (i.e., esmolol) is combined with
10% ethanol and 10 % propylene glycol, and a O.lM sodium acetate buffer.
Escobar col 10, 11. 15-27; see also Final Action 4 (discussing Escobar).
7 Mio Y., New Ulstra-Short-Acting Beta-Blockers: Landiolol and Esmolol-
the Effects on Cardiovascular System, 55 MASUI 841-8, Abstract (Jul. 2006)
(accessed at http://www.ncbi.nlm.nih.gov/pubmed/16856544 on Apr. 6,
2012) (hereinafter "Masui").
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Application 12/809,927
FF5. Tiwari disclosed, and confirmed the disclosure of Escobar, that
esmolol is unstable in water due to "the rate of acid/base catalyzed
hydrolysis." Tiwari i-f 4; see also Final Action 4 (discussing Tiwari).
FF6. Tiwari disclosed, and confirmed the disclosure of Escobar, that
"[t]he current commercial concentration formulation employs excipients
(ethanol and propylene glycol) to stabilize the hydrolytic reaction [of
esmolol, but] ... " further cautioned, "the excipients (ethanol and propylene
glycol) used to stabilize the current commercial esmolol concentration
formulation have been associated with potential injection site pain or
irritation" and "it would be desirable to provide a stabilized concentrate
esmolol composition that ... does not include potentially irritating
propylene glycol and ethanol excipients." Tiwari i-fi-1 4--5; see also Final
Action 4 (discussing Tiwari).
FF7. Loftsson disclosed "[i]n the pharmaceutical industry
cyclodextrins have mainly been used as complexing agents to increase
aqueous solubility of poorly soluble drugs, and to increase their
bioavailability and stability," and "[s]tudies in both humans and animals
have shown that cyclodextrins can be used to improve drug delivery from
almost any type of drug formulation." Loftsson 335 (Abstract), 336; see
also Final Action 4--6 (discussing Loftsson).
FF8. Loftsson disclosed, inter alia, several "intravenous solutions"
formulations as "[ s Jome examples of marketed products containing
cyclodextrin," and several "parenteral" applications as examples of a-, B-,
and y- "[ c ]yclodextrins that can be found in marketed pharmaceutical
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Appeal2014-004105
Application 12/809,927
products." Loftsson 336 (Table 1 ), 337 (Table 2); see also Final Action 5
(discussing Loftsson).
FF9. Loftsson disclosed "B-[ c ]yclodextrin and y-cyclodextrin are
also listed in the 'generally regarded as safe' list of the FDA for use as food
additives." Loftsson 337; see also Final Action 5 (discussing Loftsson).
FFlO. Loftsson advised "[fJor a variety of reasons, such as isotonicity
of parenteral formulations and formulation bulk of solid dosage forms, it is
important to include as little cyclodextrin as possible in a pharmaceutical
formulation." Loftsson 339; cf App. Br. 4 (criticizing Loftsson's disclosure
of "higher" amounts of cyclodextrin).
FF 11. Loftsson disclosed "[ s ]tability issues can limit the feasibility of
a pharmaceutical formulation. This is especially true for aqueous
formulations of drugs that are prone to hydrolysis or oxidation." Loftsson
339; see also Final Action 5 (discussing Loftsson).
FF12. Loftsson disclosed "the addition of cyclodextrins to existing
formulations without further optimisation will seldom result in acceptable
outcome." Loftsson 335 (Abstract); see also App. Br. 4 (contending
Loftsson taught away from combining cyclodextrins and B-adrenoreceptors
antagonists because a skilled artisan would not reasonably expect acceptable
outcomes).
FF 13. Loftsson disclosed:
In first-order and pseudo-first-order reactions, such as hydrolysis
or oxidation, the stabilising (or catalytic) effect will depend on
three parameters: the cyclodextrin concentration, the stability
constant of the complex and the degradation rate constant for the
drug degradation within the cyclodextrin cavity (kC). These
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Appeal2014-004105
Application 12/809,927
parameters can be determined by fitting degradation data
obtained at several cyclodextrin concentrations to Equation 7:
R~_.1
D +CV++ D/Cl)
k0 -1.. .i k.-
Degradi.1
compared with cydodextrin formulations {unpublished
results: and tmJ),
Comm~rdal
product
Diazepam intravenous solution (Roche)
Dlazeparn
Pmpylene g!ytol 40 %
Ethyl alcohol 10%
Sodium 5%
aod
B