Ex Parte Uchida et al

Patent Trial and Appeal Board

Mar 8, 2019

10515204 (P.T.A.B. Mar. 8, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/515,204 11/22/2004
5514 7590 03/11/2019
VenableLLP
1290 A venue of the Americas
NEW YORK, NY 10104-3800
FIRST NAMED INVENTOR
Akihiro Uchida
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
00005.001250. 4305
EXAMINER
BREDEFELD, RACHAEL EV A
ART UNIT PAPER NUMBER
1611
MAIL DATE DELIVERY MODE
03/11/2019 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 AKIHIRO UCHIDA, Y ASUHIRO ISHIKAWA,
Y ASUHIKO UENO, KIICHIRO KAJI, and TSUNEAKI TOTTORI
Appeal2018-003965
Application 10/515,204 1
Technology Center 1600
Before DONALD E. ADAMS, JOHN E. SCHNEIDER, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL
This Appeal under 35 U.S.C. § 134(a) involves claims 5-19, 21, 30,
32--41, and 43-53 (App. Br. l; Final Act. 2 2). Examiner entered a rejection
under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 Appellants identify "Kyowa Hakko Kirin Co., Ltd." as the real party in
interest (Appellants' September 7, 2017 Appeal Brief (App. Br.) 1).
2 Examiner's September 13, 2016 Final Office Action.
Appeal2018-003965
Application 10/515,204
STATEMENT OF THE CASE
Appellants' disclosure "relates to a solid formulation comprising
xanthine derivative or a pharmaceutically acceptable salt thereof' (Spec. 1:
5-7). Claims 5-7 are representative and reproduced below:
5. A tablet comprising (E)-8-(3,4-dimethoxystyryl)-1,3-
diethyl-7-methyl-3, 7-dihydro-lH-purine-2,6-dione represented
by formula (IA)
0 FH3
f-bC....-._. N=r~r-0··. 0 .. -CHa
OAN N ' ·~ A <\
j . . ... CH:,
H:iC- .
or a pharmaceutically acceptable salt thereof, and
microcrystalline cellulose, wherein
the proportion of the (E)-8-(3 ,4-dimethoxystyryl)-1,3-diethyl-7-
methyl-3, 7-dihydro-1 H-purine-2,6-dione or the
pharmaceutically acceptable salt thereof in the tablet is 2 to
30% of the total weight of the tablet, and the microcrystalline
cellulose content in the tablet is 10 to 3 0% of the total weight
of the tablet.
(App. Br. 16.)
(Id.)
6. The tablet according to claim 5, further comprising a sugar.
7. The tablet according to claim 6, wherein the sugar comprises
1.0 to 9.0 parts by weight per 1.0 part by weight of
microcrystalline cellulose.
(Id. at 17).
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Application 10/515,204
Grounds of rejection before this Panel for review:
Claims 5-19, 21, 30, 32--41, and 43-53 stand rejected under 35 U.S.C.
§ I03(a) as unpatentable over the combination of Shimada, 3 Oren, 4 and
Reier. 5
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
We adopt Examiner's findings concerning the scope and content of
the prior art (see Final Act. 4--7) and provide the following findings for
emphasis.
FF 1. Shimada discloses "therapeutic agents for neurodegenerative
disorders," which include "Compound 1: (E)-1,3-diethyl-8-(3,4-
dimethoxystyryl)-7-methylxanthine" (Shimada 1:6-7; id. at 4:34--35; see
Final Act. 4 (Examiner finds that Shimada discloses "compound 1, which is
identical to ... [Appellant's] claimed[, trans- or E- isomeric form of 1,3-
diethyl-8-(3 ,4-dimethoxystyryl)-7-methylxanthine, which is] compound
IA)").
FF 2. Shimada discloses that "[t]he pharmaceutical compositions ...
[ within the scope of its disclosure] can be prepared by uniformly mixing an
effective amount of compound [1] or a pharmaceutically acceptable salt
3 Shimada et al., US 6,727,259 B2, issued Apr. 27, 2004.
4 Oren et al., US 4,753,801, issued June 28, 1988.
5 George E. Reier et al., Microcrystalline Cellulose in Tableting, 55 J.
PHARMA. SCI. 510-514 (1966).
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thereof as an active ingredient with pharmaceutically acceptable carriers"
(Shimada 6:51-55; see Final Act. 4).
