Ex Parte Thompson et al

Board of Patent Appeals and Interferences

Jun 26, 2009

10767431 (B.P.A.I. Jun. 26, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte DANIEL J. THOMPSON, ELIO P. MARIANI,
R. SAUL LEVINSON, and HERBERT G. LUTHER
__________

Appeal 2009-001973
Application 10/767,431
Technology Center 1600
__________

Decided:1 June 26, 2009
__________

Before TONI R. SCHEINER, DONALD E. ADAMS, and
LORA M. GREEN, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s final rejection of claims 1-27. We have jurisdiction under 35
U.S.C. § 6(b).

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).

Appeal 2009-001973
Application 10/767,431

STATEMENT OF THE CASE
The claims are directed to a method of treating a vulvovaginal
candidiasis. Claims 1 and 9 are representative of the claims on appeal, and
read as follows:
1. A method for the local treatment of a vulvovaginal candidiasis, which
comprises:
treating said vulvovaginal candidiasis condition caused by a species of
Candida selected from the group consisting of dubliniensis, tropicalis,
glabrata, parapsilosis, krusei, and lusitaniae by applying to the vaginal
tissue of a human a formulation comprising:
about 35 to about 45% w/w sorbitol solution; about 3 to about 8%
w/w propylene glycol; about 0.001 to about 1% w/w edetate disodium; about
5 to about 11% w/w mineral oil; about 0.5 to about 5% w/w polyglyceryl-3-
oleate; about 0.5 to about 5% w/w glyceryl monoisostearate; about 0.001 to
about 1% w/w microcrystalline wax; about 0.5 to about 2% w/w silicon
dioxide; about 0.001 to about 1 % w/w methylparaben; about 0.001 to about
1% wlw propylparaben; about 25 to about 45% w/w water; and about 0.5 to
about 5% w/w butoconazole nitrate; and wherein the treatment is a single
dose treatment.

9. A method for the treatment of an unidentified vulvovaginal fungal
condition, which comprises:
administration to said fungal condition a bioadhesive, single dose
treatment formulation comprising from about 0.500 to about 5.000% w/w
butoconazole nitrate; and
wherein the unidentified vulvovaginal fungal condition is caused by a
Candida species selected from the group consisting of dubliniensis,
tropicalis, glabrata, parapsilosis, krusei, and lusitaniae.

The Examiner relies on the following evidence:
Riley, Jr. US 5,266,329 Nov. 30, 1993
Chen US 6,267,985 B1 Jul. 31, 2001

Stedman’s Medical Dictionary, 24th Edition, Williams & Wilkins, 394
(1982).
2
Appeal 2009-001973
Application 10/767,431

William Droegemueller, M.D. et al., “Three-Day Treatment with
Butuconazole Nitrate for Vulvovaginal Candidiasis,” 64(4) Obstetrics &
Gynecology, 530-534 (Oct. 1984).

Dale Brown, M.D., et al., “Butoconazole Nitrate 2% for Vulvovaginal
Candidiasis-New, Single-Dose Vaginal Cream Formulation vs. Seven Day
Treatment with Miconazole Nitrate,” 44(11) The Journal of Reproductive
Medicine 933-938 (Nov. 1999).

Sanjay Garg et al., “Compendium of Pharmaceutical Excipients for
Vaginal Formulations,” Pharmaceutical Technology 14-24 (2001).

Appellants rely on the following evidence:
M.E. Lynch et al., “Comparative in vitro activity of antimycotic
agents against pathogenic vaginal yeast isolates,” 32 Journal of Medical and
Veterinary Mycology, 267-274 (1994).

Sobel JD. et al., “Treatment of Complicated Candida vaginitis:
Comparison of single and sequential doses of fluconazole,” 185 (2) Am J
Obstet Gynecol 363-9 (Aug. 2001) (Abstract Only).

Sobel JD., “Antimicrobial Resistance in Vulvovaginitis,” 3(6) Curr
Infect Dis Rep 546-9 (Dec. 2001) (Abstract Only).

