Ex Parte Becq et al

Board of Patent Appeals and Interferences

May 3, 2010

10578328 (B.P.A.I. May. 3, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte FRẺDẺRIC BECQ and CAROLINE NOREZ
__________

Appeal 2010-002160
Application 10/578,328
Technology Center 1600
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Decided: May 3, 2010
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Before TONI R. SCHEINER, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL

This is an appeal under 35 U.S.C. § 134 involving claims to methods
of cystic fibrosis treatment by administering N-butyldeoxynojirimycin (NB-
DNJ). We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

Appeal 2010-002160
Application 10/578,328

Statement of the Case
Background
“CFTR [cystic fibrosis transmembrane conductance regulator] is
responsible for the transepithelial transport of water and electrolytes and in a
healthy individual allows the hydration of the pulmonary airways. In CF
[cystic fibrosis] patients, this protein is absent from the plasmic membranes
due to incorrect addressing of the protein which is retained in the
endoplasmic reticulum (ER)” (Spec. 1, ll. 22-25). According to the
Specification, “if the delF508 protein reaches the membrane, it functions as
a chloride channel. One of the keys to a treatment of this disease is therefore
a readdressing of delF508 towards the cell membrane” (Spec. 1, ll. 29-31).
The Claims
Claims 27-35 are on appeal. Claim 27 is representative and reads as
follows:
27. A method for the treatment of cystic fibrosis,
comprising administering a pharmaceutically acceptable
amount of a glucosidase inhibitor, wherein said inhibitor is a
compound of formula (IIbis):

in which R2 is a butyl group.

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The prior art

The Examiner relies on the following prior art references to
show unpatentability:

Tessier et al. WO 01/02862 A1 Jan. 11, 2001
Block et al. WO 03/037265 A2 May 8, 2003

Dwek et al., Targeting glycosylation as a therapeutic approach, 1
NATURE REV. DRUG DISCOVERY 65-75 (2002).

The issue
The Examiner rejected claims 27-35 under 35 U.S.C. § 103(a) as
obvious over Tessier and Block (Ans. 4-6).
The Examiner finds that Tessier teaches that “protein trafficking
disorders are disorders which affect secretory protein translocation, folding,
or assembly in the ER (endoplasmic reticulum) and these disorders include
cystic fibrosis” (id. at 4). The Examiner finds that Tessier teaches that
“animals suffering from a protein trafficking disorder (e.g. cystic fibrosis)
would benefit from the suppression of the cooperation of ERp57 with
calnexin or calreticulin. See paragraph spanning pages 14-15. Furthermore,
Tessier et al. teach cooperation of ERp57 with calnexin or calreticulin is
suppressed by glycosylation inhibitors, including deoxynojirimycin (DNJ).”
(Id.) The Examiner finds that Block teaches “administration of DNJ and
DNJ derivatives are effective to inhibit glucosidase activity. These
derivatives include the instantly claimed NB-DNJ” (id.).
The Examiner concludes that the ordinary artisan would have
recognized that the “glycosylation/glucosidase inhibiting agents (having
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identical core structures with a single n-butyl substitution for hydrogen at the
nitrogen position) taught by Block et al. could be substituted for the agent
taught by Tessier et al. to be useful for the treatment of protein trafficking
disorders, including cystic fibrosis” (Ans. 5).
Appellants argue that “one of ordinary skill in the art would have been
discouraged from using the glucosidase inhibitor of BLOCK, i.e., NB-DNJ,
for treating cystic fibrosis because TESSIER requires glycosylation
inhibitors” (App. Br. 5). Appellants argue that “Table 1 and Figure 3 of
DWEK do not show that NB-DNJ would be a glycosylation inhibitor” (id. at
6). Appellants argue that “Figure 3 of DWEK includes a legend that
specifies that ‘Inhibition of the α-glucosidase by the imino sugars N-
butlydeoxynojirimycin [sic] (NB-DNJ) and N-nonyldeoxynojirimycin (NN-
DNJ) can interfere with this process, leading to misfolded proteins’” (id. at
7). Appellants argue that Tessier “fails to disclose or suggest that
glycosylation inhibitors would also have been glucosidase inhibitors or vice-
versa” (id. at 8).
In view of these conflicting positions, we frame the obviousness issue
before us as follows:
Does the evidence of record support the Examiner’s conclusion that it
would have been obvious to apply NB-DNJ to the treatment of cystic
fibrosis as required by claim 27?
Findings of Fact (FF)
1. Tessier teaches that “‘Protein trafficking disorder’ refers to a
disorder which affects secretory protein translocation, folding or assembly in
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the ER. Representative examples of protein trafficking disorders include . . .
cystic fibrosis” (Tessier 6, ll. 13-17).
2. Tessier teaches that “[p]rotein trafficking disorders may be
treated by suppressing or stimulating the cooperation of ERp57 with
calnexin or calreticulin” (Tessier 14, ll. 23-25).
3. Tessier teaches that a
[W]arm-blooded animal suffering from a protein trafficking
disorder would benefit from the suppression of the
cooperation of ERp57 with calnexin or calreticulin if the
disorder is one in which an otherwise biologically active
protein is retained in the ER. Such disorders can be
identified by an under production of secretory protein
recognized by coimmuno-precipitation assays . . . and
include, by way of example . . . cystic fibrosis (for CFTR,
the most common allele in European and North American
populations is ∆F508 – but 17 is not the only one which
affects trafficking . . . .

