Li-Chien Hsu et al.

Patent Trials and Appeals Board

Nov 21, 2019

11308265 - (D) (P.T.A.B. Nov. 21, 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.
11/308,265 03/14/2006 Li-Chien Hsu 83338.0005 3264
128997 7590 11/21/2019
LKP Global Law, LLP
1901 Avenue of the Stars, Suite 480
Los Angeles, CA 90067
EXAMINER
HELM, CARALYNNE E
ART UNIT PAPER NUMBER
1615
MAIL DATE DELIVERY MODE
11/21/2019 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 LI-CHIEN HSU and SUN-DE TONG
__________

Appeal 2018-008068
Application 11/308,265
Technology Center 1600
__________

Before JEFFREY N. FREDMAN, JOHN G. NEW, and JAMIE T. WISZ,
Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to a
method for regulating the release of one or more drugs from a drug delivery
system. 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 Biotegra,
Inc. (see App. Br. 2).
2 We have considered and refer to the Specification of Mar. 14, 2006
(“Spec.”); Final Action of June 24, 2016 (“Final Act.”); Appeal Brief of Jan.
3, 2017 (“App. Br.”); Examiner’s Answer of Sept. 19, 2017 (“Ans.”); and
Reply Brief of Feb. 21, 2018 (“Reply Br.”).
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Statement of the Case
Background
“The ability to controllably deliver therapeutic or prophylactic agents
to a specific target site within the body has been a goal in the field of drug
delivery as a controlled level of drugs in the body provides the most
effective prophylactic or therapeutic treatment for preventing or treating
illnesses” (Spec. ¶ 2).
The Claims
Claims 1, 3, 4, 9–11, and 23–25 are on appeal. Claim 1 is
representative and reads as follows:
1. A method for regulating the release of one or more
drugs from a drug delivery system, the method comprising:
providing a coating composition having one or more
water insoluble drugs, a water insoluble bioactive
polyelectrolyte complex, and a non-ionic, water insoluble
polymeric matrix, wherein the bioactive polyelectrolyte
complex is anti-thrombotic and comprises heparin and an
oppositely charged, non-polymeric counter ion, and wherein
the counter ion is a quaternary ammonium salt, and wherein
the drug delivery system is completely soluable in an
organic solvent;
selecting a concentration of the bioactive
polyelectrolyte complex for the coating composition,
wherein the concentration of the bioactive polyelectrolyte
complex modulates the drug release from the drug delivery
system according to an elution profile that includes an initial
release rate and a subsequent release rate;
implanting the drug delivery system in a patient; and
eluting the one or more drugs from the drug delivery
system according to the elution profile.
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The Issue
The Examiner rejected claims 1, 3, 4, 9–11, and 23–25 under 35
U.S.C. § 103(a) as obvious over Davila,3 Lunn,4 Whitbourne,5 and Pacetti6
(Final Act. 3–7).
The Examiner finds Davila teaches “a stent that is coated with a
combination of heparin complexes with a hydrophobic quaternary
counterion, a hydrophobic polymer, and rapamycin, a water insoluble drug”
(Final Act. 4). The Examiner finds Davila teaches the heparin complex may
be benzalkonium heparin, the hydrophobic polymer may be “a combination
of poly(ethylene vinyl acetate) and polybutyl methacrylate” or a “water
insoluble poly(vinylidene fluoride-co-hexafluoropropene) where rapamycin
is included” and the rapamycin is eluted after implantation (Final Act. 4).
The Examiner acknowledges that Davila does not teach heparin
concentrations (Final Act. 4).
The Examiner finds Lunn teaches heparin coated stents where
“heparin concentration is taught to result in an increase in the anti-coagulant
activity it provides” and is therefore a result effective variable (Final Act. 4).
The Examiner finds Whitbourne teaches “a concentration for benzalkonium
heparin included in a hydrophobic polymer coating applied to a stent
surface” where “[i]ncubation in blood serum yields a gradual release of
heparin compound over time as assessed by heparin activity in the blood
serum” (Final Act. 4–5).

