Ex Parte Masini-Eteve

Patent Trial and Appeal Board

Nov 13, 2018

13133071 (P.T.A.B. Nov. 13, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/133,071 08/31/2011 Valerie Masini-Eteve
22428 7590 11/15/2018
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.
088734-0163 1127
EXAMINER
CORNET, JEAN P
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
11/15/2018 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-ETEVE
Appeal2017-003027
Application 13/133,071 1
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, and RYAN H. FLAX,
Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL
This Appeal under 35 U.S.C. § 134(a) involves claims 1, 11, 12, and
18-21 (Final Act. 2 2). 3 Examiner entered a rejection under 35 U.S.C.
§ 103(a). We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Appellant identifies "Besins Healthcare Luxembourg SARL" as the real
party in interest (App. Br. 3).
2 Final Office Action mailed January 4, 2016.
3 Pending claims 13-1 7 stand withdrawn from consideration.
Appeal2017-003027
Application 13/133,071
STATEMENT OF THE CASE
Appellant's disclosure "relates to SERM[ 4Lcontaining pharmaceutical
compositions, such as gels, and to methods of making and using the same"
(Spec. 1:12-13). Claims 1, 11, and 18 are representative and reproduced
below:
1. A pharmaceutical composition for topical administration to a
skin surface for percutaneous delivery of endoxifen comprising
a mixture of:
(i) 0.01 to 10 % (w/w) of endoxifen or a pharmaceutically
acceptable salt thereof,
(ii) 60 to 80 % (w/w) of at least one monoalcohol,
(iii) 0.01 to 10 % (w/w) of at least one penetration
enhancer selected from the group consisting of oleic acid,
propylene glycol, and a mixture thereof,
(iv) 0.01 to 5 % (w/w) of at least one gelling agent,
(v) 0.01 to 30 % (w/w) of at least one moisturizer, and
(vi) q.s. 100 % (w/w) water,
wherein the composition does not contain isopropyl myristate
and does not contain sodium hydroxide.
11. A dose packet, unit dose packet or multiple dose packet
containing a pharmaceutical composition according to claim 1.
18. A pharmaceutical composition according to claim 1,
comprising 2 to 5 % (w/w) of endoxifen or a pharmaceutically
acceptable salt thereof.
(App. Br. 18 (emphasis added).)
4 "The Selective Estrogen Receptors Modulators (SERMs) are a class of
pharmacological agents formerly referred to as anti-estrogens, which are
generally understood to be compounds capable of blocking the effect of
estradiol without displaying any estrogenic activity of their own" (Spec.
1:15-18).
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Claims 1 and 19-21 stand rejected under 35 U.S.C. § I03(a) as
unpatentable over the combination of Ahmad, 5 Williams, 6 Excerpt, 7 and
Hsu. 8
Claims 11 and 12 stand rejected under 35 U.S.C. § I03(a) as
unpatentable over the combination of Ahmad, Williams, Excerpt, Hsu, and
Salin-Drouin. 9
Claim 18 stands rejected under 35 U.S.C. § I03(a) as unpatentable
over the combination of Ahmad, Williams, Excerpt, Hsu, and Taravella. 10
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Ahmad "relates to the use of endoxifen[llJ in the treatment of
mammalian diseases" and "to liposomes and other formulations such as
complexes, vesicles, emulsions, micelles and mixed micelles of endoxifen,
methods of preparation, and uses" (Ahmad ,r 1; see also ,r 85 ("Complexes
can be in the form, e.g., of ... emulsions")).
5 Ahmad et al., WO 2008/070463 A2, published June 12, 2008.
6 Williams et al., Penetration enhancers, 56 ADVANCED DRUG DELIVERY
REVIEWS 603-618 (2004 ).
7 Making Solutions, 93-105, Ch. 4, Cold Spring Harbor Laboratory Press
(2003).