Moosa MY et al., “Non-albicans Candida infections in patients with
hermatologic malignancies,” 17(2) Semin Respir Infect 91-8 (Jun. 2002)
(Abstract Only).

Sobel JD., “Treatment of vaginal Candida infections,” 3(8) Expert
Opinion Pharmacother, 1059-65 (Aug. 2002) (Abstract Only).

Paul Nyirjesy et al., “Vaginal Candida parapsilosis: Pathogen or
bystander?,” 13(1) Infectious Diseases in Obstetrics and Gynecology 37-41
(March 2005).

3
Appeal 2009-001973
Application 10/767,431

The following grounds of rejection are before us for review:
Claims 9 and 24-27 stand rejected under 35 U.S.C. § 102(b) as being
anticipated by Brown; and
Claims 1-27 stand rejected under 35 U.S.C. § 103(a) as being obvious
over the combination of Riley, Brown, Garg, Droegemueller, and Chen.
We reverse the anticipation rejection, but affirm the obviousness
rejection.

ISSUE (Anticipation)
The Examiner finds that claims 9 and 24-27 are anticipated by Brown.
Appellants contend that Brown does not anticipate a method for the
treatment of an unidentified vulvovaginal fungal condition wherein the
unidentified vulvovaginal fungal condition is caused by a Candida species
selected from the group consisting of dubliniensis, tropicalis, glabrata,
parapsilosis, krusei, and lusitaniae.
Thus, the issue on appeal is: Have Appellants demonstrated that the
Examiner erred in finding that Brown teaches a method for the treatment of
an unidentified vulvovaginal fungal condition wherein the unidentified
vulvovaginal fungal condition is caused by a Candida species selected from
the group consisting of dubliniensis, tropicalis, glabrata, parapsilosis,
krusei, and lusitaniae?

4
Appeal 2009-001973
Application 10/767,431

FINDINGS OF FACT
FF1 According to the Specification, the “present invention is directed to
methods of treatment of a nonspecified Candida species isolate using
antimycotic delivery systems.” (Spec. 1.)
FF2 The Specification teaches that “[v]ulvovaginitis is a common disorder
that can affect females of all ages” that “encompasses a variety of disorders
characterized by inflammation that may be secondary to multiple causes,
including infection, irritation, allergy, and systemic disease.” (Id. at 2.)
FF3 In women of childbearing age, the Specification teaches that
vulvovaginitis is usually cause by bacterial vaginosis, Trichomonas species
and/or Candida species (id.). The Candida species that most often causes
vulvovaginitis is Candida albicans, but vulvovaginitis may also be caused
by Candida glabrata or Candida tropicalis (id.).
FF4 The Specification exemplifies a preparation of a formulations
according to the invention (id. at 19 and 21), but provides no data as to the in
vivo clinical efficacy of the formulations.
FF5 The Examiner rejects claims 9 and 24-27 under 35 U.S.C. § 102(b) as
being anticipated by Brown (Ans. 3).
FF6 The Examiner finds that Brown teaches “the use of a single dose
cream formulation of 2% butoconazole nitrate for vulvovaginal candidiasis.”
(Id.)
FF7 The Examiner finds further that Brown teaches of the 150 known
species of Candida, nine are pathogenic in humans, i.e., the albicans,
glabrata, tropicalis, pseudotropicalis, lusitaniae, crusei, rugosa,
parapsilosis, and guilliermondi species (id. at 3-4).
5
Appeal 2009-001973
Application 10/767,431

