Ex Parte Gladwin et al

Patent Trial and Appeal Board

Dec 9, 2015

10563683 (P.T.A.B. Dec. 9, 2015)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/563,683 10/04/2006
36218 7590 12/11/2015
KLARQUIST SPARKMAN, LLP (OTT-NIH)
121 S.W. SALMON STREET
SUITE#l600
PORTLAND, OR 97204-2988
FIRST NAMED INVENTOR
Mark T. Gladwin
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.
4239-67618-07 3225
EXAMINER
PAGONAKIS, ANNA
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
12/11/2015 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
tanya.harding@klarquist.com
docketing@klarquist.com
nicole. salazar@klarquist.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MARKT. GLADWIN, ALAN N. SCHECHTER,
DAVID J. LEPER, RAKESH P. PATEL, CHRISTIAN J. HUNTER,
GORDON G. POWER, DANIEL B. KIM-SHAPIRO, RYSZARD PLUTA,
EDWARD H. OLDFIELD, and RICHARD 0. CANNON III
Appeal2013-002645
Application 10/563,683
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to a
treatment method for decreasing blood pressure and/or increasing
vasodilation by administering non-acidified sodium nitrite. The Examiner
rejected the claims as obvious and on the ground of obviousness-type double
patenting. We have jurisdiction under 35 U.S.C. § 6(b ). We affirm the
double patenting rejection but reverse the obviousness rejections.
1 Appellants identify the Real Parties in Interest as The UAB
Research Foundation; The Board of Supervisors of Louisiana State
University and Agricultural and Mechanical College, Loma Linda
University, Wake Forest University, and The Government of the
United States of America (see App. Br. 3).
Appeal2013-002645
Application 10/563,683
Statement of the Case
Background
The Specification teaches "the state of the art was that nitrite was not
a significant vasodilator at concentrations below 100 µMin vitro, and even
when infused into humans at concentrations of 200 µM in the forearm"
(Spec. 2, 11. 25-27). "It was also the state of the art that nitrite was not
converted to nitric oxide in the human blood stream" (Spec. 2, 11. 27-28).
The Claims
Claims 1-3, 13-15, 17 and 18 are on appeal. Independent claim 1 is
representative and reads as follows:
1. A method for treating or ameliorating a condition
selected from:
mJury;
(a) hepatic or cardiac or brain ischemia-reperfusion
(b) pulmonary hypertension; or
( c) cerebral artery vasospasm,
in a subject by decreasing blood pressure and/or
increasing vasodilation in the subject, the method
comprising administering a therapeutically effective amount
of non-acidified sodium nitrite to the subject to decrease the
blood pressure and/or increase vasodilation in the subject,
wherein the sodium nitrite is administered to a circulating
concentration of about 0.6 to 240 µM, and wherein the
administration is by a route whereby the non-acidified
sodium nitrite contacts blood in the subject, and the route is
selected from the group consisting of intravenous,
intramuscular, rectal, ex vivo, intraocular, intraperitoneal,
intraarterial, subcutaneous, inhalation, and into a
cardiopulmonary bypass circuit, thereby treating or
ameliorating the condition.
2
Appeal2013-002645
Application 10/563,683
The Issues
A. The Examiner rejected claims 1-3, 13-15, 17, and 18 under
35 U.S.C. § 103(a) as obvious over Webb,2 Goldfrank, 3
Remington4 and Modin5 (Ans. 7-10).
B. The Examiner rejected claims 1-3, 13-15, 17, and 18 under 35 U.S.C.
§ 103(a) as obvious over Shaw, 6 Goldfrank, and Modin (Ans. 11-14).
C. The Examiner rejected claims 1-3, 13-15, 17, and 18 on the ground
of provisional nonstatutory obviousness-type double patenting as
unpatentable over claims 1--4, 10, and 14--18 of copending U.S. Pat.
Application 12/748,1847 (Ans. 14--15).
A. and B. 35 USC§ 103(a) over Webb, Gold/rank, Remington and
Modin or Shaw, Gold/rank, and Modin
Because both of these rejections rely upon the teaching of non-
acidified sodium nitrite in Modin, we will consider these rejections together.
The issues with respect to these rejections are:
(i) Does the evidence of record support the Examiner's conclusion
that the cited prior art suggests administration of "non-acidified sodium
2 Webb et al., Inorganic Nitrite: Protector Against Ischaemia
Reperfusion Injury In The Heart?, 138 BRITISH J. PHARMACOLOGY
Ul 0 (2003) (hereinafter "Webb").
3 Goldfrank's Toxicologic Emergencies 1511 (7th Ed. 2002)
(hereinafter "Goldfrank's").
4 Remington's Pharmaceutical Sciences 420--425 (16th Ed. 1980).
5 Modin et al., Nitrite-derived nitric oxide: a possible mediator
of 'acidic-metabolic' vasodilation, 171 ACT A PHYSIOL. SCAND. 9-
16 (2001).
