JEON, Hong Ryeol et al.

Patent Trials and Appeals Board

Sep 24, 2019

14783670 - (D) (P.T.A.B. Sep. 24, 2019)

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.
14/783,670 10/09/2015 Hong Ryeol JEON 16477-000043-US-NP 6409
28997 7590 09/24/2019
Harness Dickey (St. Louis)
7700 Bonhomme, Suite 400
ST. LOUIS, MO 63105
EXAMINER
SONG, JIANFENG
ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
09/24/2019 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):
bkamer@hdp.com
stldocket@hdp.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte HONG RYEOL JEON, DO-WOO KWON, BONG-SANG LEE,
SU-JUN PARK, BONG-GEUN CHA, JUN-KI KIM, JIYEONG HAN, and
MYEONGCHEOL KIL
____________

Appeal 2019-003541
Application 14/783,670
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 a
tadalafil free base-containing film. 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 CTC Bio,
Inc. (see App. Br. 3).
2 We have considered and herein refer to the Specification of Aug. 25, 2016
(“Spec.”); Final Office Action of July 3, 2018 (“Final Act.”); Appeal Brief
of Dec. 20, 2018 (“App. Br.”); Examiner’s Answer of Mar. 5, 2019
(“Ans.”); and Reply Brief of Apr. 4, 2019 (“Reply Br.”).
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Statement of the Case
Background
“Tadalafil free base is very difficult to prepare [as] a film in an
aqueous solution state due to strong hydrophobicity” (Spec. 4, 2–3). “When
tadalafil is produced in . . . a dispersed or suspended state, a layer separation
of a film preparing solution and non-uniformity of an active ingredient may
occur due to strong water repellency. Such layer separation and non-
uniformity takes place in processes of preparing the film” (Spec. 2:6–10).
“The present disclosure is based on . . . a film containing a desired
content of tadalafil free base with a thickness and a size suitable for
individual dose adaptation . . . obtained by dispersing (or suspending)
tadalafil free base in a polymer solution based on strong hydrophobicity of
tadalafil free base” (Spec. 4:4–9). “The present disclosure provides a
method of producing a tadalafil free base-containing film by which a
tadalafil free base-containing film is produced by drying a polymer solution
having tadalafil free base dispersed therein by the addition of a
vinylpyrrolidone-based polymer and/or a polyethyleneglycol-based polymer
as a dispersion stabilizing agent” (Spec. 11:23–12:4).
The Claims
Claims 13, 21, 24, and 25 are on appeal. Claims 1–12 are withdrawn.
Independent claim 13 is representative and reads as follows:
13. A method of preparing a tadalafil free base-
containing film, comprising:

adding a tadalafil free base, a dispersion stabilizing
agent, a film-forming polymer, and optionally a surfactant, a
plasticizer, or mixtures thereof to water, to prepare a polymer
solution; and
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drying a polymer solution in which the tadalafil free base
is dispersed and 2 wt% or less of the total tadalafil free base is
dissolved,

wherein the dispersion stabilizing agent is selected from
a polyvinyl alcohol-polyethylene glycol copolymer,
polyethylene glycol, a polyvinylpyrrolidone or a
vinylpyrrolidone-vinyl acetate copolymer or mixtures thereof,

wherein the film-forming polymer has a content of
20 wt% to 80 wt% based on a total weight of the dried film and
comprises:

a first polymer having a viscosity of 15 cp or less as
measured in a 2 wt% aqueous solution, and

a second polymer having a viscosity of 50 cp or more as
measured in a 2 wt% aqueous solution, the second polymer
having a content of 3 wt% or less based on a total weight of the
dried film,

wherein the tadalafil free base is stably dispersed in the
tadalafil free base-containing film,

wherein the film comprises 10 wt% to 30 wt% of the
tadalafil free base, and 0.2 wt% to 5 wt% of the dispersion
stabilizing agent, and

wherein 90 wt% or more of a solvent that is used in
producing the film is water.

