Ex Parte Lerebours-Pigeonniere et al

Patent Trial and Appeal Board

Jun 28, 2016

12590269 (P.T.A.B. Jun. 28, 2016)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/590,269 11/05/2009 Guy Lerebours-Pigeonniere SERVIER 563 US 8009
25666 7590 06/29/2016
THE FIRM OF HUESCHEN AND SAGE
SEVENTH FLOOR, KALAMAZOO BUILDING
107 WEST MICHIGAN AVENUE
KALAMAZOO, MI 49007
EXAMINER
LAMBERSKI, JENNIFER A
ART UNIT PAPER NUMBER
1618
MAIL DATE DELIVERY MODE
06/29/2016 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte GUY LEREBOURS-PIGEONNIERE, ARIANE DUBOST-
BRAMA, and CARMEN FLEURINCK1
__________

Appeal 2014-007664
Application 12/590,269
Technology Center 1600
__________

Before RICHARD M. LEBOVITZ, FRANCISCO C. PRATS, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of performing coronary angiography by multislice computed tomography,
which have been rejected as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b).
We affirm.

1 Appellants identify the Real Party in Interest as Les Laboratoires Servier.
(Appeal Br. 3.)
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STATEMENT OF THE CASE
According to Appellants, coronary angiography by multislice
computed tomography (“CT”) is an imaging procedure that “is a fast and
non-invasive technique making it possible to examine coronary arteries and
to detect . . . narrowing (stenosis) or obstruction of the coronary arteries and
also to assess the anatomy and permeability of the vessels and to
characterise atheromatous plaques at the tissue level.” (Spec. 1:23–2:5.) In
order to obtain these images, “the patient is injected with an iodinated
contrast medium” and X-ray imaging is carried out. (Spec. 2:8–11.) Image
quality of the coronary arteries is affected by heart rate. (Spec. 2:18–19.)
The invention relates to the use of ivabradine, a known pharmaceutical
compound that affects heart rate, in a method of carrying out coronary
angiography by multislice CT. (Spec. 1:16–19; 2:20–25)
Claims 1–4 are on appeal. Claim 1 is representative and reads as
follows:
1. A method for performing coronary angiography by multislice
computed tomography in a subject in need thereof, comprising
the following steps:
(i) administering an effective amount of ivabradine or an
addition salt thereof with a pharmaceutically acceptable acid or
a hydrate of the addition salt thereof;
(ii) administering a contrast medium;
(iii) acquiring an image using X-ray radiation.
(Appeal Br. 9.)

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The following ground of rejection by the Examiner is before us on
review:
Claims 1–4 under 35 U.S.C. § 103(a) as unpatentable over Schlosser2
and Sorbera.3
DISCUSSION
The Examiner finds that Schlosser discloses that “[p]atients with
depressed left ventricular function and coronary artery disease are at high
risk for sudden death, and patients with an increase in left ventricular mass
have a higher incidence of clinical events, including death, attributable to
cardiovascular disease.” (Non-Final 6 (citing Schlosser 30-31).) The
Examiner explains that Schlosser teaches a method for performing coronary
angiography multi-slice CT “in a patient with suspected coronary artery
disease to assess left ventricular function” comprising “orally and/or
intravenously administering a beta-blocker; administering Imeron 350 (a
contrast medium); and acquiring images using X-ray radiation.” (Non-Final
Action 5 (citing Schlosser Abs., 31, 34 (left col. ¶1), Fig. 1).) The Examiner
further finds that Schlosser teaches a low heart rate of <65 beats per minute
(“bpm”) “is required” “to obtain optimal image quality” and that the
requisite bpm is achieved with the “oral or intravenous administration of
beta-blockers.” (Non-Final 6 (citing Schlosser 31 (left col. ¶1)).) The

