Ex Parte Pickar

Board of Patent Appeals and Interferences

Jan 31, 2007

09808878 (B.P.A.I. Jan. 31, 2007)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte JAMES H. PICKAR
__________

Appeal 2006-3012
Application 09/808,878
Technology Center 1600
__________

HEARD December 14, 2006
__________

Before MILLS, GRIMES, and LINCK, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This appeal involves claims to a hormone replacement therapy for
menopausal women, which the examiner has rejected as obvious. We have
jurisdiction under 35 U.S.C. § 134. We affirm.
BACKGROUND
As “estrogens decline during the time preceding (perimenopause) and
following the menopause (postmenopause), various physiological changes
may result, including . . . vasomotor instability manifested as hot flushes.”
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Application No. 09/808,878

(Specification 1.) “Estrogen replacement therapy (ERT) is beneficial for
symptomatic relief of hot flushes.” (Id. at 2.)
ERT may increase the relative risk of endometrial cancer. (Id. at 3.)
“There are extensive clinical data showing that the relative risk of
endometrial cancer can be reduced by the addition of a progestin, either
sequentially or continuously.” (Id. at 4.) “Continuous combined hormone
replacement therapy (HRT) . . . has been shown to be effective in relieving
. . . vasomotor symptoms.” (Id.) PREMPRO is a commercially available
combination HRT product (id.) that contains 0.625 mg of conjugated equine
estrogens USP and 2.5 mg of medroxyprogesterone acetate (MPA) (id. at 5).
The specification discloses that administering either 0.45 mg or 0.3 mg
of conjugated equine estrogens (a.k.a. PREMARIN) in combination with 1.5
mg of MPA “reduce[s] the number and severity of hot flushes to the same
extent as the higher dose combination containing 0.625 mg PREMARIN plus
2.5 mg MPA.” (Id. at 9-10.) The specification characterizes this result as
unexpected. (Id. at 9, line 32.)
DISCUSSION
1. CLAIMS
Claims 7, 11, 12, and 69 are pending and on appeal. Claim 7, the only
independent claim, reads as follows:
7. A method of treating or inhibiting vasomotor symptoms in a
perimenopausal, menopausal, or postmenopausal woman in need thereof,
which comprises orally providing to said woman continuously and
uninterruptedly over the treatment period, a combination of conjugated
estrogens, USP and a daily dosage of about 1.5 mg of medroxyprogesterone
acetate, wherein the daily dosage of conjugated equine estrogens is between
about 0.45 mg and about 0.3 mg.

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Appellant has not argued the claims separately. Therefore, claims 11,
12, and 69 will stand or fall with claim 7. 37 CFR § 41.37(c)(1)(vii).
Claim 7 is directed to a method of hormone replacement therapy. The
claimed method comprises administering a daily dosage of about 1.5 mg of
MPA and about 0.3 to 0.45 mg of conjugated equine estrogens
“continuously and uninterruptedly over the treatment period.” The
specification defines “continuous and uninterrupted” to mean at least once-
daily administration with no break in the treatment regimen during the
treatment period. Page 7, lines 29-32.
2. OBVIOUSNESS
Claims 7, 11, 12, and 69 stand rejected under 35 U.S.C. § 103 as
obvious in view of Plunkett.1 The Examiner reasons that Plunkett “teaches a
method of treating hot flashes comprising administering continuously and
uninterruptedly both progestogen and estrogen in daily dosage units.”
(Answer, page 3.) The Examiner points out that Plunkett teaches the
specific combination of MPA and conjugated equine estrogens (CEE) and
teaches dosage ranges of 0.3 to 2.5 mg/day for CEE and 1 to 15 mg/day for
MPA. (Id.) The Examiner also characterizes as “preferred” Plunkett’s
disclosed dosages of 1 to 2.5 mg/day of MPA and 0.300 to 0.600 mg/day of
CEE. (Id., citing “claims 34-35 [sic, 32 and 35].”)
The Examiner acknowledges that Plunkett does not teach the specific
dosage combination recited in the instant claims, but concludes:
One of ordinary skill in the art would have been motivated to
employ conjugated equine estrogen/medroxyprogesterone in the