(Tessier 14, l. 27 to 15, l. 8.)
4. Tessier teaches that “ERp57 cooperation with calnexin or
calreticulin is suppressed by administering to the . . . warm-blooded animal
a suitable glycosylation inhibitor, including by way of example . . .
deoxynojirimycin [DNJ]” (Tessier 13, ll. 17-22).
5. Tessier teaches that a “therapeutically effective amount is
determined based on in vitro experiments, followed by in vivo studies. The
ERp57 suppressor agents may be administered by injection, inhalation,
infusion, orally, rectally, lingually or transdermally” (Tessier 16, ll. 2-6).
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6. The Examiner finds that “Tessier et al. do not teach the
instantly claimed DNJ derivative (N-butyl-DNJ/NB-DNJ) or a specific
dose” (Ans. 4).
7. Block teaches that
Numerous DNJ derivatives have been described. DNJ and
its alkyl derivatives are potent inhibitors of the N-linked
oligosaccharide processing enzymes, .alpha.-glucosidase I
and .alpha.-glucosidase II (Saunier et al. (1982) J Biol Chem
257:14155-14161; Elbein (1987) Ann Rev Biochem 56:497-
534). These glucosidases are associated with the
endoplasmic reticulum of mammalian cells. The N-butyl and
N-nonyl derivatives of DNJ may also inhibit
glucosyltransferases associated with the Golgi.

(Block 11 ¶ 0036.)
8. Block teaches that “Glucosidases I and II, in the endoplasmic
reticulum (ER), mediate processing of N-linked glycan on glycoproteins.
This processing is necessary for the interaction of many glycoproteins with
the protein folding chaperon, calnexin.” (Block 15 ¶ 0056.)
9. Block teaches that the “morphogenesis and secretion of
members of the hepatitis B and flavivirus families are more dependent upon
glucosidases (and presumably, calnexin) than are most cellular
glycoproteins” (Block 16 ¶ 0056).
10. Dwek teaches, in Table 1, that N-butyl-DNJ has two sites of
action, one at ceramide-specific glucosyltransferase and one at the ER α-
glucosidase I (see Dwek, 67, Table 1).

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11. Figure 3 of Dwek is reproduced below:

