Ex Parte Wirth et al

Board of Patent Appeals and Interferences

Nov 8, 2010

10586458 (B.P.A.I. Nov. 8, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte CORINNA WIRTH, RALF ROSSKOPF, and
HERWIG BUCHHOLZ
__________

Appeal 2010-007491
Application 10/586,458
Technology Center 1600
__________

Before DONALD E. ADAMS, MELANIE L. McCOLLUM, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

Opinion by the Board filed by Administrative Patent Judge FREDMAN.

Dissenting opinion filed by Administrative Patent Judge McCOLLUM.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL1

1 The two-month time period for filing an appeal or commencing a
civil action, as recited in 37 C.F.R. § 1.304, or for filing a request
for rehearing, as recited in 37 C.F.R. § 41.52, begins to run from
the “MAIL DATE” (paper delivery mode) or the
“NOTIFICATION DATE” (electronic delivery mode) shown on
the PTOL-90A cover letter attached to this decision.
Appeal 2010-007491
Application 10/586,458

2
This is an appeal under 35 U.S.C. § 134 involving claims to tiliroside
complexed with cyclodextrin. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We reverse.
Statement of the Case
The Specification teaches that the “invention relates to complexes of
certain flavonoid derivatives, to compositions which comprise such
derivatives . . . and to the use thereof, in particular for the care, preservation
or improvement of the general state of the skin or hair” (Spec. 1).
The Claims
Claims 2, 4, 9, 12-15, 19, 21, 22, 24, 26, and 27 are on appeal. Claim
4 is representative. Claim 4 reads as follows:

4. A complex compound of the following formula
wherein
CD is a gamma-cyclodextrin,
o is 1, and
p is 2.

Appeal 2010-007491
Application 10/586,458

3
The issues
A. The Examiner rejected claims 2, 4, 9, 12, 13, 15, 19, 21, 22, and 24
under 35 U.S.C. § 103(a) as obvious over Wirth2 and Miyake3 (Ans. 3-5).
B. The Examiner rejected claims 4, 14, and 27 under 35 U.S.C. § 103(a)
as obvious over Wirth, Miyake, and Rosenbloom4 (Ans. 5-6).
C. The Examiner rejected claims 4 and 26 under 35 U.S.C. § 103(a) as
obvious over Wirth, Miyake, and Wollenberg5 (Ans. 6-7).
A. 35 U.S.C. § 103(a) over Wirth and Miyake
The Examiner finds that “WIRTH teaches the flavonoid of the instant
application, formula IIA1, tiliroside” (Ans. 3). The Examiner finds that
“WIRTH teaches using the disclosed flavonoids for cosmetic,
pharmaceutical & food supplement compositions” (id.).
The Examiner finds that “MIYAKE teaches a complexion of Rutin, a
flavonoid as is tiliroside ,with hydroxypropyl-gamma-cyclodextrin and a few
other cyclodextrins” (id. at 4). The Examiner finds that “[c]omplexion of

2 Wirth et al., WO 02/069926 A1, published Sep. 12, 2002. The
Examiner relies upon Wirth et al., US 2004/0081675 A1, published
Apr. 29, 2004 for the translated text of the Wirth WO document,
which is not disputed, so we will also rely on this text for the
translation of the Wirth WO document.
3 Miyake et al., Improvement of Solubility and Oral Bioavailability
of Rutin by Complexation with 2-Hydroxypropyl-β-cyclodextrin, 5
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 399-407
(2000).
4 Richard Rosenbloom, US 2003/0105031 A1, published Jun. 5,
2003.
5 A. Wollenberg and T. Bieber, Topical Immunomodulatory Agents
and Their Targets in Inflammatory Skin Diseases, 33
TRANSPLANTATION PROC. 2212-2216 (2001).
Appeal 2010-007491
Application 10/586,458