1 Plunkett et al., Re. 36,247, issued Jul. 6, 1999.
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specific dosages claimed herein in a method of treating hot
flashes because they (dosages herein) fall within the therapeutic
ranges of the conjugated equine estrogen/medroxyprogesterone
taught by the prior art. Optimization of amounts is within the
purview of the Skilled Artisan, and is therefore obvious absent
evidence to the contrary.

(Id. at 4.)
We agree with the Examiner that Plunkett’s teachings would have
made the method of claim 7 prima facie obvious. Plunkett does not
specifically disclose a method of controlling hot flushes by administering 1.5
mg/day of MPA in combination with 0.3 to 0.45 mg/day of CEE. However,
Plunkett teaches a method of controlling hot flushes (col. 3, ll. 51-53) by
“continuously and uninterruptedly administering a progestogen and an
estrogen” (col. 3, ll. 8-9). One “especially preferred combination[ ]” is
conjugated equine estrogen and medroxyprogesterone acetate (col. 6, l. 53;
col. 7, ll. 10-11), the same compounds recited in claim 7.
Plunkett discloses dosages of conjugated equine estrogens ranging
from a minimum of 0.300 mg/day to a maximum of 2.5 mg/day; 0.600
mg/day is disclosed as preferred (col. 4, l. 65). Plunkett discloses dosages of
MPA ranging from a minimum of 1 mg/day to a maximum of 15 mg/day;
2.5 mg/day is disclosed as preferred (col. 5, l. 50). Plunkett claims methods
involving administering less than the “preferred dosage” of MPA or
conjugated equine estrogens. See claim 32 (about 1 to about 2.5 mg/day
MPA); claim 35 (about 0.300 to about 0.600 mg/day CEE); and claim 42
(about 2.5 mg/day MPA and about 0.300 mg/day CEE). Thus, Plunkett
discloses dosage ranges for those compounds that encompass the dosages
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recited in claim 7 and teaches specific dosage ranges that are less than the
disclosed “preferred” dosages.
Finally, Plunkett teaches that patients should be given only as much
hormone as necessary to achieve the desired result (col. 4, ll. 1-5):
The actual unit dosages are selected according to conventionally
known methods, e.g. body weight of patient and biological
activity of the hormones, with the ultimate goal of producing the
desired result with the minimum quantities of hormones.