8 Hsu et al., US 6,582,724 B2, issued June 24, 2003.
9 Salin-Drouin, EP 1 634 583 Al, published Mar. 15, 2006.
10 Taravella et al., US 2004/0175416 Al, published Sept. 9, 2004.
11 "4-hydroxy-N-desmethyl-Tamoxifen (endoxifen)" (Ahmad ,r 3).
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FF 2. Ahmad discloses compositions for topical administration (Ahmad
,r 18; see Final Act. 6).
FF 3. Ahmad discloses a "composition comprising endoxifen [] formulated
in a hydroalcoholid 12J composition containing a penetration enhancer, an
aqueous vehicle, an alcoholic vehicle and a gelling agent" (Ahmad ,r 21; see
id. ,r 20 ("the composition comprising endoxifen is formulated in a
hydroalcoholic gel, a hydroalcoholic solution, a patch, a cream, an emulsion,
a lotion, an ointment, a powder or an oil"); see also id. ,r 135 ("For
percutaneous administration, the formulation or composition of [Ahmad's]
invention containing endoxifen may be delivered in the form of ... [a] gel");
see Final Act. 5---6).
FF 4. Ahmad's "composition or formulation ... comprises an aqueous
vehicle that permits solubilization of hydrophilic molecules, and promotes
moisturization of skin" (Ahmad ,r 140; see id. ("Aqueous vehicles include
... purified water"); see Final Act. 6).
FF 5. Ahmad discloses that "[t]he amount of an aqueous vehicle preferably
ranges between O .1 % to 65% by weight of the pharmaceutical composition,
preferably between 15% to 50%, and more preferably between 25% to 40%"
(Ahmad ,r 140).
FF 6. Ahmad's compositions comprise "excipient additives, including ...
glycerine ... [and] urea" (Ahmad ,r 135; cf Spec. 5: 25 ("The moisturizer
may comprise glycerine"); Spec. 16: 1-27).
12 Ahmad discloses that "the term 'hydroalcoholic' as used in reference to a
substance or composition indicates that [the] substance or composition
comprises both water and alcohol" (Ahmad ,r 66).
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FF 7. Ahmad discloses that "the gelling agent is selected from the group
consisting of polyacrylic acid, hydroxypropylcellulose and a cellulose
derivative other than hydroxypropylcellulose" (Ahmad ,r 26; see also id.
,r 67; cf Spec. 5: 22-23 ("The gelling agent may be selected from the group
consisting of polyacrylic acids, cellulosics, and mixtures thereof'); Spec. 15:
1-17 ("examples of gelling agents")).
FF 8. Ahmad discloses that the gelling agent "may constitute between
0.1 % to 20% by weight of [the] formulation depending on the nature of
gelling agent, preferably between 0.5% to 10% and more preferably between
0.5% to 5%" (Ahmad ,r 141; see Final Act. 6).
FF 9. Ahmad discloses that the "alcohol is ethanol or isopropanol, and
constitutes in absolute form" (Ahmad ,r 24; see id. ,r 139 ("ethanol may
effectively contribute to the percutaneous absorption of endoxifen by rapidly
evaporating upon contact with skin" ( emphasis added)); see Final Act. 6; cf
Spec. 5: 16-17 ("The monoalcohol may be selected from the group
consisting of ethanol and isopropanol")).
FF 10. Ahmad discloses "[t]he amount of absolute nonaqueous vehicle in a
gel formulation ranges from 35% to 99% by weight, preferably between
50% to 85% and more preferably between 60% to 75%" (Ahmad ,r 139).
FF 11. Ahmad discloses that "[p ]ercutaneous administration of the
endoxifen composition ... may be advantageous because this may reduce
systemic drug exposure and the risks from non-specifically activating
estrogen receptors throughout the body" (Ahmad ,r 132).
