Ex Parte Ueda et al

Patent Trial and Appeal Board

Dec 20, 2012

10482704 (P.T.A.B. Dec. 20, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
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Ex parte SHIGERU UEDA and TOSHIAKI HIRAYAMA
____________

Appeal 2011-010028
Application 10/482,704
Technology Center 1600
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Before DONALD E. ADAMS, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims 8, 10, and 12-21
(App. Br. 4; Ans. 3). We have jurisdiction under 35 U.S.C. § 6(b).
STATEMENT OF THE CASE
The claims are directed to a method of stabilizing human alkaline
phosphatase during storage in a freeze-dried composition (Claims 8, 12, 14,
16, 17, and 20) and a stabilized freeze-dried human alkaline phosphatase
composition (claims 10, 13, 15, 18, 19, and 21). Claims 8, 12, and 16 are
representative and are reproduced in the Claims Appendix of Appellants‟
Brief.
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Claims 8, 10, and 12-21 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Aoki,
1
Ford,
2
and Garman.
3

We affirm.
ISSUE
Does the preponderance of evidence on this record support a
conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Aoki suggests a stabilized enzyme composition comprising alkaline
phosphatase and a stabilizer component (Ans. 5).
FF 2. Aoki exemplifies a composition comprising “3% bovine serum
albumin (BSA) …, 526 U/L alkaline phosphatase (ALP)…, and [5%]
galactose or lactose,” wherein the BSA and galactose/lactose are stabilizing
components (id.).
FF 3. For clarity we reproduce Aoki‟s Tables 2 and 3 below:

Table 2 illustrates “[t]he respective residual activities (%) of the enzymes
after the storage at 5°C for 3 weeks” in a composition comprising 3% BSA

1
Aoki et al., WO 96/15256, published May 23, 1996.
2
Annette W. Ford and Peter J. Dawson, The Effect of Carbohydrate
Additives in the Freeze-Drying of Alkaline Phosphatase, 45 J. PHARM.
PHARMACOL. 86-93 (1993).
3
Garman et al., EP 0 431 882 A2, published June 12, 1991.

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and the saccharides listed in the table (Aoki 42: 18-20). Table 3 is the same
as Table 2 with the exception that the residual activities were measured after
storage at -20°C for 3 weeks (Aoki 42: 20-22).
FF 4. Aoki suggests that “[t]he activity of ALP was maintained at
substantially the same level as the original level of activity, with respect to
all of the samples (including the sample containing no saccharide” after
storage at 5°C for 3 weeks (Aoki 44: 24 - 45: 3).
FF 5. Examiner finds that Aoki fails to suggest “freeze-drying the
stabilized alkaline phosphatase composition” (Ans. 6).
FF 6. Ford suggests freeze-dried alkaline phosphatase preparations
formulated with lactose, which “retained maximal activity through an 84 day
period … [at] -20, 20, 37, [and] 45°C” (id.).
FF 7. Ford suggests that “[a]lthough lactose is used as a cryoprotectant and
also used pharmaceutically as an inert bulking agent … the balance of
advantages and disadvantages in freeze-dried standards should be carefully
evaluated because of its ability to participate in the Maillard reaction” (Ford
91: col. 2, ll. 48-52).
FF 8. For clarity, we reproduce Ford‟s FIG. 3 below:

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FF 9. Examiner relies on Garman suggests “that an alkaline phosphatase
composition comprising BSA and 1% lactose can be successfully freeze-
dried without destruction of the enzyme activity” (id. at 8; Garman 9: 20-26
(“To a solution of alkaline phosphatase … was added … SIAB … BSA and
… 1% lactose … and then freeze-dried overnight”)).
FF 10. For clarity, we reproduce the Table presented in the Ueda
Declaration
4
below:

According to Ueda the data presented in the Table
clearly show that virtually no loss or gain of activity was seen
for the freeze-dried alkaline phosphatase even after three years
(36M) of storage even at a temperature as high as 5°C. Two
percent activity loss after three years (98%, 5°C, 36M) is
actually within the scope of experimental error[] and is
negligible.