Thus, Plunkett directs those skilled in the art to use the minimum
dosage needed to produce the desired effect. We agree with the examiner
that these teachings would have suggested to those of ordinary skill in the art
a method of treating hot flushes by continuously administering about
1.5 mg/day of MPA in combination with about 0.3 to 0.45 mg/day of CEE;
i.e., the method recited in claim 7.
Appellant argues that Plunkett “does not provide any suggestion or
motivation to use the claimed lower dosage amount of CEE and MPA.” (Br.
6.) Appellant also argues that “one skilled in the art would have to perform
undue experimentation to arrive at Appellant’s particular low dose
combination among the vast possibilities contemplated by Plunkett.” (Id. at
7.) Along the same line, Appellant argues that those skilled in the art would
not have been led to optimize the dosages in Plunkett’s method because “in
designating the preferred amounts, Plunkett et al. taught that those particular
amounts were the optimal amounts.” (Reply Br., page 3.)
This argument is not persuasive. While Plunkett discloses that a
variety of estrogens and progestogens would be suitable for use in the
disclosed method, it describes the specific combination of CEE and MPA as
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especially preferred. It also provides specific dosage ranges for both CEE
and MPA, and the disclosed dosage ranges encompass the dosages recited in
claim 7. Finally, Plunkett directs the skilled artisan to the lower part of the
disclosed dosage ranges, in its direction to use the minimum amount of
hormones necessary to produce the desired result (col. 4, ll. 1-5) and in its
description of specific dosage ranges that are less than the disclosed
“preferred” dosages (claims 32, 35, and 42).
We do not agree with Appellant that those skilled in the art would
have considered Plunkett’s “preferred” dosages to be the optimal dosages.
Plunkett discloses a range of dosages for each hormone to be used in the
disclosed method and teaches that the actual dosages are selected according
to conventional methods, based on factors including the body weight of the
patient and the biological activity of the hormone. Plunkett specifically
claims methods that comprise administering less than the “preferred”
dosages of both MPA (claim 32) and CEE (claims 34 and 42). Thus, we do
not agree with Appellant’s implicit assertion that the only dosage disclosed
by Plunkett that those skilled in the art would have found obvious to use is
the single dosage described as “preferred.”
Appellant also argues that those skilled in the art would have
understood from Plunkett that the “preferred” dosages were thought to be the
minimum effective doses. (Reply Br. 4-5.) Appellant cites the Second Lobo
Declaration as providing evidence that the preferred dosages disclosed by
Plunkett would have been considered the minimum effective dosages. (Br.
8-9; Reply Br. 4-5.) Appellant argues that “[a]ccordingly, the teachings of
the prior art and the knowledge generally available in the art would not have
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suggested to those skilled in the art that the use of 1.5 mg MPA in
combination with about 0.3 to about 0.45 mg CEE would have been
reasonably successful in providing relief of vasomotor symptoms of
menopause.” (Br. 8.)
The evidence of record does not support Appellant’s position that
those skilled in the art would have expected the lower dosages of MPA and
CEE disclosed by Plunkett to be unsuccessful in controlling hot flushes. The
Second Lobo Declaration does not support the weight Appellant puts on it.
In that declaration, Dr. Lobo declares that “[f]or the past 20 years, the
dosage of 0.625 mg CEE has been accepted as the minimum dosage of
estrogen necessary to relieve the symptoms of menopause, including hot
flushes and bone loss.” ¶ 2. As support for this statement, Dr. Lobo cites
Sobel2 and Kronenberg.3 These references, however, do not state that 0.625
mg/day of CEE was accepted as the minimum effective dosage.
Sobel states that the standard dose of conjugated estrogens was 0.625
mg (page 313). Kronenberg states that the “most commonly used regimen
for treating hot flashes in the United States is 0.625 to 1.25 mg of oral
conjugated equine estrogens (Premarin)” (page 109, emphasis added). A
dose that is “standard” or a regimen that is “most commonly used,”
however, is not necessarily the same as a dosage or regimen that is
considered the minimum effective dose. Rather, a standard or most

2 Sobel, “Progestins in preventative hormone therapy,” Obstetrics and
Gynecology Clinics of North America, Vol. 21, No. 2, pp. 299-319 (1994).
3 Kronenberg, “Chap. 9 Hot Flashes,” in Treatment of the Postmenopausal
Woman: Basic and Clinical Aspects, R.A. Lobo (ed.), Raven Press, NY, pp.
97-117 (1994).
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commonly used dosage represents a commercially marketed product that is
designed to be administered to many patients. A dosage intended for
administration to many patients would necessarily contain a dosage that is
large enough to be effective in a large majority of patients but not so much
as to cause side effects or complications in a significant number. As taught
by Plunkett, the minimum effective dosage is determined patient-by-patient
and depends on factors including the body weight of an individual patient.
In addition, the method of claim 7 only requires administration of
CEE and MPA to control hot flushes (“vaosmotor symptoms”). Dr. Lobo’s
declaration, by contrast, addresses the amount of hormones allegedly
thought necessary “to relieve the symptoms of menopause, including hot
flushes and bone loss.” ¶ 2. The amount of hormones required to alleviate
hot flushes is not necessarily the same as the amount required to alleviate all
of the symptoms of menopause, including bone loss.
Finally, the evidence of record includes Utian.4 Utian states that
“[n]umerous small studies of short duration have found lower doses of
various estrogens to be effective in reducing the number and severity of hot
flushes, the effect being almost as great as that seen with the most
commonly prescribed HRT doses.” (Page 1066, left-hand column.) Utian
was published after the effective filing date asserted for the present
application but cites at least three prior art references in support of the
quoted statement.

