Ex Parte Wang

Patent Trial and Appeal Board

Mar 14, 2017

12844369 (P.T.A.B. Mar. 14, 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.
12/844,369 07/27/2010 Changjin Wang 392130-0201 7927
88984 7590 03/16/2017
FOT FY Rr T ARDNFR T T P
EXAMINER
3000 K STREET N.W. COUGHLIN, DANIEL F
SUITE 600
WASHINGTON, DC 20007-5109 ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
03/16/2017 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):
ipdocketing @ foley. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte CHANGJIN WANG
Appeal 2015-002237
Application 12/844,369
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
RYAN H. FLAX, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35U.S.C. § 134 involving a pharmaceutical
transdermal formulation. The Examiner rejected the claims as obvious. We
have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 Appellant identifies the real party in interest as ABSIZE, INC. (see App. Br. 1).
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Application 12/844,369
Statement of the Case
Background
“The preparations of this invention have a saturated solution of an
active pharmaceutical ingredient in a solvent therefor in intimate
combination and contact with a suspension of nanoparticles of the active
pharmaceutical ingredient in the solvent, and a pharmaceutically acceptable
carrier therefor suitable for topical administration” (Spec. 11).
The Claims
Claims 1—12 and 16—18 are on appeal.2 Claim 1 is representative and
reads as follows:
1. A pharmaceutical transdermal formulation comprising an
active pharmaceutical ingredient wherein said formulation
contains a saturated aqueous solution of the active
pharmaceutical ingredient in intimate combination with a
suspension of nanoparticles having a size distribution of from 1
to 100 nm,
said formulation, when transdermally administered,
provides for a dynamic equilibrium with the amount of said
active pharmaceutical ingredient delivered transdermally and
the amount in suspension so that the solution retains a saturated
concentration of said active pharmaceutical ingredient until the
suspension is exhausted, provided that said formulation is
maintained in a pharmaceutically acceptable non-nanoparticle
carrier.
The Issue
The Examiner rejected claims 1—12 and 16—18 under 35 U.S.C.
§ 103(a) as obvious over Bae,3 Murrell,4 and Lee5 (Non-Final Act. (mailed
June 17, 2013) 3-8).
2 Claims 13—15 and 19-37 were cancelled (see App. Br. 17—18 (Claims App’x)).
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The Examiner finds Bae teaches “a composition comprising
nanoparticles of a sparingly water-soluble drug . . . wherein the particles of
the composition display a particle size distribution of 10 to 1000 nm” and
where “the sparingly water-soluble drug is . . . piroxicam” (Ans. 4—5).
The Examiner acknowledges Bae does not teach “a composition that
is a transdermal formulation” (id. at 5). The Examiner finds Murrell teaches
“a transdermal patch for the delivery of a nitric oxide-donor, such as
nitroglycerin, and a second active agent (see Abstract), wherein the second
active agent can be an NS AID, such as piroxicam” (id.). The Examiner
finds Lee teaches transdermal delivery compositions where the
active ingredient is present in the composition in a combination
of a solid microparticulate state and a solubilized state . . .
wherein, the composition comprises microreservoirs containing
the solid and solubilized forms of the active ingredient, where
the drug solids act as a depot and, as the solubilized fraction is
depleted by diffusion to and permeation into/across a patient's
skin, more drug is drawn into solution from the particulate
depot, thus enabling controlled release over time.
(Id.)
The Examiner finds it obvious
to arrive at particle size distributions encompassing the claimed
limitations by the express teachings of Bae [’]416 as to the
increase in solubility arising from smaller particle sizes . . . and,
perhaps more importantly, the increased bioavailability realized
from the enhanced solubility ... as well as by the express
teachings of Lee [’]349 as to the control of active ingredient
3 Bae et al., WO 2008/013416 Al, published Jan. 31, 2008 (“Bae”).
4 Murrell et al., US 2007/0059351 Al, published Mar. 15, 2007 (“Murrell”).
5 Lee et al., US 2007/0264349 Al, published Nov. 15, 2007 (“Lee”).
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release over time that the equilibrium-controlled depot of solid
drug particles provides.
(Ans. 7.)
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that Bae, Murrell, and Lee render
claim 1 obvious?
