Ex Parte Vogel et al

Patent Trial and Appeal Board

Sep 12, 2013

10220982 (P.T.A.B. Sep. 12, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE PATENT TRIAL AND APPEAL BOARD
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Ex parte JEAN-MARIE VOGEL and EGISTO BOSCHETTI
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Appeal 2012-005408
Application 10/220,982
Technology Center 1600
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Before TONI R. SCHEINER, FRANCISCO C. PRATS, and
SUSAN L. C. MITCHELL, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 from the final rejection of
claims 102-150, directed to a method for the treatment of a solid tumor by
active embolization. The claims have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We reverse.

1 Appellants identify the Real Party-In-Interest as BioSphere Medical, Inc.
(App. Br. 4.)

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STATEMENT OF THE CASE
Claims 102-150 are pending and on appeal. Claims 1-101 have been
canceled (App. Br. 6).
Claim 102 is representative of the subject matter on appeal, and is
reproduced below:
102. A method for the treatment of a solid tumor by active embolization,
comprising administering to a patient having the solid tumor a microsphere
comprising a biocompatible sodium acrylate and vinyl alcohol copolymer,
wherein the microsphere is loaded with doxorubicin, and wherein the
doxorubicin is released at the site of the tumor.
The Examiner relies on the following evidence:
Okada et al. US 5,202,352 Apr. 13, 1993
Weissleder et al. US 5,514,379 May 7, 1996
Hori JP 60 56676 A Mar. 1, 1994
(English language translation, hereinafter “Hori-I”)
Shuji Kitamura et al., Polymer with a High Water Absorption Property –
Sumika Gel, SUMITOMO CHEMICAL 1-9 (1980).
Yao Jiaqi et al., A New Embolic Material: Super Absorbent Polymer (SAP)
Microsphere and Its Embolic Effects, 56 NIPPON ACTA RADIOLOGICA 19-24
(1996).
Shinichi Hori et al., Study on the effect of arterial embolism with super-
absorbent polymer, 11 INTERVENTIONAL RADIOLOGY 1-11 (1996)
(hereinafter “Hori-II”).
Appellants rely, in relevant part, on the following additional evidence:
P.M.J. Flandroy, Clinical Applications of Microspheres in Embolization and
Chemoembolization: A comprehensive Review and Perspectives, in
PHARMACEUTICAL PARTICULATE CARRIERS 321-366 (A. Rolland, ed., 1993).
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The Examiner rejected the claims as unpatentable under 35 U.S.C.
§ 103(a) as follows:
I. Claims 102-150 over Okada in combination with Jiaqi “or vice
versa” (Ans. 7-8).
II. Claims 102-150 over Hori-I or Hori-II, further in view of
Okada “or vice versa” (Ans. 8-9).
III. Claims 102-150 over Okada in combination with Kitamura
(Ans. 6-7).
IV. Claims 109-111 over Okada in combination with Kitamura;
Okada in combination with Jiaqi; Hori-I or Hori-II further in view of Okada
“or vice versa” and further in view of Weissleder (Ans. 9-10).
FINDINGS OF FACT
The following findings of fact (FF) are supported by a preponderance
of the evidence of record.
Okada
1. Okada discloses “a therapeutic agent for the treatment of cancer
which forms emboli in the vascular system surrounding the cancer lesion or
tumor” (Okada, col. 1. ll. 8-11). The therapeutic agent comprises “an
intravascular embolizing agent containing an angiogenesis-inhibiting
substance and an intravascular embolizing substance” (id. at col. 1, ll. 59-
61).
2. Examples of Okada’s intravascular embolizing substances
include: oils, metals, insoluble salts of metals, waxes, activated carbon, and
natural or synthetic polymers (Okada, col. 7, ll. 15-25). “Examples of the
polymers include polypeptides, polysaccharides, poly fatty acid ester,
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poly(amino acids), polyaldehyde, polyvinyl polymer, maleic anhydride
polymer, etc.” (Id. at col. 7, ll. 25-28.)
“Examples of the polypeptides include gelatin, collagen, elastin,
albumin . . . etc.” (Id. at col. 7, ll. 40-41.)
“Examples of the poly-fatty acid esters include . . . homopolymers or
copolymers of lactic acid, glycolic acid, hydroxybuteric acid, malic acid . . .
etc.” (Id. at col. 7, ll. 50-52.)
Examples of the polyvinyl polymers include homo
polymers and copolymers of ethylene, propylene, butadiene,
acrylic acid, acrylic acid ester, methacrylic acid, methacrylic
acid ester, vinyl acetate, vinyl chloride, vinyl alcohol, vinyl
pyrrolidone, vinyl ether, vinyl carbazole, styrene, styrene
derivatives, α-cyano acrylic acid ester, acrylamide, divinyl
benzene, etc.
(Id. at col. 7, ll. 63-68.)
3. According to Okada, “[a]mong these, gelatin, albumin,