FF 3. Shimada discloses that pharmaceutical compositions comprising
compound 1 in the form of "[p ]owder, pills, capsules and tablets can be
prepared using excipients such as lactose ... ; disintegrating agents such as
starch ... ; lubricants such as magnesium stearate ... ; binders such as ...
hydroxypropyl cellulose ... ; surfactants ... ; [and] plasticizers" (Shimada
7:3-10; id. at 7:7-9 ("Tablets and capsules are the most useful oral unit
dosage because of the readiness of administration"); see Final Act. 4--5).
FF 4. Shimada exemplifies a tablet comprising:
(Shimada 7:47-55.)
TABLE:;
E·iy,.i,-:',:-.:J''P ~·:::-p~·J (\.:lfoJ,:-~:1::
~'\:fo~:s1;::.:~·~:.:.u~ .S;-i:~::~·::il-:~
FF 5. Shimada exemplifies a capsule comprising 20 mg Compound 1, 99.5
mg Avicel, and 0.5 mg magnesium stearate (Shimada 7:57-8:10; cf Spec.
17:27-29 (Appellants disclose that Avicel is a commercially available form
of microcrystalline cellulose); see Final Act. 5).
FF 6. Examiner finds that Shimada does "not teach tablet formulations
comprising microcrystalline cellulose in an amount of 10-30 wt.% of the
tablet" (Final Act. 5).
FF 7. Oren
relates to a sustained release pharmaceutical formulation in
tablet unit dosage form which provides prolonged plasma levels
of an active agent and comprises about 60.0% to about 80.0%
by weight of the active agent, about 1.0% to about 15.0% by
weight of a pharmaceutically acceptable excipient, about 3.0%
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to about 15.0% by weight of a disintegrant, about 2.0% to
about 10. 0% by weight of a pharmaceutically acceptable binder
and about 0.5% to about 3.0% by weight of a tablet lubricant.
(Oren 1:20-30 (emphasis added); see generally id. 2:15-3:19 (Oren's
formulation may also comprise a binder, lubricant, and surface active agent);
Final Act. 5.)
FF 8. Oren discloses that lactose is a preferred excipient, starch as a
preferred or suitable disintegrant, magnesium stearate is a preferred
lubricant, and acceptable binders include microcrystalline cellulose (see
Oren 2:15-3:28; see generally Final Act. 5).
FF 9. Oren discloses that its
tablets may be coated, if desired, with one of many readily
available coating systems. Coating the tablets serves to mask
the taste of the drug, make the tablet easier to swallow and, in
some cases, improve the appearance of the dosage form. The
tablets can be sugar coated according to procedures well known
in the art, or can be coated with any one of numerous polymeric
film coating agents frequently employed by formulation
chemists. Representative examples of such film coating agents
include hydroxypropyl methyl cellulose, carboxymethylcellu-
lose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose,
acrylic resins, povidone, polyvinyl diethylaminoacetate,
cellulose acetate phthalate, polyvinyl acetate phthalate,
hydroxypropyl methyl cellulose phthalate, acrylic latex
emulsions, ethyl cellulose latex emulsions or other
commercially available preparations such as Pharmacoat.
(Oren 3:58--4:6; see Final Act. 5.)
FF 10. Reier discloses "[t ]he development of microcrystalline cellulose has
made available to the pharmaceutical industry an extremely valuable
tableting agent. . . . Microcrystalline cellulose tablets will disintegrate very
slowly in solvents of a relatively low polarity" (Reier, Abstract; see Final
Act. 6 ("one would have been motivated to use microcrystalline cellulose in
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Shimada' s composition since Reier ... [discloses] the excipient is extremely
valuable in that it does not separate components during compression and
does not negatively affect the release of medicinal compounds from
tablets").
ANALYSIS
Based on the combination of Shimada, Oren, and Reier, Examiner
concludes that, at the time Appellants' invention was made, a person of
ordinary skill in this art would have understood that Oren's
"micro crystalline cellulose and Shimada' s binder (hydroxypropyl cellulose)
are both conventional binders utilized in tablets," therefore, it would have
been prima facie obvious to "utilize the binders of Oren ... or Shimada"
(Final Act. 6; see id. ("one would have been motivated to incorporate
microcrystalline cellulose in the composition of Shimada ... with an
expectation of similar results since Oren ... teach the instant binder's
equivalency with hydroxypropyl cellulose")). In re Fout, 675 F.2d 297, 301,
213 USPQ 532,536 (CCPA 1982) ("Express suggestion to substitute one
equivalent for another need not be present to render such substitution
obvious"). As Examiner explains, those of ordinary skill in this art would
have had "a reasonable expectation [ of success in using] microcrystalline
cellulose in Shimada's composition because Reier ... [discloses] that the
characteristics of tablets produced with microcrystalline cellulose are
outstanding" (Final Act. 6-7).