Findings of Fact
1. Bae teaches “nanoparticles of a sparingly water-soluble drug,
which exhibits enhanced bioavailability and particle size stability of the
drug” (Bae 1:7—9). Bae teaches “a powder composition comprising the
particles of the sparingly water-soluble drug prepared by the inventive
method, which shows a particle size distribution of 10 to 1000 nm for 10 to
90% of the drug particles ... an average particle size of 10 to 400 nm in an
aqueous medium” {id. at 3:26-4:3).
2. Bae teaches “examples of the sparingly water-soluble dmg
include non-steroidal anti-inflammatory drugs including . . . piroxicam” (id.
at 5:23-26).
3. Bae teaches “the process time can be adjusted according to the
kind of the active ingredient.... As the process time of step 2) is longer,
the particle size of the active ingredient becomes smaller and more
homogeneous” (id. at 9:8—15).
4. Murrell teaches “devices for transdermally co-delivering low
doses of a nitric oxide-donor with other active agents. The devices can be
used for variety of treatment regimens including pain relief’ (Murrell 12).
5. Murrell teaches “[ejxamples of NSAIDS which can be used as
the second active agent include . . . piroxicam” (id. 128).
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6. Lee teaches: “Transdermal delivery also creates steady levels
of a drug in the bloodstream and helps to improve drug efficacy. Depending
on various ingredients that are used to formulate the drug, as well as
technical aspects of the patch ... the rate of release of the drug can be
precisely manipulated” (Lee 110).
7. Lee teaches:
The active pharmaceutical ingredient can be present in (a) a
solid nanoparticulate state; (b) a solid microparticulate state; (c)
solubilized; or (d) any combination thereof. In another
embodiment of the invention, the composition is suitable for
transdermal delivery. In yet another embodiment of the
invention, the composition which is suitable for transdermal
delivery provides for a depot effect.
{id. 118.)
8. Lee teaches:
By varying different parameters of Route I and Route II, the
size and integrity of such globules can be modified. Hence, the
stability of globules comprising dissolved API can be altered to
enable the release of API, either as a solution or precipitate.
This is a microreservoir-dissolution-controlled system, where
the drug solids act as depot and, as the solubilized fraction is
depleted, more drug is drawn into solution [from] the
particulate depot. Thus, the emulsion globules comprising
solubilized API enable controlled API release over time.
{id. 1107.)
9. Lee teaches “the emulsion globules comprising solubilized API,
API nanoparticles, or a combination thereof can be diluted with aqueous
solutions without stability loss. . . . The concentration of API, however,
depends on the solubility of the actual drug and the amount of solvent used
to dissolve it” {id. 1109).
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Principles of Law
“Absent an express definition in their specification, the fact that
appellants can point to definitions or usages that conform to their
interpretation does not make the PTO’s definition unreasonable when the
PTO can point to other sources that support its interpretation.” In re Morris,
127 F.3d 1048, 1056 (Fed. Cir. 1997).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Non-Final Act. 3—8; FF 1—9) and agree
that the claims are obvious over Bae, Murrell, and Lee. We address
Appellant’s arguments below.
Appellant contends the “structure of Appellant’s recited formulation
enables the dynamic equilibriums to remain equal. Appellant’s recited
transdermal formulation comprises a ‘saturated aqueous solution’ of API
that is ‘transdermally administered’” (App. Br. 8). Appellant contends “[n]o
cited reference teaches such a relationship. Moreover, none of the cited
references teach a saturated aqueous solution of the API, which retains its
saturated concentration upon transdermal application” (id. ).
The Examiner responds
that Appellant is claiming a well-recognized phenomenon of
solution thermodynamics whereby, when solute is present in a
solvent medium at levels above the saturation solubility of that
solute in the selected solvent, the solute will exist in both a
solid state as well as in solution. As would be recognized by
one of ordinary skill in the art, in such situations there would be
a solution equilibrium in place whereby a constant, balanced
interchange between solute particles (molecules or ions) in the
solid state and in solution would occur, such phenomenon
considered to be a “dynamic equilibrium,” which equilibrium
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would necessarily encompass the “self-replenishing”
phenomenon argued by Appellant, all in accord with well-
accepted applications of Le Chatelier’s Principle.
(Ans. 5.)
We find that the Examiner has the better position. Claim 1 recites a
formulation that comprises a pharmaceutical ingredient, here elected as
piroxicam, in two forms. The first form is a nanoparticle made of the
pharmaceutical and the second form is a saturated aqueous solution of the
pharmaceutical. As the Examiner points out, as pharmaceutical diffuses
from the aqueous solution in the transdermal patch into the patient, reducing
the amount of pharmaceutical in the aqueous solution, the dynamic
equilibrium between the nanoparticles composed of pharmaceutical and the
saturated aqueous solution will result in dissolution of sufficient solid
nanoparticle to replace the pharmaceutical that diffused into the patient, until
the nanoparticle has fully dissolved (see id.).
