Ex Parte Philips et al

Patent Trial and Appeal Board

Feb 28, 2017

12089609 (P.T.A.B. Feb. 28, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/089,609 06/02/2008 Betty Philips 0727-1022 4863
466 7590 03/02/2017
YOUNG fr THOMPSON
EXAMINER
209 Madison Street BASQUILL, SEAN M
Suite 500
Alexandria, VA 22314 ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
03/02/2017 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):
DocketingDept@young-thompson.com
y andtpair @ firsttofile. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte BETTY PHILIPS, SEVERINE BAGUE,
LAURA RABINOVICH-GUILATT, and GREGORY LAMBERT1
Appeal 2015-007583
Application 12/089,609
Technology Center 1600
Before ERIC B. GRIMES, TIMOTHY G. MAJORS, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an
emulsion composition, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
Prostaglandins such as latanoprost are used in ophthalmic preparations
to treat glaucoma. (Spec. 1:15—19.) Latanoprost is almost insoluble in water
but “[i]n recent years, oil-in-water type emulsions . . . gained increasing
1 Appellants identify the Real Party in Interest as SANTEN SAS. (Appeal
Br. 2.)
Appeal 2015-007583
Application 12/089,609
importance.” (Id. at 2:1—8.) “[C]ationic emulsions have been developed as
topical ophthalmic vehicles; they have the advantage of increasing the
bioavailability of the drugs.” (Id. at 2:12—14.)
The Specification states that
[o]ne known approach to stabilize an emulsion is to confer an
electrostatic charge to the droplets[’] surface which will result in
droplet repulsion and less droplet coalescence. Colloidal
particles dispersed in a solution are electrically charged due to
their ionic characteristics and dipole attributes. This charge,
which can be negative resulting in anionic emulsions or positive
producing cationic emulsions ... is known in the art as the “zeta
potential”. The zeta potential is a measure of the magnitude of
the repulsion or attraction between particles.
(Id. at 2:18—28.) The Specification describes four tests (Tests A, B, C, and
D) that measure the stability of an emulsion’s zeta potential over time under
thermal stress conditions. (Id. at 13:19 to 15:17.)
Claims 1—10, 16, 21, 27, and 31 are on appeal. Claim 1 is illustrative
and reads as follows:
1. A cationic ophthalmic oil-in-water type emulsion, comprising
colloid particles having an oily core surrounded by an interfacial film, said
emulsion comprising:
cetalkonium chloride as a cationic agent present in an amount of from
0.001 to 0.1% w/w; and
at least one non ionic surfactant selected from the group consisting of
poloxamers, tyloxapol, polysorbates, polyoxyethylene castor oil derivatives,
sorbitan esters, polyoxyl stearates and a mixture of two or more thereof,
said oily core being medium chain triglycerides, and said oily core
comprising a drug, the drug selected from the group consisting of
latanoprost, unoprostone isopropyl, travoprost, bimatoprost, tafluprost, 8-
isoprostaglandin E2 or a mixture of two or more thereof, the oily core
present in an amount of from 0.5 to 5% w/w and the drug present in an
amount of from 0.001 to 1% w/w,
2
Appeal 2015-007583
Application 12/089,609
said emulsion being free of water-soluble polymer selected from a
polyvinyl compound, a water-soluble cellulose compound and a
polysaccharide,
wherein the emulsion meets zeta potential Test A, B, C and D
requirements.
The claims stand rejected as follows:
Claims 1—4, 6—10, 16, 21, 27, and 31 under 35 U.S.C. § 103(a) based
on Ueno,2 Gewirtz,3 Vallet Mas,4 and Luyckx5 (Ans. 2) and
Claims 1—10, 16, 21, and 27 under 35 U.S.C. § 103(a) based on Ueno,
Gewirtz, Vallet Mas, Luyckx, and Hellberg6 (Ans. 8).
I
The Examiner has rejected claims 1—4, 6—10, 16, 21, 27, and 31 as
obvious based on Ueno, Gewirtz, Vallet Mas, and Luyckx. The Examiner
finds that Ueno discloses “an ophthalmic composition comprising
latanoprost and ‘substantially no’ benzalkonium chloride (‘BAC’),” where
Ueno defines “‘substantially no’ BAC” to mean less than 0.02%. (Ans. 3.)
