Ex Parte Srivastava et al

Patent Trial and Appeal Board

Nov 20, 2012

11210283 (P.T.A.B. Nov. 20, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte SATISH K. SRIVASTAVA,
K. VENKAT RAMANA, and ARUNI BHATNAGAR
__________

Appeal 2011-011408
Application 11/210,283
Technology Center 1600
__________

Before FRANCISCO C. PRATS, MELANIE L. McCOLLUM, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

McCOLLUM, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a sepsis
treatment method. The Examiner has rejected the claims as anticipated
and/or obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

STATEMENT OF THE CASE
Claims 10, 22, 41, and 42 are on appeal (App. Br. 2). We will focus
on independent claims 10 and 41, which read as follows:
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10. A method of treating sepsis in a patient having or suspected of
having sepsis comprising administering to the patient having or suspected of
having sepsis an effective amount of a pharmaceutically acceptable
composition comprising a small molecule inhibitor of aldose reductase
catalytic activity.
41. A method of treating sepsis in a patient having or at risk of
developing sepsis comprising:
a) identifying a patient having or at risk of developing sepsis;
b) administering to the patient an effective amount of a
pharmaceutically acceptable composition comprising a small
molecule inhibitor of aldose reductase catalytic activity.
Claims 10, 22, 41, and 42 stand rejected under 35 U.S.C. § 102(e) as
anticipated by Stenzler
1
(Ans. 5).
Claims 10, 22, and 41 stand rejected under 35 U.S.C. § 102(b) as
anticipated by Nakamura
2
(Ans. 6).
Claims 10, 22, 41, and 42 stand rejected under 35 U.S.C. § 103(a) as
obvious over Nakamura in view of Mackenzie
3
(Ans. 8).

I
In rejecting claims 10, 22, 41, and 42 as anticipated by Stenzler, the
Examiner finds that “Stenzler discloses a method of treating septic shock
comprising the administration of nitric oxide via inhalation in mechanically
ventilated patients” (Ans. 5). The Examiner also finds: “According to the
specification as filed a nitric oxide inducer, refers to any compound that

1
Stenzler, US 6,581,599 B1, Jun. 24, 2003.
2
Nakamura et al., Effectiveness of Aldose Reductase Inhibitor for Diabetic
Gastroenteropathy with Constipation, 36 INTERNAL MEDICINE 479 (1997).
3
Mackenzie et al., The Management of Sepsis, 13 UPDATE IN ANAESTHESIA
16 (2001).
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increases the amount of available nitric oxide. Moreover, the specification
teaches that this inducer functions as an inhibitor of aldose reductase.” (Id.)
The Examiner concludes that, “absent evidence to the contrary, the ordinary
skilled artisan following the teachings of the Stenzler, wherein the amount of
nitric oxide is increased in a patient via direct inhalation would inherently
practice the methods of the claimed invention” (id. at 6).
Appellants argue: “The Examiner has not established that NO is an
aldose reductase inhibitor. In fact, Nitric oxide is not an aldose reductase
inhibitor.” (App. Br. 6.) Appellants also argue that Stenzler describes “the
use of nitric oxide in treating respiratory conditions, such as hypertension –
not treating sepsis” (id.).
Issue
Does the preponderance of evidence on this record support the
Examiner’s conclusion that Stenzler teaches the use of an aldose reductase
inhibitor to treat sepsis?
Findings of Fact
1. Stenzler discloses a “device and method . . . for delivering NO
to a patient” (Stenzler, Abstract).
2. Stenzler also discloses that “respiratory diseases where NO
inhalation therapy is thought to be beneficial include . . . septic shock” (id. at
col. 1, ll. 53-57).
3. The Specification discloses: “In some embodiments of the
invention, a nitric oxide inducer is provided or administered to the cell to
modulate an aldose reductase polypeptide in a cell. In particular
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embodiments, the inducer inhibits AR [aldose reductase].” (Spec. 11: 1-3 &
2: 11.)
4. The Specification also discloses: “A nitric oxide inducer (NO
inducer) refers to any compound that increases the amount of available nitric
oxide. A nitric oxide inducer includes, but is not limited to, nitric oxide
precursors, nitric oxide donors, or inhibitors of nitric oxide synthase
inhibitor. Furthermore, nitric oxide donors include nitric oxide synthase
substrates.” (Id. at 11: 12-15.)
5. Appellants provided Srivastava
4
as evidence that “[n]itrosation
of aldose reductase upregulates the activity of this enzyme” (App. Br. 6).
6. Srivastava discloses that modification of AR by specific
nitrosothiols (SNAP and glyco-SNAP) resulted in an increase in its K(cat)
and its K(m) for glyceraldehyde (Srivastava, Abstract).
7. Srivastava also discloses:
Electrospray ionization MS revealed that the modification
reaction proceeds via the formation of an N-hydroxy-
sulphenamide-like adduct between glyco-SNAP and AR. In
time, the adduct dissociates into either nitrosated AR (AR-NO)
or a mixed disulphide between AR and glyco-N-acetyl-
penicillamine (AR-S-S-X). Removal of the mixed-disulphide
form of the protein . . . enriched the preparation in the high-
K(m)-high-k(cat) form of the enzyme, suggesting that the
kinetic changes are due to the formation of AR-NO. . . .
Modification of AR by the non-thiol NO donor diethylamine
NONOate (DEANO) increased enzyme activity and resulted in
the formation of AR-NO.
(Id.)