FF8 The Examiner finds further that Brown teaches that 10-20% of
vulvovaginal candidiasis are not caused by C. albicans, thus “[s]imply
because Brown [ ] did not test for the presence of other fungal species of
Candida, does not mean that they were not present especially in light of the
fact that 10-20% of the cases are caused by non-albicans Candida species.”
(Id. at 9.)
FF9 Thus, the Examiner finds that treatment of other Candida species is
inherent in the method of Brown (id.).
FF10 The objective of Brown is to “compare the safety and efficacy of a
single vaginal dose of a butaconazole nitrate 2% bioadhesive, sustained
release cream (butoconazole 1-BSR) with a seven-day schedule of
micanazole nitrate vaginal cream 2%.” (Brown, Abstract.)
FF11 Brown found that “[b]utaconazole 1-BSR rapidly relieved the signs
and symptoms of vulvovaginal candidiasis.” (Id.)
FF12 In the clinical study performed by Brown, patients were tested for the
presence of C. albicans, and those with “negative initial fungal cultures were
withdrawn from the study.” (Id. at 935, second column.) In addition, the
microbiologic cure was measured by absence of C. albicans in fungal
cultures (id. at 936, first column).
FF13 Brown does teach, however, that there are 150 known species of
Candida, of which about nine are pathogenic in humans, including the
albicans, glabrata, tropilcalis, psuedotropilcalis, lusitaniae, crusei, rugosa,
parapsilosis, and guilliermondi (id. at 934, first column).
FF14 Brown notes that C. albicans is responsible for the development of
vulvovaginal candididiasis in 80-92% of the cases, but that there has been an
6
Appeal 2009-001973
Application 10/767,431

increase in non-C. albicans vulvovaginal candididiasis, which is of concern
(id.). Brown also notes that C. glabrata is the second most encountered
species, and “is considered to be less susceptible to standard treatment.”
(Id.)
FF15 Brown teaches that Butoconozole was chosen for the one dose-
treatment because of “its highly acceptable safety profile and proven clinical
efficacy,” and “its broad antifungal spectrum, consistently showing high
activity against the most important eight non-albicans Candida species.”
(Id. at 934, second column.)
FF16 Brown also notes that while “in vitro susceptibility cannot always be
extrapolated into clinical results, in vitro tests predicted clinical failure of
flucanazole and tercanazole with respect to C. glabrata and Saccharomyces
cerevisiae.” (Id.)

PRINCIPLES OF LAW
“It is well settled that a claim is anticipated if each and every
limitation is found either expressly or inherently in a single prior art
reference.” Celeritas Techs. Ltd. v. Rockwell Int’l Corp., 150 F.3d 1354,
1361 (Fed. Cir. 1998).
We note, however
Inherency . . . may not be established by probabilities or
possibilities. The mere fact that a certain thing may result from
a given set of circumstances is not sufficient. If, however, the
disclosure is sufficient to show that the natural result flowing
from the operation as taught would result in the performance of
the questioned function, it seems to be well settled that the
disclosure should be regarded as sufficient.

7
Appeal 2009-001973
Application 10/767,431

In re Oelrich, 666 F.2d 578, 581 (CCPA 1981)(quoting Hansgirg v.
Kemmer, 102 F.2d 212, 214 (CCPA 1939)) (internal citations
omitted).

ANALYSIS
Appellants argue that independent claims 9 and 24 are directed to a
method of treating an unidentified vulvovaginal fungal condition, wherein
the condition is caused by a Candida species selected from the group
consisting of dubliniensis, tropicalis, glabrata, parapsilosis, krusei, and
lusitaniae (App. Br. 14). Brown, Appellants assert, does not teach treatment
of those Candida species, but only Candida albicans, as the patients studied
were strictly chosen on the basis of the presence of C. albicans (id. at 16-
17). Thus, Appellants assert, “[n]owhere in Brown [ ] is it expressly or
inherently taught that any one of the 101 patients tested positive for a
condition caused by a species of Candida selected from the group
consisting of C. dubliniensis, C. tropicalis, C. glabrata, C. parapsilosis, C.
krusei, C. lusitaniae or that the same could be treated.” (Id. at 17.)
We find that Appellants have the better position. While we agree with
the Examiner that there is a possibility that the sample patient population
were infected with a second Candida species, such as dubliniensis,
tropicalis, glabrata, parapsilosis, krusei, and lusitaniae, inherency may not
be established by probabilities or probabilities. Although Brown was aware
of other pathogenic species of Candida, only those patients who tested
positive for the albicans species were admitted to the study, and
8
Appeal 2009-001973
Application 10/767,431

microbiologic cure was measured by absence of the albicans species in
fungal cultures.