The Examiner also finds that Ueno discloses that latanoprost is highly fat-
soluble but can form aqueous compositions if a dissolving agent such as
Polysorbate 80 is included. {Id.) The Examiner finds that Ueno discloses
that its compositions can take the form of an aqueous emulsion with an oil
phase emulsion base. {Id. at 4.)
2 Ueno, US 2004/0082660 Al, published Apr. 29, 2004.
3 Gewirtz, US 2004/0115234 Al, published June 17, 2004
4 Vallet Mas et al., US 5,588,559, issued Dec. 31, 1996.
5 Luyckx et al., US 7,064,109 B2, issued June 20, 2006.
6 Hellberg et al., US 6,342,524 Bl, issued Jan. 29, 2002.
3
Appeal 2015-007583
Application 12/089,609
The Examiner finds that Vallet Mas discloses cetalkonium chloride as
an alternative to benzalkonium chloride and Luyckx discloses that using
medium chain triglycerides to dissolve poorly water-soluble compounds has
the benefit of reducing risk of ocular irritation. (Id. at 5—6.7) The Examiner
concludes that Ueno would have made obvious a topical ophthalmic
emulsion containing latanoprost, polysorbate 80, and BAC, in an aqueous
oily emulsion. (Id. at 5.) The Examiner also concludes that it would have
been obvious to include a medium chain triglyceride in the emulsion,
because Luyckx teaches that the triclyceride improves the solubility of
poorly water-soluble compounds and reduces eye-irritating effects, and to
substitute cetalkonium chloride for Ueno’s benzalkonium chloride because
Vallet Mas teaches that they are equivalents. (Id. at 5—7.)
We agree with the Examiner that the composition of claim 1 would
have been obvious based on the cited references. Ueno states that
“[b]enzalkonium chloride is a preservative most commonly used in
commercially available ophthalmic solution[s].” (Ueno 13.) “However,
preservatives are known as the major etiology of keratoconjunctive
disorders, and for safety purpose, it is preferred that the concentration of a
preservative such as benzalkonium chloride is below 0.01%.” (Id. 14.)
Ueno discloses treating glaucoma by “administering an ophthalmic
composition comprising latanoprost as an active ingredient. . . , wherein the
7 The Examiner finds that Gewirtz discloses emulsions comprising
latanoprost, cosolvents, and benzalkonium chloride. (Ans. 6.) Thus,
Gewirtz appears to be cited for the same teachings as Ueno, at least as
relevant to claim 1.
4
Appeal 2015-007583
Application 12/089,609
ophthalmic composition contains substantially no benzalkonium chloride.”
{Id. 1 8.) Ueno states that preferable amounts of latanoprost include 0.001 to
0.01%. {Id. 118.) “The phrase of ‘the ophthalmic composition contains
substantially no benzalkonium chloride’ used herein means that the
composition contains no benzalkonium chloride, or the composition contains
benzalkonium chloride at... a concentration of less than 0.02%, preferably
0.01% or less, more preferably 0.005% or less.” {Id. 111.)
Ueno states that “the ophthalmic composition may be in liquid form
such as solution, emulsion and suspension or semisolid form such as gel and
eye ointment.” {Id. 113.) Ueno states that, when the composition is an eye
ointment, it may contain ordinarily used eye ointment bases, including
“emulsion base in which oil phase and aqueous phase have been emulsified
with a surface active agent or the like.” {Id. 116.)
“[T]he composition may further contain a dissolving agent. . . [that]
helps to disperse or dissolve latanoprost homogeneously and stably in an
aqueous vehicle containing substantially no benzalkonium chloride.” {Id.
114.) Ueno states that examples of dissolving agents include polysorbate 80
and polyoxyethylene hydrogenated castor oils. {Id.) Ueno provides five
working examples of its compositions, none of which contain a polyvinyl
compound, a water-soluble cellulose compound, or a polysaccharide. {Id.
1121-25.)
Vallet Mas discloses ophthalmic solutions that include preservative
systems, such as quaternary ammonium compounds, to prevent or limit the
growth of contaminating microorganisms. (Vallet Mas 1:24—34.) Vallet
Mas states that “[w]ithin the compounds belonging to this group that are
5
Appeal 2015-007583
Application 12/089,609
included in pharmaceutical formulations as the preservative system,
benzalkonium chloride . . . [and] cetalkonium chloride . . . , among others,
stand out.” (Id. at 1:54—59.)