collagen, starch, hyaluronic acid, lactic acid-glycolic acid copolymers, etc.,
which are polymers dissolving or decomposing gradually in vivo, are
preferable” (Okada, col. 8, ll. 1-4).
4. Okada teaches that “the intravascular embolizing agent
containing the angiogenesis-inhibiting substance and the intravascular
embolizing substance [is more effective] . . . in concert with an anti-
neoplastic agent” which “may be mixed with, or . . . contained in the above-
mentioned intravascular embolizing agent” (Okada, col. 10, ll. 1-7).
5. Examples of suitable anti-neoplastic agents include “popular
anti-neoplastic agents, such as doxorubicin hydrochloride” (Okada, col. 10,
l. 53). Example 5 describes co-administration of an aqueous solution of
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doxorubicin hydrochloride with microparticles made from a poly(lactide-
glycolide) copolymer (PLGA) (id. at col. 14, ll. 3-15).
Kitamura
6. Kitamora discloses “a polymer (Sumika Gel®) with a high
water absorption property mainly composed of a vinyl alcohol-acrylate
copolymer” (Kitamura 7). Kitamura teaches that “[t]he Sumika Gel[®] in a
fine powder state exhibits considerable thickening [viscosity improving]
effect when it absorbs water” (id. at 19), and suggests the gel would be
useful as a water retention agent for agriculture, an absorbent for sanitary
materials, a perfume carrier, a drying agent, and a thickening agent (id. at
20-22).
7. Kitamura does not disclose microspheres made from the gel,
nor does the reference discuss the use of the gel as an embolizing agent.
Hori-I, Hori-II, and Jiaqi
8. All three of these references discuss multiple advantages of the
SAP-Microsphere, an arterial embolic material comprising particles of a
super absorbing sodium acrylic acid-vinyl alcohol copolymer.
9. According to Hori-II:
After embolization and even after 16 weeks, the SAP-
Microsphere retains the spherical shape in the artery. Its
destruction [decomposition] was not observed. . . . [I]f the SAP-
Microsphere is used as the embolization material, . . . there is
no problem in classifying it as a long-term-use embolus
material.
(Hori-II 11.)
10. Neither Hori-I, Hori-II, nor Jiaqi discloses an anti-neoplastic
agent or an anti-angiogenesis agent in the resin particles.
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Flandroy
11. Flandroy teaches that “[t]he chemoembolization of tumors
relies on two basic principles: (a) the embolization of the vessels that feed
the tumor and (b) the kinetics of drug release from the emboli . . .” (Flandroy
330 (internal citation omitted)).
The kinetics of drug release from the emboli and the
biodegradation rate of the drug carrier are of major importance,
since they determine the amount of drug released per unit of
time and, accordingly, the bioavailability of the drug and its
antitumor effect. The biodegradation of the embolic agent
allows the treatment to be repeated according to a precise
schedule. For the application of a sequential treatment to be
applied, microspheres must indeed disappear before the foreign
body reaction occurs . . . [which] is observed between the
seventh and tenth day after the embolization. The optimum
degradation time of the carrier should thus be about 10 days.
The control of drug release in vivo is still a challenge. It
depends on the nature and the internal structure of the carrier.
The former characteristic determines the possible erosion of the
particles and the latter feature has a decisive effect on the drug
diffusion. As a rule, drug release systems show an initial fast
efflux of drug (diffusion) followed by a protracted phase of
release (diffusion and/or biodegradation). The initial efflux is
known as the “burst effect.” . . . Ideally, the burst effect should
be as small as possible and the rate of drug release as constant
as possible.
(Id. at 330-332 (internal citations omitted).)
Accordingly, Flandroy teaches that “biodegradability of the carrier
and a constant protracted efflux make up the best situation” while “[a]
nondegradable carrier combined with a burst effect is the worst situation”
(id. at 332). Given these considerations, Flandroy teaches that polylactide
(PLA) and poly (lactide-glycolide) copolymer (PGLA) microspheres “seem
to be . . . the best materials . . . for chemoembolization purposes” (id.).
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DISCUSSION
Each of the rejections is based, in part, on the teachings of Okada, in
view of additional teachings of Kitamura, Jiaqi, or Hori-I/Hori-II. The issue
raised by each of the rejections is whether the Examiner has established by a
preponderance of the evidence that it would have been obvious for one of
