Ex Parte Dahlen et al

Board of Patent Appeals and Interferences

Jan 27, 2009

09835298 (B.P.A.I. Jan. 27, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte
JEFFREY R. DAHLEN, KENNETH F. BUECHLER,
and GUNARS E. VALKIRS
__________

Appeal 2008-12301
Application 09/835,298
Technology Center 1600
__________

Decided: January 27, 2009
__________

Before TONI R. SCHEINER, DEMETRA J. MILLS, and ERIC GRIMES,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for assigning a prognosis to a patient with an acute coronary syndrome. The
Examiner has rejected the claims as obvious over the prior art. We have
jurisdiction under 35 U.S.C. § 6(b). We reverse.

1 Heard September 9, 2008.

Appeal 2008-1230
Application 09/835,298

STATEMENT OF THE CASE
Claim 23 is representative of the claimed subject matter:
23. A method for predicting cardiac mortality rate in a patient with an
acute coronary syndrome, comprising:
drawing a sample of a body fluid from said patient,
contacting said sample with a first antibody that specifically binds to a
first marker selected from the group consisting of cardiac Troponin-T and
cardiac Troponin-I;
contacting said sample with a second antibody that specifically binds
to a second marker selected from the group consisting of BNP, NT-proBNP,
and pro-BNP;
providing means for determining binding between each of said
respective markers and each of said respective antibodies,
whereby said binding provides a means for determining cardiac
mortality rate.

The Examiner relies on the following evidence:
Jackowski U.S. 5,290,678 Mar. 1, 1994

Elliott M. Antman et al., Cardiac-Specific Troponin I Levels to Predict the
Risk of Mortality in Patients with Acute Coronary Syndromes, 335 THE NEW
ENGLAND JOURNAL OF MEDICINE 1342-1349 (1996).

A.M. Richards et al., Neuroendocrine Prediction of Left Ventricular
Function and Heart Failure after Acute Myocardial Infarction, 81 HEART
114-120 (1999).

Appellants rely, in part, on the following additional evidence:

Marc S. Sabatine et al., Multimarker Approach to Risk Stratification in Non-
ST Elevation Acute Coronary Syndromes, 105 CIRCULATION 1760-63
(2002).

Marc A. Silver et al., BNP Consensus Panel 2004: A Clinical Approach for
the Diagnostic, Prognostic, Screening, Treatment Monitoring, and
Therapeutic Roles of Natriuretic Peptides in Cardiovascular Diseases,
2
Appeal 2008-1230
Application 09/835,298

10(5 Supp. 3) CONGESTIVE HEART FAILURE 1-30 (2004).

Claims 23-28, 32-34, and 382 stand rejected under 35 U.S.C. § 103(a)
as unpatentable over Jackowski, in view of Antman and Richards.
ISSUE ON APPEAL
The Examiner concluded that it would have been obvious for one
skilled in the art to establish the prognosis of a patient with an acute
coronary syndrome (ACS) by measuring cardiac troponin I and BNP, both
of which were known in the art as “powerful predictor[s] of death” (Ans.
7-8), because multimarker approaches to diagnosis and/or prognosis were
conventional in the art, and “detecting both troponin I and BNP [would]
provide the advantage of a better prediction of likelihood of death as these
cardiac markers are disclosed as being detectable at different times” (id. at
8).
Appellants acknowledge that “the individual use of cardiac troponin
and BNP for prognosis in myocardial infarction” is disclosed in the art, but
contend that nothing in the art “indicates that cardiac troponins and BNP are
independent of one another, or that they should be used together for
purposes of prognosis in ACS” (App. Br. 12). Appellants contend that even
if measuring both troponin I and BNP would have been prima facie obvious,
evidence of secondary considerations “demonstrates that the claimed
invention is, in fact, non-obvious” (id.).
The issue raised by this appeal is whether the Examiner has
established, by a preponderance of the evidence, that it would have been

2 Claims 29-31 and 35-37 have been withdrawn from consideration.
3
Appeal 2008-1230
Application 09/835,298

obvious to measure both cardiac troponin I and BNP to determine the
prognosis of a patient with an acute coronary syndrome.
FINDINGS OF FACT
FF1 The claims on appeal are directed to a method of determining
the cardiac mortality rate and/or prognosis of a patient with an acute
coronary syndrome, by determining antibody binding to two different
markers in a sample of body fluid from the patient. One of the markers is
the B-type natriuretic peptide (BNP), or one of its precursors (NT-proBNP
or pro-BNP); the other marker is cardiac troponin-T or cardiac troponin-I.
FF2 According to the Specification,
The term “acute coronary syndromes” (“ACS”) has been
applied to a group of coronary disorders that result from
ischemic insult to the heart. Patients with ACS form a
heterogeneous group, with differences in pathophysiology,
clinical presentation, and risk for adverse events. Such patients
present to the physician with conditions that span a continuum
that includes unstable angina, non-ST-elevation non-Q wave
myocardial infarction (“NST”-“MI”), ST-elevation non-Q wave
MI, and transmural (Q-wave) MI.