Claim 1:
The evidence of record establishes that those of ordinary skill in this
art recognized that microcrystalline cellulose is known in "the
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Application 10/515,204
pharmaceutical industry [as] an extremely valuable tableting agent,"
specifically a binder (see FF 7-10). The evidence of record exemplifies a
tablet comprising 10% 6 Appellants' compound IA; 71. 7% 7 lactose, an
excipient; 15%8 potato starch, a disintegrating agent; 0.3%9 magnesium
stearate, a lubricant; and 3% 10 hydroxypropyl cellulose, a binder (see FF 3-
4). This record also establishes that tablet formulations were known in this
art comprising:
about 60.0% to about 80.0% by weight of [an] active agent,
about 1.0% to about 15.0% by weight of a pharmaceutically
acceptable excipient,[ such as lactose;] about 3.0% to about
15.0% by weight of a disintegrant,[ such as starch;] about 2.0%
to about 10. 0% by weight of a pharmaceutically acceptable
binder[, such as microcrystalline cellulose;] and about 0.5% to
about 3.0% by weight of a tablet lubricant[, such as magnesium
stearate].
(FF 7-8.) Thus, the evidence of record establishes the general conditions of
the tablet set forth in Appellants' claim 5. In this regard, we note that
"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 (CCP A 1955).
Furthermore, "[a] prima facie case of obviousness typically exists when the
6 20 mg Compound I + 200 mg total weight X 100% = 10% Compound I by
weight of the tablet (see FF 4).
7 143.4 mg Lactose+ 200 mg total weight X 100% = 71.7% Lactose by
weight of the tablet (see FF 4).
8 30 mg Potato Starch + 200 mg total weight X 100% = 15% Potato Starch
by weight of the tablet (see FF 4).
9 0.6 mg Magnesium Stearate + 200 mg total weight X 100% = 0.3%
Magnesium Stearate by weight of the tablet (see FF 4).
10 6 mg Hydroxypropyl Cellulose+ 200 mg total weight X 100% = 3%
Hydroxypropyl Cellulose by weight of the tablet (see FF 4).
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ranges of a claimed composition overlap the ranges disclosed in the prior
art." In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). We note that a
claimed range overlaps with a prior art range if the two ranges share a
common endpoint. See, e.g., In re Geisler, 116 F.3d 1465,1469 (Fed. Cir.
1997) (noting that a claim range of 50-100 A overlapped with a prior art
range of 100-600 A). Therefore, we find no error in Examiner's conclusion
that the combination of Shimada, Oren, and Reier makes obvious a tablet
comprising 2-30% by total weight of the tablet of (E)-1,3-diethyl-8-(3,4-
dimethoxystyryl)-7-methylxanthine or a pharmaceutically acceptable salt
thereof and 10-30% by total weight of the tablet of microcrystalline
cellulose (see FF 1-8).
We are not persuaded by Appellants' contention that "[t]here is no
reason of record why those of ordinary skill would expect that
microcrystalline cellulose prevents olefin bond [ cis-trans or E-Z]
isomerization" (App. Br. 8; see also Reply Br. 11 7-8). Notwithstanding
Appellants' contention to the contrary, the inquiry is not whether a person of
ordinary skill in this art would have used microcrystalline cellulose to
prevent olefin bond isomerization. To the contrary, the question is whether
the combination of Shimada, Oren, and Reier makes obvious a tablet
comprising: (a) 2-30% by total weight of the tablet of (E)-1,3-diethyl-8-
(3,4-dimethoxystyryl)-7-methylxanthine or a pharmaceutically acceptable
salt thereof and (b) 10-30% by total weight of the tablet of microcrystalline
cellulose (see App. Br. 16). For the reasons discussed above, we find that
the evidence of record supports Examiner's conclusion of obviousness. The
11 Appellants' March 2, 2018 Reply Brief.
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Application 10/515,204
fact that Appellants use microcrystalline cellulose "for a different purpose
does not alter the conclusion that its use in a prior art composition would be
prima facie obvious [for] the purpose disclosed in the references." In re
Lintner, 458 F.2d 1013, 1016 (CCPA 1972).