ordinary skill in the art to treat solid tumors by administering doxorubicin-
loaded embolic particles made from a sodium acrylate-vinyl alcohol
copolymer, given Okada’s teachings, together with the teachings of
Kitamura, Jiaqi, Hori-I, or Hori-II, when considered in light of Flandroy’s
teachings.
As described above, Okada discloses an “embolizing agent”
comprising an “angiogenesis-inhibiting substance” and an “intravascular
embolizing substance” (FF1). The intravascular embolizing substance is
selected from a wide variety of polymeric and non-polymeric materials
(FF2), of which, “gelatin, albumin, collagen, starch, hyaluronic acid, lactic
acid-glycolic acid copolymers, etc., which are polymers dissolving or
decomposing gradually in vivo, are preferable” (FFs 2, 3; Okada, col. 8, ll.
1-4). Okada also teaches that the embolizing agent may be administered
with an anti-neoplastic agent, which “may be mixed with, or . . . contained in
the . . . embolizing agent” (FF4).
In addition, Jiaqi, Hori-I, and Hori-II suggest that particles made from
a copolymer of sodium acrylate and vinyl alcohol make superior embolizing
microspheres (FF9), although none of these references discusses
chemoembolization or discloses loading the microspheres with a therapeutic
drug (FF10).
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Given these teachings, the Examiner concludes that “[o]ne of ordinary
skill in the art would be motivated to select the acrylic-vinyl alcohol
combination suggested by Okada among other polymers” (Ans. 7), “based
on the super water absorption property and their use as embolic agents
taught by Jiaqi” (id.). Alternatively, the Examiner concludes that “[t]he
inclusion of drugs in the compositions of [Hori-I] would have been obvious
. . . since Okada teaches that the drugs can be incorporated in the embolizing
particles” (id. at 9), and “the use of the copolymers of acrylate and vinyl
alcohol . . . would have been obvious . . . since [Hori-I] shows their routine
use in the embolizing compositions” (id.).
Appellants contend, in relevant part, that Flandroy provides evidence
that only biodegradable embolizing substances were considered suitable for
chemoembolization at the time of the invention, and that polylactide (PLA)
and poly(lactide-glycolide) copolymer (PLGA) microspheres were
considered to be “the best materials . . . for chemoembolization purposes”
(Flandroy 332; App. Br. 24; FF11). Appellants further contend that this
“understanding of those skilled in the art” is consistent with Okada, which
teaches that biodegradable substances, in general, and “lactic acid-glycolic
acid copolymers,” in particular, are preferable embolizing substances (App.
Br. 23; FF3).
Specifically, Appellants contend that:
[O]ne skilled in the art reading Okada and/or Kitamura, Jiaqi,
[Hori-I] and/or [Hori-II], with the understanding of the state of
the art as exemplified by Flandroy, would appreciate, among
other things, that non-biodegradable polymers were considered
to be ineffective for drug loading, and only biodegradable
polymers were preferred for drug-loading because it was
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thought that the degradation was the only means for release of
the drug from the microsphere.
(App. Br. 35.)
Accordingly, Appellants contend that “one skilled in the art would not
have looked to . . . non-biodegradable, sodium acrylate and vinyl alcohol
copolymer” microspheres for loading doxorubicin to treat solid tumors (id.
at 25).
Appellants’ argument is persuasive. Despite Flandroy’s seemingly
relevant teaching that microspheres suitable for chemoembolization should
be biodegradable within ten days or so (FF11), the Examiner simply
dismisses the reference as “pertain[ing] to vinyl alcohol, and not copolymers
of acrylic acid and vinyl alcohol” (Ans. 12). In the absence of any
meaningful discussion of Flandroy’s teachings, we agree with Appellants
that the Examiner has not established that it would have been obvious for
one of ordinary skill in the art to treat solid tumors by administering
doxorubicin-loaded onto “long-term-use” embolic particles made from a
sodium acrylate-vinyl alcohol copolymer (FF9) at the time of the invention.
SUMMARY
The rejection of claims 102-150 over Okada in combination with Jiaqi
is reversed.
The rejection of claims 102-150 over Hori-I or Hori-II, and Okada is
reversed.
The rejection of claims 102-150 over Okada and Kitamura is reversed.
The rejection of claims 109-111 over Okada, Kitamura, Jiaqi, Hori-I,
Hori-II and Weissleder is reversed.

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REVERSED

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