(Ueda Declaration 2: 12-15.)
ANALYSIS
Based on the combination of Aoki, Ford, and Garman Examiner
concludes that, at the time Appellants‟ invention was made, it would have
been prima facie obvious to modify Aoki‟s method to include the step of

4
Declaration of Shigeru Ueda, executed March 5, 2008.
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freeze-drying the alkaline phosphatase composition as suggested by Ford
(Ans. 7; FF 1, 2, 5, and 6).
Appellants provide separate arguments for the following groups of
claims: (I) claims 8 and 10; (II) claims 12-15; (III) claims 16 and 18; and
(IV) claims 17 and 19-21. Claims 8, 12, 16, and 17 are representative.

Claim 8:
Claim 8 is drawn to a method of stabilizing human ALP during
storage in a freeze-dried composition comprising: freeze-drying 45 to 1300
U/L of human ALP solution comprising (a) 3 to 5 % (W/V) of lactose and
(b) 1 to 5 % (W/V) of albumin (Claim 8).
Appellants contend that the combination of Aoki and Ford fails to
make obvious the use of lactose to stabilize alkaline phosphatase because
Aoki suggests that “the activity of ALP after freezing was „substantially the
same‟ as the sample which did not include a sugar” and Ford suggests that
“lactose „is not an ideal excipient since … it is reactive with proteins by the
Maillard reaction‟” (App. Br. 11-12). We are not persuaded.
While Ford may suggest that lactose may participate in a Maillard
reaction, Appellants fail to establish (a) that the lactose of their composition
would not be involved in a Maillard reaction or (b) that a Maillard reaction
would have any effect on ALP activity. We are also not persuaded by
Appellants‟ contention that lactose‟s potential involvement in a Maillard
reaction would lead a person of ordinary skill in this art away from the use
of lactose to stabilize “freeze-dried ALP for use in clinical examinations”
(id. at 15). No limitation in Appellants‟ claim 8 requires the ALP to be used
in clinical examinations. Further, Ford recognizes lactose‟s use as a
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cryoprotectant and suggests that one balance the advantages and
disadvantages of using lactose in freeze-dried standards (FF 7). Therefore,
notwithstanding Appellants‟ contention to the contrary, rather than teach
away from the use of lactose in favor of another reagent, such as trehalose,
Ford suggests a balanced approach to the selection of an appropriate reagent
for a particular purpose (id.). In sum, we are not persuaded by Appellants‟
contentions regarding the Maillard reaction or a teaching away in the art
(App. Br. 12 and 14-15).
While Aoki suggests that lactose is a compatible ingredient in a
storage composition comprising alkaline phosphatase, Aoki does not suggest
freeze-dried alkaline phosphatase (FF 5). Therefore, notwithstanding
Appellants‟ contention to the contrary, Aoki‟s activity data related to non-
freeze-dried alkaline phosphatase does not establish non-obviousness for
Appellants‟ claimed invention (Cf. App. Br. 12-13; Reply Br. 2-3). To the
contrary, Ford suggests the use of lactose to stabilize freeze-dried alkaline
phosphatase and thereby supports Examiner‟s conclusion that it would have
been prima facie obvious to freeze-dry Aoki‟s ALP preparation (Ans. 7).
We recognize Appellants‟ contention that “the present invention
relates to a stabilized freeze-dried preparation which does not have either an
increase or a decrease in alkaline phosphatase (ALP) activity after
reconstitution” (App. Br. 12). We also recognize the caveat to Appellants‟
contention; specifically that a 2% activity loss after three years of storage at
5°C is within the scope of Appellants‟ claimed invention (FF 10).
We also recognize Appellants‟ contention that
The Ueda Declaration states that “virtually no loss or gain of
activity was seen for the freeze dried alkaline phosphatase even
after three years”…. Thus, it is incorrect to say that “The
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increase from 100% to 103% … in residual ALP activity … is
also minimal and on the same level as reported by the appellant
in … [Ueda‟s] Declaration”

