Doxey, Ryan

Patent Trials and Appeals Board

Mar 23, 2020

14381370 - (D) (P.T.A.B. Mar. 23, 2020)

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.
14/381,370 08/27/2014 Ryan Doxey 9729-40TS 9306
20792 7590 03/23/2020
MYERS BIGEL, P.A.
PO BOX 37428
RALEIGH, NC 27627
EXAMINER
ALLEY, GENEVIEVE S
ART UNIT PAPER NUMBER
1617
MAIL DATE DELIVERY MODE
03/23/2020 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte RYAN DOXEY
____________

Appeal 2019-003847
Application 14/381,370
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW,
Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL

This is an appeal1,2 under 35 U.S.C. § 134(a) involving claims to nitric
oxide releasing pharmaceutical compositions. The Examiner rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as Novan Inc.
(see Appeal Br. 2).
2 We have considered and herein refer to the Specification of Aug. 27, 2014
(“Spec.”); Final Office Action of Apr. 25, 2018 (“Final Act.”); Appeal Brief
of Oct. 25, 2018 (“Appeal Br.”); Examiner’s Answer of Feb. 15, 2019
(“Ans.”); and Reply Brief of Apr. 15, 2019 (“Reply Br.”).
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Statement of the Case
Background
“Numerous skin diseases or disorders result from inflammation with
the associated release of mediators from a variety of inflammatory and
resident cells” (Spec. ¶ 3). Delivery of a moisture activated therapeutic
agent “should be provided without substantial irritation or exacerbation of
the inflammatory condition” (id. ¶ 4). Aqueous vehicles may be
inappropriate for moisture activated therapeutic agents; however, mineral oil
ointments may reduce the effectiveness of the therapeutic agent when
applied (id.). “The present invention provides pharmaceutical composition
that may be administered topically . . . [that] may comprise . . . a
hydrophobic base, [] an amphiphilic compound . . . [and] a moisture
activated active pharmaceutical ingredient.” (id. ¶ 27).
The Claims
Claims 1, 3, 7–10, 12–14, 18–21, and 25–31 are on appeal.3
Independent claim 1 is representative and reads as follows:
1. A nitric oxide (NO)-releasing pharmaceutical
composition, the NO-releasing pharmaceutical composition
comprising:
a hydrophobic base present in the NO-releasing
pharmaceutical composition at a concentration from about 35%
to about 90% by weight of the NO-releasing pharmaceutical
composition;
an amphiphilic compound present in the NO-releasing
pharmaceutical composition at a concentration from about 1%
to about 30% by weight of the NO-releasing pharmaceutical
composition, wherein the amphiphilic compound is a
polyethylene glycol (PEG) caprylic/capric glyceride;

3 Claims 22 and 23 were withdrawn and claims 2, 4–6, 11, 15–17, and 24
were cancelled (see Appeal Br. 16–19).
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water at a concentration of less than about 2% by weight
of the NO-releasing pharmaceutical composition; and
diazeniumdiolate-functionalized polysiloxane
macromolecules that are NO-releasing co-condensed silica
particles.

(Appeal Br. 16).

The issues
The Examiner rejected claims 1, 3, 7–10, 14, 18–21, and 25–30 under
35 U.S.C. § 103(a) as obvious over Stasko4 and Embil5 (Final Act. 3–9).
The Examiner rejected claims 12 and 13 under 35 U.S.C. § 103(a) as
obvious over Stasko, Embil, and Barthez6 (Final Act. 9–11).
Because both of these rejections rely on the same combination of
references, and Barthez is added solely to address 1–25 wt.% of a humectant
that comprises a polyhydric alcohol (see Final Act. 10), we consider these
rejections together.
The Examiner finds Stasko teaches topical non-aqueous gel
compositions containing diazeniumdiolate-functionalized polysiloxane
macromolecules that are nitric oxide (NO)-releasing co-condensed
silica particles (NitricilTM) (Final Act. 4–5). The compositions may include
1–10% NitricilTM, 10–90 wt.% mineral oil (a hydrophobic base), 5–20 wt.%
cyclomethicone (a hydrophobic polymer and siloxane), 25–55 wt.% caprylic
or capric triglyceride (a co-solvent), and 10–85 wt.% isopropyl myristate (an
amphiphilic compound) (id.). The Examiner finds that any differences in