(Spec. 1.)
FF3 The Specification states that “the level of BNP in a patient
sample, alone or in combination with one or more additional prognostic
markers, can provide prognostic information useful for predicting near-term
morbidity and/or mortality across the entire spectrum of acute coronary
syndromes” (Spec. 3).
FF4 Further according to the Specification,
When stratification was performed based on the
concentration of cTnI [cardiac troponin-I] at the time of
4
Appeal 2008-1230
Application 09/835,298

enrollment, increasing BNP concentration remained associated
with higher 10-month mortality, both among those with a cTnI
≤ 0.1 ng/mL (n=882; p=0.01) and those with a cTnI > 0.1
ng/mL (n=1630; p<0.0001) . . . After adjustment for other
independent predictors of long-term mortality, including ST
deviation and cTnI, increasing concentration of BNP remained
associated with a higher rate of death by 10 months . . .

(Spec. 22-23).
FF5 Antman et al., cited by both Appellants and the Examiner,
compared the prognostic value of measuring serum levels of creatine kinase-
MB (CK-MB) and troponin I in patients presenting with unstable angina or
non-Q-wave myocardial infarction (Antman et al. 1342, 1344). According
to Antman et al., troponin I is a more specific and sensitive marker of
cardiac necrosis than CK-MB (id. at 1342), and detection of cardiac troponin
I in blood “is an independent risk factor that identifies patients presenting
with unstable angina or non-Q-wave myocardial infarction who are at
increased risk of death” (id. at 1347).
FF6 Richards et al., cited by both Appellants and the Examiner,
determined the relationships of plasma levels of BNP, atrial natriuretic factor
(ANF), N-terminal ANF (N-ANF), cyclic guanosine monophosphate
(cGMP), and plasma catecholamines to left ventricular function and to
prognosis in patients with acute myocardial infarction (Richards et al. 114,
col. 1), and concluded that
BNP had the highest sensitivity, specificity, positive
predictive value, and negative predictive value . . . for heart
failure during follow up. Multivariate analyses indicated that
any one of BNP, ANF, N-ANF, or cGMP added additional
information beyond clinical features, noradrenaline
concentrations, and LVEF [left ventricular ejection fraction] in
5
Appeal 2008-1230
Application 09/835,298

predicting heart failure or the composite end point of death
and/or heart failure. Among the cardiac peptides, BNP and
ANF were the most powerful in this regard, with nothing to be
gained from measuring more than one of these, or N-ANF or
cGMP.

(Richards et al. 118-119.)
FF7 Sabatine et al., in a post-filing reference cited by Appellants,
teach that troponin I, BNP, and high-sensitivity C-reactive protein (hs-CRP),
“assess different pathophysiological mechanisms in myocardial ischemia:
elevations in troponin indicate myocardial necrosis; CRP is a marker of
inflammation; and BNP is elevated in response to left ventricular overload”
(Sabatine et al. 1760, col. 1 (internal citations omitted)). In a multivariable
model containing all three biomarkers, “TnI, CRP, and BNP each provided
independent and incremental prognostic information” (id. at 1762, col. 1),
and “[t]he 30-day risk of death increased in proportion to the number of
cardiac biomarkers elevated at baseline . . . , with a near doubling of the
mortality risk for each additional biomarker that was elevated” (id. at 1761,
col. 1).
FF8 Silver et al., members of the BNP Consensus Panel of 2004, in
a post-filing comprehensive review of the role of natriuretic peptides in
cardiovascular disease, conclude that “in the setting of HF [heart failure],
both troponin I and BNP were independent predictors of survival” and “[t]he
two together gave additive prognostic risk” (Silver et al. 15, col. 1).
In the setting of acute coronary syndrome and coronary artery disease
(CAD), Silver et al. conclude that “[s]ensitivity and specificity for BNP will
not be adequate to diagnose ischemia because many patients with unstable
6
Appeal 2008-1230
Application 09/835,298

angina do not have BNP elevation and the levels detected among those with
elevation are similar to those seen in other conditions” (id.). Silver et al.
concur with studies (including Sabatine et al.’s, discussed in FF7) showing
that cardiac troponin I, C-reactive protein, and BNP, in combination, are
“independently associated with adverse cardiac events, demonstrating the
unique predictive information that each of these biomarkers provides” (id. at
15, col. 2).
FF9 The members of the BNP Consensus Panel (Silver et al.) issued
the following consensus statements:
Several studies suggest that BNP levels are predictive of sudden
cardiac death. Thus, BNP levels might help us further stratify
patients who might benefit from newer therapies . . .