Lee teaches this process, explaining that “drug solids act as a depot
and, as the solubilized fraction is depleted, more drug is drawn into solution
[from] the particulate depot” (FF 8). This understanding is also consistent
with the Specification, which teaches the nanoparticle “pharmaceutical
preparation of the present invention serves as a self-replenishing depot for as
long as the active pharmaceutical ingredient remains in suspension and for
some time thereafter until all or substantially all of the active pharmaceutical
ingredient is depleted” (Spec. 151).
Therefore, the broadest reasonable interpretation of claim 1, consistent
with the Specification, is that the “saturated aqueous solution” necessarily
results in a solution comprising a mixture combining nanoparticles with
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pharmaceutical and an aqueous solution with pharmaceutical in equilibrium.
“[DJuring patent prosecution when claims can be amended, ambiguities
should be recognized, scope and breadth of language explored, and
clarification imposed.” In re Zletz, 893 F.2d 319, 322 (Fed. Cir. 1989).
We note:
Appellant does not contest that both a solid particulate state and
a solubilized state can be present in the emulsion taught by Lee;
however, [Appellant contends] in no way does the presence of
both a particulate state and a solubilized state necessarily imply
that “said formulation contains a saturated aqueous solution of
the active pharmaceutical ingredient,” nor does it imply that
“said formulation, when transdermally administered, provides
for a dynamic equilibrium with the amount of said active
pharmaceutical ingredient delivered transdermally and the
amount in suspension so that the solution retains a saturated
concentration of said active pharmaceutical ingredient,” as
required by [c]laim 1.
(App. Br. 10.) Similarly, Appellant contends “dynamic equilibrium is not
equilibrium per se because the rate of dissolution of the drug is not based on
equilibrium constants for the drug but rather on the rate of delivery of the
drug to the body” (Reply Br. 7).
We find this argument unpersuasive because Appellant has provided
no evidence, other than attorney argument, that the obvious combination of
Bae, Murrell, and Lee, resulting in a transdermal delivery system with
piroxicam nanoparticles and a piroxicam aqueous solution, would not result
in a “saturated aqueous solution” or “dynamic equilibrium” as required by
claim 1 and expected based on Le Chatelier’s principle as discussed by the
Examiner (see Ans. 6—7). See In re Pearson, 494 F.2d 1399, 1405 (CCPA
1974) (“Attorney’s argument in a brief cannot take the place of evidence.”).
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Appellant contends the “processes disclosed in Bae produce
nanoparticles with enhanced bioavailability for the purpose of providing a
direct and immediate bolus releasethat “Murrell does not remedy the
above deficiencies of the teachings of Bae, nor is Murrell cited for this
purpose”; and that “Lee provides no discussion of: the solubilized portion
being at saturation, a dynamic equilibrium, or Le Chatelier’s Principle”
(App. Br. 9, 11).
We find these arguments unpersuasive because they do not address
the references in combination, nor do these arguments address the
knowledge of the skilled artisan of the prior art Le Chatelier’s principle. See
In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (“Non­
obviousness cannot be established by attacking references individually
where the rejection is based upon the teachings of a combination of
references.”) A reference “must be read, not in isolation, but for what it
fairly teaches in combination with the prior art as a whole.” (Id.) See also
Perfect Web Techs., Inc. v. Info USA, Inc., 587 F.3d 1324, 1329 (Fed. Cir.
2009) (explaining that the obviousness analysis “may include recourse to
logic, judgment, and common sense available to the person of ordinary skill
that do not necessarily require explication in any reference or expert
opinion”).
Appellant contends: “If the movement of API from particulate form
to soluble form is a consequence of a dynamic equilibrium in Lee, such a
teaching is not enabled by Lee” (App. Br. 11). Appellant further contends
“in various embodiments described in Lee, the solid state is formed through
instability of the emulsion and the application of shear forces. Thus, it
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cannot be implied from the presence of both a solid state and a soluble state
in Lee that the solution is at a saturated concentration” {id. at 12).
