Ex Parte Buck et al

Board of Patent Appeals and Interferences

Nov 30, 2010

11328247 (B.P.A.I. Nov. 30, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte CHARLES BUCK, HELMUT DENK, ELEONORE FROHLICH,
BIRGIT GUTMANN, PETER HECHT, IVICA KVIETIKOVA,
MARCUS OTTE, GOTTFRIED SCHATZ, CORNELIA STUMPTNER,
LIONEL WIGHTMAN, and KURT ZATLOUKAL
__________

Appeal 2010-000939
Application 11/328,247
Technology Center 1600
__________

Before ADRIENE LEPIANE HANLON, DEMETRA J. MILLS, and
KAREN M. HASTINGS, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL1

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

Appeal 2010-000939
Application 11/328,247

2

This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).

STATEMENT OF CASE
The following claim is representative.
1. A method of treating a patient with a drug-induced liver disease,
comprising administering, to a patient in need thereof, a therapeutically
effective amount of a mitochondrially targeted antioxidant compound
comprising a lipophilic cation covalently coupled to an antioxidant moiety.

Cited References

Murphy et al. US 6,331,532 B1 Dec. 18, 2001
Wang et al. US 2003/0027806 A1 Feb. 6, 2003
Yodoi et al. US 2004/0109870 A1 Jun. 10, 2004

O’Connor et al., Hepatocellular damage from non-steroidal anti-
inflammatory drugs, 96 Q J MED 787-791 (2003).

Smith et al., Delivery of bioactive molecules to mitochondria in vivo, 100
PNAS 5407-5412 (2003).

Bissell et al., Drug-Induced Liver 1njury: Mechanisms and Test Systems, 33
HEPATOLOGY 1009-1013 (2001).

Grounds of Rejection
1. Claims 1-11 and 14-19 are rejected under 35 U.S.C. § 103(a) as being
unpatentable over Murphy in view of Yodoi in further view of O’Connor.

FINDINGS OF FACT
The findings of fact relevant to all rejections are set forth below.
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1. “Murphy et al. teaches methods of therapy of patients who would benefit
from reduce oxidative stress by administering compositions containing
mitrochondrially charged compounds, and that a compound of the invention
comprises a lipophilic cation covalently coupled to an antioxidant moiety
(Abstract, claim 23).” (Ans. 3.)
2.
Murphy et al. teaches that the preferred lipophilic cation is the
triphenylphosphonium cation (Abstract, column 1, lines 63-64).
Murphy et al. teaches that the method constitutes a major
advantage over current therapies by enabling antioxidants to
accumulate in the mitochondria, the part of the cell under the
greatest oxidative stress; and that this would greatly increase
the efficacy of antioxidant therapies (column 20, lines 14-20).

(Id.)
3. “Murphy et al. teaches that oxidative stress also contributes to
inflammation (column 1, lines 18-20). It is widely known in the art that
hepatitis is the medical name for liver inflammation.” (Id.)
4.
Murphy et al. teaches a compound of formula of instant claim
9, where Z- is an anion, preferably a pharmaceutically
acceptable anion, and R is an antioxidant moiety (column 2,
lines 1 - 16, lines 25-27); and that quinols or general radical
scavengers are antioxidants that can be used in the invention to
make a wide range of mitochondrially targeted compounds
(column 6, lines 33-43).

(Id. at 3-4.)
5.
Murphy et al. teaches that the anion of the compound as
prepared by the method of the patent, will be an halogen, but
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can readily be changed with any other pharmaceutically or
pharmacologically acceptable anion (column 6, lines 26-32);
and that Br is the halogen (column 2, lines 44-45, column 3,
lines 26, column 6, lines 1-12). Murphy et al. teaches a
particular preferred embodiment, the mitochondrially targeted
antioxidant has the formula of the compound of instant claim
11 (column 3, lines 11 -27).

(Ans 4.)
6. “It is known in the art that mitochondrially target molecules with the
triphenylphosphonium cation are taken up by liver mitochondria (see Smith
et al., PNAS, 2003). Murphy et al. does not teach the methods of treating
patient with NSAID-induced acute hepatitis with the compounds or that the
anion can be methylsulfonate.” (Id.)
7. “Yodoi et al. teaches that medicaments generate reactive oxygen species
in the liver to induce the apoptosis of hepatocytes and cause acute hepatitis,
paragraph [0003].” (Id.)
8.
O'Connor et al. teaches that NSAlDs are widely used for
the management of rheumatological disorders, and as analgesics
and antipyretics, i.e. medicaments (page 787, Summary,
Introduction). O'Connor teaches that hepatoxicity is
uncommon, but can occur with all NSAlDs (Summary); and
that one of the main clinical patterns of hepatoxicity due to
NSAlDs is acute hepatitis (page 788, 2nd column, 1st
paragraph).

(Ans.5.)
9.
O'Connor et al. also teaches that diphenylamine, which is
common in the structure of NSAIDs, uncouples oxidative
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phosphorylation, decreases hepatic ATP content and induces
hepatocyte injury (page 789, 1st column, 2nd paragraph).

10. It is known in the art that drugs which reduce mitochondrial
oxidative phosphorylation and deplete ATP also can generate
excessive levels of reactive oxygen species, causing further cellular
injury (see Bissell et al., Hepatol., 2001).

(Id.)

