Ex Parte 6407079 et al

Patent Trial and Appeal Board

Apr 28, 2014

90010886 (P.T.A.B. Apr. 28, 2014)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
90/010,886 03/04/2010 6407079 JJ-0264 / JAB445581 2270
23377 7590 04/28/2014
BAKER & HOSTETLER LLP
CIRA CENTRE 12TH FLOOR
2929 ARCH STREET
PHILADELPHIA, PA 19104-2891
EXAMINER
JONES, DWAYNE C
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
04/28/2014 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 JANSSEN PHARMACEUTICA N.V.
Appellant
__________

Appeal 2014-001666
Reexamination Control 90/010,886
Technology Center 1600
Patent No. US 6,407,079 B1
__________

Before DONALD E. ADAMS, ERIC GRIMES, and ULRIKE W. JENKS,
Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
Janssen Pharmaceutica (“Janssen”)1 appeals under 35 U.S.C. § 134(b)
and 35 U.S.C. § 306 from a final rejection of claims 1-20 and 22-40. We
have jurisdiction under 35 U.S.C. §§ 134(b) and 306. An oral hearing was
held on April 9, 2014.
We reverse.

1 Janssen Pharmaceutica N.V. is said to be the real party in interest and
assignee of the patent under reexamination. (App. Br. 1.)
Appeal 2014-001666
Reexamination Control 90/010,886
Patent No. US 6,407,079 B1

2
STATEMENT OF THE CASE
Reexamination Proceedings
A request for ex parte reexamination of U.S. Patent No. 6,407,079
(the ’079 patent) was filed on March 4, 2010, and was assigned
Reexamination Control No. 90/010,886. The ’079 patent, entitled
“PHARMACEUTICAL COMPOSITIONS CONTAINING DRUGS
WHICH ARE INSTABLE OR SPARINGLY SOLUBLE IN WATER AND
METHODS FOR THEIR PREPARATION,” issued June 18, 2002, to Bernd
W. Müller, and Ulrich Brauns, based on Application No. 07/264,726, filed
Oct. 31, 1988. The ’079 patent claims the benefit, under 35 U.S.C. § 120, to
Application No. 06/756,498. The effective filing date of the ’079 patent is
said to be July 3, 1985.

Appellant’s Invention
The ’079 patent relates to pharmaceutical compositions comprising a
partially etherified β-cyclodextrin in combination with a drug that is
sparingly soluble in water and that fits into the cavity of the β-cyclodextrin
ring.
The claims are reproduced in the Claims Appendix of the Appeal
Brief. For reference convenience, independent claim 1 is reproduced below:
1. Pharmaceutical composition comprising an inclusion
compound of
(i) a drug capable of fitting into the cavity of the
cyclodextrin ring system which is instable or only sparingly
soluble in water with
(ii) a partially etherified β-cyclodextrin of the formula
(β-CD)-OR wherein
Appeal 2014-001666
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Patent No. US 6,407,079 B1

3
the residues R are hydroxyalkyl groups and part of
said residues R may optionally be alkyl groups,
the β-cyclodextrin ether having a water solubility
of greater than 1.8 g in 100 ml water,
wherein said composition has considerably increased
water solubility and stability relative to said drugs, with very
low toxicity.
(App. Br. 20)

The Rejections
I. Claims 1, 2, 4, 5, 18, 19, and 23 stand rejected under 35 U.S.C.
§ 103(a) as being obvious over Fenyvesi;2
II. Claims 6-11, 20, 22, 24, 36, and 40 stand rejected under
35 U.S.C. § 103(a) as being obvious over Fenyvesi;
III. Claim 3 stands rejected under 35 U.S.C. § 103(a) as being
obvious over Fenyvesi in view of Gramera;3 and
IV. Claims 12-17, 25-35, and 37-39 stand rejected under 35 U.S.C.
§ 103(a) as being obvious over Fenyvesi in view of Gramera.

ISSUE
Does the evidence of record support the Examiner’s conclusion that
Fenyvesi alone or in combination with Gramera renders the claimed
pharmaceutical composition obvious?

