Ex Parte Masini-Eteve

Patent Trial and Appeal Board

Aug 16, 2016

11249122 (P.T.A.B. Aug. 16, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
111249,122 10/13/2005 Valerie Masini-Eteve
22428 7590 08/18/2016
Foley & Lardner LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
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.
088734-1121 1575
EXAMINER
WESTERBERG, NISSA M
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
08/18/2016 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):
ipdocketing@foley.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte VALERIE MASINI-ETEVE1
Appeal2014-000820
Application 11/249, 122
Technology Center 1600
Before ERIC B. GRIMES, ULRIKE W. JENKS,
and TIMOTHY G. MAJORS, Administrative Patent Judges.
MAJORS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to
compositions of 4-hydroxy tamoxifen ("4-0HT") which have been rejected
as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 Appellant identifies the Real Party in Interest as Besins Healthcare
Luxembourg SARL. (App. Br. 3.)
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Application 11/249, 122
STATEMENT OF THE CASE
"The compound 4-hydroxy tamoxifen (hereinafter referred to as 4-
0 HT) ... constitutes an active metabolite of the well characterized anti-
estrogen compound, tamoxifen." (Spec. i-f 3.) "The present invention
provides 4-0HT-containing pharmaceutical compositions and gels" and
particularly formulations "suitable for topical and transdermal application."
(Id. at i-f 6.) According to the Specification, such compositions and gels are
useful for, among other things, "treating and/or preventing conditions
involving dense breast tissue ... [and] treating and/or preventing benign
breast diseases." (Id. at i-f 55 (emphasis omitted).)
Claims 1---6 and 8-17 are on appeal. 2 Claim 1 is illustrative:
1. A transdermal pharmaceutical composition
formulated for topical administration comprising:
0.105 - 0.350 % of 4-hydroxy tamoxifen,
50 - 7 5 % of a [sic] least one C2-C6 alcohol,
0.1- 5.0 % of at least one gelling agent,
0.1 - 5.0 % of isopropyl myristate as a penetration
enhancer, and
20 - 50 % of an aqueous vehicle,
wherein percentages (%) are weight to weight of the
composition.
(App. Br. 23 (Claims App'x).)
The claims stand rejected as follows:
I. Claims 1---6, 8-15, and 17 are rejected under 35 U.S.C. § 103(a)
over Bua (US 2004/0138314 Al, published July 15, 2004) ("Bua")
2 Claim 18 is presently withdrawn from consideration. (See Final Act. dated
Oct. 22, 2012; Remarks dated Feb. 22, 2013 (and accompanying claim set).)
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Application 11/249, 122
optionally further in view of Mauvais-Jarvis et al. (US 4,919,937, issued
Apr. 24, 1990) ("Mauvais-Jarvis") and Masini-Eteve et al. (US
2003/0087885 Al, published May 8, 2003) ("Masini-Eteve").
II. Claim 12 is rejected under 35 U.S.C. § 103(a) over Bua, optionally
further in view of Mauvais-Jarvis and Masini-Eteve, and further in view of
Azamoff et al. (US 2003/0175329 Al, published Sept. 18, 2003)
("Azamoff').
III. Claim 16 is rejected under 35 U.S.C. § 103(a) over Bua,
optionally further in view of Mauvais-Jarvis and Masini-Eteve, and further
in view of Walters et al. (US 2003/0150876 Al, published Aug. 14, 2003)
("Walters").
IV. Claims 1-6, 8, 9, 12-15, and 17 are rejected under 35 U.S.C.
§ 103(a) over Mauvais-Jarvis in view of Masini-Eteve.
V. Claims 10 and 11 are rejected under 35 U.S.C. § 103(a) over
Mauvais-Jarvis and Masini-Eteve, and further in view of Azamoff.
VI. Claim 16 is rejected under 35 U.S.C. § 103(a) over Mauvais-
Jarvis and Masini-Eteve, and further in view of Walters.
With respect to Rejection I and Rejection IV, the Examiner includes
claim 7 within the range of claims being rejected. (Id. at 2, 6.) This appears
to be incorrect as claim 7 was canceled earlier in prosecution. (See Sept. 7,
2012 Response to Office Action.)
REJECTION I
Issue
The patentability of the pending claims hinges on (i) whether it would
have been prima facie obvious through routine optimization to modify the 4-
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Application 11/249, 122
OHT concentration in formulations taught or suggested in the prior art; and
(ii), if so, whether Appellant's evidence (e.g., of alleged unexpected results)
is sufficiently persuasive to outweigh the evidence supporting the
Examiner's prima facie case.