Additional biomarkers (troponin and C-reactive protein) may
provide unique, adjunctive, and independent information to a
BNP measurement with regard to patient outcomes.

When used together in a combined strategy, BNP and cardiac
troponin provide a more effective tool for identifying patients at
an increased risk for clinically important cardiac events related
to HF and acute coronary syndrome. Such information is likely
to enhance our ability to appropriately triage higher-risk HF
patients and more reliably identify low-risk HF patients who
may be candidates for less intensive evaluation and therapy.

(Silver et al. 16, Consensus Statements 7.1.1-7.1.3.)
PRINICIPLES OF LAW
The Examiner’s rejections must be supported by a preponderance of
the evidence. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427 (Fed.
Cir. 1988).
7
Appeal 2008-1230
Application 09/835,298

“The concept of prima facie obviousness in ex parte patent
examination is but a procedural mechanism to allocate in an orderly way the
burdens of going forward and of persuasion as between the examiner and the
applicant.” In re Piasecki, 745 F.2d 1468, 1471-72 (Fed. Cir. 1984). “If
rebuttal evidence of adequate weight is produced, the holding of prima facie
obviousness, being but a legal inference from previously uncontradicted
evidence, is dissipated. Regardless of whether the prima facie case could
have been characterized as strong or weak, the examiner must consider all of
the evidence anew.” Id. at 1472.
ANALYSIS
The Examiner concluded, based on the teachings of Antman et al. and
Richards et al., that it would have been obvious for one skilled in the art to
measure both troponin I and BNP because each is a “powerful predictor of
death,” but the two markers are expressed and peak at different times
following a cardiac event (Ans. 7-8). The Examiner’s rationale is essentially
that the markers provide comparable prognostic information, but measuring
both markers increases the probability of detecting an elevation in at least
one of the markers because they peak at different times following a cardiac
event.
We conclude that the Examiner has provided evidence and a rational
basis sufficient to establish that the claimed invention would have been
prima facie obvious to one of ordinary skill in the art. Nevertheless, this is
not the end of the matter. Appellants have presented objective evidence in
rebuttal. Therefore, both Appellants’ evidence and the Examiner’s must be
8
Appeal 2008-1230
Application 09/835,298

reconsidered without regard to the prima facie case (see Piasecki, 745 F.2d
at 1472).
The Specification teaches that measuring BNP levels provides
prognostic information that is independent of cardiac troponin I levels, thus,
the Specification teaches that BNP and cardiac troponin I do not provide the
same basic prognostic information (FF6). This observation is confirmed by
Sabatine et al., a post-filing reference submitted by Appellants as rebuttal
evidence. Specifically, Sabatine et al. teach that troponin I, BNP, and high-
sensitivity C-reactive protein (hs-CRP) each provide independent and
incremental prognostic information, and “[t]he 30-day risk of death
increased in proportion to the number of cardiac biomarkers elevated at
baseline . . . with a near doubling of the mortality risk for each additional
biomarker that was elevated” (FF7).
Similarly, Silver et al. teach that, rather than providing comparable, or
cumulative prognostic information, measuring cardiac troponin I together
with BNP provides “unique, adjunctive, and independent information to a
BNP measurement with regard to patient outcomes” and “when used
together in a combined strategy, BNP and cardiac troponin provide a more
effective tool for identifying patients at an increased risk for clinically
important cardiac events” than either alone (FF8, 9).
The Examiner has not cited evidence that shows that the improved
prognostic accuracy resulting from measuring both cardiac troponin I and
BNP, compared to measuring either alone, would have been expected based
on the prior art. Having considered the Examiner’s evidence in light of
Appellants’ rebuttal evidence, we find that Appellants’ rebuttal evidence
9
Appeal 2008-1230
Application 09/835,298

goes directly to the merits of the invention - the “unique,” “independent,”
and “incremental” nature of the prognostic information provided by the
particular combination of BNP and cardiac troponin I - and outweighs the
evidence underlying the Examiner’s prima facie case of obviousness.
CONCLUSION OF LAW
The Examiner has not established, by a preponderance of the
evidence, that it would have been obvious to measure both cardiac troponin I
and BNP to determine the prognosis of a patient with an acute coronary
syndrome.
The rejection of claims 23-28, 32-34, and 38 under 35 U.S.C. § 103(a)
as unpatentable over Jackowski, Antman, and Richards is reversed.

REVERSED

cdc

INVERNESS MEDICAL INNOVATIONS/WSGR
WILSON SONSINI GOODRICH & ROSATI, P.C.
650 PAGE MILL ROAD
PALO ALTO, CA 94304

10