4
cyclodextrins is well known to improve the usefulness & properties &
increase stability of cosmetics & drugs in water (Introduction-p. 400) and as
shown in TABLE 1” (Ans. 4).
The Examiner finds it obvious “to make a composition comprising
tiliroside as taught by WIRTH, as a complex of any of the CyD’s, including
gamma-CyD, as taught by MIYAKE, in order to improve the usefulness &
properties & increase stability of the tiliroside” (id. at 4-5). The Examiner
finds that “[o]nly limited testing would have been required to determine the
optimal CyD, from a short list of 6 forms, to complex with the flavonoid of
choice” (id. at 5).
Appellants contend that “[n]owhere does Wirth teach or suggest that
the compounds of formula I therein or tiliroside need to be stabilized.
Instead, Wirth teaches that the objects of the invention could overcome prior
art disadvantages by the use of the compounds of formula I (which includes
tiliroside)” (App. Br. 3). Appellants contend that “Miyake compares
gamma-cyclodextrins with various beta-cyclodextrins as a complexing
agents [sic] with rutin and concludes that gamma-cyclodextrins are not as
stable as beta-cyclodextrins . . . . Thus, one of ordinary skill in the art based
on the teaching of the prior art would conclude that beta-cyclodextrins
should be preferred over gamma-cyclodextrins” (id.).
Appellants contend that they “demonstrated in the [Wirth] declaration
that the complex of tiliroside with hydroxypropyl-gamma-cyclodextrin was
more than a 1000 fold soluble in water than tiliroside, which is a significant
unexpected advantage not expected from the teachings of the prior art” (id.
at 4). Appellants also point to “the solubility studies in Miyake, e.g., in
Appeal 2010-007491
Application 10/586,458

5
Figure 2 therein on page 402 teaching that the solubility of rutin with HP-γ-
CyD and γ-CyD were less than those of rutin with G2-β-CyD, β-CyD and
HP-β-CyD” (App. Br. 4).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that Wirth and Miyake render prima facie obvious the claimed formulation?
(ii) If so, does the evidence of the Wirth Declaration demonstrate an
unexpected result sufficient to overcome the prima facie case of
obviousness?
Findings of Fact
1. Wirth teaches “cosmetic formulations comprising one or more
compounds of the formula I” (Wirth 2 ¶ 0018) where “[k]nown compounds
of the formula I are, for example . . . kaempferol 3-(6”-p-
coumarylglucoside), which is also known as tiliroside

(Wirth 3-4 ¶¶ 0026-0027).
Appeal 2010-007491
Application 10/586,458

6
2. Wirth teaches that the “protective action of the cosmetic
formulations according to the invention against UV radiation and/or
oxidative stress can also be improved if the formulation comprises one or
more compounds selected from flavonoids and coumaranones in addition to
the compounds of the formula I” (Wirth 13 ¶ 0138).
3. Wirth teaches that of “the flavonoids, particular preference is
given to rutin” (Wirth 13 ¶ 0140).
4. Wirth teaches that the “compounds of the formula I can be
incorporated into cosmetic formulations in a conventional manner” (Wirth
14 ¶ 0155).
5. Miyake teaches to “enhance the solubility, dissolution rate, and
oral bioavailability of rutin by complexation with 2-hydroxypropyl-β-
cyclodextrin” (Miyake abstract).
6. Miyake teaches that the “usefulness of chemically modified
CyDs for improving the pharmaceutical properties of drugs, cosmetics, and
foods is well-demonstrated” (Miyake 400, col. 1).
7. Table I of Miyake is reproduced below:

Appeal 2010-007491
Application 10/586,458

7
“The apparent 1 : 1 stability constants (K), calculated from the initial
straight-line part of the solubility curves, are summarized in Table I”
(Miyake 402, Table I and 403, col. 1)
8. Miyake teaches that the “solubility of rutin increased linearly as
a function of the CyD concentration” (Miyake 403, col. 1). Miyake teaches
that the “stability constants increased in the order of α-CyD < HP-γ-CyD <
γ-CyD < G2-β-CyD < β-CyD < HP-β-CyD” (Miyake 403, col. 1).
9. Figure 4 of Miyake is reproduced below:

Figure 4 shows the “[d]issolution profiles of rutin or its β-CyD complexes in
water at 37°C, measured by dispersed amount method” (Miyake 403, col. 1).
10. The Wirth6 Declaration states that it “was not possible to
synthesize stable tiliroside beta-cyclodextrin compounds” (Wirth Dec. 1).
11. The Wirth Declaration states that “the inventive complex
compounds of tiliroside with gamma-cyclodextrin e.g. with hydroxypropyl-