The Rejection
The Examiner rejected the claims under 35 U.S.C. § 103 as obvious
over Bangalore3 and Andrews.4

3 Bangalore, US 2009/0047330 A1, published Feb. 19, 2009.
4 Andrews et al., US 2011/0136814 A1, published Jun. 9, 2011.
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Obviousness
The Examiner finds Bangalore teaches a process to make a film
dosage form containing tadalafil as an active agent (Ans. 4). The Examiner
finds the film dosage form may include 0.01 to 80% by weight tadalafil, 5 to
99% by weight film-forming polymers, 0.5 to 20% by weight plasticizer,
and 0.1 to 10% emulsifier (id.). More particularly, the Examiner finds
Bangalore teaches a combination of first and second film formers, such as
pullulan and xanthan gum, or Methocel hydroxypropyl methylcellulose
(HPMC) and Maltodextrin, as shown in the working examples (id. at 20).
The Examiner finds that the process includes adding a film-forming polymer
to water to form a polymer solution, dispersing the bioactive agent in water,
adding the bioactive agent along with additional ingredients to the mixture,
and forming a film (id. at 4–5).
The Examiner states that “Bangalore does not expressly teach the film
former comprising a first polymer having a viscosity of 15 cp or less . . . and
a second polymer having a viscosity of 50 cp or more . . . the second
polymer at 3 wt% or less of the total weight of dried film” (Ans. 6).
However, the Examiner finds the amount of “film former is an adjustable
and optimizable parameter” (id. at 7). The Examiner finds “although
Bangalore is silent about all the functional properties instantly claimed [i.e.,
tadalafil is dispersed] it does not appear that the claim language or
limitations result in a manipulative difference in the method steps when
compared to the prior art disclosure” (id. at 8). Therefore, the Examiner
concludes that “the same tadalafil is being dispersed with the polymers . . .
in the water in both the instant claims and the prior art reference” (id.).
The issue with respect to this rejection is:
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(i) Does a preponderance of evidence of record support the
Examiner’s conclusion that the prior art renders the claims obvious?
(ii) If so, has Appellant presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact (“FF”)
1. Bangalore teaches “water soluble polymer based edible films for the
oral delivery of Sildenafil citrate, [] Tadalafil, or Vardenafil HCl as active
agents” (Bangalore ¶ 18).
2. Bangalore teaches “the polymers include [] water soluble polymers
. . . along with suitable amounts of . . . plasticizers, buffering agents,
sweeteners, emulsifying agents and suitable amounts of drug substance. . . .
The resultant combination . . . can be a solution, suspension or emulsion
which can be spread to form films” (Bangalore ¶ 26).
3. Bangalore teaches “a film former concentration can be in the range of
5–99% of the dry weight of the films” (Bangalore ¶ 40).
4. Bangalore teaches the film forming polymers may include
Hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC),
pullulan, polyethylene glycols, polyvinylpyrrolidone (PVP), xanthan gum,
and maltodextrin, used “by themselves or in combination with other
polymers” (Bangalore ¶¶ 41, 42, 44).
5. Bangalore teaches:
In a preferred embodiment, the percentage dry weight
concentration of at least single ingredients incorporated in a
film in each of the following categories is as follows:
emulsifying agent (0.1%–10%), plasticizer(0.5–20%), active
agents (0.01–80%), taste modifying agents (0.1–10%), coloring
agents (0.01–5% ), water soluble inert fillers (0.5–50% ),
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preservatives (0.01–10%), buffering agents (0.1–10%) and
stabilizers (0.01–5%)

(Bangalore ¶ 45).

6. Bangalore teaches a method in which:
[T]he film forming polymer was dissolved in water or
hydroalcoholic mixture. The bioactive agent was either
dissolved or dispersed in water or hydroalcoholic mixture and
added to the polymer solution under mild agitation. In addition
to the active agent and the film forming polymer, any of the
ingredients listed above may be added and dispersed or
dissolved uniformly in to [sic] hydrocolloid solution.