4 Stasko et al., WO 2011/022652 A1, published Feb. 24, 2011.
5 Embil et al., WO 2012/001403 A1, published Jan. 5, 2012.
6 Barthez et al., US 2010/0286285 A1, published Nov. 11, 2010.
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concentration between the prior art components and the claimed components
would have been the obvious result of routine experimentation (id. at 7).
The Examiner finds Stasko does “not specifically teach wherein the
amphiphilic compound is PEG-6 caprylic/capric glyceride at a concentration
of from about 1% to less than 5% by weight” (id. at 6). The Examiner finds
that Embil teaches topical compositions substantially free from water that
include flurbiprofen and 1–10 wt.% polyglycerides, such as PEG-6 caprylic
capric glyceride (id.). PEG-6 caprylic capric glyceride functions as a co-
solvent and skin penetration enhancer (id.). The Examiner finds Stasko and
Embil teach nonaqueous pharmaceutical compositions used for topical drug
delivery of anti-inflammatory drugs, e.g., flurbiprofen (id. at 8). The
Examiner determines “it would have been prima facie obvious for a person
of ordinary skill in the art to combine their respective teachings and to
incorporate 1–10% by weight PEG-6 caprylic/capric glycerides into the
composition of [Stasko], with a reasonable expectation of success, at the
time of the instant application” (id.).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that the combination of Stasko, Embil,
and Barthez renders the claims obvious?
Findings of Fact (“FF”)
1. Stasko teaches topical gels including 0.1–20 wt.% NO-releasing
diazeniumdiolate-functionalized polysiloxane macromolecules and a
hydrophobic, non-aqueous gel base (Stasko ¶¶ 8–10).
2. Stasko teaches the NO-releasing macromolecules may have a
hydrodynamic range of 1–100 nm, “which may maximize trans-epidermal
skin penetration and enhance nitric oxide delivery to deeper skin structures”
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or a hydrodynamic range of 101–1000 nm which may “limit skin
penetration, systemic absorption, and any resulting toxicity of the
macromolecular scaffold . . . . Selective delivery to the stratum corneum,
epidermis or dermis may be achieved by varying the particle size” (Stasko ¶
71).
3. Stasko teaches that:
The properties of the topical gels, including the NO-
release profile may be tailored by the selection of the gel
composition. The gels may also provide beneficial or
therapeutic action to the skin or wound bed (e.g., moisturize,
absorb wound exudate, provide an occlusive barrier, etc.) that
may directly affect skin conditions or wound healing. The
excipients that form the gels may also indirectly affect wound
healing by affecting the stability of the diazeniumdiolate-
functionalized polysilane macromolecules or other therapeutic
agents within the medicament.

(Stasko ¶ 74).

4. Stasko teaches “excipients for use in topical gels are well-
known in the art . . . Exemplary excipients may include” humectants,
glycerol, polyethylene glycols, solvents, and emollients, e.g., glycerine and
pentylene glycol. “Emollients may be useful to prevent stratum corneum
dehydration occurring due to the use of anhydrous solvents in the
formulation” (Stasko ¶ 75).
5. Stasko teaches polymers may act as excipients, including
hydrophobic polymers, e.g., polysiloxanes and polyethylene. Compositions
containing hydrophobic polymers may include 60–70 wt.% silicon elastomer
(Stasko ¶¶ 79, 105).
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6. Stasko teaches surfactants may be used to reduce the interfacial
surface energy and “may facilitate spreading of the ointment or liquid over a
wider area” (Stasko ¶ 84).
7. Stasko teaches “[e]xemplary solvent excipients that may be
useful in hydrophobic formulations may include capric/caprylic
triglycerides, isopropyl myristate, [and] mineral oil” (Stasko ¶ 86).
8. Stasko teaches “[i]n addition to the diazeniumdiolate-
functionalized polysiloxane macromolecules and excipients, the topical gels
may also include at least one additional therapeutic agent such as . . . anti-
inflammatory agents,” e.g., “flurbiprofen” (Stasko ¶¶ 87, 92).
9. Stasko teaches a gel including:
diazeniumdiolate-functionalized polysiloxane macromolecules,
caprylic or capric triglyceride at a concentration in a range of
25 to 55 weight percent; fumed silica at a concentration in a
range of 4 to 8 weight percent; cyclomethicone at a
concentration in a range of 5 to 20 weight percent; optionally,
isopropyl myristate at a concentration in a range of 10 to 85
weight percent; and optionally, mineral oil at a concentration in
a range of 10 to 90 weight percent.