6 Wirth Declaration, filed Feb. 19, 2008.
Appeal 2010-007491
Application 10/586,458

8
gamma-cyclodextrin, enhances the solubility of tiliroside in water more than
1000fold based on the observations of the supervised experiments” (Wirth
Dec. 4).
12. The Wirth Declaration states that the “complex showed
excellent water solubility until receiving a highly viscous honey like
solution. It was possible to solve at least 1000mg/ml tiliroside-
hydroxypropyl-gamma-cyclodextrine [sic] complex in water at 20°C, which
corresponds to 140mg/ml tiliroside. Tiliroside itself in [sic] not soluble in
water at 20°C (less than 0.05mg/ml)” (Wirth Dec. 4).
Principles of Law
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992). “The combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield
predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Prima facie obviousness can be rebutted by presenting evidence of
secondary considerations and when such evidence is submitted, all of the
evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472-
1473 (Fed. Cir. 1984). Secondary considerations include: long-felt but
unsolved needs, failure of others, unexpected results, commercial success,
copying, licensing, and praise. In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir.
1998); U.S. Surgical Corp. v. Ethicon, Inc., 103 F.3d 1554, 1565 (Fed. Cir.
1997).

Appeal 2010-007491
Application 10/586,458

9
Analysis
Wirth teaches conventional tiliroside cosmetic formulations that may
further incorporate flavonoids such as rutin (FF 1-4). Miyake teaches that
the “usefulness of chemically modified CyDs [cyclodextrins] for improving
the pharmaceutical properties of drugs, cosmetics, and foods is well-
demonstrated” (Miyaki 400, col. 1; FF 6).
Miyake teaches that the “solubility of rutin increased linearly as a
function of the CyD concentration” (Miyake 403, col. 1; FF 8). Miyake
specifically teaches six cyclodextrin compounds which enhance solubility,
with α-CyD having the least effect, HP-β-CyD having the greatest effect and
γ-CyD falling in the middle (FF 8).
We conclude that the combination of Wirth and Miyake reasonably
suggests the addition of cyclodextrins, and in particular the six named
cyclodextrin compounds in Miyake, to tiliroside, for the purpose of
increasing the solubility and other properties of tiliroside.
However, having found a prima facie case of obviousness, we must
now consider Appellants’ evidence of secondary considerations.
The Wirth Declaration states that it “was not possible to synthesize
stable tiliroside beta-cyclodextrin compounds” (Wirth Dec. 1; FF 10). The
Wirth Declaration states that “the inventive complex compounds of tiliroside
with gamma-cyclodextrin e.g. with hydroxypropyl-gamma-cyclodextrin,
enhances the solubility of tiliroside in water more than 1000fold based on
the observations of the supervised experiments” (Wirth Dec. 4; FF 11).
Thus, the Wirth Declaration provides two results which are reasonably
denominated as unexpected. First, the Wirth Declaration discloses that
Appeal 2010-007491
Application 10/586,458

10
stable tiliroside beta-cyclodextrin compounds could not be synthesized,
which undercuts the reasoning that all six cyclodextrins would have roughly
equivalent functionality apart from their differences in solubility (FF 10).
Second, the Wirth Declaration showed that tiliroside solubility was
enhanced by more than 1000 fold relative to the solubility of tiriloside alone
(FF 11). This differs from Miyake, who shows in Figure 4, that rutin alone
will dissolve, but that the addition of the β-cyclodextrin increases solubility
at saturation from about 0.5 x 104M to greater than 1 x 104M, a 2-fold
increase in solubility (FF 9). Thus, incorporation of the cyclodextrin as
taught by Miyake might suggest a 2-fold increase in solubility, so that the
1000 fold increase in solubility of tiriloside disclosed in the Wirth
Declaration represents an unexpected result (FF 11).
No rebuttal of this evidence of unexpected results from the Wirth
Declaration was found in the Examiner’s answer or the final rejection.
Conclusion of Law
(i) The evidence of record supports the Examiner’s conclusion that
Wirth and Miyake render prima facie obvious the claimed formulation.
(ii) The evidence of the Wirth Declaration demonstrates an
unexpected result sufficient to overcome the prima facie case of
obviousness.
B. and C. 35 U.S.C. § 103(a) over Wirth, Miyake and Rosenbloom or
Wollenberg
Neither of the obviousness rejections on dependent claims using the
Rosenbloom or Wollenberg references addresses or rebuts the unexpected
Appeal 2010-007491
Application 10/586,458

11
results shown for the independent claim 4. We reverse these rejections for
the reasons given above for the independent claim.