We are also not persuaded by Appellants' evidence of unexpected
results (see App. Br. 8-14; see also Reply Br. 8-12). Evidence of
"unexpected results must be commensurate in scope with the claimed
range." In re Greenfield, 571 F.2d 1185, 1189 (CCPA 1978) ("Establishing
that one ( or a small number of) species gives unexpected results is
inadequate proof, for 'it is the view of this court that objective evidence of
non-obviousness must be commensurate in scope with the claims which the
evidence is offered to support"') ( quoting In re Tiffin, 448 F .2d 791, 792
(CCPA 1971)).
On this record, Appellants contend that the August 12, 2009
Declaration of Dr. Ishikawa (August 12, 2009 Ishikawa Dec.) provides
evidence that "the claimed process yields tablets that exhibit 74% less
decomposition than those of Shimada, the closest prior art" (App. Br. 10).
In support of this contention, Appellants direct attention to comparisons
between compositions, within the scope of Appellants' claimed invention,
that comprise about 23% microcrystalline cellulose and various other
compositions (see id. at 10-12 (citing the August 12, 2009 Ishikawa Dec.;
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May 16, 2012 Ishikawa Dec.; 12 June 27, 2012 Ishikawa Dec.; 13 October 20,
2014 Ishikawa Dec.; 14 and February 29, 2016 Ishikawa Dec. 15)). 16, 17
Although Appellants' contentions relate to a composition comprising
as little as 23 wt% microcrystalline cellulose, Appellants recognize that their
"claims recite [] 10-30 wt% microcrystalline cellulose" (App. Br. 13; see
Reply Br. 6 (Appellants' "claims relate to tablets comprising compound (IA)
and 10 to 30% total weight microcrystalline cellulose")). Thus, it is unclear
on this record if a composition comprising 10 wt% to not quite 23 wt%
microcrystalline cellulose would exhibit the unexpected properties asserted
by Appellants. Given the foregoing, we find no evidentiary basis on this
record that supports Ishikawa's "opinion that those of ordinary skill in this
art understand the evidence of record [] establishes that unexpected results
are obtained for tablets and processes throughout the scope from 10 to 30
total wt.% microcrystalline cellulose" (May 16, 2012 Ishikawa Dec. ,r 11;
see also June 27, 2012 Ishikawa Dec. ,r 11). The evidence on this record
only supports a conclusion that a tablet comprising as little as 23 wt%
12 Declaration of Dr. Ishikawa, signed May 16, 2012.
13 Declaration of Dr. Ishikawa, signed June 27, 2012.
14 Declaration of Dr. Ishikawa, signed October 20, 2014.
15 Declaration of Dr. Ishikawa, signed February 29, 2016.
16 Ishikawa states that the August 14, 2009 Ishikawa Dec. "evaluated an
example with 23 wt.% microcrystalline cellulose" and "that Table 3 at
specification page 21 evaluated Tablet obtained in Example 2 having 24.1
wt.% microcrystalline cellulose" (June 27, 2012 Ishikawa Dec. ,r 7).
17 Ishikawa takes "note of[] Examiner's contention that the evidence of
record indicates superior results only for 29.9 and 32.9 wt.%
microcrystalline cellulose, whereas the claims [] recite a range of 10 to 30
wt.% microcrystalline cellulose" (May 16, 2012 Ishikawa Dec. ,r 4; see also
June 27, 2012 Ishikawa Dec. ,r 4).
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microcrystalline cellulose will exhibit the "unexpected results" asserted by
Appellants and Declarant, with no evidence that such would be observed at
less than 23 wt% microcrystalline cellulose. Stated differently, we find
Appellants' evidence of unexpected results is not commensurate in scope
with the microcrystalline cellulose range set forth in Appellants' claimed
invention. See In re Greenfield, 571 F.2d at 1189.
Appellants' contentions regarding disintegration rates, hardness and
corresponding discussion of Oren, Reier and Fox 18 also relate to the amount
of microcrystalline cellulose in Appellants' tablet and are, therefore, as
discussed above, not commensurate in scope with Appellants' claimed
invention (see App. Br. 13 ("those of ordinary skill understand that
microcrystalline cellulose slows dissolution of the active ingredient so as to
achieve sustained release. . . . In contrast, the claimed tablets disintegrate
rapidly and so increase availability of the active ingredient" and "one of
ordinary skill herein would not have expected simultaneous improvements in
each of hardness, disintegration time and formulation stability"); see also
Reply Br. 12 ("The record does not establish that those of ordinary skill
herein would have expected either the improved photostability or the
improved disintegration rate attained by the present invention, let alone the
simultaneous improvements in both, even in view of Fox and Reier"); see
generally Reply Br. 6-7 and 10-12).