CONCLUSION(S) OF LAW
We thus find that Appellants have demonstrated that the Examiner
erred in finding that Brown teaches a method for the treatment of an
unidentified vulvovaginal fungal condition wherein the unidentified
vulvovaginal fungal condition is caused by a Candida species selected from
the group consisting of dubliniensis, tropicalis, glabrata, parapsilosis,
krusei, and lusitaniae.
The rejection of claims 9 and 24-27 under 35 U.S.C. § 102(b) as being
anticipated by Brown is therefore reversed.

ISSUE (Obviousness)
The Examiner concludes that claims 1-27 are rendered obvious by the
combination of Riley, Brown, Garg, Droegemueller, and Chen.
Appellants contend that the combination as set forth by the Examiner
does not teach or suggest a method for the treatment of an unidentified
vulvovaginal fungal condition wherein the unidentified vulvovaginal fungal
condition is caused by a Candida species selected from the group consisting
of dubliniensis, tropicalis, glabrata, parapsilosis, krusei, and lusitaniae; and
that the Examiner used improper hindsight in combining the references.
Thus, the issue on appeal is: Have Appellants demonstrated that the
Examiner erred in concluding that Riley, Brown, Garg, Droegemueller, and
Chen, as combined, teach or suggest a method for the treatment of an
9
Appeal 2009-001973
Application 10/767,431

unidentified vulvovaginal fungal condition wherein the unidentified
vulvovaginal fungal condition is caused by a Candida species selected from
the group consisting of dubliniensis, tropicalis, glabrata, parapsilosis,
krusei, and lusitaniae; and/or that the Examiner erred in using improper
hindsight in combining the references?

FINDINGS OF FACT
FF17 The Examiner rejects claims 1-27 under 35 U.S.C. § 103(a) as being
obvious over the combination of Riley, Brown, Garg, Droegemueller, and
Chen (Ans. 4-8).
FF18 The Examiner addresses each of the Graham factors in reaching the
determination of obviousness (id.).
FF19 Specifically, as to the limitation at issue, the Examiner cites Riley for
teaching “a vaginal fungal infection wherein the active antimicrobial agent is
an imidazole agent.” (Id. at 6.)
FF20 The Examiner relies on Brown for its teachings as set forth in the
anticipation rejection (id.).
FF21 The Examiner cites Garg for its teaching of pharmaceutical excipients
for vaginal formulations (id.).
FF22 The Examiner cites Droegemueller for its teaching that “one dose of
2 % butoconazole nitrate vaginal cream results in a maximum plasma level
24 hours after dosing.” (Id.)
FF23 Chen is cited by the Examiner for teaching “improved delivery of
therapeutic agents, including anti-fungal agents, such as butoconazole, in a
composition comprising polyglyceryl 2-4 oleate.” (Id. at 7.)
10
Appeal 2009-001973
Application 10/767,431

FF24 The Examiner concludes that it would have been obvious to use the
formulations as required by the claimed methods as Riley suggests the use of
imadazole as the anti-fungal in the formulations, and Brown demonstrates
the effectiveness of butaconazole administered as a single dose (id. at 7-8).
FF25 Appellants have submitted a number of Abstracts from Sobel, without
submitting the underlying documents.
FF26 However, for example, one Abstract, Sobel (Expert Opinion in
Pharmacotherpy 2002), states that “vaginitis due to Candida glabrata is
associated with a high treatment failure rate,” and that “considerable
limitations in available therapy exist in the effective management of
complicated vaginitis.”
FF27 Lynch, relied upon by Appellants, looks at the in vitro activity of
antimyotic agents against pathogenic vaginal yeast isolates (Lynch, Title).
FF28 Lynch found that butoconazole had a “consistently high level of
activity . . . against virtually all isolates tested.” (Lynch, 273.)
FF29 Lynch acknowledged that “in vitro susceptibility cannot be
extrapolated into predicting in vivo activity or clinical success,” but that “in
vitro sensitivity tests performed on C. glabrata and S. cervisae were useful
in predicting clinical failure with TER and FLU and moderate success with
CLO.” (Id.)
FF30 Lynch further acknowledges the need “for further investigation of the
role of BUTO [butoconazole] and ITRA in experimental and clinical
vaginitis, especially when caused by non-albicans species.” (Id.)
11
Appeal 2009-001973
Application 10/767,431

FF31 Nyirjesy was published in March 2005, which was after the instant
filing date of January 30, 2004, and thus is not evidence of the state of the
art at the time of filing.