FF 12. Ahmad discloses that "[t]he effectiveness of percutaneous drug
administration depends on many factors, such as drug concentration, surface
area of application, time and duration of application, skin temperature, skin
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Application 13/133,071
hydration, previous irradiation, physiochemical properties of the drug, and
partitioning of the drug between the formulation and the skin" (Ahmad
,r 134).
FF 13. Ahmad discloses that "to enhance percutaneous effectiveness, the
compositions or complexes comprise penetration enhancers that improve
percutaneous absorption," wherein such penetration "enhancers include but
are not limited to ... propoylene [sic] glycol,[ 13J fatty acids ... and their
derivatives ... and mixture[s] thereof' (Ahmad ,r 134; see also id. ,r 138 ("In
other embodiments, the composition ... comprises one or more fatty acid
esters as a penetration enhancer. One of the highly preferred examples of a
fatty acid ester penetration enhancer is isopropyl myristate"); see Final Act.
6 (Ahmad discloses a "composition comprising penetration enhancers such
as ... fatty acids and fatty acid alcohol or mixtures thereof," wherein
"isopropyl myristate is the preferred permeation enhancer" ( emphasis
omitted)); cf Spec. 5: 19-20 ("The penetration enhancer may be selected
13 Appellant recognizes that, in discussing penetration enhancers, Ahmad
misspelled propylene glycol, a penetration enhancer known to those of
ordinary skill in this art prior to Appellant's filing date (App. Br. 11 (citing
Ahmad ,r 134); see FF 22). Nonetheless, Appellant contends "that when a
prior art reference contains an obvious typographical error-as is the case
here-'it cannot be said that one of ordinary skill in the art would do
anything more than mentally disregard [ the erroneous compound] as a
misprint" (App. Br. 11 (alteration original) (citing In re Yale, 434 F.2d 666,
668---69 (CCPA 1970)); see also Reply Br. 3-5). In addition, Appellant
contends that because Ahmad discusses "polypropylene glycol" in the
context of additional excipients, a "skilled artisan would have interpreted
[Ahmad's] typographical error[, made in the context of penetration
enhancers, as] "'polypropylene glycol,"' an additional excipient in Ahmad,
and not the known penetration enhancer, propylene glycol (App. Br. 11
(citing Ahmad ,r 135); see Reply Br. 3-5).
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from the group consisting of oleic acid, and propylene glycol"); id. 13:25-26
(Appellant's "composition ... comprises a penetration enhancer with the
proviso of isopropyl myristate"); see also id. 13:28-31 ("when the SERM is
endoxifen ... the composition of [Appellant's] invention preferably
comprises a penetration enhancer with the proviso of isopropyl myristate").
FF 14. Ahmad discloses a
hydroalcoholic composition compris[ing] endoxifen at about
0.01 % to 0.20% by weight; isopropyl myristate at about 0.1 %
to 2.0%, preferably 0.5% to 2.0% by weight; alcohol at about
50.0% to 80.0%, preferably about 60.0% to 75.0% by weight;
aqueous vehicle at about 20.0% to 60.0%, preferably 25.0% to
50.0% by weight; and gelling agent at about 1.0% to 10.0%,
preferably about 0.5% to 5.0% by weight. In some
embodiments, the wherein the percentage of components is
weight to weight of the composition.
(Ahmad ,r 23; see also id. ,r 37 and 48: 4--15; see Final Act. 5---6.)
FF 15. Examiner finds that Ahmad does not disclose the meaning of "q.s
100% (w/w)" and relies on Excerpt to teach that "q.s. 100% (w/w) water[]"
means add enough water to bring the total of amount of the formulation to
100% (Final Act. 7).
FF 16. Examiner finds that Ahmad does not disclose a composition
comprising glycerine, a moisturizer, in the amount required by Appellant's
claimed invention and relies on Hsu to make up for this deficiency in Ahmad
(Final Act. 7; see FF 6).
FF 17. Hsu "relates generally to the topical and transdermal administration
of pharmacologically active agents, and more particularly relates to
permeation enhancer compositions for enhancing the permeability of skin or
mucosal tissue to topically applied pharmacologically active agents" (Hsu 1:
16-20).