Appellants do not identify and we do not find evidence of a long felt
need or commercial success on this record (cf App. Br. 14). Therefore, we
are not persuaded by Appellants' contention that "the secondary
18 C. David Fox et al., Microcrystalline Cellulose in Tableting, 92 DRUG AND
COSMETIC INDUSTRY 161 (1963).
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considerations of the claimed invention's satisfaction of a long felt need and
commercial success would overcome ... [the] primafacie case" of
obviousness on this record (App. Br. 14).
Claim 7:
Examiner reasons that because Oren discloses tablet formulations
compnsmg
amounts of microcrystalline cellulose and sugar that
encompass[ es] the limitations of ... [Appellants'] claims.
Thus, ... [E]xaminer's position [is] that it would have been
obvious to an artisan of ordinary skill to manipulate and
optimize the relative amount of the sugar component ( e.g.
lactose) and the microcrystalline cellulose as taught by Oren.
(Final Act. 7.) Examiner further reasons that "[ o ]ptimization of parameters
is a routine practice that would be obvious to a person of ordinary skill in the
art to employ and reasonably expect success," thus, "[ o ]ne would have been
motivated to determine the optimal amount of each ingredient in order to
best achieve the desired results" (id. ( citing In re Aller, 220 F .2d at 456).
Appellants contend, however, that "there is no appreciation in the art
that the ratio of sugar to microcrystalline cellulose is a result-effective
variable" (App. Br. 14). Thus, Appellants contend that a tablet that
comprises, inter alia, a sugar to microcrystalline cellulose ratio of 1: 1-9: 1
parts by weight is "not prima facie obvious over the prior art" relied on by
Examiner (id. at 15). We are not persuaded.
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The evidence of record exemplifies tablets comprising a sugar to
binder ratio of23.9:l 19 (FF 4) and between 0.1:1-7.5:1 20 (FF 7), wherein
the evidence of record recognizes that microcrystalline cellulose is a suitable
binder (FF 7-8). Thus, the evidence of record establishes that the sugar to
microcrystalline cellulose ratio of tablets suggested by the prior art overlaps
Appellants' claimed ratio. Overlapping ranges support a prima facie case of
obviousness. See In re Geisler, 116 F.3d 1465, 1468 (Fed. Cir. 1997). In
addition, the evidence of record establishes the general conditions of the
tablet set forth in Appellants' claim 7 and "it is not inventive to discover the
optimum or workable ranges by routine experimentation." In re Aller, 220
F.2d at 456.
Thus, we find that a person of ordinary skill in this art would have
found it prima facie obvious to adjust the ratio of the sugar to
microcrystalline cellulose, as well as other ingredients, within the finite
ranges expressly disclosed for the tablet suggested by the combination of
Shimada, Oren, and Reier in order to optimize the manufacture and
properties of the tablet (see FF 3--4 and 7-8; see generally FF 1-10).
Therefore, we are not persuaded by Appellants' contentions that
if the ratio of microcrystalline cellulose: sugar is greater than
1: 1, problems in manufacturing are engendered, and the
stability of tablets is adversely influenced. On the other hand, if
the ratio of microcrystalline cellulose: sugar is less than 1: 10,
19 71.7% lactose to 3% binder equals a sugar to binder ratio of23.9:1 parts
by weight (see FF 4)
20 1.0% lactose to 10% microcrystalline cellulose binder equals a sugar to
microcrystalline cellulose binder ratio of 0.1: 1 parts by weight (see FF 7).
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the tablets will be insufficiently hard and disintegration time is
adversely influences.
(Reply Br. 13.)
CONCLUSION
The preponderance of evidence relied upon by Examiner support a
conclusion of obviousness. The rejection of claims 5 and 7 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Shimada, Oren, and Reier
is affirmed. Claims 5, 6, 19, 21, 30, 32, 33, 36-41, and 43-53 are not
separately argued and fall with claim 1. Claims 8, 9, 34, and 35 are not
separately argued and fall with claim 7.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 3 7 C.F .R. § 1.13 6( a).
AFFIRMED
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