(Stasko ¶ 112).

10. Embil teaches topical flurbiprofen-containing compositions
useful for treating conditions associated with inflammation and pain (Embil
1).
11. Embil teaches the “compositions are substantially free from
water (i.e., they are substantially anhydrous)” and include a solubilizing
system (Embil 3.)
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12. Embil teaches the solubilizing system may include co-solvents
having skin penetration enhancing properties, including polyoxyglycerides,
such as PEG-6-caprylic/capric glyceride (Embil 5).
13. Embil teaches the polyoxylgyceride co-solvent may be present
in a concentration of 1–10 wt.% (Embil 8).
14. Barthez teaches an anhydrous ointment containing a water
sensitive active ingredient and an emollient to promote the well-being of
skin (Barthez ¶¶4, 69).
15. The emollient may include liquid fatty acid substances,
including humectants such as polyols or glycerol, in an amount of 0.01–30
wt.% (Barthez ¶¶ 69, 71, 78).
Principles of Law
“In determining whether the subject matter of a patent claim is
obvious, neither the particular motivation nor the avowed purpose of the
patentee controls. . . . [A]ny need or problem known in the field of endeavor
at the time of invention and addressed by the patent can provide a reason for
combining the elements in the manner claimed.” KSR Int’l Co. v. Teleflex
Inc., 550 U.S. 398, 419–20 (2007).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. 3–9; FFs 1–15) and agree that
the claims are rendered obvious by Stasko, Embil, and Barthez. We address
Appellant’s arguments below.
Appellant argues “[t]here is no reason to select a [PEG]
caprylic/capric glyceride in a composition as claimed” (Appeal Br. 4,
emphasis omitted). Appellant contends both Stasko’s isopropyl myristate
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and Embil’s PEG caprylic/capric glyceride are optional components, chosen
from a “laundry list” of excipients (id. at 5–7). Appellant argues “[t]he
disclosure in Stasko of isopropyl myristate fails to describe or suggest a PEG
caprylic/capric glyceride” (id. at 5, emphasis omitted). Appellant argues that
“Embil fails to provide the requisite motivation or suggestion to specifically
select and include a PEG caprylic/capric glyceride in the compositions of
Stasko” (id. at 6, emphasis omitted).
More specifically, Appellant contends that Embil describes a
solubilizing system for a small molecule active agent, e.g., flurbiprofen (id.
at 6). Appellant contends that the solubilizing system forming a solution
would not have been used for a diazeniumdiolate-functionalized
polysiloxane macromolecule particulate (id.). Appellant submits a
Declaration7 by the Inventor, attesting that one skilled in the art would not
“have had any reason to believe that a PEG-8 caprylic/capric glyceride could
be used to increase percutaneous absorption of the diazeniumdiolate-
functionalized polysiloxane macromolecules of Stasko, particularly since it
would require absorption of a particulate” (id., citing Decl. ¶ 11).
We find these arguments unpersuasive. Appellant’s claim 1 recites
“the NO-releasing pharmaceutical composition comprising . . . .” (Appeal
Br. 16, 19). “Comprising is a term of art used in claim language which
means that the named elements are essential, but other elements may be
added and still form a construct within the scope of the claim.” Amgen Inc.
v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1344–45 (Fed. Cir. 2003).