2 Fenyvesi et al., Water-Soluble Cyclodextrin Polymers and Their
Complexing Properties, Int'l Symposium on Cyclodextrins, 1981.
3 Gramera et al., US 3,459,731, issued Aug. 5, 1969.
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Reexamination Control 90/010,886
Patent No. US 6,407,079 B1

4
FINDINGS OF FACT
’079 Patent
1. The background section of the ’079 patent teaches that “the
β-cyclodextrin itself is only poorly water-soluble (1.8 g/100 ml).” (Col. 1,
ll. 51-52.) However, derivatives of β-cyclodextrin are found to be
considerably more soluble. (Col. 1, ll. 54-55.) Specifically, the background
teaches that a German reference “discloses a solubilization method using
methylated β-cyclodextrin as monomethyl derivative with 7 methyl groups
and especially as dimethyl derivative with 14 methyl groups. With the 2,6-
di-O-methyl derivative it is for instance possible to increase the water
solubility of indometacin [sic] 20.4-fold and that of digitoxin 81.6-fold.”
(Col. 1, ll. 57-62.)
2. The background section of the ’079 patent further teaches that
“for therapeutical use the methyl derivatives of β-cyclodextrin show serious
draw backs. Due to their increased lipophility they have a haemolytic effect
and they further cause irritations of the mucosa and eyes. Their acute
intravenous toxicity is still higher than the already considerable toxicity of
the unsubstituted β-cyclodextrin.” (Col. 1, l. 63 to col. 2, l. 1; see also col.
7, ll. 26-32 (“the haemolytic effect of the hydroxypropylmethyl ether is
about 5 to 8 times weaker than that of the dimethyl ether according to the
prior art. Animal tests have further shown that the hydroxyalkyl ethers do
not cause irritation of the mucosa and eyes in contrast to the methyl
ethers”).)
App
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yvesi 346.
01666
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01666
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6,407,079
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354.)
uest

Appeal 2014-001666
Reexamination Control 90/010,886
Patent No. US 6,407,079 B1

7
9. The Examiner finds that Fenyvesi disclosed monomeric inclusion
complexes.
Fenyvesi specifically discloses that the molecular weight (MW)
of cyclodextrin is 1134 (page 349). Accordingly, a multiple, n,
where n is a positive integer of the MW of β-CD (n *MW of
β-CD) would result in a particular oligomer or polymer of β -
CD. For example, a dimer (n = 2) of β-CD would need to have
at least a MW = 2268 (two times the MW of the monomer),
while a tetramer (n = 4) of β -CD would need to have at least a
MW = 4536 (four times the MW of the monomer), and a
septamer (n = 7) of β-CD would need to have at least a MW =
7938. Thus, Fenyvesi clearly teaches partially etherified
(derivatized) monomers of β-CD.
(Ans. 6; 7, 22, 24, 28; see also Fenyvesi 349, 351, 352, Figs. 5 & 6.)

ANALYSIS
There are four rejections based on obviousness, and all are premised,
in whole or in part, on the teachings of Fenyvesi, so we will discuss them
together.
Based on Fenyvesi, the Examiner concludes that, at the time
Appellant’s invention was made, it would have been prima facie obvious to
an ordinary artisan to take Fenyvesi’s disclosed partially etherified
β-cyclodextrin monomer and add a poorly water soluble drug to form an
inclusion complex. Specifically, the Examiner asserts that “[a]t the time of
the invention, one having ordinary skill in the art would have been motivated
to select a monomeric species of a partially etherified β-CD from the
teachings of Fenyvesi to form an inclusion complex of a partially etherified
monomer of β-CD and a poorly soluble pharmaceutical with a predictable
and reasonable expectation of successfully improving the solubility of the
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Patent No. US 6,407,079 B1

8
drug in order to arrive at the claimed invention” (Ans. 7). We are not
persuaded.
Appellant’s claim 1 requires an inclusion compound of (1) a drug that
is (a) capable of fitting into the cavity of the cyclodextrin ring system and
(b) which is instable or only sparingly soluble in water and (2) a partially
etherified β-cyclodextrin. Fenyvesi disclosed monomeric β-cyclodextrin
derivatives complexed with Congo red as a guest molecule (Ans. 7; see also
FFs 4-7). In addition, Fenyvesi also disclosed polymeric β-cyclodextrin
complexed not only with Congo red but also with indomethacin as a guest
molecule (FFs 7 & 8). The Examiner acknowledges “Fenyvesi does not
specifically disclose or provide an example of a partially etherified
(derivatized) monomer of β-CD that is complexed with a drug as claimed”
(Ans. 7). The Examiner, nevertheless, reasons that the inclusion complex of
a drug with a monomeric β-cyclodextrin derivative would be obvious based
on Fenyvesi’s disclosure (id.).
Appellant contends, among other things, that the Examiner is
impermissibly relying on an obvious to try rationale, especially in light of
the assertion that at time the invention was made one of ordinary skill in the
art would have recognized that “for therapeutical use the methyl derivatives
of β-cyclodextrin show serious draw backs. Due to their increased
lipophility they have a haemolytic effect and they further cause irritations of
the mucosa and eyes.” (App. Br. 11; see also Reply Br. 3; FFs 2 & 3.)
Appellant additionally points to the Specification’s evidence that shows “the
claimed compositions are [indeed] less haemolytic and irritating to mucosa
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Patent No. US 6,407,079 B1