4 Utian et al., “Relief of vasomotor symptoms and vaginal atrophy with
lower doses of conjugated equine estrogens and medroxyprogesterone
acetate,” Fertility and Sterility, Vol. 75, p. 1065-1079 (2001). The
co-authors of Utian include inventor James H. Pickar.
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In summary, after considering all of the evidence of record, we find
that the weight of the evidence does not support Dr. Lobo’s assertion that
0.625 mg/day of CEE was considered the minimum daily dosage required to
control hot flushes at the time the claimed method was made.
Dr. Lobo also states that the “dosage of 2.5 mg of MPA has been
recognized as the minimum amount needed to oppose 0.625 mg CEE and
protect the endometrium.” ¶ 2. No evidence is cited to support this
assertion but regardless of its accuracy, Dr. Lobo’s declaration does not
address what dosages of MPA would have been expected to be necessary to
oppose CEE at the lower dosages suggested by Plunkett – 0.3 to 0.6 mg/day.
Appellant also asserts that he has provided evidence of unexpected
results to rebut any prima facie case of obviousness. (Br. 9-12; Reply Br.
5-8.) Appellant points to Dr. Lobo’s discussion of the “Women’s Health,
Osteoporosis, Progestin, Estrogen (H.O.P.E.)” study and the results of that
study that are reproduced in the instant specification. In his first declaration,
Dr. Lobo states:
I and others expected that the study would show that there
would be a dose response such that the lower combination
doses of CEE and MPA would have some effect in reducing the
number and severity of hot flushes compared with the placebo,
but far less of an effect than the standard dose of CEE 0.625
[mg] plus 2.5 mg MPA. In fact, I and others were interested in
seeing the results of the various lower doses, but doubted the
study was worth the economic effort.

(First Lobo Declaration, ¶ 12.) Dr. Lobo states that “[i]t was very surprising
and unexpected” that a daily dosage of 1.5 mg MPA combined with 0.3 or
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0.45 mg CEE reduced the number and severity of hot flushes to the same
extent as 2.5 mg MPA combined with 0.625 mg CEE. (Id. at ¶ 14.)
We do not find Dr. Lobo’s declarations to outweigh the evidence of
obviousness. Dr. Lobo’s statements may reflect his own state of mind, but
the determination of obviousness is not based on the expectations of any
single individual.5 Rather, obviousness under § 103 is determined based on
the expectations of a hypothetical person of ordinary skill in the art fully
aware of the state of the prior art. See In re Rouffet, 149 F.3d 1350, 1357, 47
USPQ2d 1453, 1457 (Fed. Cir. 1998) (“Obviousness is determined from the
vantage point of a hypothetical person having ordinary skill in the art to
which the patent pertains. . . . The legal construct also presumes that all prior
art references are available to this hypothetical skilled artisan.”).
Here, the evidence of record shows that such a person would not have
found the results shown in the specification to be unexpected. Utian reports
the results of the HOPE study. The results shown in Utian’s Figure 1B and
Figure 3B appear to correspond to those shown in the instant specification,
page 9, lines 15-20 and 20-25, respectively. Utian states that the results of
the HOPE study “showed that lower-dosage combinations of CEE and
CEE/MPA were effective in decreasing the number and severity of hot
flushes. . . . In general, the lower-dosage combinations, especially CEE
0.45/MPA 1.5 and CEE 0.3/MPA 1.5, were as effective for symptom relief