The Examiner rejected claims 1---6, 8-15, and 17, concluding that
those claims would have been obvious over Bua, in further view of Mauvais-
J arvis and Masini-Eteve. 3 The Examiner finds that Bua teaches a
formulation containing 4-0HT along with the other ingredients (C2---C6
alcohol, isopropyl myristate, etc.) in overlapping ranges/concentrations as
recited in claim 1, for example. The Examiner finds that Bua discloses
"about 0.001 g- about 1.0 g or about 0.01 to about 0.1 g of [ 4-0HT] in
100 g of gel (about 0.001 %- about 1.0%, about 0.01 % to about 0.1 %,
i-f [0046])." (Ans. 2, 11-12.) The Examiner finds that "the amount of 4-
0HT in the gel formulation is a results effective parameter that a person of
ordinary skill in the art would routinely optimize" and further that "[i]t
would have been customary for an artisan of ordinary skill to determine the
optimal amount of each ingredient to add in order to best achieve the desired
results, such as the 0.15% [ 4-0HT] concentration disclosed by Mauvais-
Jarvis." (Id. at 4.) Also, according to the Examiner:
ranges of these claims lie within the broad range disclosed by
Bua and the person of ordinary skill in the art would routinely
optimize the amount of the active ingredient depending on the
particular condition being treated and dosing frequency, for
3 The Examiner indicates that the teachings of Mauvais-Jarvis and Masini-
Eteve are "optionally" combined with Bua. (Ans. 2.) On appeal and in
order to consolidate issues where appropriate, we address the rejection based
on the combination of Bua, Mauvais-Jarvis, and Masini-Eteve.
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example, with higher concentrations possibly resulting in greater
therapeutic effect and/ or less frequent dosing.
(Id. at 11-12.)
Appellant contends "the § 103 rejections rely on an improper
hindsight selection of the recited amounts of 4-0HT from broad disclosures
in Bua and/or Mauvais-Jarvis, but the cited references fail to provide any
teachings, suggestions or guidance that would have led the skilled artisan to
a composition as claimed." (App. Br. 11.) More specifically, Appellant
argues "routine optimization" does not apply because the amount of 4-0HT
disclosed in Bua is a "broad range [about 0.001 to about 1.0%] ... that spans
three orders of magnitude" relative to "the claimed amounts of 4-0HT
(0.105 - 0.350%)." (Id. at 12.) Plus, Appellant contends, "other teachings
in Bua, such as its narrower, preferred range and specific examples that are
outside of the claimed range, would have led the skilled artisan away from
compositions with an amount of 4-0HT as recited in the claims." (Id.)
Finally, Appellant argues the "rejections are improper because the invention
identifies and solves a problem that was not even recognized in the art, and
the claimed compositions achieve unexpected results." (Id. at 11-12.)
Findings of Fact
FF 1. The Examiner's findings of fact and statement of the rejection
of claims 1---6, 8-15, and 17 under 35 U.S.C. § 103(a) over Bua, Mauvais-
Jarvis, and Masini-Eteve may be found at pages 2-6 and 10-13 of the
Examiner's Answer dated August 23, 2013. (See also, Final Act. dated Oct.
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22, 2012 at 4--9.)4 We adopt those findings unless otherwise stated, and
provide below certain illustrative disclosures of the prior art.
FF 2. Bua teaches "treatment [that] comprises administering 4-
hydroxytamoxifen percutaneously to a patient having dense breast tissue."
(Bua Abstract.) According to Bua "[t]he concentration of [ 4-0HT] in these
formulations may vary, but a dose should result in local [ 4-0HT]
concentrations that effectively oppose estrogenic driven effects." (Id. at
i-f 15.) Bua discloses "preferred formulations contain [ 4-0 HT] in a
hydroalcoholic gel. The amount of [ 4-0HT] per 100 grams of gel may
range from about 0.001 gram to about 1.0 gram. Preferably, it ranges from
about 0.01 gram to about 0.1 gram." (Id. at i-f 46.) Bua further describes
"two highly preferred [ 4-0HT] gel formulations" that include 0.02 g (20
mg) and 0.057 g (57 mg) of 4-0HT per 100 g of gel, as well as various other
ingredients such as isopropyl myristate (as a penetration enhancer),
hydroxypropylcellulose, and a phosphate buffer. (Id., see also i-f 44.)