7. Bangalore teaches specific formulations containing Sildenafil Citrate,
Methocel E15 (HPMC), Methocel E4 M (HPMC), Plasdone K 29-32 (PVP),
maltodextrin, propylene glycol, glycerol, sorbitol, sucralose, tween 80 and
water (Spec. ¶ 53, Table 1, Examples 2, 3).
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Analysis
We adopt the Examiner’s findings of fact and conclusion of law (Ans.
4–25; FFs 1–7) and agree that Bangalore and Andrews render the claims
obvious. We address Appellant’s arguments below.
Appellant contends “the Examiner provides no reason to select
tadalafil rather than sildenafil citrate” (App. Br. 8). Appellant contends
“Bangalore exemplifies only 0.5–5 wt% sildenafil citrate in each of the 9
working examples” (id.). Appellant contends sildenafil and tadalafil “are
structurally distinct compounds, having different chemical properties (e.g.,
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sildenafil citrate has an aqueous solubility of 3.5 mg/mL whereas tadalafil is
insoluble in water)” and “there is no reason to expect that tadalafil films can
be formulated as sildenafil citrate films in the absence of any additional
evidence” (id.).
We find this argument unpersuasive. Bangalore expressly teaches
tadalafil as one of three active agents to be used in the film formulations (FF
1). “A reference must be considered for everything that it teaches, not
simply the described invention or a preferred embodiment.” In re Applied
Materials, Inc., 692 F.3d 1289, 1298 (Fed. Cir. 2012). Moreover, Bangalore
teaches a method in which the active agent, e.g., tadalafil, is dispersed in
water and combined with a dissolved polymer to form a film (FF 6).
Because Bangalore suggests tadalafil is one of three active agents, and
teaches that the active agents may be dispersed rather than dissolved in
water, we are not persuaded that the Examiner erred.
Appellant contends “the method of Claim 13 is distinguished from
Bangalore through the presence of the particular dispersion stabilizing agent,
. . . a first polymer having a viscosity of 15 cp or less, and a second polymer
having a viscosity of 50 cp or more” (App. Br. 9). Appellant argues
“[n]either the cited art nor Examiner provide any rationale for selecting
polyethylene glycol, pullulan, and xanthan gum from among the 109,736
three-polymer combinations of the eighty-eight film-forming polymers of
Bangalore” (id.).
We not find Appellant’s argument persuasive. The disclosure of “a
multitude of effective combinations does not render any particular
formulation less obvious. This is especially true because the claimed
composition is used for the identical purpose taught by the prior art.”
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Merck, 874 F.2d at 807. “[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). Bangalore teaches that the film forming composition
may include combinations of film forming polymers, plasticizers, and
emulsifiers (FFs 4, 5). The film forming polymers may include
combinations, such as pullulan and xanthan gum (FF 4), or Methocel E15,
Methocel E4M, and Maltodextrin, along with PVP (FF 7). Within these
known film forming polymers, it would have been obvious for a person of
ordinary skill in the art to modify the formulations in order to prepare a
tadalafil containing film. “The combination of familiar elements according
to known methods is likely to be obvious when it does no more than yield
predictable results.” KSR, 550 U.S. at 416.
Appellant contends “neither reference reports the tadalafil free base
comprising ‘10 wt% to 30 wt%’ of the film and the second polymer
comprising ‘3 wt% or less’” (App. Br. 10). Appellant argues “Bangalore’s
disclosure of an active agent comprising ‘0.01–80%’ of the combination
. . . . is so broad as to be meaningless” (id.). Appellant argues “[w]ithout
any guidance by the art or Examiner, there is simply no suggestion that
xanthan gum in particular, out of the eighty-eight polymers disclosed, should
be selected and present in an amount of 3 wt% or less” (id. at 11). Appellant
contends Peterson “implies that the claimed range needs to be relatively
close to the cited art range, which is not the case here” (Reply Br. 2 (citing
In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)).
We find Appellant’s argument unpersuasive. “[A] prima facie case of
obviousness arises when the ranges of a claimed composition overlap the
ranges disclosed in the prior art.” In re Harris, 409 F.3d 1339, 1341 (Fed.
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Cir. 2005 (citing Peterson, 315 F.3d at 1329)). “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 (Fed. Cir. 1990) (citations omitted).
We address both the range of active agent and second polymer. First,
as to the active agent, Bangalore discloses a broad range of active agent and
a narrower range of sildenafil citrate in the working examples (FF 5, 7). A
person of ordinary skill in the art would have readily optimized the amount
of active agent within the range for the appropriate dosing of tadalafil. The
obviousness analysis “can take account of the inferences and creative steps
that a person of ordinary skill in the art would employ.” KSR, 550 U.S. at
418. “A person of ordinary skill is also a person of ordinary creativity, not
an automaton.” Id. at 421.