Luyckx discloses “an eye lotion containing, as therapeutically active
agent, an antibiotic compound of the macrolide class in solution in an oily
vehicle.” (Luyckx 2:33—36.) Luyckx states that azalides are virtually
insoluble in water, so the use of an oily vehicle makes it possible to achieve
complete dissolution of the active agent and thus homogeneous application
over the eye surface, “whereas, in the case of a suspension, there is uneven
contact of the particles of active compound on the eye.” (Id. at 2:46—66.)
Luyckx states that the requirements for its oily vehicle “are
particularly well satisfied by the fatty oils commonly called medium-chain
triglycerides.” (Id. at 4:45 47.) “[A] vehicle consisting of medium-chain
triglycerides is particularly suitable for ophthalmic treatment by local
application, since it makes it possible, inter alia, to . . . ensur[e] that the risk
of irritation of the eye tissues by the composition is reduced to a minimum.”
(Id. at 4:55-61.)
Thus, Ueda would have made obvious an oil-in-water emulsion in
which the aqueous phase contains 0.001-0.01% latanoprost, less than 0.2%
benzalkonium chloride, Polysorbate 80, and none of the types of compounds
excluded by claim 1. It would have been obvious to modify this
composition by replacing the benzalkonium chloride with cetalkonium
chloride, because Vallet Mas discloses that both are quaternary ammonium
compounds that are used as preservatives in ophthalmic solutions. It also
would have been obvious to use medium chain triglycerides as the oily
6
Appeal 2015-007583
Application 12/089,609
phase in the oil-in-water emulsion, because Luyckx discloses that they
minimize the risk of irritation of eye tissues.
Although Ueda seeks to disperse or dissolve latanoprost in the
aqueous phase (Ueda 114), it also discloses that latanoprost is highly fat-
soluble {id. 1 6). Thus, it is reasonable to expect that, in an oil-in-water
emulsion, the latanoprost would predominantly solubilize in the oily phase,
as recited in claim 1. In addition, although none of the cited references
addresses the zeta potential tests recited in claim 1, it is reasonable to expect
that a composition meeting all of the physical requirements of the claim
would share its properties, including the magnitude of repulsion or attraction
that is measured by a composition’s zeta potential.
Appellants argue that “UENO does not suggest mixing the latanoprost
with an oil phase, such as medium chain triglycerides” and “does not suggest
adding latanoprost to the oily core of an O/W emulsion.” (Appeal Br. 8.)
As noted above, however, Ueno discloses that latanoprost is highly fat-
soluble, and it is reasonable to expect that, in a mixture of aqueous and oily
phases, a drug that is highly fat-soluble will be found mostly in the phase in
which it is most soluble; in this case, the oil phase. Ueno discloses that
preferred amounts of latanoprost can be up to 1% (Ueno 118), so only a
small amount needs to solubilize in the oil phase of its oil-in-water emulsion
to meet claim l’s requirement of 0.001—1% in the oily core.
Appellants also argue that Vallet Mas prevents all contact of the eye
with quaternary ammonium compounds “through the modification of the
container holding the solution.” (Appeal Br. 10.) Appellants reason that,
“[b]ecause UENO proposes ‘no’ preservatives such as benzalkonium
7
Appeal 2015-007583
Application 12/089,609
chloride (in [0006]) and VALLET MAS seeks to prevent all contact with
such preservatives,” these references would not have led a skilled worker to
substitute cetalkonium chloride for benzalkonium chloride in Ueno’s
composition. {Id.)
This argument is also unpersuasive, because Ueno expressly defines
“substantially no” as including 0.02% benzalkonium chloride or less. Thus,
it does not seek to eliminate benzalkonium chloride completely from its
compositions. In fact, three of the five exemplary compositions disclosed by
Ueno include 0.01% benzalkonium chloride. (Ueno 125.)
Appellants also argue that Luyckx implicitly teaches away from oil-
in-water emulsions, because it describes its composition as a “true solution.”
(Appeal Br. 12.)
However, while Luyckx’s invention may be a solution containing a
macrolide antibiotic in an oily vehicle such as medium chain triglycerides,
“[t]he test for obviousness is what the combined teachings of the references
would have suggested to one of ordinary skill in the art.” In re Young, 927
F.2d 588, 591 (Fed. Cir. 1991). Here, Ueno suggests an oil-in-water
emulsion, and Luyckx teaches that medium chain triglycerides minimize the
chances of eye irritation, so it would have been obvious to use medium chain
triglycerides as the oily phase in Ueno’s emulsion.