PRINCIPLES OF LAW
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
In KSR Int’l v. Teleflex Inc., 550 U.S. 398, 415 (2007), the Supreme
Court rejected a rigid application of a teaching-suggestion-motivation test in
the obviousness determination. The Court emphasized that “the
[obviousness] analysis need not seek out precise teachings directed to the
specific subject matter of the challenged claim, for a court can take account
of the inferences and creative steps that a person of ordinary skill in the art
would employ.”Id. at 418. Thus, an “[e]xpress suggestion to substitute one
equivalent for another need not be present to render such substitution
obvious.” In re Fout, 675 F.2d 297, 301 (CCPA 1982).
Further,
[i]f a person of ordinary skill can implement a predictable
variation, § 103 likely bars its patentability. For the same
reason, if a technique has been used to improve one device, and
a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using the
technique is obvious unless its actual application is beyond his
or her skill.

12
Appeal 2009-001973
Application 10/767,431

KSR, 550 U.S. at 417. It is proper to “take account of the inferences and
creative steps that a person of ordinary skill in the art would employ.” Id. at
418. See also id. at 421 (“A person of ordinary skill is also a person of
ordinary creativity, not an automaton.”).
“When there is a design need or market pressure to solve a problem
and there are a finite number of identified, predictable solutions, a person of
ordinary skill has good reason to pursue the known options within his or her
technical grasp. If this leads to the anticipated technical success, it is likely
the product not of innovation but of ordinary skill and common sense.” Id.
at 421.
Moreover, obviousness is determined in from the context of a person
of ordinary skill in the art at the time the invention was made. “[T]he level
of skill in the art is a prism or lens through which a judge, jury, or the Board
views the prior art and the claimed invention. This reference point prevents
these factfinders from using their own insight or, worse yet, hindsight, to
gauge obviousness.” Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir.
2001), (citation omitted). Therefore, the evidence of record must be viewed
through the lens of a person of ordinary skill in the art with consideration of
common knowledge and common sense. Graham, 383 U.S. at 17-18;
DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464
F.3d 1356, 1367 (Fed. Cir. 2006).

ANALYSIS
Appellants argue that the references as combined do not teach all of
the elements of the claimed method. As to Riley, Appellants contend that
13
Appeal 2009-001973
Application 10/767,431

the patent teaches the use of the formulations in the treatment of C. albicans,
but not a Candida selected from dubliniensis, tropicalis, glabrata,
parapsilosis, krusei, and lusitaniae (App. Br. 26). Appellants argue, that as
discussed with respect to the anticipation rejection, Brown does not remedy
that deficiency, and nor does Grag, Droegmueller, or Chen (id. at 27-29).
Appellants argue further that the Examiner has engaged in
impermissible hindsight in combining the references to arrive at the claimed
method (App. Br. 22). Appellants assert that the “teachings of Brown [ ] as
evidenced by the additional publications of J.D. Sobel, demonstrate that
Brown [ ] were unaware of a viable method for effectively treating the non-
albicans Candida species.” (Id. at 23.) According to Appellants, the
attached Sobel abstracts “relate to treatment of the different Candida species
using various active agents in order to determine efficacy,” demonstrating
that “much remained unknown at the time Brown [ ] was written.” (Id.)
Appellants further rely on Lynch, which was cited by Brown, for its
teaching that there have been few studies comparing the in vitro activity of
azoles against non-C. albicans species, as well as the clinical outcome in
animal models or patients, and for its teaching that more work needed to be
done to investigate the role of azoles such as butaconazole in experimental
and clinical vaginitis, especially when not caused by C. albicans (id. at 24).
Appellants also rely on Nyirjesy, filed after the filing date of the instant
application, for its teaching that it was unclear whether non-C. albicans
species caused vulvovaginal symptoms (id. at 24-25). Thus, Appellants
assert, in view of the above cited references, “a person of ordinary skill in
14
Appeal 2009-001973
Application 10/767,431