Hydroxypropylcellulose is a gelling agent. (Spec. i-f 12.)
FF 3. Mauvais-Jarvis teaches percutaneous administration of 4-0HT
"for the treatment of breast affections [sic, afflictions], particularly benign
cancerous affections [sic] of the breast." (Mauvais-Jarvis Abstract.)
Mauvais-Jarvis further teaches a formulation of a hydroalcoholic gel that
includes 0.15 g of 4-hydroxytamoxifen per 100 g of gel (0.15% by weight),
along with other ingredients such as progesterone, Carbopol® 934, and
triethanolamine. (Id. at col. 3, 11. 29--42.)
4 We also adopt the Examiner's findings for Rejections II-III (adding the
Azamoff and Walters references respectively). (Ans. 5---6, 8-10.)
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FF 4. Masini-Eteve discloses pharmaceutical hydroalcoholic gel
compositions for transdermal application. (See, e.g., Masini-Eteve i-fi-122,
25, 31, 32.) Masini-Eteve teaches the gel may contain dihydrotestosterone
and isopropyl myristate as a preferred penetration enhancer, along with other
ingredients such as a gelling agent (e.g., Carbopol® 980) and
triethanolamine as a base. (Id. at i-fi-1 22, 31, 50, 51.)
Analysis
Claim 1
The concentration range of 4-0HT in claim 1is0.105---0.350%. As
discussed above, the Examiner determined that a composition having a
concentration within that range would have been prima facie obvious
through routine optimization in view of Bua's teaching of a 4-0HT
concentration of about 0.001-1 %, preferably about 0.01---0.1 %, and the
teaching in Mauvais-Jarvis of a 4-0HT concentration of0.15%.
We agree with the Examiner. A prima facie case of obviousness
typically exists when claimed ranges overlap with ranges disclosed in the
prior art. In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) ("In cases
involving overlapping ranges, we and our predecessor court have
consistently held that even a slight overlap in range establishes a prima facie
case of obviousness."). The prior art range in Bua "completely
encompass[ es]" the 4-0HT concentration range recited in claim 1-
meaning the "conclusion [of obviousness] is even more compelling than in
cases of mere overlap." Id. at 1330. (FF 2.)
Moreover, the Examiner finds that the concentration of 4-0HT in Bua
is a results-effective variable, and Appellant does not persuasively show
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otherwise. We thus agree with the Examiner that the skilled artisan would
reasonably be expected to modify and optimize the concentration of 4-0HT
within the ranges taught in Bua. In re Boesch, 617 F .2d 272, 27 6 (CCP A
1980) ("[D]iscovery of an optimum value of a result effective variable in a
known process is ordinarily within the skill of the art.").
As the Examiner correctly points out, the skilled artisan would
routinely optimize the concentration of the active drug to improve
therapeutic effect and patient compliance (e.g., less frequent dosing). (Ans.
11-12; Final Act. 6.) Bua also teaches that "the initial dose [of 4-0HT] may
be optimized in each patient, depending on individual responses." (Bua
,-r 38.) Here, for example, it would have been routine for the person of
ordinary skill in the art to increase the 4-0HT concentrations in Bua's
examples and so decrease the dosing frequency. Instead of the patient
receiving a dose of 1-2 mg/day of the 0.057% concentration in two or four
metered doses respectively (Bua ,-r 66, Table 5), it would have been obvious
to the skilled artisan to instead administer a single daily dose at 4-0HT
concentrations of 0.114% or 0.228% (2--4 times the concentration in Bua),
concentrations within the 0.105---0.350% range of claim 1.
Appellant counters that the range recited in Bua is too broad
compared to the "relatively narrow" concentration range in claim 1 (and
other claims) to support the Examiner's obviousness rationale. (Reply Br.
3--4.) Appellant describes the claimed range as a species within a much
broader genus disclosed in the prior art, and further points out that Bua's
range "spans three orders of magnitude" compared to the claimed range.
(App. Br. 10-12.)
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Application 11/249, 122
We are not persuaded that the prior-art range of Bua is so large,
encompassing so many possibilities, that the Examiner erred in concluding
that claim 1 is prima facie obvious. On this point, In re Peterson is
instructive. In that case, like here, the patent applicant argued that "a skilled
artisan would not have assumed from [the prior art] that using the claimed
amounts" would provide the improvements of the invention "because [the
prior art] defines very broad ranges." In re Peterson, 315 F.3d at 1328.