“Figure 3 │ The role of glycosylation in protein folding . . . chaperones
such as calnexin . . . act as quality-control factors by retaining glycoproteins
in the ER until they are correctly folded. Inhibition of the α-glucosidases by
the imino sugars N-butyldeoxynojirimycin (NB-DNJ) . . . can interfere with
this process, leading to misfolded proteins” (Dwek 69).
12. The Specification teaches that “N-butyl-deoxynojirimycin (NB-
DNJ), is a glucosidase I and II inhibitor of the endoplasmic reticulum, which
was first developed as an anti-viral molecule for humans” (Spec. 3, ll. 5-6).
13. The Specification teaches that “clinical trials revealed that NB-
DNJ also had an inhibiting effect on the glucosyltransferases . . . NB-DNJ, a
glucosyltransferase inhibitor involved in the biosynthesis of the
glucocerebrosides, thus prevents their synthesis and accumulation” (Spec. 3,
ll. 12-18).
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Principles of Law
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
The Supreme Court has emphasized that “the [obviousness] analysis need
not seek out precise teachings directed to the specific subject matter of the
challenged claim, for a court can take account of the inferences and creative
steps that a person of ordinary skill in the art would employ.” KSR Int'l Co.
v. Teleflex Inc., 550 U.S. 398, 418 (2007).
Analysis
It is undisputed that Tessier teaches “treating protein trafficking
disorders, such as cystic fibrosis, by suppressing the cooperation of ERp57
with calnexin or calreticulin with glycosylation inhibitors, such as
deoxynojirimycin (DNJ)” (App. Br. 4; FF 1-5). The dispute centers on
whether it would have been obvious to substitute NB-DNJ for DNJ in the
treatment of cystic fibrosis.
The prior art recognizes that NB-DNJ is a derivative of DNJ which
may have multiple activities (FF 7, 10). Specifically, Block teaches that
NB-DNJ is a more potent form of DNJ which has both glucosidase and
glycosyltransferase inhibiting activities (FF 7). Block also connects NB-
DNJ to calnexin, recognized by Tessier, and teaches that by inhibiting
glucosidase, NB-DNJ also functions to inhibit glycoprotein interaction with
calnexin, consistent with the goals of Tessier (FF 8-9).
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Dwek also teaches that NB-DNJ has both glucosidase and
glycosyltransferase inhibiting activities (FF 10) and shows that inhibition by
NB-DNJ will inhibit calnexin (FF 11).
Thus, Tessier teaches that DNJ compounds treat cystic fibrosis by
inhibiting calnexin (FF 1-5) and both Block and Dwek teach that NB-DNJ is
a potent derivative of DNJ which shares the glucosidase activity of DNJ and
which inhibits calnexin (FF 7-11). We agree with the Examiner’s finding
that the ordinary artisan “would have recognized that the
glycosylation/glucosidase inhibiting agents (having identical core structures
with a single n-butyl substitution for hydrogen at the nitrogen position)
taught by Block et al. could be substituted for the agent taught by Tessier et
al. to be useful for the treatment of protein trafficking disorders, including
cystic fibrosis” (Ans. 5; FF 1-11).
Appellants argue that “one of ordinary skill in the art would have been
discouraged from using the glucosidase inhibitor of BLOCK, i.e., NB-DNJ,
for treating cystic fibrosis because TESSIER requires glycosylation
inhibitors” (App. Br. 5). Appellants argue that “Table 1 and Figure 3 of
DWEK do not show that NB-DNJ would be a glycosylation inhibitor” (id. at
6).
We are not persuaded. Block, Dwek and Appellants’ own
Specification teach that the prior art understood and appreciated that NB-
DNJ has both glucosidase and glycosylation inhibitory activities (FF 7, 10,
12-13). Block expressly states that the “N-butyl and N-nonyl derivatives of
DNJ may also inhibit glucosyltransferases associated with the Golgi” (Block
11 ¶ 0036: FF 7). Dwek teaches that NB-DNJ inhibits “ceramide-specific
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glucosyltransferase” (FF 10). Finally, the Specification teaches that “clinical
trials revealed that NB-DNJ also had an inhibiting effect on the
glucosyltransferases . . . NB-DNJ, a glucosyltransferase inhibitor involved in
the biosynthesis of the glucocerebrosides, thus prevents their synthesis and
accumulation” (Spec. 3, ll. 16-18: FF 13).
Thus, the ordinary artisan would have understood that NB-DNJ would
have been expected to inhibit calnexin and would function as both a
glucosidase and glycosylation inhibitor (FF 7-13), which reasonably
supports the obviousness argument that if DNJ functions to treat cystic
fibrosis as taught by Tessier, DNJ derivatives such as NB-DNJ, which are
more potent, would also be reasonably expected to function in the treatment
of cystic fibrosis, since the DNJ derivatives share the activities of DNJ (FF
1-13).
We are not persuaded by Appellants’ argument that Tessier “fails to
disclose or suggest that glycosylation inhibitors would also have been
glucosidase inhibitors or vice-versa” (App. Br. 8). As Block, Dwek and the
Specification teach, NB-DNJ was expected by the prior art to have both the
glycosylation and glucosidase inhibiting activity. Whether Tessier
recognized this fact or not, we conclude that the ordinary artisan apprised of
the functionality of the DNJ derivative NB-DNJ by Block would have
reasonably substituted this more potent compound in the treatment of cystic
fibrosis taught by Tessier (FF 1-9).
Appellants also argue that “Figure 3 of DWEK includes a legend that
specifies that ‘Inhibition of the α-glucosidase by the imino sugars N-
butlydeoxynojirimycin [sic] (NB-DNJ) and N-nonyldeoxynojirimycin (NN-
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DNJ) can interfere with this process, leading to misfolded proteins’” (App.
Br. 7).
We are not persuaded because figure 3 of Dwek shows that NB-DNJ
interferes with calnexin’s activity (FF 11), which is the same ER-retention
pathway that Tessier suggests DNJ inhibitors must suppress in order to treat
cystic fibrosis (FF 1-5). Thus, based on the disclosure of Dwek, the ordinary
artisan would reasonably expect that treatment with NB-DNJ would
suppress calnexin, which Tessier teaches is a desirable treatment for cystic
fibrosis (FF 4-5).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that it
would have been obvious to apply NB-DNJ to the treatment of cystic
fibrosis as required by claim 27.
SUMMARY
In summary, we affirm the rejection of claim 27 under 35 U.S.C.
§ 103(a) over Tessier, Block, and Dwek. Pursuant to 37 C.F.R.
§ 41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 28-35, as
these claims were not argued separately.

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv)(2006).
AFFIRMED

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