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FF 18. Hsu discloses that an "enhancer composition may [] contain
irritation-mitigating additives[, such as glycerin,] to minimize or eliminate
the possibility of skin irritation or skin damage resulting from the enhancer,
the drug to be administered, or other components of the composition,"
wherein "[t]he irritant-mitigating additive, if present, may be incorporated
into the present enhancer compositions at a concentration effective to
mitigate irritation or skin damage, typically representing not more than about
20 wt. %, more typically not more than about 5 wt. %, of the composition"
(Hsu 11: 8-23).
FF 19. Examiner finds that, although Ahmad discloses that "permeation
enhancers can include fatty acids and propylene glycol," Ahmad does not
exemplify a "permeation enhancer [that] is a mixture of oleic acid and
propylene glycol" (Final Act. 7).
FF 20. Williams discloses that "[p]ercutaneous drug absorption has been
increased by a wide variety of long chain fatty acids, the most popular of
which is oleic acid" (Williams 609: § 3.5).
FF 21. Williams discloses that "fatty acids have been used to improve
transdermal delivery of, amongst others, estradiol" (Williams 610: § 3.5).
FF 22. Williams discloses that "[p]enetration enhancers tend to work well
with co-solvents such as PG [(propylene glycol)] or ethanol. Synergistic
effects are found between enhancers such as ... oleic acid ... with PG"
(Williams 615: § 4; see also id. at 610: § 3.5; see also id. at Abstract
("propylene glycol, PG, [is] a common excipient in topically applied dosage
forms")).
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FF 23. Williams discloses:
It is difficult to select rationally a penetration enhancer for a
given permeant. Penetration enhancer potencies appear to be
drug specific, or at best may be predictive for a series of
permeants with similar physico-chemical properties (such as
similar partition coefficients, molecular weights and
solubilities). Some broad generic trends are apparent, such as
the use of hydrocarbon monoterpenes for lipophilic permeants,
but the level of enhancement expected for these agents is
unpredictable.
(Williams 615: § 4.)
FF 24. Ahmad discloses that "[i]n the complexes, the active agent can be
bound to the lipid by covalent, hydrophobic, electrostatic, hydrogen, or other
bonds, and is considered bound even where the drug is simply entrapped
within the interior of lipid structures" (Ahmad ,r 85).
FF 25. Ahmad's compositions include "complexes with free and/or salts or
esters of fatty acid," wherein the fatty acid may be "oleic acid (C1s:1)"
(Ahmad ,r 89).
ANALYSIS
The combination of Ahmad, Williams, Excerpt, and Hsu:
Based on the combination of Ahmad, Williams, Excerpt, and Hsu,
Examiner concludes that, at the time Appellant's invention was made, it
would have been prima facie obvious
to modify the composition taught by Ahmad et al[.] by using
the amount of glycerine i.e.[,] 5-20% (w/w) as an irritation-
mitigating additive, taught by Hsu et al[.] in order to ...
minimize or eliminate the possibility of skin irritation or skin
damage resulting from the enhancer and the drug to be
administered, and further substitute the isopropyl myristate
taught by [ Ahmad]
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... with the mixture of penetration enhancers i.e.[,] the oleic
acid and propylene glycol taught by Williams.
(Final Act. 8; see FF 1-23.) We find no error in Examiner's prima facie
case.