Nevertheless, the Federal Circuit affirmed the Board's determination that the
claims were prima facie obvious. Id. at 1330.
Here, Appellant focuses on the broadest range disclosed by Bua
(about 0.001 to 1 %) rather than Bua's preferred range of about 0.01 to 0.1 %,
where the upper limit of Bua's preferred range differs from the lower end of
the claimed range by only 0.005%. We agree with the Examiner that Bua
would have made obvious a composition comprising a 4-0HT concentration
encompassed by claim 1, particularly in view of its disclosure that preferred
4-0HT concentrations are "about" 0.01---0.1 %. (FF 2.)
Appellant's argument that 4-0HT concentrations in certain
embodiments of Bua, having concentrations below the ranges claimed,
would have "led the skilled artisan away" from the claimed compositions is
also unpersuasive. (App. Br. 12.) Bua's teaching is not limited to the
example formulations having 4-0HT concentrations of 0.02% and 0.057%,
which are cited by Appellant. Merck & Co., Inc. v. Biocraft Labs., Inc., 874
F.2d 804, 807 (Fed. Cir. 1989) ("[I]n a section 103 inquiry, the fact that a
specific [embodiment] is taught to be preferred is not controlling, since all
disclosures of the prior art, including unpreferred embodiments, must be
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considered.") (Internal quotation marks omitted). To the contrary, Bua
expressly teaches the "amount of [ 4-0HT] per 100 grams of gel may range
from about 0.001 to about 1.0 gram" and "[p ]referably" may be "about 0.1
gram," which abuts the range recited in claim 1. (FF 2.)
Mauvais-Jarvis further supports the rejection- leading the skilled
artisan toward the claimed subject matter - by teaching 0.15% 4-0HT,
which is within the range of claim 1. (FF 3.) On this record, Appellant has
not persuasively shown that Bua would have led the skilled artisan away
from a formulation with a 4-0HT concentration within the scope of the
claims. In re Peterson, 315 F.3d at 1332 (rejecting teaching away argument
because "[w]hile [the prior art] mentions a preferred alloy that does not
contain rhenium, it does not disparage or otherwise discourage the use of
alloys containing rhenium. ")5
Appellant also argues the "skilled artisan practicing Bua would have
been wary of using a concentration double that of the highest end of Bua's
preferred range, or four times to ten times the amounts exemplified in Bua"
5 Appellant also argues "routine optimization" does not apply, citing Ex
Parte Whalen II. (Reply Br. 5.) But Whalen II is distinguishable for at least
the reason that the Board found "the prior art teaches away from the claimed
solution." Ex Parte Whalen II, No. 2007-4423, 2008 WL 2957928, at *9
(BP AI July 23, 2008). The claims in that case related to embolic
compositions having "a viscosity of at least about 150 cSt." Id. at *2.
Among other things, the Board held that "the [prior art] references teach that
low viscosity is a desirable characteristic for embolic compositions" and that
prior art compositions with viscosities approaching the claimed amount
failed to work appropriately. Id. at *8 (discussing a prior art composition
with a viscosity of 145 cSt that was injected into the vascular site only with
significant difficulty).
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based on concerns about "avoiding systemic effects and minimizing side
effects." (Reply Br. 6.) Yet, as discussed above, Bua discloses a broader
range of from 0.001-1%of4-0HT- completely encompassing the claimed
ranges -that is suitable for use. (FF 2.) Appellant does not persuasively
identify any actual side effects or systemic problems that arose at higher
concentrations of the 4-0HT gel in Bua that would have steered the skilled
artisan away. Instead, portions of Bua cited by Appellant indicate that
systemic and side effects of administering the percutaneous 4-0HT gel
formulations did not pose significant problems, including at daily doses of
0.5, 1, and 2 mg. (Bua i-fi-163, 75.) In any event, that a skilled artisan might
proceed with care and awareness of potential side effects when increasing 4-
0 HT concentrations does not mean the skilled artisan would forego
proceeding at all.
For these reasons, we conclude the Examiner established a prima facie
case that claim 1 would have been obvious over Bua, in view of Mauvais-
J arvis and Masini-Eteve.