(Reply Br. 2 (emphasis added)). Appellants‟ contention, however, is not
supported by, and directly conflicts with, Ueda who declares that the
increase from 100% to 103% in residual ALP activity after two years (24M)
of storage at -20°C represents virtually no loss or gain of activity (FF 10; Cf.
App. Br. 12 (Table 3 “of Aoki demonstrate[s] an increase of up to … 103%
after three weeks at -20°C”)).
In sum, Appellants fail to establish the precise level of increase or
decrease in ALP activity that (a) falls within the scope of their claimed
invention or (b) is attributable to experimental error. Accordingly, we are
not persuaded by Appellants‟ contentions regarding an alleged difference
between their claimed invention and the residual enzymatic activity of ALP
stabilized in a composition of BSA and lactose as suggested by the prior art.
Appellants failed to present persuasive evidence or reasoning to
establish that, contrary to the suggestion in the art relied upon by Examiner,
BSA and lactose are incompatible for use, in combination, in a freeze-dried
enzyme composition. Accordingly, we are not persuaded by Appellants‟
contention that a person of ordinary skill in this art would not combine BSA
with lactose to stabilize alkaline phosphatase, because the methods of Aoki
and Ford are different, i.e. Ford suggests freeze-drying and Aoki does not
(App. Br. 13-14).
Appellants fail to establish that Ford‟s “chromatographic traces” relate
to ALP activity; therefore, we are not persuaded by Appellants‟ contentions
relating to Ford‟s “chromatographic traces” (id. at 14). Nevertheless, we
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recognize Appellants‟ contentions relating to Ford‟s figure 3 (Reply Br. 3;
FF 8). According to Appellants, Ford establishes that “a formulation with
lactose had lower activity that the trehalose formulation” (id.). We are not
persuaded. Ford‟s figure 3 expresses activity “relative to the most stable
preparation, alkaline phosphatase + trehalose,” not relative to a control that
does not comprise a stabilizing sugar (FF 8). Therefore, Ford‟s figure 3 does
not speak to the ability of lactose to stabilize an ALP preparation relative to
an ALP preparation that does not include a sugar. Further, Ford suggests a
balanced approach to the selection of an appropriate reagent for a particular
purpose (FF 7). Accordingly, we are not persuaded by Appellants‟
contention that “one of skill in the art would be discouraged from
substituting the lactose for trehalose in a stabilized composition,” based on
the combination of Aoki and Ford (Reply Br. 3). Further, we note that
Appellants‟ alleged substitution is unnecessary as Aoki suggests a method of
stabilizing ALP with lactose and BSA (FF 2).
Because the combination of Aoki and Ford makes obvious
Appellants‟ claimed invention, we are not persuaded by Appellants‟
contentions regarding Garman (App. Br. 16-18; Reply Br. 4-5).

Claim 12:
Claim 12 depends from and further limits the method of claim 8 to a
method, “wherein said human alkaline phosphatase maintains a constant
enzymatic activity during storage for at least one year and up to 13.8 years”
(Claim 12).
Appellants rely on their arguments with regard to claim 8 to support a
contention that Aoki‟s ALP activity increased and Ford “describes a drastic
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decrease in the alkaline phosphatase activity after storage in freeze-dried
form” (App. Br. 19; Reply Br. 5). We are not persuaded for the reasons set
forth above.
Appellants contend that “[t]he time of stability [(i.e., for at least one
year and up to 13.8 years)] is not specified in the combined prior art” (id.;
see also Reply Br. 5 (emphasis removed)). We are not persuaded. On this
record, the preponderance of evidence supports Examiner‟s conclusion that
it would have been prima facie obvious to freeze-dry Aoki‟s preparation
comprising ALP, lactose, and BSA, as suggested by Ford, resulting in the
exact same method of stabilizing ALP as required by claim 12 (Ans. 7).
Appellants fail to establish through persuasive evidence or reasoning that the
method suggested by the combination of Aoki and Ford would not have
resulted in the same stability time required by Appellants‟ claim 12, i.e., that
the claimed stability time is not a property of the freeze-dried ALP, lactose,
and BSA formulation itself. Cf. In re Kubin, 561 F.3d 1351, 1357 (Fed. Cir.
2009).