Second, as to the amount of polymers, Bangalore teaches the total
amount of film forming polymer ranges from 5–99% by weight (FF 4).
Bangalore further teaches that combinations of polymers may be used (id.).
In the Examples, Bangalore teaches combinations of multiple film forming
polymers, e.g., Maltodextrin, Methocel E15, and Methocel E4M of specific
amounts, falling with the larger range (FF 7). The Examiner has shown the
prior art teaches overlapping ranges that encompass the claimed amount of
polymers. Appellant has not shown that the claimed ranges of polymers are
critical. For example, none of the working examples, including those
described as superior by Appellant (see below), appear to contain a second
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polymer separate from a dispersion stabilizing agent (see Spec. 15, Table 1).
Therefore, we are not persuaded that the Examiner has erred.
Appellant contends the “Examiner has no basis for asserting that the
inherency conclusion is ‘reasonable’” (App. Br. 13). Appellant contends
Bangalore teaches “a solution, suspension, or emulsion” rather than a
dispersion (id.). Appellant further contends “inherency by itself is not
sufficient to establish obviousness . . . as unexpected properties may cause
what may appear to be an obvious composition to be nonobvious” (id. at 14,
citing Honeywell Int’l., Inc. v. Mexichem Amanco Holding S.A. DE C.V.,
865 F.3d 1348, 1355 (Fed. Cir. 2017)). Appellant contends the “Examiner
has not shown that tadalafil would be expected to be dispersed in a
pullulan/xanthan gum/polyethylene glycol mixture” (Appeal Br. 14).
We do not find Appellant’s argument persuasive. Bangalore teaches
the compositions may be formed by preparing a solution or dispersion of
active agent in water which is combined with a dissolved polymer (FF 6).
We do not agree with Appellant’s argument that forming a suspension
suggests a solution rather than a dispersion. Given tadalafil’s known
properties as a water insoluble drug, it would not have been unexpected by
the artisan that tadalafil would be dispersed, rather than dissolved, in an
aqueous solvent and water soluble polymer as suggested by Bangalore.
After a prima facie case is made out, the burden shifts to the Appellant to
show an unobvious difference between the prior art compounds and the
claimed compound because the PTO lacks the resources to do such
comparisons. In re Best, 562 F.2d 1252, 1254–1255 (CCPA 1977).
Accordingly, we are not persuaded that the Examiner erred. Because
Appellant does not argue the dependent claims separately, we agree with the
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Examiner that claims 21, 24, and 25 are prima facie obvious over the prior
art.
Appellant contends the “Examiner has not considered unexpected
results” (App. Br. 14) (emphasis omitted). Appellant contends “films
prepared by the method of Claim 13 have a dispersion stability relative
standard deviation (RSD%) of 0.5–1.1 (Examples 4, 6, 7, and 13[]). In
contrast, compositions prepared by a method utilizing compounds not
recited in Claim 13 but disclosed in Bangalore (Examples 5, 8, 19–12, and
14) have an inferior dispersion stability . . . hav[ing] RSD% of 2.9 and
above” (App. Br. 14–15).
We are not persuaded by Appellant’s evidence for a number of
reasons. First, we begin with Appellant’s submission of the wrong table in
the Appeal Brief, which was corrected in the Reply Brief (Reply Br. 4–5).
Due to Appellant’s submission, the Examiner did not have the opportunity
make the proper comparison and we do not have the Examiner’s expert
opinion before us. Second, Appellant has not submitted evidence in the
Specification or by affidavit that the results are unexpected. “It is well
settled that unexpected results must be established by factual evidence.
Mere argument or conclusory statements . . . [do] not suffice.” In re Soni,
54 F.3d 746, 750 (Fed. Cir. 1995). Third, the results are not commensurate
with the scope of the claims. “It is well established that the objective
evidence of nonobviousness must be commensurate in scope with the
claims.” In re Lindner, 457 F.2d 506, 508 (CCPA 1972). “Commensurate
in scope” means that the evidence provides a reasonable basis for concluding
that the untested embodiments encompassed by the claims would behave in
the same manner as the tested embodiment(s). See id. at 508. The claims
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recite broad ranges encompassing numerous formulations, particularly as to
the film-forming polymers. However, all of the examples are limited to
hydroxypropyl cellulose as the first polymer (see Spec. 15, Table 1).
Moreover, there is no indication that the exemplary formulations include a
second polymer separate from a dispersion stabilizing agent as claimed (see
id.).
Conclusion of Law
A preponderance of the evidence of record supports the Examiner’s
conclusion that the prior art renders the claims obvious. Appellant has not
presented evidence of secondary considerations, that when weighed with the
evidence of obviousness, is sufficient to support a conclusion of non-
obviousness.

CONCLUSION
In summary:
Claims
Rejected
Basis Affirmed Reversed
13, 21, 24, 25 § 103 Bangalore,
Andrews
13, 21, 24, 25

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