We do not find this argument persuasive and agree with the Examiner
that in Lee,
the equilibrium between solid and solvated fractions must
necessarily exist in order for the dosage form to perform as
described. Nor is the inherent instability of emulsion systems
over time relevant to the obviousness issue. The fact that the
emulsion may become unstable is immaterial as long as the
emulsion remains stable long enough to perform as taught. In
this regard, the invention as claimed recites no limitations
directed to time-related factors and, thus, can be read to
encompass a system that displays stability even if for only a
limited time, a teaching, incidentally, absent from the cited
reference.
(Ans. 6—7.)
We also note that Lee directly contradicts Appellant’s concerns
regarding enablement of the composition or the composition’s stability and
solubility, teaching that “the emulsion globules comprising solubilized API,
API nanoparticles, or a combination thereof can be diluted with aqueous
solutions without stability loss. . . . The concentration of API, however,
depends on the solubility of the actual drug and the amount of solvent used
to dissolve it” (PL 9). Thus, Lee recognizes the emulsion may be in aqueous
solution in a stable form, and that the concentration depends solely upon
solubility and solvent amounts, supporting the Examiner’s argument that
Lee teaches, and Le Chatelier’s principle inherently results, in a solution
where the solvent solubilizes pharmaceutical from the nanoparticles until the
solvent is saturated, and then remains in equilibrium with the nanoparticles
until they completely dissolve (see PL 8).
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Appellant contends “there is no obvious reason a person skilled in the
art would combine the elements of each reference in a manner that would
have led to Appellant’s recited formulation” (App. Br. 12). Appellant
contends that because “Lee, however, already teaches the formation of API
nanoparticles within emulsion globules having diameters of about 10 nm to
about 1000 nm” then “[a]ny positive impact of using such particle
distributions would already be present in the Lee system. Thus, Appellant
fails to understand, and the Examiner fails to articulate, why a person skilled
in the art would be motivated to combine the cited references” {id. at 13—14).
We do not find this argument persuasive because we agree with the
Examiner that Bae teaches “the increase in solubility arising from smaller
particle sizes, particularly advantageous for sparingly soluble active species,
and, perhaps more importantly, the increased bioavailability realized from
the enhanced solubility” which provide reasons to use nanoparticles of
piroxicam at those sizes in combination with Lee’s teaching of a transdermal
delivery formulation for “control of active ingredient release over time that
the equilibrium-controlled depot of solid drug particles provides” (Ans. 7).
That is, Lee teaches a transdermal delivery system comprising
nanoparticles in equilibrium with an aqueous solution so “the rate of release
of the drug can be precisely manipulated” (FF 6—9). Murrell teaches that
piroxicam, the elected species, may be incorporated into transdermal
delivery systems (FF 4—5). The ordinary artisan, interested in increasing
ingredient release and bioavailablity of piroxicam in a transdermal delivery
system rendered obvious by Lee and Murrell, would have reasonably used
nanoparticles as prepared by Bae for a sparingly water soluble drug like
piroxicam because Bae teaches “nanoparticles of a sparingly water-soluble
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drug, which exhibits enhanced bioavailability and particle size stability of
the drug” (FF 1). See KSR Inti Co. v. Teleflex Inc., 550 U.S. 398, 416
(2007) (“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”)
Appellant does not identify any unexpected result.
We recognize, but find unpersuasive, Appellant’s contention that
the claimed feature of a dynamic equilibrium requires that, as
the active ingredient is delivered through the skin, the
suspension acts as a reservoir to maintain a steady state system
for the sustained release of the active ingredient through the
skin. To create a dynamic equilibrium, suspended particles of
the active pharmaceutical ingredient replenish the active
pharmaceutical ingredient in solution as it is delivered
transdermally through the patient’s skin.
(Reply Br. 10.) As already discussed, Appellant’s argument fails to explain
why the system in Lee, a transdermal delivery system comprised of
nanoparticles with active pharmaceutical agent in an aqueous solution also
containing active pharmaceutical agent (FF 6—9), does not necessarily and
inherently result in the same dynamic equilibrium claimed by Appellant.
See In re Best, 562 F.2d 1252, 125^55 (CCPA 1977) (“[W]here the Patent
Office has reason to believe that a functional limitation asserted to be critical
for establishing novelty in the claimed subject matter may, in fact, be an
inherent characteristic of the prior art, it possesses the authority to require
the applicant to prove that the subject matter shown to be in the prior art
does not possess the characteristic relied on.”)
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SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) as obvious over Bae, Murrell, and Lee. Claims 2—12 and 16—18 fall
with claim 1.
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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