4
PubMed Abstract for Srivastava et al., Structural and kinetic modifications
of aldose reductase by S-nitrosothiols, 358 BIOCHEM J. 111 (2001).
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8. In response to Appellants’ evidence, the Examiner provided
Nishikawa
5
and Chandra
6
as evidence that “nitric oxide functions to down
regulate the activity of aldose reductase” (Ans. 9-10).
9. Nishikawa discloses:
The activity of aldose reductase is reversibly down-regulated by
nitric oxide modification of a cysteine residue in the enzyme’s
active site. ROS [reactive oxygen species] appear to reduce
nitric oxide levels and thus may activate aldose reductase. . . .
In a euglycemic environment, oxidant stress (i.e., ROS)
increases the concentration of toxic aldehydes. At the same
time, nitric oxide levels are reduced, converting aldose
reductase to a higher activity form.
(Nishikawa S-27.)
10. Chandra discloses: “Our results show that increasing NO
availability inhibits AR, whereas inhibiting NO synthesis promotes the
activation of the enzyme. These results could form the basis of a new
therapeutic approach for treating diabetes complications with donors or
precursors of NO to inhibit AR.” (Chandra 3095.)
Analysis
Stenzler discloses that “respiratory diseases where NO inhalation
therapy is thought to be beneficial include . . . septic shock” (Finding of Fact
(FF) 2). In addition, while we recognize that Appellants have provided
some evidence indicating that at least some NO inducers increase AR
activity (FF 6-7), we conclude that the evidence of record, on balance,

5
Nishikawa et al., The missing link: A single unifying mechanism for
diabetic complications, 58 KIDNEY INT’L S-26 (2000).
6
Chandra et al., Nitric Oxide Prevents Aldose Reductase Activation and
Sorbitol Accumulation During Diabetes, 51 DIABETES 3095 (2002).
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supports the Examiner’s conclusion that NO is an inhibitor of aldose
reductase catalytic activity (FF 3-4 & 9-10).
Conclusion
The preponderance of evidence on this record supports the
Examiner’s conclusion that Stenzler teaches the use of an aldose reductase
inhibitor to treat sepsis. We therefore affirm the anticipation rejection over
Stenzler of claim 10. Claims 22, 41, and 42 have not been argued separately
and therefore fall with claim 10. 37 C.F.R. § 41.37(c)(1)(vii).

II
In rejecting claims 10, 22, and 41 as anticipated by Nakamura, the
Examiner finds that Nakamura teaches “the administration of an aldose
reductase inhibitor, Epalrestat, to a diabetic patient with long-standing
constipation complicated by paralytic ileus and septic shock” (Ans. 6-7).
The Examiner also finds that Nakamura teaches “that constipation
predisposes patients to the development of sepsis” (id. at 7).
In rejecting claims 10, 22, 41, and 42 as obvious, the Examiner relies
on Nakamura as discussed above (id. at 8). In addition, the Examiner relies
on Mackenzie for teaching that, in the initial management of sepsis,
“[p]atients with inadequate airway reflexes should be . . . mechanically
ventilated” (id.).
Appellants argue that Nakamura teaches that an “aldose red[uc]tase
inhibitor was only administered after sepsis was successfully treated – the
patient no longer had sepsis when treated for persistent constipation” (App.
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Br. 8). We agree.
7
We therefore reverse the anticipation rejection over
Nakamura of claim 10 and of claims 22 and 42, which depend from
claim 10. For the same reason, we reverse the obviousness rejection of
claims 10, 22, and 42 over Nakamura in view of Mackenzie.
However, claim 41 encompasses the treatment of a patient “at risk of
developing sepsis.” In addition, the Examiner finds that “the remaining
symptom of constipation in [Nakamura’s] patient caused the patient to
remain at risk for developing sepsis again” (Ans. 11-12). Appellants have
not adequately explained why the Examiner’s position is in error. We
therefore affirm the anticipation rejection of claim 41 over Nakamura. Since
“anticipation is the epitome of obviousness,” we also affirm the obviousness
rejection of claim 41 over Nakamura in view of Mackenzie. In re McDaniel,
293 F.3d 1379, 1385 (Fed. Cir. 2002).

SUMMARY
We affirm the rejection of claims 10, 22, 41, and 42 as anticipated by
Stenzler. We also affirm the rejections of claim 41 as anticipated by
Nakamura and as obvious over Nakamura in view of Mackenzie. However,

7
As noted by the Examiner (Ans. 7), the Specification states: “In certain
embodiments, methods include a step of identifying a patient with or
suspected of having a condition described herein that can be treated with an
aldose reductase inhibitor. Methods may include . . . determining the patient
is at risk for a disease, condition, or disorder.” (Spec. 8.) However, we do
not agree with the implication that, in the context of the Specification, a
patient at risk of developing sepsis is a patient “suspected of having sepsis,”
as recited in claim 10.
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we reverse the rejections of claims 10, 22, and 42 as anticipated by
Nakamura and as obvious over Nakamura in view of Mackenzie.

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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