Appellant contends, however, that the evidence relied upon by
Examiner fails to provide a person of ordinary skill in this art with a
reasonable expectation of success in formulating an endoxifen composition
for topical administration, wherein "oleic acid (OA), propylene glycol (PG),
[or] a mixture thereof' is substituted for Ahmad's preferred penetration
enhancer, isopropyl myristate (IPM) (see App. Br. 9; see also id. at 10
("Williams does not provide any reasonable expectation that OA would be
an effective enhancer for endoxifen"); Reply Br. 3). In this regard,
Appellant contends that Ahmad does not expressly disclose OA, PG, or a
mixture thereof as a penetration enhancer for endoxifen and "Williams'
explicitly discusses the high level of unpredictability in the art with regard to
the selection of an effective penetration enhancer for a given drug, and
expressly advises against generalizing penetration enhancers across drug
classes as [] Examiner has done here" (App. Br. 10; Reply Br. 6-7; see FF
23). We are not persuaded.
Ahmad discloses an endoxifen composition comprising penetration
enhancers, such as fatty acids, and discloses a preference for, and
exemplifies the use of, the fatty acid ester, isopropyl myristate (FF 13).
Given Ahmad's disclosure of a variety of penetration enhancers useful in
Ahmad's compositions, we decline to limit Ahmad to its preferred and
exemplified penetration enhancer, isopropyl myristate. In re Lamberti, 545
F .2d 7 4 7, 7 50 (CCP A 197 6) ( a reference disclosure is not limited only to its
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preferred embodiments, but is available for all that it discloses and suggests
to one of ordinary skill in the art).
Given Ahmad's disclosure of the use of fatty acid penetration
enhancers, one of ordinary skill in this art would reasonably look to
Williams' disclosure of "penetration enhancers," and, specifically, fatty acid
penetration enhancers (FF 21 ). In this regard, Williams discloses that "oleic
acid" is "the most popular" choice of a fatty acid penetration enhancer (FF
20).
Appellant recognizes that Ahmad expressly discloses the use of oleic
acid to formulate endoxifen complexes for transdermal delivery (see App.
Br. 9; Reply Br. 5---6; see also FF 24--25). Thus, the evidence of record
supports the reasonable expectation of those of ordinary skill in this art that
the presence of oleic acid in a transdermal endoxifen composition would not
inhibit the transdermal delivery of endoxifen ( cf App. Br. 14; Reply Br. 7
( citing Piette Dec. 14 ,r,r 7-8); see also Reply Br. 5 ( citing Piette Declaration)
("Given such unpredictability, Ahmad's generic disclosure of a 'fatty acid'
penetration enhancer cannot provide a reasonable expectation that oleic acid
could be successfully used in endoxifen formulations as claimed"); Reply
Br. 10 (Although "Williams teaches oleic acid is the most popular
permeation enhancing fatty acid. . . . [Piette' s] experiments show that IPM
and OA are not per se interchangeable")).
In addition, Ahmad discloses that ethanol facilitates transdermal
delivery of endoxifen (FF 9). In this regard, we note that Williams discloses
that "[p ]enetration enhancers[, such as oleic acid,] tend to work well with
co-solvents such as PG [(propylene glycol)] or ethanol" and "[s]ynergistic
14 Declaration of Paul Piette, PharmD., signed Sept. 1, 2015.
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effects are found between enhancers such as ... oleic acid ... with PG" (FF
22).
Therefore, we find no error in Examiner's conclusion that a person of
ordinary skill in this art would have found it prima facie obvious to
substitute oleic acid, the most popular choice of fatty acid penetration
enhancer, and propylene glycol, a known co-solvent that acts synergistically
with oleic acid, for the isopropyl myristate in Ahmad's preferred
composition. Thus, we agree with Examiner's conclusion that the
combination of Ahmad, Williams, Excerpt, and Hsu provides a person of
ordinary skill in this art with a reasonable expectation of successfully
formulating an endoxifen composition for topical administration within the
scope of Appellant's claimed invention (see FF 1-25). For the foregoing
reasons, we are not persuaded by Appellant's contention that the
combination of Ahmad, Williams, Excerpt, and Hsu fails to provide a person
of ordinary skill in this art with a reasonable expectation of success in
formulating a composition within the scope of Appellant's claimed invention
(see App. Br. 9; see also id. at 9-16). In re O'Farrell, 853 F.2d 894,903
(Fed. Cir. 1988) ("Obviousness does not require absolute predictability of
success ... all that is required is a reasonable expectation of success").