SUMMARY
In summary, we reverse the rejection of claims 2, 4, 9, 12, 13, 15, 19,
21, 22, and 24 under 35 U.S.C. § 103(a) as obvious over Wirth and Miyake.
We reverse the rejection of claims 4, 14, and 27 under 35 U.S.C. §
103(a) as obvious over Wirth, Miyake, and Rosenbloom.
We reverse the rejection of claims 4 and 26 under 35 U.S.C. § 103(a)
as obvious over Wirth, Miyake, and Wollenberg.

REVERSED

cdc
Appeal 2010-007491
Application 10/586,458

12
McCOLLUM, Administrative Patent Judge, dissenting.

I agree with my colleagues that the Examiner has set forth a prima
facie case of obviousness. However, I am not persuaded by the Declaration
evidence. Accordingly, I would affirm the obviousness rejections.

Additional Findings of Fact
14. The Wirth Declaration states that “the inventive complex . . .
enhances the solubility of tiliroside in water more than 1000fold,” but does
not state that this result would have been unexpected based on the teachings
in Miyake (Wirth Dec. 4).
15. Appellants’ attorney states that the 1000 fold increase in
solubility “is a significant unexpected advantage not expected from the
teachings of the prior art” (App. Br. 4). In support of this position,
Appellants’ attorney points to Miyake Figure 2 (id.).
16. Miyake Figure 2 demonstrates that the solubility of rutin
increases linearly with the concentration of γ-CyD and HP-γ-CyD
(Miyake 402).

Principles of Law
“If a prima facie case is made in the first instance, and if the applicant
comes forward with reasonable rebuttal, whether buttressed by experiment,
prior art references, or argument, the entire merits of the matter are to be
reweighed.” In re Hedges, 783 F.2d 1038, 1039 (Fed. Cir. 1986).
Appeal 2010-007491
Application 10/586,458

13
“[B]y definition, any superior property must be unexpected to be
considered evidence of non-obviousness. Thus, in order to properly evaluate
whether a superior property was unexpected, the [fact-finder] should have
considered what properties were expected.” Pfizer, Inc. v. Apotex, Inc., 480
F.3d 1348, 1371 (Fed. Cir. 2007) (citation omitted).
“Attorney’s argument in a brief cannot take the place of evidence.” In
re Pearson, 494 F.2d 1399, 1405 (CCPA 1974).

Analysis
As noted by the majority, the Wirth Declaration states that it “was not
possible to synthesize stable tiliroside beta-cyclodextrin compounds”
(FF 10). The majority finds that this “undercuts the reasoning that all six
cyclodexrins would have roughly equivalent functionality apart from their
differences in solubility” (Majority opinion, supra). However, Appellants
have not presented any evidence that, in view of this failure, one of ordinary
skill in the art would not have expected to be able to synthesize other stable
tiliroside cyclodexrins.
As also noted by the majority, the Wirth Declaration states that “the
inventive complex compounds of tiliroside with gamma-cyclodextrin e.g.
with hydroxypropyl-gamma-cyclodextrin, enhances the solubility of
tiliroside in water more than 1000fold” (FF 11). Appellants’ attorney states
that this would have been unexpected (FF 15). In support of this position,
Appellants point to Miyake Figure 2, which demonstrates that the solubility
of rutin increases linearly with the concentration of γ-CyD and HP-γ-CyD
(FF 15 & 16). However, I do not find Appellants’ attorney argument,
Appeal 2010-007491
Application 10/586,458

14
together with the evidence presented in Miyake Figure 2, sufficient to
convince me that the increase in solubility discussed in the Wirth
Declaration is unexpected.

Conclusion
In my opinion, the evidence in the Wirth Declaration is insufficient to
demonstrate an unexpected result sufficient to overcome the prima facie case
of obviousness. I would therefore affirm the rejections over Wirth and
Miyake, alone or in view of Rosenbloom or Wollenberg.

DISSENTING

MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON, VA 22201