Claims 2---6, 8-15, and 17
Appellant argues the patentability of these claims because claims 2
and 3 recite narrower 4-0HT ranges than claim 1. In particular, claim 2
includes the range 0.205---0.350% and claim 3 includes the range 0.220-
0.350%. Appellant repeats the arguments concerning claim 1, but notes also
that the 4-0HT concentration in Mauvais-Jarvis (0.15%) lies outside the
ranges of claims 2 and 3. (App. Br. 14; Reply Br. 4.)
For reasons similar to those discussed above, Appellant's arguments
are unpersuasive. Bua's range still encompasses the 4-0HT ranges recited
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in claims 2 and 3, and we do not agree that Bua's examples teach away from
increasing the concentrations as a matter of routine optimization of a results-
eff ective variable. That, plus the Examiner's citation to potential for
increased therapeutic effect at lower dosing frequencies when increased
concentrations are used (Ans. 11-12) provides reasoning sufficient to
support the conclusion that claims 2 and 3 would have been prima facie
obvious. We further conclude that the Examiner established a prima facie
case that claims 4---6, 8-15, and 17 would have been obvious as these claims
are not separately argued, except insofar as they depend (directly or
indirectly) from claim 2.
Secondary Considerations
We tum next to Appellant's attempt to rebut the Examiner's prima
facie case with "secondary considerations of non-obviousness." (App. Br.
13, 16-21.) Appellant contends the claims are nonobvious for two reasons.
First, according to Appellant, "the claimed compositions address a problem
that was not recognized in the prior art." (Id. at 16.) Second, Appellant
argues that compositions "having an amount of 4-0HT as recited in the
claims, exhibit unexpected results with regard to reduced absorption
variability." (Id. at 17.) We address these arguments below.
Appellant argues the invention recognizes and addresses a
"variability" problem related to administration of topical 4-0HT gel
compositions. (App. Br. 16.) Appellant contends "the inventors
surprisingly and unexpectedly determined that the amount of drug absorbed
from transdermal 4-0HT hydroalcoholic gel compositions ... depends on
how much product is applied to a given surface area." (Id.) Because of this,
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Appellant contends, patients applying the same amount of a composition
may absorb different amounts of 4-0HT due to differences in breast sizes.
(Id.) According to Appellant, "[t]his problem can be clinically significant,
because it makes it difficult to ensure that a given patient is absorbing an
appropriate amount of 4-0HT." (Id.) And, Appellant's argument goes,
"without the teachings provided in the specification, the skilled artisan
would have had no reason to formulate compositions having the recited
amounts of 4-0HT." (Id. at 17.)
Appellant's "unrecognized problem" argument is not persuasive. As
an initial matter, we are not persuaded that the skilled artisan would have
been unaware that absorption of the active ingredient 4-0HT would vary
depending on how much is applied to a given surface area. Bua, for
example, teaches that "[t]he effectiveness of percutaneous drug
administration depends on many factors, including drug concentration [and]
surface area of application" among others, and that "those in the
pharmaceutical field can manipulate the various factors and methods to
achieve efficacious percutaneous delivery." (Bua i-fi-1 42--43.)
It is true, however, that the cited art does not discuss the precise effect
that 4-0HT concentration and surface area of administration have on
absorption in the same manner as Appellant's Specification. But even
assuming Appellant was the first to describe the extent of variability in
absorption when different concentrations of otherwise known or obvious 4-
0HT compositions are applied to different surface areas, we are not
persuaded the Examiner's prima facie case has been overcome. In re Baxter
Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) ("Mere recognition of
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latent properties in the prior art does not render nonobvious an otherwise
known invention.") Indeed, separate and apart from Appellant's disclosure,
there is adequate reason to conclude that the skilled artisan would have
optimized the 4-0HT concentrations within the range disclosed in Bua. As
discussed above, we agree with the Examiner that the skilled artisan would
have predictably increased the 4-0HT concentrations from Bua's examples
in order to decrease dosing frequency.
Also, contrary to Appellant's argument, it is not necessary that the
skilled artisan optimize the formulation for the same reasons set forth in the
Specification. KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007) ("In
determining whether the subject matter of a patent claim is obvious, neither
the particular motivation nor the avowed purpose of the patentee controls.
What matters is the objective reach of the claim.") If optimization for
conventional reasons (e.g., improving therapeutic effect and decreasing
dosing frequency) would have led to the compositions within the scope of
the claims, the compositions would be no less obvious.