6 Shaw et al., US 4,650,484, issued Mar. 17, 1987.
7 US 12/748,184 issued as US 8,927,030 B2 on Jan. 6, 2015.
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Application 10/563,683
nitrite ... to decrease the blood pressure and/or increase vasodilation" as
required by claim 1 ?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. Webb teaches:
To investigate the effect of nitrite on I/R
[ischaemia/reperfusion] injury, hearts were subject to 30 min
global ischaemia and 120 min reperfusion in the absence or
presence of 10 or 100 µM nitrite . . . . NO produced via
XOR-mediated nitrite reduction protects against I/R injury
and as such may have an important protective endogenous or
therapeutic role in myocardial infarction.
(Webb UlO).
2. Goldfrank teaches that in "canines poisoned with subcutaneous
1'-JaCJ\J injection and then treated \~1ith amyl nitrite or intravenous sodium
nitrite, both nitrite forms increased the LD50 fourfold . . . . One ...
mechanism may be nitrite induced vasodilation and enhanced hepatic and
other organ blood flow" (Goldfrank's 1511, col. 1).
3. Remington teaches that "any active molecule may be
transformed into a complex or salt" (Remington 424, col. 2).
4. Modin teaches that "[ s ]odium nitrite evoked a dose-dependent
relaxation of the phe-precontracted aorta segments . . . . In the neutral buffer
solution, the threshold dose of sodium nitrite was 10 µM, the EC50 value
200 µMand the aortic segment relaxed almost to basal tone following the
highest dose of 1000 µM nitrite" (Modin 11, col. 2).
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5. Modin teaches that the "relaxatory effect of nitrite was
increased in an acidic buffer solution (pH 6.6) compared with neutral pH"
(Modin 9, abstract).
6. Modin teaches that
the present study demonstrates that inorganic nitrite in
physiological concentrations evokes vasodilation, most
likely through NO release. This NO release and in parallel
the vasodilatory effect, is increased if the pH of the
environment is reduced to levels normally found in tissues
during ischaemia/hypoxia or increased metabolic activity.
(Modin 15, col. 1 ).
7. The Freeman Declaration 8 states that the "evidence prior to
October 14, 2003, was that non-acidified sodium nitrite was inert and not a
vasodilator in vivo, particularly in the human circulation, and it was accepted
in the pharmacology, chemistry and NO therapeutics fields of research that
inorganic nitrite was an inert oxidation product of nitric oxide metabolism"
(Freeman Dec. i-f 5).
8. The Lundberg Declaration9 states that:
The experimental model we used in this publication did not
include the regulatory factors present in blood, such as
hemoglobin in red blood cells, that are known to inhibit the
effects of nitric oxide and nitric oxide donor medications.
Because of this, our finding that concentrations of non-
acidified (pH 7.45) inorganic nitrite greater than 25
micromolar concentration cause vasodilation of excised rat
aorta were not considered predictive of whether or not
similar concentrations of inorganic nitrite would cause
8 Declaration of Dr. Bruce Freeman, dated Aug. 27, 2009.
9 Declaration of Dr. Jon Lundberg, dated Sept. 9, 2009.
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vasodilation under non-acidic/non-hypoxic physiological
conditions in vivo.
(Lundberg Dec. i-f 3).
9. The Lundberg Declaration states that:
Although we published that inorganic nitrite caused
vasodilation of isolated segments of rat aorta in vitro at
neutral pH with an EC50 value of 200 µM, the overwhelming
evidence in the scientific literature prior to October 14,
2003, was that near physiological concentrations, non-
acidified sodium nitrite was vasodilator-inactive under
normoxic conditions - particularly in vivo.
(Lundberg Dec. i-f 4).
10. The Kelm Declaration 10 states "our strong belief, based on our
research studies and others in the field, that plasma nitrite had no
physiological effect on vasodilation. I believe the results of this study were
widely accepted at the time by the broad scientific community" (Kelm Dec.
,-r 6).
11. The Ignarro Declaration 11 states that
prior to October 14, 2003, I would not have expected
sodium nitrite to have any beneficial therapeutic effect to
induce vasodilation or increase blood flow when
administered (for instance by injection or inhalation) to a
subject at circulating concentrations of 25 µMor less,
regardless of the in vitro results in rat aorta provided by
Modin et al.
(Ignarro Dec. i-f 9).
10 Declaration of Dr. Malte Kelm, dated Aug. 28, 2009.
11 Declaration of Dr. Louis Ignarro, dated Sept. 14, 2009.
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12. The Gladwin Declaration states that
Based upon the cited references and the general knowledge
available in the field as of the priority date of the current
application, one of skill in the field would not have
concluded that the concentration of sodium nitrite identified
by Modin et al. as inducing relaxation of the aortic segment
in an aortic ring bioassay would be the same concentration
of sodium nitrite that causes vasodilation in vivo. Our
results were extremely unexpected and highly controversial
in the field when they were first published in Nature
Medicine ....
(Gladwin Dec. i-f 6).