Appellants argue that the zeta potential tests recited in claim 1
“determine the stability of the emulsion zeta potential under thermal stress
conditions” and “[t]he claimed stability . . . results from the fact that the
prostaglandin is solublized [sic] in the oily core of the emulsion.” (Appeal
8
Appeal 2015-007583
Application 12/089,609
Br. 6—7.) Appellants point to the Specification and the Philips Declaration8
as evidence that latanoprost tends to degrade or hydrolyze when exposed to
water. (Id. at 7.)
Similarly, Appellants argue that, in the claimed composition, “the
stability of the prostaglandin ... is improved because the prostaglandin is
solublized [sic] in the oily core of the emulsion. . . . This stability is
confirmed by the emulsion meeting zeta potential stability Test A, B, C and
D requirements as claimed.” (Id. at 15.) Appellants argue that the cited
references do not recognize the problem of thermal stress stability or solve
that problem by solubilizing latanoprost in the oily phase of an oil-in-water
emulsion. (Id.)
This argument is unpersuasive. The Specification explains that
“[z]eta potential measures a physical property which is exhibited by any
particle in suspension. Zeta potential can be used to predict behaviour of the
suspension in different environments, to optimize the formulations of
suspensions and emulsions as well as to predict overtime stability.” (Spec.
11:5—9, emphasis added.)
The stability measured, however, is not chemical stability with respect
to degradation or hydrolysis, but the physical stability of droplets to resist
aggregation:
In order to avoid the emulsion droplets to adhere to one another
and form aggregates of successively increasing size, it is
necessary to confer repulsive forces to the particles. One of the
8 Declaration under 37 C.F.R. § 1.132 of Betty Philips, signed April 13,
2011.
9
Appeal 2015-007583
Application 12/089,609
means to confer repulsive forces to a colloidal system is by
electrostatic or charge stabilization. . . .
To utilize electrostatic control of dispersions, it is the zeta
potential of the particle that must be measured rather than its
surface charge. Charged particles will attract ions of opposite
charge in the dispersant. Ions close to the surface are strongly
bound; those further away form a more diffuse region. Within
this region is a notional boundary, known as the slipping plane,
within which the particle and ions act as a single entity. The
potential at the slipping plane is known as the zeta potential. It
has long been recognised that the zeta potential is a very good
index of the magnitude of the interaction between colloidal
particles.
(Spec. 11:10 to 12:4.) As the Specification puts it, “[t]he zeta potential is a
measure of the magnitude of the repulsion or attraction between particles.”
{Id. at 2:18-28.)
The Philips Declaration, by contrast, addresses the chemical stability
that is achieved by limiting the exposure of latanoprost to water. Ms. Philips
states that “prostaglandin derivatives are effectively susceptible to hydrolyze
in presence of water.” (Philips Decl. 1.) Ms. Philips states that Ueno’s
composition is a micellar aqueous solution {id.), while the claimed
composition is “an oil-in-water emulsion where the prostaglandin
derivative is solubilized in the oily core which avoids contact with water”
and “ensures the chemical stability of prostaglandin derivative” {id. at 2).
Ms. Philips also states that “the presence of cationic charges on the
surface of the nanosized MCT [medium chain triglyceride] droplets
significantly contributes to the overall stability of the emulsion” and
“avoids their coalescence.” {Id.) Thus, consistent with the Specification, the
10
Appeal 2015-007583
Application 12/089,609
Philips Declaration states that the charged surface of the droplets prevents
them from aggregating or coalescing.
Neither the Specification nor the Philips Declaration supports
Appellants’ argument that the zeta potential tests recited in claim 1 measure
the chemical stability of latanoprost in the claimed composition, as opposed
to the physical stability of the droplets in the emulsion. And, as discussed
above, in the oil-in-water emulsion suggested by the cited references, the
majority of an oil-soluble compound like latanoprost would be expected to
be found in the oil phase in which it is more soluble.
Finally, Appellants argue that they have provided evidence that the
claimed compositions—containing cetalkonium chloride—provide
unexpectedly better stability, as measured by zeta potential, compared to
Ueno’s benzalkonium chloride-containing compositions. (Appeal Br. 18.)