7 Declaration of Ryan Doxey dated Jun. 9, 2017 (“Decl.”) We note that the
Declaration addresses a different rejection than that currently pending and
does not directly address the obviousness of combining Embil with Stasko
(see Doxy Decl. ¶¶ 4, 8).
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We note that Appellant’s Specification teaches that “combinations of
[active pharmaceutical ingredients] may be included in the compositions”;
that “[e]xamples of anti-inflammatory agents include . . . flurbiprofen”; and
that “[a]ny suitable NO-releasing compound may be used in a
pharmaceutical composition” “[i]n some embodiments, the nitric oxide-
releasing compound comprises diazeniumdiolate-functionalized
polysiloxane” (Spec. ¶¶ 46, 53, 57, 61).
Thus, when the term “comprising” in claim 1 is read in light of a
Specification that expressly contemplates compositions with combinations
of active pharmaceutical agents including flurbiprofen and NO-releasing
compounds, we interpret claim 1 to allow for additional active components,
e.g., flurbiprofen, and additional excipients other than those claimed.
“[D]uring examination proceedings, claims are given their broadest
reasonable interpretation consistent with the specification.” In re Hyatt, 211
F.3d 1367, 1372 (Fed. Cir. 2000).
Both Stasko and Embil teach anhydrous compositions for treating
inflammation that may include flurbiprofen (FFs 8, 10, 11). Both Stasko and
Embil teach compositions containing hydrophobic bases and amphiphilic
compounds, e.g., isopropyl myristate and PEG caprylic/capric glycerides,
respectively (FFs 1, 7, 9, 12, 13). Stasko suggests the anhydrous
compositions may be modified to improve NO-release, provide benefits to
the skin or wound bed, and incorporate excipients that improve the stability
of other therapeutic compounds in the formulation, e.g., flurbiprofen (FF 3).
Embil teaches solvent systems including PEG-6-caprylic/capric glyceride to
enhance penetration of flurbiprofen (FF 12). Because Stasko teaches that
compositions may be modified to improve the therapeutic properties of
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NitricilTM and additional active agents, a person of ordinary skill in the art
would have been motivated to improve the composition for delivering
flurbiprofen as taught by Embil. Therefore, we agree with the Examiner that
the prior art provides a reason for combining the references in the manner
claimed.
We also do not find the “laundry list” argument persuasive. Simply
because the prior art “discloses a multitude of effective combinations does
not render any particular formulation less obvious.” Merck & Co. v.
Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). “[P]icking and
choosing may be entirely proper in the making of a 103, obviousness
rejection.” In re Arkley, 455 F.2d 586, 587 (CCPA 1972). Appellant does
not identify a secondary consideration demonstrating criticality or anything
unexpected about the combination of two known prior art pharmaceutical
agents (FF 1, 8).
Appellant further argues the “combination fails to provide a
reasonable expectation of success” (Appeal Br. 7, emphasis omitted).
Appellant contends that the “compositions of Embil are distinctly different
than those of Stasko in that the composition[s] of Embil comprises a glycol
ether and glycol ester and are for solubilizing flurbiprofen” (id. at 7–8).
Appellant argues that there is no teaching that optional compounds for
solubilizing a small molecule active agent would have been suitable for the
diazeniumdiolate functionalized macromolecules of Stasko. Appellant
contends “Stasko describes embodiments to selectively accumulate
diazeniumdiolated macromolecules in the stratum corneum and limit skin
penetration” (id. at 8, citing Stasko ¶¶ 71, 102).
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We are not persuaded by Appellant’s argument. As discussed above,
the Examiner has identified a reason in the prior art to combine the
references. The combined prior art teaches topical compositions containing
the same anhydrous excipients, used for the same purpose, i.e., treating
inflammation. Moreover, Stasko teaches varying the particle size of the
diazeniumdiolated macromolecules may limit skin penetration or may
maximize skin penetration (FF 2, emphasis added). Contrary to Appellant’s
argument, Stasko teaches that a person of ordinary skill in the art would
have had a reasonable expectation of success in varying the parameters of
the diazeniumdiolated macromolecules, excipients, and additional active
agents, e.g., flurbiprofen, as combined with Embil, to obtain a
therapeutically effective composition. “Obviousness does not require
absolute predictability of success . . . all that is required is a reasonable
expectation of success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009).
Finally, Appellant contends the Examiner relies on impermissible
hindsight by using the Specification as a guide (Appeal Br. 5). We are not
persuaded. Because the Examiner “takes into account only knowledge that
was within the level of ordinary skill in the art at the time the claimed