13. Pawloski 12 states that "Schechter and Gladwin ... propose that
in red cells, iron-nitrosyl hemoglobin (in which nitric oxide is bound to
heme) and nitrite ions may serve as sources of nitric oxide but provide no
references for either contention. This is because the former has not been
demonstrated to be a source of nitric oxide, and the latter has been shown to
lack vasoactivity under physiologic conditions" (Pav,rloski 403).
14. Lauer teaches that nitrite "was found to be devoid of vasodilator
activity at doses up to 36 µmol/min" (Lauer 12816, col. 2).
Principles of Law
Skepticism within the industry supports unobviousness of the
invention. See Transocean Offshore Deepwater Drilling, Inc. v. Maersk
Contractors USA, Inc., 699 F.3d 1340, 1352-1353 (Fed. Cir. 2012).
12 Pawloski, J., Letter to the Editor, 349 NEW ENGLAND J.
MEDICINE 403--404 (2003).
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Appeal2013-002645
Application 10/563,683
Analysis
We agree with the Examiner that the combination of Webb,
Goldgrank, Remington, Modin, and Shaw provide a prima facie case of
obviousness for the administration of non-acidified nitrite to decrease the
blood pressure and/or increase vasodilation, consistent with Modin's
teaching that there was some effect in neutral pH (FF 5).
Appellants present arguments disputing the prima facie case of
obviousness, but we do not find it necessary to address these arguments
because, as discussed below, we conclude that the evidence of secondary
considerations has successfully rebutted the prima facie case of obviousness.
We agree with Appellants that the evidence of skepticism by experts,
when weighed with the cited references and evidence adduced by the
Examiner supporting obviousness, is sufficient in this case to support the
conclusion that the instant claims are not obvious.
In Transocean, the persuasive evidence of skepticism was limited to
two inventors who "recounted several occasions when industry experts ...
were skeptical." Transocean, 699 F.3d at 1353.
In the current case, five different expert Declarations, executed by
respected scientists, four of whom are not inventors and lack any financial
interest in the outcome, 13 one of them an author on the cited Modin paper,
state in varying language that the ordinary artisan would not have expected
non-acidified sodium nitrite to induce vasodilation or treat ischemia at the
time of invention (FF 7-12). In addition, a contemporaneous letter to the
editor by Dr. Pawloski also evidences that a skilled artisan at the time of
13 See paragraph 1 of the Freeman, Lundberg, Kelm, and Ignarro
Declarations.
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Application 10/563,683
invention did not expect sodium nitrite to function as a vasodilator in vivo
(FF 13). Moreover, Lauer teaches that nitrite "was found to be devoid of
vasodilator activity at doses up to 36 µmol/min" (FF 14).
We recognize, but are not persuaded by the Examiner's attempt to
rebut these five Declarations, Lauer, and the Pawloski letter by citing
evidence that aortic ring bioassays are predictive of in vivo effects and
therefore Modin's teaching is not overcome (see Ans. 21-22). The ultimate
issue is not whether aortic ring bioassays are sometimes predictive, nor even
whether the specific aortic ring bioassay in Modin may have some predictive
value for non-acidified nitrite use in vasodilation, but rather whether the
strong evidence that experts were skeptical that non-acidified nitrite had
vasodilatory activity is sufficient to rebut the prima facie case of
obviousness.
We conclude that the balance of the evidence supports Appellants'
reliance on the secondary consideration of skepticism by experts to rebut the
Examiner's prima facie case that the prior art, including Modin, would have
rendered it obvious to treat the claimed conditions with non-acidified
sodium nitrite.
Conclusions of Law
(i) The evidence of record supports the Examiner's conclusion that
the cited prior art suggests administration of "non-acidified sodium nitrite ..
. to decrease the blood pressure and/or increase vasodilation" as required by
claim 1.
(ii) Appellants have presented evidence of secondary considerations,
that, when taken into account with the evidence presented by the Examiner,
is sufficient to support a conclusion of non-obviousness.
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C. Double Patenting
Appellants do not specifically argue the double patenting rejection.
We, therefore, summarily affirm the obviousness-type double patenting
rejection. See Manual of Patent Examining Procedure§ 1205.02 ("If a
ground of rejection stated by the examiner is not addressed in the appellant's
brief, that ground of rejection will be summarily sustained by the Board.")
SUMMARY
In summary, we reverse the rejection of claims 1-3, 13-15, 17, and 18
under 35 U.S.C. § 103(a) as obvious over Webb, Goldfrank, Remington and
Modin.
We reverse the rejection of claims 1-3, 13-15, 17, and 18 under 35
U.S.C. § 103(a) as obvious over Shaw, Goldfrank, and Modin.
We affirm the rejection of claims 1-3, 13-15, 17, and 18 on the
ground of provisional nonstatutory obviousness-type double patenting as
unpatentable over claims 1--4, 10, and 14--18 of copending U.S. Pat.
Application 12/748,184, now US 8,927,030 B2.
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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