the art could only arrive at the presently pending subject matter by way of
impermissible hindsight.” (Id. at 25.)
We conclude that the obviousness rejection stands on a different
footing than the anticipation rejection. Although Brown does not
specifically teach testing for any pathogenic Candida species other than
albicans, Brown clearly teaches that other pathogenic Candida species were
known to cause vulvovaginal candidiasis, including those claimed by
Appellants, i.e., dubliniensis, tropicalis, glabrata, parapsilosis, krusei, and
lusitaniae. Brown also teaches that that butoconozole was chosen for the
one dose-treatment because of “its highly acceptable safety profile and
proven clinical efficacy,” and “its broad antifungal spectrum, consistently
showing high activity against the most important eight non-albicans
Candida species.” (FF15.) Thus, Brown clearly suggests treating
vulvovaginal candidiasis caused by non-albicans Candida species, such as
those claimed in the instant methods, with a one-dose treatment of
butoconozole.
We have considered the Sobel abstracts submitted by Appellants, and
we do not find that they teach otherwise. For example, while Sobel (Expert
Opinion in Pharmacotherpy 2002), states that “vaginitis due to Candida
glabrata is associated with a high treatment failure rate,” and that
“considerable limitations in available therapy exist in the effective
management of complicated vaginitis” (FF26), the claims are not limited to
the treatment of C. glabrata. In addition, Lynch, also cited by Appellants
teaches that butoconazole had a consistently high level of activity against
virtually all the Candida isolates tested. Although both Brown and Lynch
15
Appeal 2009-001973
Application 10/767,431

acknowledge that in vitro activity is not absolutely predictive of in vivo
activity, all that is required is a reasonable expectation of success, not
absolute predictability. In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).
Moreover, both Brown and Lynch teach that in vitro tests predicted clinical
failure of flucanazole and tercanazole with respect to C. glabrata and
Saccharomyces cerevisiae (FF16, FF29). Given those teachings, along with
Brown’s success in treating C. albicans with a one-dose treatment of
butoconazole, as well as both Brown’s and Lynch’s teaching that
butacanazole has a high level of activity against Candida species other than
albicans, we conclude that the ordinary artisan would have had a reasonable
expectation of success of treating the Candida species of dubliniensis,
tropicalis, glabrata, parapsilosis, krusei, and lusitaniae, with a one-dose
treatment of butoconazole, as required by the instant method claims.
Appellants’ reliance on the teachings of Nyirjesy does not convince us
otherwise, as that reference was published after the instant filing date, and
obviousness is determined as of the filing date.

CONCLUSIONS OF LAW
We conclude that Appellants have not demonstrated that the Examiner
erred in concluding that Riley, Brown, Garg, Droegemueller, and Chen, as
combined, teach or suggest a method for the treatment of an unidentified
vulvovaginal fungal condition wherein the unidentified vulvovaginal fungal
condition is caused by a Candida species selected from the group consisting
of dubliniensis, tropicalis, glabrata, parapsilosis, krusei, and lusitaniae; or
16
Appeal 2009-001973
Application 10/767,431

that the Examiner erred in using improper hindsight in combining the
references.
We thus affirm the rejection of claims 1-27 under 35 U.S.C. § 103(a)
as being obvious over the combination of Riley, Brown, Garg,
Droegemueller, and Chen.
SUMMARY
The rejection of claims 9 and 24-27 under 35 U.S.C. § 102(b) as being
anticipated by Brown is reversed; and
The rejection of claims 1-27 under 35 U.S.C. § 103(a) as being
obvious over the combination of Riley, Brown, Garg, Droegemueller, and
Chen, is affirmed.

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

Ssc:
KV PHARMACEUTICAL COMPANY
ONE CORPORATE WOODS DRIVE
BRIDGETON, MO 63044

17