3 Davila et al., US 2002/0111590 A1, published Aug. 15, 2002.
4 Lunn, US 5,876,433, issued Mar. 2, 1999.
5 Whitbourne et al., US 2002/0018795 A1, published Feb. 14, 2002.
6 Pacetti et al., US 2004/0224001 A1, published Nov. 11, 2004.
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The Examiner finds the “existence of an initial and subsequent drug
release rate is an inherent feature of any drug delivery system that contains a
drug” (Final Act. 6). The Examiner cites Pacetti as demonstrating “that the
initial and subsequent release rate of a hydrophobic drug from a hydrophobic
polymer matrix is increased by the inclusion of a hydrophilic additive that is
entangled with the polymer matrix” (Final Act. 6).
The Examiner finds it obvious
to prepare the stent of Davila et al. where a coating is composed
of rapamycin, benzalkonium heparin, polybutylmethacrylate,
and poly(ethylene vinyl acetate) because they explicitly teach
the combination of these polymers with rapamycin and provide
this heparin complex as an envisioned heparin to additionally
include in the rapamycin and polymer coating. The selection of
poly(vinylidene fluoride-co-hexafluoropropene) as the polymer
matrix also would have been obvious since Davila et al. provide
it as another desired option. Further following the guidance of
Davila et al. in terms of the proportion of rapamycin to include
in the coating, it would have been obvious to select a 9 wt% or
30 wt% loading level for this drug as is envisioned by Davila et
al. The selection of a concentration of benzalkonium heparin as
taught by Whitbourne in the coating would have also been
obvious since it was previously employed in a hydrophobic
polymer stent coating. This modification would have been
obvious as the combination of prior art elements according to
known methods to yield predictable results. Since heparin
concentration is a result effective variable, it would have been
obvious to one of ordinary skill to adjust the proportion of
benzalkonium heparin upwards to achieve greater anti-
coagulant effect.
(Final Act. 5). The Examiner also finds “it would be expected that some
portion of the benzalkonium heparin complexes of Davila et al. in view of
Lunn, Whitbourne et al., and Pacetti et al. would also elute from their
polymer matrix when incubated in serum or saline” (Final Act. 7).
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The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that Davila, Lunn,
Whitbourne, and Pacetti render the claims obvious?
Findings of Fact
1. Davila teaches “a stent may be utilized in combination with
rapamycin and heparin to treat vascular disease” (Davila ¶ 134).
2. Davila teaches that “a rapamycin coating may be applied to
stents . . . Various polymers may be utilized. For example, as described
above, poly(ethylene-co-vinyl acetate) and polybutyl methacrylate blends
may be utilized. Other polymers may also be utilized, but not limited to, for
example, polyvinylidene fluoride-cohexafluoropropylene” (Davila ¶ 137).
3. Davila teaches “heparin may be complexed with hydrophobic
quaternary ammonium salts, rendering the molecule soluble in organic
solvents (e.g. benzalkonium heparinate, troidodecylmethylammonium
heparinate). Such a formulation of heparin may be compatible with the
hydrophobic rapamycin coating” (Davila ¶ 138).
4. Davila teaches “the rapamycin is directly incorporated into a
polymeric matrix and sprayed onto the outer surface of the stent. The
rapamycin elutes from the polymeric matrix over time and enters the
surrounding tissue” (Davila ¶ 85).
5. Davila teaches
a top coating may be applied to delay release of the
pharmaceutical agent, or they could be used as the matrix for
the delivery of a different pharmaceutically active material.
Layering of coatings may be used to stage release of the drug or
to control release of different agents placed in different layers.
(Davila ¶ 102).
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6. Lunn teaches that “heparin coatings appear highly effective in
inhibiting thrombus formation in this highly thrombotic model of the stent
placed in the ex vivo AV shunt” (Lunn 5:8–11).
7. Lunn teaches “there is indeed a relationship between the
amount and activity of heparin initially coated on the stent, and the reduction
of thrombus at the lesion sites. . . . the more heparin coated, the less
thrombogenic the stent when emplaced at a lesion and expanded beyond its
elastic limit” (Lunn 5:12–18).
8. Whitbourne teaches stent coatings that comprise 2%
benzalkonium heparinate and teaches “[e]ach of the coatings was applied to
a tube substrate to approximate the loading on a stent and the resulting
devices were tested for drug release by placing them in serum and
incubating them at 37° C” (Whitbourne ¶¶ 82–83).
9. Table V of Whitbourne is reproduced below:

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Table V shows “that samples C provided a longer and more uniform release
of the drug than did either of the other two samples” (Whitbourne ¶ 84).
10. Figure 4 of Pacetti is reproduced below:

“As seen from FIG. 4, the rate of release of EVEROLIMUS through the
PBMAPEG topcoat is about twice the rate of release through the PBMA
topcoat” (Pacetti ¶ 73).
11. Pacetti claims a medical article “wherein by increasing the ratio
of the additive polymer to the bulk polymer, the rate of release of the drug is
increased” (Pacetti 7, claim 24).
Principles of Law
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003) and “a reason that would have prompted a person of
ordinary skill in the relevant field to combine the elements in the way the
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claimed new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. 3–7; FF 1–10) and agree that
the claims are rendered obvious by Davila, Lunn, Whitbourne, and Pacetti.
We begin with claim interpretation, since before a claim is properly
interpreted, its scope cannot be compared to the prior art. The phrase at
issue in Claim 1 is the requirement for “an elution profile that includes an
initial release rate and a subsequent release rate.” The phrase appears to
broadly encompass three possible situations: (i) where the initial release rate
is lower than the subsequent release rate; (ii) where the initial release rate is
the same as the subsequent release rate; and (iii) where the initial release rate
is higher than the subsequent release rate.
We first turn to the Specification which is, “[i]n most cases, the best
source for discerning the proper context of claim terms.” Metabolite Labs.,
Inc. v. Lab. Corp. of Am. Holdings, 370 F.3d 1354, 1360 (Fed. Cir. 2004).
The Specification teaches that “the release rate of a water insoluble drug
may be increased in the presence of a bioactive polyelectrolyte complex. In
contrast, the release rate of a water-soluble drug may be reduced in the
presence of a bioactive polyelectrolyte complex” (Spec. ¶ 22). The
Specification further explains that the “bioactive polyelectrolyte complex
may alter the diffusion rate of the polymer matrix. That is, the bioactive
polyelectrolyte complex may increase or decrease the diffusion rate of a
drug from the polymer matrix” (Spec. ¶ 23). Thus, the Specification appears
to encompass both increased and decreased release rates.
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The Specification teaches one factor is the “desired release rate (e.g.,
initial burst and subsequent release rate)” (Spec. ¶ 28), but provides no
discussion on whether the initial burst is lower, the same, or higher than the
subsequent release rate.
As the Specification does not define the relationship between the
initial release rate and the subsequent release rate, we interpret claim 1 as
broadly encompassing all three situations discussed above, where the initial
release rate may be lower, the same, or higher than the subsequent release
rate. See Sjolund v. Musland, 847 F.2d 1573, 1581 (Fed. Cir. 1988) (“while
it is true that claims are to be interpreted in light of the specification and with
a view to ascertaining the invention, it does not follow that limitations from
the specification may be read into the claims”).
Having interpreted claim 1, we now turn to a comparison of the prior
art and the limitations of claim 1. Davila teaches regulating the release of
drugs from a drug delivery system (“control release of different agents
placed in different layers” FF 5). Davila teaches a method comprising
providing a coating composition that comprises: the water insoluble drug
rapamycin (FF 1); a water insoluble polymeric matrix such as poly(ethylene-
co-vinyl acetate) (FF 2; cf. Spec. ¶ 25 “poly(ethylene- vinyl acetate)”) and a
bioactive polyelectrolyte complex that comprises heparin and a quaternary
ammonium salt that is soluble in organic solvents (FF 3). Davila teaches
selecting the composition to control release rates (FF 5) of the drug as placed
on a stent implanted into a body that allows elution of the drug over time (FF
4).
While Davila does not specifically suggest optimization of the heparin
amounts on stents, Lunn teaches that amounts of heparin may be optimized
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finding “the more heparin coated, the less thrombogenic the stent when
emplaced at a lesion and expanded beyond its elastic limit” (FF 7).
Whitbourne evidences that different coatings provide different release rates
at the initial time point and later time points (FF 8–9).
We therefore agree with the Examiner that Davila, Lunn, and
Whitbourne render claim 1 obvious7 because we agree that it would have
been obvious to administer optimized amounts of bioactive polyelectrolyte
complex that comprises heparin and a quaternary ammonium salt in stents to
patients along with rapamycin as suggested by Davila and Lunn. “Where
the general conditions of a claim are disclosed in the prior art, it is not
inventive to discover the optimum or workable ranges by routine
experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955).
As to the elution profile, we agree with the Examiner that “[t]he
existence of an initial and subsequent drug release rate is an inherent feature
of any drug delivery system that contains a drug” (Final Act. 6). That is, the
stent rendered obvious by Davila and Lunn must necessarily have an initial
release rate that is lower, the same, or higher than the subsequent release
rate, consistent with our claim interpretation discussed above. “Where, as
here, the claimed and prior art products are identical or substantially
identical, or are produced by identical or substantially identical processes,
the PTO can require an applicant to prove that the prior art products do not
necessarily or inherently possess the characteristics of his claimed product.”