There is no doubt that Ahmad is the closest prior art on this record
(see Ans. 17). Piette does not provide a comparison against the closest prior
art, Ahmad (see id.; see also id. at 18; cf Piette Dec. ,r,r 7-8; Reply Br. 9
("Appellant does not rely on the results with OA/4-0HT[ 15J formulations as
predictive of OA/endoxifen formulations; to the contrary, Appellant relies
15 "4-0H tamoxifen" (Spec. 30:32). Cf footnote 11, supra ("4-hydroxy-N-
desmethyl-Tamoxifen (endoxifen)" (Ahmad ,r 3).)
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on the data to demonstrate a general unpredictability in the field"). See In re
Fenn, 639 F.2d 762, 765 (CCPA 1981) ("comparative testing must be
between the claimed invention and the closest prior art").
Piette does not provide data based on endoxifen compositions, but
instead tests 4-0HT compositions 16 (Piette Dec. ,r 7; cf Ans. 18; see also
Ans. 23 ("4-0HT and endoxifen have different physico-chemical
properties")). Further, Piette's study uses two different concentrations of
ethanol, a known facilitator of permeation (FF 9): (a) 37.38% of 96%
ethanol in "4-0HT Formulations with OA" and (b) 72% of absolute 17
ethanol in "4-0HT Formulations with IPM" (Piette Dec. ,r 7; cf Ans. 18). In
addition, Piette's "4-0HT Formulations with OA" comprise "Alpha-
tocopherol," whereas this ingredient is excluded from Piette's "4-0HT
Formulations with IPM" (Piette Dec. ,r 7; cf Ans. 18). As Examiner
explains, "[a]lpha-tocopherol is not present in the formulations of Ahmad"
and "is not disclosed in ... [Appellant's] [S]pecification as well" (Ans. 18).
Thus, Piette' s Declaration is "not commensurate in scope with [Appellant's]
claimed invention" (Ans. 18). In re Dill, 604 F.2d 1356, 1361 (CCPA 1979)
("[E]vidence presented to rebut a prima facie case of obviousness must be
commensurate in scope with the claims to which it pertains").
16 Endoxifen and 4-0H tamoxifen ( 4-0HT) are metabolites of Tamoxifen
(App. Br. 13).
17 Because Piette does not identify a lower percent alcohol in this
formulation, a person of ordinary skill in this art would consider this ethanol
to be absolute (see FF 9).
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In addition, we recognize Piette's reference to Lee 18 who "evaluated
the relative efficiency of skin permeation of 4-0HT and [ endoxifen] in vitro,
and tested oleic acid (OA) as a permeation-enhancer" (Lee 61 ). As Piette
acknowledges, Lee does not demonstrate Appellant's and Piette' s asserted
inhibitory effect of OA on permeation of 4-0HT (see Piette Dec. ,r 9; cf
App. Br. 14; Reply Br. 7-8; Piette Dec. ,r 7). To the contrary, Lee discloses
that the addition of 1 o/o-5% OA to compositions comprising 4-0HT or
endoxifen increased both the absorption and total penetration of both 4-
0HT and endoxifen (Lee 64 (emphasis added)).
In view of the foregoing, we note that Piette confirms that
formulations and experimental conditions are important in assessing the
effectiveness of penetration enhancers for any particular reagent (Piette Dec.