9
and eyes than the noted prior art methyl derivatives.” (App. Br. 11; see also
FFs 2 & 3.)
The Examiner acknowledged that Appellant’s compositions are less
haemolytic and less irritating, specifically recognizing that “[t]he data
presented in Table 6 does show improvement over methylated derivatives of
β-cyclodextrins is not contested” (Ans. 36). The Examiner, nevertheless,
maintains the position that
Fenyvesi makes use of the hydroxyalkyl group of a
dihydroxypropyl moiety to partially etherify a β-cyclodextrin as
does the ’079 Patent. Therefore, one skilled in the art would
predictably and reasonably expect the derivatized
β-cyclodextrin monomers of Fenyvesi to possess similar
properties (i.e., less haemolytic and irritating to mucosa and
eyes than noted prior art[ ] methyl derivatives) with success.
(Ans. 36-37.)
Thus, the Examiner’s position is that compounds having similar
structure would be expected to have similar properties. We recognize, but
are not persuaded by the Examiner’s assertion. First, the reaction that the
Examiner identifies as producing a dihydroxypropyl β-cyclodextrin
derivative is characterized by Fenyvesi as a side reaction (Fenyvesi 346:
“side reactions can occur of which the most important is the hydrolysis of
epoxy groups”). Fenyvesi discloses that the resulting hydroxy groups can
react with another molecule of epichlorohydrin or an epoxy group coupled to
cyclodextrin, resulting in chains of different length connecting cyclodextrin
rings (id.). Thus, although Fenyvesi’s reaction product contains some
monomeric dihydroxypropyl β-cyclodextrin ether derivative, Fenyvesi does
not describe it as an intended or desired product. In addition, even if
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Patent No. US 6,407,079 B1

10
Fenyvesi’s disclosed β-cyclodextrin monomers are expected to behave in the
same way as the claimed β-cyclodextrin monomers if they were complexed
with a poorly soluble drug, the fact remains that Fenyvesi does not disclose a
monomeric β-cyclodextrin derivative complexed with “a drug capable of
fitting into the cavity of the cyclodextrin ring system which is instable or
only sparingly soluble in water.” As such, Fenyvesi’s disclosure does not
provide a composition that is identical to the claimed composition.
What is missing from the Examiner’s analysis is an explanation why
the ordinary artisan knowing that β-cyclodextrin derivatives are haemolytic
and irritating would have even looked to Fenyvesi’s monomeric
β-cyclodextrin derivatives and considered formulating these derivatives into
a pharmaceutical as a carrier (FFs 2-3). A rejection for obviousness must
include “articulated reasoning with some rational underpinning to support
the legal conclusion.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418
(2007), quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). Because
the Examiner’s rejection does not explain why the ordinary artisan would
have considered it reasonable to investigate a particular class of compounds,
especially a class that was known to include members that are toxic, and
formulate them into a pharmaceutical we find that the Examiner has not met
the burden of articulating a sufficient reason for a finding of obviousness.
Accordingly, we agree that the Examiner has failed to identify a sufficient
evidentiary basis on this record that supports the Examiner’s rationale of
formulating a poorly soluble drug with the β-cyclodextrin derivative of
Fenyvesi as a carrier.
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Patent No. US 6,407,079 B1

11
Appellant’s remaining independent claims 12, 24, 27, and 31 also
require the combination of a drug and a monomeric β-cyclodextrin
derivative. For the reasons discussed above, the Examiner has not shown
that this combination would have been obvious based on the cited prior art.

DECISION
The preponderance of evidence relied on by the Examiner fails to
support a conclusion of obviousness. The rejections of claims 1-20 and
22-40 under 35 U.S.C. § 103(a) are reversed.

REVERSED
cam