7 We note the Board may rely on less than all of the references applied by
the Examiner in an obviousness rationale without designating it as a new
ground of rejection. In re Bush, 296 F.2d 491, 496 (CCPA 1961). Here, we
find no reason to rely on Pacetti.
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In re Best, 562 F.2d 1252, 1255 (CCPA 1977). Appellant provides no
evidence that the release rate of the method as claimed differs from that
rendered obvious by Davila and Lunn.
Appellant contends
that the Examiner has not established a prima facie case of
obviousness because the cited references fail to disclose
“selecting a concentration of the bioactive polyelectrolyte
complex for the coating composition, wherein the
concentration of the bioactive polyelectrolyte complex
modulates the drug release from the drug delivery system
according to an elution profile that includes an initial release
rate and a subsequent release rate.”
(App. Br. 4). Appellant specifically contends “the presence of the polymeric
matrix maintains the stability of the bioactive polyelectrolyte complex.
Accordingly, there is no hydrophilic heparin component in the coating
composition” (App. Br. 4).
We are not persuaded because Davila teaches an embodiment that
uses a bioactive polyelectrolyte complex containing heparin and a
hydrophobic quaternary ammonium salt soluble in organic solvent (FF 3) as
required by claim 1. The presence or absence of “hydrophilic heparin” is
irrelevant because claim 1 neither requires nor excludes the presence of
hydrophilic heparin and to the extent that the Examiner or Appellant address
“hydrophilic heparin”, these arguments are not addressed to claim 1 as
written.
Claim 1 simply requires the heparin/quaternary ammonium salt
complex results in initial and subsequent release rates. As discussed above,
claim 1 may encompass embodiments where the initial rate is lower, the
same, or higher than subsequent release rates. We agree with the Examiner
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that Davila necessarily and inherently anticipates at least one of these
embodiments in claim 1 (see Final Act. 6). To the extent that Appellants
disagree, we are not persuaded and conclude that “appellant’s arguments fail
from the outset because . . . they are not based on limitations appearing in
the claims.” In re Self, 671 F.2d 1344, 1348 (CCPA 1982).
Appellant then discusses the hydrophilicity or hydrophobicity of
benzyalkonium heparin and submits “that heparin alone is hydrophilic, but
ben[z]alkonium heparin is hydrophobic” (App. Br. 5; cf. Reply Br. 3).
Appellant asserts “the Examiner has not provided any reasoning that a
hydrophobic component (benzalkonium heparin) would behave the same
way as a hydrophilic component (heparin). . . . there is no reasonable
expectation of success for using a hydrophobic component in lieu of a
hydrophilic component” (App. Br. 6; cf. Reply Br. 3).
We find this argument regarding hydrophilicity/hydrophobicity
unpersuasive because it sidesteps the central obviousness issue, which is
whether the prior art, as represented by Davila, Lunn, and Whitbourne,
suggest a method of drug release on an implanted stent coated with a water
insoluble rapamycin, a complex of heparin and quaternary ammonium salt,
where the complex results in elution with an initial release rate that is either
lower, the same, or higher than the subsequent release rate, where the drugs
are eluted into the patient (FF 1–9). Appellant provides no persuasive
evidence that Davila’s composition would not inherently achieve an initial
release rate followed by a subsequent release rate, whether or not it included
an additional form of heparin other than the heparin and quaternary
ammonium salt complex.
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Conclusion of Law
A preponderance of the evidence of record support the Examiner’s
conclusion that Davila, Lunn, and Whitbourne render the claims obvious.

DECISION SUMARY
In summary:
Claim(s)
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 3, 4, 9–11,
23–25
103(a) Davila, Lunn,
Whitbourne
1, 3, 4, 9–
11, 23–25

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