5: n. * ("The difference in the reported effect of [Lee's] OA on 4-0HT
permeation is believed to stem from the different formulations tested and
different experimental conditions"); cf Reply Br. 8 ( citing Ans. 21 and 30)
(Examiner's "assertion [ relating to the 'different components and different
amounts' in the formulations set forth in Piette's Declaration] is inaccurate,
because the effects of OA and IPM can be compared in these
experiments")). Piette and Appellant both compare the results of Piette' s
Experiments 1 and 2 asserting that IPM and OA are not interchangeable and
18 Lee et al., In vitro human skin permeation of endoxifen: potential for
local transdermal therapy for primary prevention and carcinoma in situ of
the breast, 3 Breast Cancer: Targets and Therapy 61-70 (2011). Appellant
contends that Lee, which published after the priority date of Appellant's
application "is based on scientific facts that were in existence at the time the
application was filed ... and that did not change between the time the
application was filed and the time Lee was published" (App. Br. 13, n. 1; see
also Reply Br. 11 ).
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that one formulation inhibits transdermal penetration and the other does not
(see Reply Br. 9 ("Even though the experiments used 4-0HT, the data still
show that for a given drug IPM and OA are not interchangeable"); id. at 9
("Appellant does not rely on the results with OA/4-0HT formulations as
predictive of OA/endoxifen formulations; to the contrary, Appellant relies
on the data to demonstrate a general unpredictability in the field"); see
generally Piette Dec. ,r 7; App. Br. 14; Reply Br. 7-8). Therefore, we are
not persuaded by Appellant's contention that "[a]s discussed in the Piette
Declaration, such a comparison is possible because 'OA is the only tested
variable in [Experiment 1]' and 'IPM is the only tested variable in
[Experiment 2]"' (Reply Br. 8). For the foregoing reasons, we are not
persuaded by Appellant's assertion that Examiner's "concerns are
unfounded" (id.). Instead, we find that the evidence on this record supports
Examiner's assertion that "[i]n order for the data in the Declaration to
compare OA vs IPM, [as Appellant and Piette have done,] the components
and their amounts have to be the same [in] each formulation" (Ans. 22; cf
Piette Dec. 5: n. *).
Notwithstanding Appellant's assertion to the contrary, we find no
evidence on this record supporting Appellant's intimation that the
experiments set forth in the Piette Declaration represent a "direct or indirect
comparison" (see Reply Br. 8-9 (citing MPEP § 716.02(b)), that is sufficient
to outweigh the preponderance of evidence on this record supporting
Examiner's conclusion of obviousness. See Ryko Mfg. Co. v. Nu-Star, Inc.,
950 F.2d 714, 719 (Fed. Cir. 1991) (The weight of the secondary
considerations, as here, may be of insufficient weight to override a
determination of obviousness based on primary considerations). Thus, for
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the reasons set forth above, we are not persuaded by the comparative
evidence set forth in Piette' s Declaration or Appellant's reliance thereon.
Lee, which Appellant concedes "is based on scientific facts that were
in existence at the time the application was filed ... and did not change
between the time the application was filed and the time Lee was published"
(App. Br. 13, n. 1), further explains that, although
[i]t is not clear why [endoxifen] benefited more from the
addition of OA than 4-0HT, [] this [benefit] may be related to a
difference in their structure. [ Endoxifen] is smaller and more
polar than 4-0HT because one methyl group at a tertiary
amine is replaced with a hydrogen, resulting in a secondary
amine that is more hydrophilic than the tertiary amine of 4-
0HT. Because OA appears to make the stratum comeum
fluidic and ethanol gives a continuous driving force,
[Endoxifen] may move faster through the skin than 4-0HT.
The amine group of [Endoxifen] may have a favorable balance
of hydrophilic and hydrophobic properties to deal with the
stratum comeum, which would allow [Endoxifen] to transverse
the stratum comeum more easily. The results here agree with
previous findings using hairless rat skin, which showed that the
co-solvent system of DA-ethanol-water efficiently increased
skin permeation of both lipophilic and hydrophilic drugs.
(Lee 66-67 (emphasis added); see also Williams 610 § 3.5 ("fatty acids ...
can be used to promote delivery of both lipophilic and hydrophilic
permeants").)