invention was made and does not include knowledge gleaned only from
applicant’s disclosure,” reconstructing the composition is proper. In re
McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
Claim 19
Appellant argues claim 19 is separately patentable from claim 1
(Appeal Br. 8). Appellant repeats the argument against combining Stasko
and Embil, discussed above as to claim 1 (id. at 8–9). Appellant further
argues that Stasko does not describe or suggest a composition containing
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35–80 wt.% hydrophobic hydrocarbon polymer, 1–20 wt.% mineral oil, and
1–20 wt.% PEG caprylic/capric glyceride (id. at 9). Appellant argues
“Embil fails to even mention mineral oil and does not describe a
hydrophobic hydrocarbon polymer” (id.).
We are not persuaded by Appellant’s argument. Appellant argues
against the separate teachings of Stasko and Embil and not the combination.
“Non-obviousness cannot be established by attacking references individually
where the rejection is based upon the teachings of a combination of
references. . . . [The reference] must be read, not in isolation, but for what it
fairly teaches in combination with the prior art as a whole.” In re Merck &
Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
The combination of Stasko and Embil teaches a hydrophobic
hydrocarbon polymer (polyethylene), mineral oil, and a PEG caprylic/capric
glyceride, along with overlapping ranges of these or functionally similar
excipients (FFs 5, 7, 9, 12, 13). Stasko and Embil teach modifying the
amount of excipients to optimize the delivery of active agents, including,
e.g., flurbiprofen (FFs 3, 12). “The law is replete with cases in which the
difference between the claimed invention and the prior art is some range or
other variable within the claims. These cases have consistently held that in
such a situation, the applicant must show that the particular range is critical,
generally by showing that the claimed range achieves unexpected results
relative to the prior art range.” In re Woodruff, 919 F. 2d 1575, 1578, 16
USPQ2d 1934, 1936 (Fed. Cir. 1990) (internal citations omitted). Appellant
has not provided any evidence showing that the claimed ranges are critical.
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Claims 12 and 13
Appellant contends claims 12 and 13 are separately patentable
(Appeal Br. 9–11). Appellant argues that the prior art does not teach a
polyhydric alcohol humectant at a concentration from about 1–25 wt.% of
the composition (id.). Appellant contends Barthez’s compositions
containing solubilized vitamin D are distinctly different from Stasko’s
compositions containing an insoluble particulate and thus the references
cannot be combined (id. at 10).
We are not persuaded by Appellant’s argument. As discussed above,
Stasko teaches compositions that may provide a number of benefits, in
addition to topical application of NO-releasing compounds. For example,
the composition may provide other beneficial or therapeutic action to the
skin and thus include humectants to promote skin well-being as taught by
Barthez (FFs 3, 14). Moreover, both Stasko and Barthez teach topical
compositions including humectants, e.g., polyhydric alcohols, such as
glycerol and pentylene glycol (FFs 4, 14, 15). Because the prior art teaches
the benefits to the skin of including 0.01–30 wt.% of a polyhydric alcohol
humectant, we agree with the Examiner that a person of ordinary skill in the
art would have been motivated to combine the references.
Claims 25–31
Appellant argues claims 25–31 are separately patentable (Appeal Br.
11–14). However, Appellant merely restates the limitations of the claims
and repeats the previous arguments against combining Stasko and Embil.
(see id.). As to claim 29, Appellant further contends the prior art does not
teach the claimed ranges of mineral oil and PEG caprylic/capric glyceride,
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and the Examiner has not established that it would have been “obvious to
try” the claimed amounts (id. at 13).
We are not persuaded by Appellant’s arguments. With respect to
claims 25–28, 30, and 31, we sustain the Examiner’s rejection for the
reasons set forth above, namely that a person of ordinary skill in the art
would have been motivated to combine Stasko and Embil, with a reasonable
expectation of success in the combination. As to claim 29, Appellant has not
provided any evidence of criticality for the claimed ranges (as discussed
above for claim 19). Thus, we sustain the Examiner’s rejection.
Conclusion of Law
A preponderance of the evidence of record support the Examiner’s
conclusion that claims 1, 3, 7–10, 12–14, 18–21, and 25–31 would have
been obvious over the combined prior art.

DECISION
In summary:
Claims
Rejected
35 U.S.C. §  Reference(s)Basis Affirmed Reversed
1, 3, 7–10,
14, 18–21,
25–31
103(a)  Stasko, Embil 1, 3, 7–10, 14,
18–21, 25–31

12, 13 103(a)  Stasko, Embil,
Barthez
12, 13
Overall
Outcome
1, 3, 7–10, 12–14,
18–21, 25–31

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