Appellant cites the 2010 KSR Guidelines Update, and particularly its
discussion of In re Omeprazole Patent Litigation, 536 F.3d 1361 (Fed. Cir.
2008), from which Appellant contends "an invention that might otherwise
appear obvious can be non-obvious when the invention addresses 'a
previously unknown problem."' (App. Br. 16 (citations omitted).) Although
a patent applicant's solution to an unknown problem is a factor entitled to
due consideration, Appellant's evidence does not persuade us that the claims
are nonobvious for the reasons discussed above. Moreover, we disagree that
the issues in this appeal are analogous to In re Omeprazole. In that case, the
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Federal Circuit affirmed a district court's determination (following a bench
trial) that the patent challenger did not establish by "clear and convincing
evidence that a person of skill in the art would have appreciated the need to
include a subcoating" to a particular drug formulation disclosed in the prior
art. Id. at 1380. The district court had further found that, even if the skilled
person had recognized the problem the patent owner solved (i.e., the
negative interaction between the drug core and the enteric coating causing
the drug to degrade), the skilled person would have pursued other solutions
and not the one claimed by the patent owner. (Id. at 1380-81.) The record
in the present appeal is quite different, involving routine optimization of the
active ingredient's concentration within a range disclosed in a single prior
art reference. And, based on conventional reasons cited in the record (e.g.,
to decrease dosing frequency), the skilled person would have predictably
arrived at a composition with the 4-0HT concentrations claimed.
Appellant's "unexpected results" argument also points to the property
of absorption variability. More specifically, Appellant argues that, when 4-
0HT concentrations of 0.114% and 0.228% that are within the scope of the
claims are used, there is "reduced variability" compared to the variability
seen when compositions having a 4-0HT concentration of 0.057% are used.
(App. Br. 18.) To illustrate this "reduced variability," Appellant cites in
vitro testing in Example 2 of the Specification and a document identified as
"Statistical Analysis of Data Presented in U.S. 11/249,122" (hereafter
"Statistical Analysis"). (Id. at 17-20.) Appellant contends the in vitro
testing shows, for example, "four times as much of the 0.057% composition
(outside the claimed range) results in about 23.5 times as much 4-0HT being
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absorbed" compared to "only 17.7 times as much 4[-]0HT being absorbed"
when four times as much of the 0.114% composition is applied. (Id. at 18.)
Moreover, Appellant contends that when the same absolute amount of 4-
0HT is applied (e.g., 20µL of0.057%, lOµL of0.114%, and 5µL of
0.228% ), the absorption of the 0.114% and 0.228% is "similar" at "34.105
ng vs. 20.300 ng," yet "twice" to "more than three times as much" of the
0.057% composition is absorbed at "74.312 ng." (Id. at 19 (incl. graph).)
Citing the "Statistical Analysis," Appellant states "the analysis 'determined
with 95% confidence' that absorption of the 0.057 % 4-0HT composition
'varied non-linearly with the volume of gel applied,' while absorption of
compositions within the scope of the claims 'did not show much [sic] non-
linear variability."' (Reply Br. 7 .) Appellant argues the reduced variability
with compositions having 4-0HT concentrations within the scope of the
claims "offer significant advantages in the clinical context" and "lends more
predictability to dosing decisions." (Id. at 8; App. Br. 20.)
The Examiner determined that Appellant's argument and evidence of
unexpected results is not sufficiently persuasive to overcome the prima facie
case. The Examiner graphically represents the values from Example 2 in the
Specification (Ans. 15; Final Act. 7-8) and finds, for example, that "[t]aking
into account the standard deviations associated with these values and the
variability between the 114-20 and 228-10 compositions that both lie
with[ in] the scope of the instant claims, the data show that the differences
are a matter of degree rather than kind." (Ans. 15.) Moreover, the Examiner
finds that "[ w ]ithout data for a concentration above the claimed range, the
criticality of the claimed range cannot be determined." (Id.) The Examiner
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further finds that Appellant did not provide sufficiently persuasive evidence
to support other contentions about the alleged unexpected results: "[ w ]hile
Appellant[] state[ s] that this [reduced variability] results in a significant
advantage in the clinical context, no data to support this statement are of
record" (id. at 15-16); "[t]he statements regarding the effect or lack of effect
of various alcohols, gelling agents was not presented in a declaration or
other forms of evidence" (Final Act. 8).