Appellants state that the Lallemand Declaration9 “compares two cationic
O/W emulsions that fall within the composition according to claim 1 (absent
the active) that differ solely by the addition of CKC or BAK.” (Id. at 19.)
Appellants also concede, however, that the emulsions differ from claim 1 in
using light and heavy mineral oil for the oily core. (Id. (“The [tested]
emulsions differ from claim 1 by the omission of the active and the use [of]
both light and heavy mineral oil for the oily core.”).)
The Lallemand Declaration compares two compositions, one including
cetalkonium chloride (CKC) and one including benzalkonium chloride
(BAK). (Lallemand Decl. 2.) However, neither composition includes the
9 Declaration under 37 C.F.R. § 1.132 of Frederic Lallemand, signed Jan. 15,
2014.
11
Appeal 2015-007583
Application 12/089,609
medium chain triglycerides required by claim 1. Instead, the compositions
contain a mixture of light mineral oil and heavy mineral oil. (Id.) The
Specification makes clear, however, that mineral oils are not medium chain
triglycerides, as required by claim 1. The Specification states that “[t]he oily
phase of the emulsion may comprise one or more components selected from
. . . mineral oil (i.e. petrolatum and liquid paraffin), medium chain
triglycerides (MCT) (i.e. a triglyceride oil in which the carbohydrate chain
has about 8—12 carbon atoms),” etc. (Spec. 8:9—15.)
Thus, neither of the compositions tested in the Lallemand Declaration
represent the claimed invention. “Although it is well settled that
comparative test data showing an unexpected result will rebut a prima facie
case of obviousness, the comparative testing must be between the claimed
invention and the closest prior art.” In re Fenn, 639 F.2d 762, 765 (CCPA
1981) (emphasis added). Thus, the results shown in the Lallemand
Declaration do not provide persuasive evidence of unexpected results for the
claimed composition.
In addition, the Declaration’s results are inconsistent with those
shown in the Specification itself. The Specification provides working
examples of compositions that comprise benzalkonium chloride (BAK) and
medium chain triglycerides (MCT). (Spec. 17, compositions Z29EM005,
Z29EM007, Z29EM008, and Z29EM0011.) The compositions for which
zeta potential test results are provided appear to show that each of those
compositions showed a change of less than 10 units over the course of
12
Appeal 2015-007583
Application 12/089,609
fifteen days (i.e., at T15).10 (Id.) This change appears to satisfy the
requirements of claim 1. (Spec. 14:16 to 15:17 (tests are met if the zeta
potential changes by less than 10 mV over the course of each test).) Thus,
the Specification appears to show that benzalkonium chloride would also
work as the cationic agent in the claimed composition. (See also id. at 9:lb-
23 (describing preferred embodiments that include benzalkonium chloride as
the cationic agent).)
We therefore affirm the rejection of claim 1 under 35 U.S.C. § 103(a)
based on Ueno, Gewirtz, Vallet Mas, and Luyckx. Claims 2-4, 6—10, 16,
21, 27, and 31 have not been argued separately and therefore fall with claim
1. 37C.F.R. §41.37(c)(l)(iv).
II
The Examiner has rejected claims 1—10, 16, 21, and 27 as obvious
based on Ueno, Gewirtz, Vallet Mas, Luyckx, and Hellberg. The Examiner
cites Hellberg to show that it would have been obvious to add an anti­
inflammatory compound to the composition made obvious by the other
references. (Ans. 8.) We agree with the Examiner’s findings and
conclusion.
Appellants argue that Hellberg does not remedy the deficiencies of the
other references in making claim 1 obvious. (Appeal Br. 20.)
This argument is unpersuasive because, for the reasons discussed
above, we conclude that claim 1 would have been obvious based on Ueno,
10 The Specification explains the testing method used (Spec. 18:26—30) but
does not explain the results.
13
Appeal 2015-007583
Application 12/089,609
Gewirtz, Vallet Mas, and Luyckx, considered with or without Hellberg.
Appellants have not provided sufficient evidence to show nonobviousness.
We therefore affirm the rejection of claim 1 under 35 U.S.C. § 103(a) based
on Ueno, Gewirtz, Vallet Mas, Luyckx, and Hellberg. Claims 2—10, 16, 21,
and 27 fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm both of the rejections on appeal.
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
14