ISSUE
The Examiner argues that the cited prior art renders the claimed
invention obvious.
Appellants argue that “Murphy fails to teach treatment of liver
diseases (including liver inflammation, i.e. hepatitis) by administering
the recited antioxidants.” (App. Br. 10.) Appellants argue that the
“compounds of Yodoi are structurally very different from the
compounds used in the present invention.” (Id. at 11.)
The issue is: Does the combination of the cited references teach the
claimed method of treating a patient with drug-induced liver disease caused
by NSAIDS?

PRINCIPLES OF LAW
When the Examiner has required the applicant to elect single chemical
species for examination, the issue on appeal is the patentability of the single
elected species. It is appropriate to limit discussion to that single issue and
take no position respecting the patentability of the broader generic claims,
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including the remaining, non-elected species. See Ex parte Ohsaka, 2
USPQ2d 1461 (BPAI 1987).
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
Cir. 1993) (citations omitted). In order to determine whether a prima facie
case of obviousness has been established, we consider the factors set forth in
Graham v. John Deere Co., 383 U.S. 1, 17 (1966): (1) the scope and content
of the prior art; (2) the differences between the prior art and the claims at
issue; (3) the level of ordinary skill in the relevant art; and (4) objective
evidence of nonobviousness, if present.
The test for obviousness is what the combined teachings of the
references as a whole would have suggested to those of ordinary skill in the
art. In re Keller, 642 F.2d 414, 425 (CCPA 1981). “Non-obviousness
cannot be established by attacking references individually where the
rejection is based upon the teachings of a combination of references. . . .
[The reference] must be read, not in isolation, but for what it fairly teaches
in combination with the prior art as a whole.” In re Merck & Co., Inc., 800
F.2d 1091, 1097 (Fed. Cir. 1986).

ANALYSIS
We select claim 1 as it relates to the elected species as representative
claim, as Appellants have not separately argued individual claims.
Murphy teaches mitochodrially targeted antioxidants comprising the
elected triphenyl phosphonium lipophilic cation for the treatment of patients
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who would benefit from reduced oxidative stress. (Abstract). The lipophilic
cations target antioxidant to the major source of free radicals and reactive
oxygen species causing the oxidative stress. (Col. 1, ll. 45-51.) Compounds
such as the claimed mitoquinol and mitoquinone are disclosed. (Col. 4, ll.
36-37.) In Murphy, mitochondria from rat liver were exposed to oxidative
stress caused by iron/ascorbate. (Col. 14, ll. 27-35.) Murphy does not teach
that the patient who would benefit from reduced oxidative stress is a patient
who has hepatitis caused by NSAIDS (non-steroidal anti-inflammatory
drugs). However, the combination of Yodoi, O’Connor and Bissell teach
that a patient who would benefit from reduced oxidative stress is a patient
who has hepatitis caused by NSAIDS (non-steroidal anti-inflammatory
drugs).
“Yodoi et al. teaches that medicaments generate reactive oxygen
species in the liver to induce the apoptosis of hepatocytes and cause acute
hepatitis, paragraph [0003].” O’Connor teaches that there are two main
clinical patterns from toxicity due to NSAIDS and these include hepatitis.
(Page 788, col. 2.) O’Connor further discloses that NSAIDS uncouple
oxidative phosphorylation and decrease ATP content of mitochondria.
(Page 789, col. 1.) Bissell discloses that reducing oxidative phosphorylation
and ATP levels generates reactive oxygen species. (Page 1012, col. 2.)
Since Murphy discloses that a patient with oxidative stress is a patient
exposed to reactive oxygen species, and Yodoi, O’Conner and Bissell
together disclose that medicaments such as NSAIDS cause hepatitis and
generate reactive oxygen species, it would have been obvious to administer
the compounds comprising the lipophilic cations of Murphy to patients with
oxidative stress and hepatitis caused by exposure to NSAIDS.
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Appellants argue that Murphy fails to teach the treatment of liver
diseases including hepatitis. (App. Br. 10.) However Murphy teaches the
treatment of patients with oxidative stress and also rat liver exposed to
oxidative stress and reactive oxygen species induced by drugs such as iron
and ascorbate. Yodoi, O’Conner and Bissell together disclose that
medicaments such as NSAIDS cause hepatitis and generate reactive oxygen
species. One of ordinary skill in the art would have understood from the art
taken as a whole that the NSAIDS cause hepatitis and reactive oxygen
species which can be treated with the compounds of Murphy. Thus
Appellants have failed to consider what the combined teachings of the
references as a whole would have suggested to those of ordinary skill in the
art.
Appellants also argue that the determination of O’Connor that
NSAIDS induce liver disease by generation of reactive oxygen species does
not suggest the use of the particular compounds of the invention for the
treatment of drug induced liver disease. (App. Br. 11.) Appellants argue
that there is no pointer to target the increased oxidative stress in the
mitochondrial compartments in the management of hepatotoxicity caused by
NSAIDS. (Id.) We are not persuaded, as it is Murphy that is relied on for
the treatment of reactive oxygen species using the claimed compounds, and
again the Appellants have failed to consider what the prior art as a whole has
taught one of ordinary skill in the art.
Appellants argue that the compounds of Yodoi are structurally
different than the compounds of the present invention. (Id.) However, the
Examiner relies in-part on Yodoi for the teaching that medicaments generate
reactive oxygen species in the liver to induce the apoptosis of hepatocytes
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and cause acute hepatitis. For the stated reasons, the prior art as a whole,
suggests the invention as claimed. Thus we are not persuaded by
Appellants’ argument.

CONCLUSION OF LAW
The cited references support the Examiner’s obviousness rejection.
Appellants have not provided sufficient rebuttal argument or evidence to
overcome the obviousness rejection.
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

cdc

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