Based on the record before us and the strength of the prima facie case,
we agree with the Examiner. Pfizer Inc. v. Apotex Inc., 480 F.3d 1348, 1372
(Fed. Cir. 2007) ("[W]e hold that even if Pfizer showed that amlodipine
besylate exhibits unexpectedly superior results, this secondary consideration
does not overcome the strong showing of obviousness in this case.
Although secondary considerations must be taken into account, they do not
necessarily control the obviousness conclusion.")
We have considered Appellant's data from Example 2, but like the
Examiner, we find that it reflects a difference in degree (extent of absorption
variability) not kind and thus is less persuasive in showing unexpected
results. Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967,
977 (Fed. Cir. 2014). At best, Appellant's evidence and argument show that
when 4-0HT concentrations of 0.057% are used, there is a degree of non-
linear variability in absorption and, at concentrations of 0.114% and 0.228%,
there is less non-linear variability. Yet a substantial degree of variability
still exists across all concentrations. (See, e.g., Final Act. 7-8 (graphs).)
Moreover, Appellant has not provided sufficiently persuasive evidence to
demonstrate the practical and clinical significance of, for example, the 23 .5x
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absorption variability seen when 4 times the amount of 0.057% is applied
compared to the 17.7 x absorption variability seen with the 0 .114 %
formulation.
So too, the data does not consistently show reduced absorption
variability at 4-0HT concentrations within the scope of the claims. For
example, the Examiner points to "the variability between the 114-20 [20 µL
of 0.114%] and 228-10 [10 µL of 0.228%] compositions that both lie within
the scope of the claims," which exhibited average absorption of 185. 592 ng
versus 56.048 ng respectively-more than three times as much 4-0HT
being absorbed at the 0.114% concentration compared to the 0.228%
concentration. (Ans. 15; Spec. i-f 110.) Appellant, citing a different subset of
data, argues that a 2x and 3x difference in absorption when the same
absolute amount of 4-0HT is applied unexpectedly and surprisingly
distinguishes the claimed compositions from the prior art. (App. Br. 19-20.)
Appellant states that "applying the same absolute amount of 4-0HT by
applying equivalent doses of two compositions [10 µL of0.114% and 5 µL
of 0.228%] within the scope of the claims ... results in a similar amount of
4-0HT being absorbed." (App. Br. 19.) Yet, according to Appellant, when
the same absolute amount of the 0.057% (20 µL) formulation that is outside
the claimed range is applied, "twice" to "more than three times as much" 4-
OHT is absorbed. (App. Br. 19.) From this, Appellant argues:
That a patient could effectively experience double or
triple the amount of drug from a composition outside the scope
of the claims as compared with the same absolute dose of a
composition within the scope of the claims certainly makes the
claimed compositions surprisingly and unexpectedly
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advantageous with regard to improved reproducibility and
reduced variability.
(App. Br. 20.) But, as the data cited by the Examiner makes clear, the same
3x absorption variability is seen even among compositions with
concentrations that are claimed. (Ans. 15; Spec. i-f 110.)
Appellant's argument and evidence is also unpersuasive because it
does not show unexpected results commensurate in scope with the claims,
nor does it demonstrate the criticality of the particular 4-0HT concentration
range that is claimed. In re Peterson, 315 F.3d at 1330-31 ("[T]he
applicant's showing of unexpected results must be commensurate in scope
with the claimed range. . . . Although those data [showing results for 1 %
and 2% rhenium] show that alloy strength improved with the addition of
rhenium, they do not evidence unexpected results for the entire claimed
range of about 1-3% rhenium.") The upper limit of 4-0HT concentration in
all the claims is 0.350%. Appellant, however, does not provide data for
concentrations above 0.228%. Nor does Appellant provide data for
concentrations above 0.350% such that "the criticality of the claimed range
cannot be determined." (Ans. 15.) Without this evidence, and given the
closeness of the prior art and the strength of the prima facie case, we are not
persuaded that the claimed compositions would have been nonobvious.
Conclusion of Law
We conclude the Examiner established by a preponderance of the
evidence that claims 1---6, 8-15, and 17 would have been obvious over Bua,
in view of Mauvais-Jarvis and Masini-Eteve. Appellant's argument and
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evidence of secondary considerations is not sufficiently persuasive to
overcome the Examiner's prima facie case.