5 We do not find credible Dr. Lobo’s statement that his expectations were
shared by “others” because Appellant has provided no evidence to support
that statement.
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as the most commonly prescribed dosage combination of CEE and MPA.”
(Page 1073, right-hand column.)
Importantly, Utian expresses no surprise at this result: “These
findings are consistent with results of previous studies that examined the
efficacy of lower estrogen dosages for relief of vasomotor symptoms. . . .
The results reported here are especially relevant because they confirm the
effectiveness of lower doses of CEE and MPA . . . in the context of a large
clinical trial.” (Paragraph bridging pages 1073 and 1074, emphases added.)
Thus, Utian provides evidence that a person of ordinary skill in the art
in the field of hormone replacement therapy would have been aware of
“numerous small studies” showing that low doses of estrogen had been
shown to be effective in treating hot flushes. Utian also provides evidence
that a person of ordinary skill in the art would have found the results of the
HOPE study – and the results reported in the instant specification – to be not
unexpected but “consistent with results of previous studies”; in other words,
expected.
Appellant also argues that “the H.O.P.E. study further unexpectedly
showed an additive effect of MPA at low doses.” (Br. 10, citing the First
Lobo Declaration.) In that declaration, Dr. Lobo declares that the “H.O.P.E.
study demonstrated that dosages of CEE and MPA may be better than
equivalent dosages of unopposed CEE for vasomotor symptom relief.” ¶ 15.
This result is said to be unexpected because “[p]revious studies with various
dosages of CEE showed no additive effect of MPA on vasomotor relief.” Id.
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(citing Greendale6). Thus, Dr. Lobo declares that the “H.O.P.E. study
surprisingly demonstrated that at these low doses [1.5 mg MPA plus 0.3 or
0.45 mg CEE] MPA may contribute to ameliorating the vasomotor
symptoms.” Id.
We do not find the additive effect of MPA on vasomotor symptoms,
in combination with low doses of estrogen, to overcome the prima facie case
of obviousness. It is true that Greendale reports that MPA does not
contribute to reducing vasomotor symptoms when administered in
combination with 0.625 mg of CEE. See, e.g., page 986, last paragraph. It
is also true that Utian reports that the results of the HOPE study “suggest
that lower doses of CEE combined with MPA may be better than equivalent
lower doses of unopposed CEE for vasomotor symptom relief.” Page 1074,
left-hand column. Thus, this result of the HOPE study might well have been
unexpected in comparison to the earlier PEPI study reported by Greendale.
Unexpected results, however, must be established in comparison to
the closest prior art. See In re Baxter-Travenol Labs., 952 F.2d 388, 392, 21
USPQ2d 1281, 1285 (Fed. Cir. 1991).
Here, Greendale is not the closest prior art. The embodiment in the
prior art that is closest to the claimed method is that of Plunkett’s claim 42:
2.5 mg of MPA combined with 0.3 mg of CEE. Thus, the relevant question
is not whether the combination of claim 7 (1.5 mg MPA and 0.3 - 0.45 mg
CEE) is unexpectedly superior to 0.3 - 0.45 mg CEE alone. The relevant

6 Greendale et al., “Symptom relief and side effects of postmenopausal
hormones: Results from the Postmenopausal Estrogen/Progestin
Interventions Trial,” Obstetrics & Gynecology, Vol. 92, pp. 982-988 (1998).
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question is whether the combination of claim 7 is unexpectedly superior to
the prior art combination of 2.5 mg MPA and 0.3 mg CEE. Appellant’s
evidence provides no comparison to the closest prior art and therefore shows
no unexpected properties compared to the closest prior art.
SUMMARY
The reference relied on by the examiner shows that claim 7 would
have been prima facie obvious to those of ordinary skill in the art.
Appellant’s evidence does not outweigh the evidence of obviousness. We
affirm the rejection of claim 7. Claims 11, 12, and 69 fall with claim 7.

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 CFR § 1.136(a).

AFFIRMED

DEMETRA J. MILLS )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
ERIC GRIMES )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
NANCY J. LINCK )
Administrative Patent Judge )
EG
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