Claim 16:
Claim 16 differs from claim 8 by requiring 3 to 5 % (W/V) of
galactose instead of lactose.
For the reasons set forth above, we are not persuaded by Appellants‟
contentions relating to Aoki‟s enzymatic activity or the Maillard reaction
(App. Br. 20).
Appellants contend that since “Ford … and Garman do not teach the
use [of] galactose at all … [and] Aoki does not teach freeze-drying …
Examiner … failed to establish prima facie obviousness for freeze-drying
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and the addition of albumin” (id.). We are not persuaded. Aoki suggests a
composition comprising ALP, galactose, and albumin (FF 2). In this regard,
Aoki suggests the use of galactose or lactose (id.). Ford suggests freeze-
drying an ALP composition comprising lactose (FF 6). Accordingly, we
find no error in Examiner‟s conclusion that it would have been prima facie
obvious to a person of ordinary skill in this art at the time of Appellants‟
claimed invention to freeze-dry Aoki‟s composition comprising ALP,
galactose, and albumin with a reasonable expectation of obtaining a method
of stabilizing human ALP.
We are not persuaded by Appellants‟ contention that “one of skill in
the art would not necessarily substitute galactose for lactose” (App. Br. 21;
Reply Br. 6). Notwithstanding Appellants‟ contention to the contrary, no
substitution is necessary as Aoki suggests a composition comprising ALP,
galactose and BSA (FF 2). Accordingly, we are not persuaded by
Appellants‟ intimation that the combination of art relied upon by Examiner
teaches away from Appellants‟ claim 16 (see, e.g., Reply Br. 6). Further,
notwithstanding Appellants‟ contention to the contrary, Ford suggests a
balanced approach to the selection of an appropriate reagent for a particular
purpose (FF 7). Therefore, we are not persuaded by Appellants‟ contention
that the combination of prior art relied upon by Examiner teaches away from
the use of galactose (FF 7; Cf. Reply Br. 6 (“Aoki teaches that galactose is
inferior to trehalose”)).

Claim 17:
Claim 17 depends from and further limits the method of claim 16 to a
method, “wherein said human alkaline phosphatase maintains a constant
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enzymatic activity during storage for at least one year and up to 15.8 years”
(Claim 17).
For the reasons set forth above, we are not persuaded by Appellants‟
contention that Aoki and Ford teach away from the inclusion of galactose
(App. Br. 21).
Appellants contend that “the time of stability [(i.e., for at least one
year and up to 15.8 years)] is not specified in the combined prior art” (id. at
20 (emphasis removed); Reply Br. 7). We are not persuaded. On this
record, the preponderance of evidence supports Examiner‟s conclusion that
it would have been prima facie obvious to freeze-dry Aoki‟s preparation
comprising ALP, galactose, and BSA, as suggested by Ford, resulting in the
exact same method of stabilizing ALP as required by claim 17 (Ans. 7).
Appellants fail to establish through persuasive evidence or reasoning that the
method suggested by the combination of Aoki and Ford would not have
resulted in the same stability time required by Appellants‟ claim 17, i.e., that
the claimed stability time is not a property of the freeze-dried ALP, lactose,
and BSA formulation itself. Cf. Kubin, 561 F.3d at 1357.
CONCLUSION OF LAW
The preponderance of evidence on this record supports a conclusion
of obviousness. The rejection of claims 8, 12, 16, and 17 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Aoki, Ford, and Garman is
affirmed. Because they are not separately argued (a) claim 10 falls together
with claim 8; (b) claims 13-15 fall together with claim 12; (c) claim 18 falls
together with claim 16; and (d) claims 19-21 fall together with claim 17. 37
C.F.R. § 41.37(c)(1)(iv).
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TIME PERIOD FOR RESPONSE
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

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