REJECTIONS II & III
The Examiner rejected claim 12 over Bua, Mauvais-Jarvis, and
Masini-Eteve, in further view of Azamoff (Rejection II). The Examiner
rejected claim 16 over Bua, Mauvais-Jarvis, and Masini-Eteve, in further
view of Walters (Rejection III). Appellant does not separately argue
Rejections II and III, and instead agrees those rejections stand or fall with
Rejection I. (App. Br. 11; Reply Br. 2.) So, having affirmed Rejection I, we
also affirm Rejections II and III.
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Issue
REJECTION IV
The Examiner rejected claims 1---6, 8, 9, 12-15, and 17 over Mauvais-
Jarvis in view of Masini-Eteve. The issues with respect to this rejection are
similar to those discussed above, except the Examiner is not relying on Bua
and, instead, relies on Mauvais-Jarvis alone with respect to the concentration
of 4-0HT, which in Mauvais-Jarvis is 0.15%.
Here again, we decide on appeal whether the Examiner established a
prima facie case of obviousness and, if so, whether secondary considerations
(the same as discussed above) overcome the prima facie case.
Findings of Fact
FF 5. The Examiner's findings of fact and statement of the rejection
of claims 1---6, 8, 9, 12-15, and 17 under 35 U.S.C. § 103(a) overMauvais-
Jarvis and Masini-Eteve may be found at pages 6-8 and 13 of the
Examiner's Answer dated August 23, 2013. (See also, Final Act. dated Oct.
22, 2012 at 4--9.) We adopt those findings unless otherwise stated, and
further incorporate by reference Findings of Fact 3 and 4 above.
Analysis
The Examiner finds that Mauvais-Jarvis discloses a composition
having a 4-0HT concentration of 0.15% along with the other elements of
claim 1 except "the inclusion of isopropyl myristate" as a penetration
enhancer. (Ans. 7.) The Examiner concludes that it would have been
obvious to include isopropyl myristate "because Masini-Eteve et al.
discloses that the inclusion of an ingredient such as isopropyl myristate
promotes diffusion of the active ingredient through the skin." (Id.)
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As to claim 1, Appellant does not contest that Mauvais-Jarvis and
Masini-Eteve disclose a composition within the scope of the claim and,
instead, Appellant "primarily relies on the secondary considerations of non-
obviousness." (App. Br. 13.)
The Examiner has the better position. We are not persuaded that
Appellant's evidence of secondary considerations overcomes the Examiner's
prima facie case for the reasons discussed above. Moreover, we note that
Appellant does not provide evidence of unexpected results compared to the
4-0HT formulation disclosed in Mauvais-Jarvis. In re Baxter Travenol
Labs., 952 F.2d at 392 ("[W]hen unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art."). We thus affirm the rejection as to claim 1.
As to claims 2---6, 8, 9, 12-15, and 17, however, we reach a different
result. In the absence of Bua' s teachings, we are not persuaded these
narrower claims would have been prima facie obvious over Mauvais-Jarvis,
which "discloses a single composition comprising 4-0HT and progesterone,
which includes 0.15% by weight 4-0HT" that is outside the claimed ranges.
(App. Br. 14.) Masini-Eteve does not mention 4-0HT, much less any
particular concentration. We thus reverse the rejection of claims 2---6, 8, 9,
12-15, and 17 over Mauvais-Jarvis and Masini-Eteve.
Conclusion of Law
We conclude the Examiner established by a preponderance of the
evidence that claim 1 would have been obvious over Mauvais-Jarvis and
Masini-Eteve. We conclude that a preponderance of the evidence does not,
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however, show that claims 2---6, 8, 9, 12-15, and 17 would have been
obvious over Mauvais-Jarvis and Masini-Eteve.
REJECTIONS V & VI
The Examiner rejected claims 10 and 11 over Mauvais-Jarvis and
Masini-Eteve, in further view of Azamoff (Rejection V). The Examiner
rejected claim 16 over Mauvais-Jarvis and Masini-Eteve, in further view of
Walters (Rejection VI). Appellant does not separately argue Rejections V
and VI, and instead agrees those rejections stand or fall with Rejection IV.
(App. Br. 11; Reply Br. 2.) Because claims 10, 11, and 16 depend directly
or indirectly from claim 2, and because we reverse Rejection IV as to claim
2, we also reverse Rejections V and VI.
SUMMARY
We affirm the rejection of claims 1-6 and 8-17.
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
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