Although Lee discloses that endoxifen benefited more from the
addition of OA than 4-0HT (Lee 66-67), Lee established that the addition of
1 o/o-5% OA to compositions comprising 4-0HT or endoxifen increased both
the absorption and total penetration of both 4-0HT and endoxifen (Lee 64
( emphasis added)). We find no requirement in Appellant's claimed
invention of a particular "benefit" from the choice of OA as the penetration
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enhancer. In addition, as discussed above, Lee explains that the differences
in the hydrophilic and hydrophobic properties, as well as, the structure of
endoxifen relative to 4-0HT contribute to the different benefits, which is
supported by Williams and the "previous findings" discussed in Lee (see Lee
66-67 (emphasis added); see also Williams 610 § 3.5 ("fatty acids ... can
be used to promote delivery of both lipophilic and hydrophilic permeants").
Therefore, we are not persuaded by Appellant's contention that "Lee's
conclusion on page 66 that '[i]t is not clear why [endoxifen] benefited more
from the addition of OA than 4-0HT' ( emphasis added) demonstrates an
unpredictability in the field of transdermal drug delivery" (Reply Br. 11
(emphasis and alteration original)).
For the foregoing reasons, we find the evidence relied upon by
Examiner supports a conclusion of obviousness and that Appellant's
Declaratory evidence fails to overcome Examiner's prima facie case. Ryko
Mfg., 950 F.2d at 719. For the reasons set forth above, we are not persuaded
Appellant's contentions based on the Piette Declaration.
The combination of Ahmad, Williams, Excerpt, Hsu, and Salin-Drouin:
Examiner finds that the combination of Ahmad, Williams, Excerpt,
and Hsu "do not teach a dose packet, unit dose packet or multiple dose
packet and dispenser, and optionally with hand pump" and relies on Salin-
Drouin to make up for this deficiency (Final Act. 9-10).
Based on the combination of Ahmad, Williams, Excerpt, Hsu, and
Salin-Drouin, Examiner concludes that, at the time Appellant's invention
was made, it would have been prima facie obvious to modify the
composition suggested by the combination of Examiner finds that the
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Application 13/133,071
combination of Ahmad, Williams, Excerpt, and Hsu "to provide the
composition in a dispenser or a unit dose packet or multiple dose packets ...
to make the application easier for the patient who is taking said
composition" (Final Act. 10).
Having found no error in Examiner's combination of Ahmad,
Williams, Excerpt, and Hsu, we are not persuaded by Appellant's contention
that Salin-Drouin "does not cure [Appellant's asserted] deficiencies of the
cited primary references" (App. Br. 16).
The combination of Ahmad, Williams, Excerpt, Hsu, and Taravella:
Examiner finds that the combination of Ahmad, Williams, Excerpt,
and Hsu "do not teach the amount ... of endoxifen recited in [Appellant's]
claim 18" and relies on Taravella to make up for this deficiency (Final Act.
10-11).
Based on the combination of Ahmad, Williams, Excerpt, Hsu, and
Taravella, Examiner concludes that, at the time Appellant's invention was
made, it would have been prima facie obvious, in view of Taravella, to
adjust, through routine optimization, the amounts taught by the combination
of Ahmad, Williams, Excerpt, and Hsu (Final Act. 11-12). Having found no
error in Examiner's combination of Ahmad, Williams, Excerpt, and Hsu, we
are not persuaded by Appellant's contention that Taravella "does not cure
[Appellant's asserted] deficiencies of the other cited references" (App. Br.
16).
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Application 13/133,071
CONCLUSION
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness.
The rejection of claim 1 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Ahmad, Williams, Excerpt, and Hsu is affirmed.
Claims 19-21 are not separately argued and fall with claim 1.
The rejection of claim 11 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Ahmad, Williams, Excerpt, Hsu, and Salin-Drouin
is affirmed. Claim 12 is not separately argued and falls with claim 11.
The rejection of claim 18 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Ahmad, Williams, Excerpt, Hsu, and Taravella 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
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