2 T. Schlosser et al., Assessment of Left Ventricular Function and Mass in
Patients Undergoing Computed Tomography (CT) Coronary Angiography
Using 64-DetectorRow CT: Comparison to Magnetic Resonance Imaging,
48 Acta Radiologica, 30–35 (2007).
3 L. A. Sorbera et al., Ivabradine Hydrochloride, 28 Drugs of the Future,
652–658 (2003).
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Examiner finds Sorbera teaches that prior art beta blockers are known to
“exert other unwanted activities such as negative inotropic and hypotensive
effects which could have serious consequences in individuals with depressed
left ventricular function.” (Non-Final 6 (citing Sorbera Abs., 653 (left col)).)
The Examiner explains that Sorbera teaches that ivabradine “reduces heart
rate in a manner more potent than esmolol (a beta-blocker) but does not
compromise left ventricular function [or] flow,” that “[n]o negative inotropic
or vasoconstrictor effects are observed with ivabradine treatment,” and,
unlike propranolol, ivabradine “has no effect on resting epicardial coronary
artery diameter and attenuates its increase during exercise.” (Non-Final 6,
citing Sorbera 652 (left col.), 654 (left col.), 655 (left col.).) The Examiner
further finds that “Sorbera teaches that the side effects of [prior art] beta-
blockers could have serious consequences in individuals with depressed left
ventricular function.” (Non-Final 7.)
The Examiner concludes that it would have been obvious to orally
and/or intravenously use ivabradine as the beta-blocker in the Schlosser
method rather than those disclosed in Schlosser because Sorbera “suggests
that ivabradine would provide the advantages of reducing heart rate in a
manner more potent than [the] beta-blockers [disclosed in Schlosser] and
without the side effects seen with [other] beta-blockers.” (Non-Final 7.)
After considering all the evidence anew before us, we conclude
that Appellants have not provided sufficient evidence to show the
non-obviousness of the claimed subject matter (In re Piasecki, 745
F.2d 1468, 1472 (Fed. Cir. 1984); In re Rinehart, 531 F.2d 1048, 1052
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(CCPA 1976)), and have not demonstrated an error in the Examiner’s
rejection.
Representative claim 1 has a step of “administering an effective
amount of ivabradine or an addition salt thereof with a pharmaceutically
acceptable acid or a hydrate of the addition salt thereof.” Appellants
contend the disclosure in Schlosser would not have led one of ordinary skill
in the art to “reasonably expect any and/or all beta-blockers [would] be
effective in a single dose to reduce heart rate sufficiently for the tomography
procedure.” (Appeal Br. 6 (emphasis added).) This argument is not
persuasive for at least the following reasons. First, claim 1 is not limited to
administration of a single dose of ivabradine to reduce heart rate. (Appeal
Br. 9.) Claim 1 simply requires that ivabradine be administered in an
effective amount such that in coronary angiography by multislice computed
tomography an image can be obtained. Second, “[n]on-obviousness cannot
be established by attacking references individually where the rejection is
based upon the teachings of a combination of references.” In re Merck &
Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Schlosser “must be read, not in
isolation, but for what it fairly teaches in combination with the prior art as a
whole,” including Sorbera. Id. Appellants’ argument does not take into
consideration Sorbera’s explicit disclosure of “the benefits of using
ivabradine over prior art beta-blockers for heart rate reduction,” i.e., that
“ivabradine reduces heart rate in a manner more potent than [prior art] beta-
blockers and without the side effects seen with [prior art] beta-blockers.”
(Ans. 5.) The use of the known compound ivabradine for its established use
as a beta-blocker that decreases heart rate with fewer side effects—and in
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particular, without compromising left ventricular flow (Sorbera 654), in the
method of Schlosser, which uses a beta-blocker to lower heart rate, is no
more than the predictable use of a prior art element according to its
established function. We conclude, therefore, that the prior art provides an
adequate reason to support the Examiner’s rejection of claim 1. See KSR
Int’l. Co. v. Teleflex, Inc., 550 U.S. 398, 417 (2007)
Appellants contend that the “human clinical study described in
Example 2 of the instant specification” and the Declaration of Lerebours-
Pigeonniere4 demonstrate “the superior and unexpected effects associated
with the instantly claimed method.” (Appeal Br. 6.) The Declaration asserts
that the study in Shapiro5 compared with Example 2 of the specification
shows that a higher percentage of patients reached a target heart rate of 65
bpm after intravenous administration of a particular amount of ivabradine
compared to the percentage of patients who reached a heart rate of 65 bpm
after intravenous administration of a particular amount of metoprolol ().
(Non-Final 2–3; Declaration at 2.) Similar assertions are made with respect

4 The Declaration by Guy Lerebours-Pigeonniere (“Declaration”), one of the
listed inventors of the present invention, dated Oct. 11, 2012, was entered
into the record on Dec. 13, 2013. Guaricci observes that “[d]ifferences in
beta-blocking strategy as well as in clinical characteristics of study
populations may account for the observed variation in efficacy.” (Guaricci 4
(col. 2).)
5 Michael D. Shapiro et al., Efficacy of pre-scan beta-blockade and impact of
heart rate on image quality in patients undergoing coronary multidetector
computed tomography angiography, 66 Eur. J. Radiology 37–41 (2008).
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to oral administration of atenolol (Guarrici6) as compared to ivabradine.
(Non-Final 3; Declaration at 3.)
We have considered Appellants’ invention in light of the Declaration
evidence and the data provided in Example 2, but agree with the Examiner
that the evidence presented is insufficient to establish that the process recited
in claim 1 would not have been obvious over the prior art. First, Example 2
does not provide a comparison to any drug. Thus, it cannot by itself
establish an unexpected result. See In re Baxter-Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence
of nonobviousness, the results must be shown to be unexpected compared
with the closest prior art.”).
Second, the studies the Declarant relies upon themselves are not
consistent with the Declarant’s conclusion that ivabradine has superior and
unexpected effects compared to prior art beta-blockers (Declaration 2–3). In
particular, as the Examiner explained, Shapiro “admits that in their methods,
a titration of beta-blockade [by metoprolol] to lower heart rates was not
tested to see if a larger proportion of patients would ultimately reach the goal
heart rate.” (Non-Final 3; Ans. 5; Shapiro 40 (rt. col.).) Guaricci observes,
with respect to the Shapiro study, that “[d]ifferences in beta-blocking
strategy as well as in clinical characteristics of study populations may
account for the observed variation in efficacy.” (Guaricci § 4 (col. 2).)
Shapiro, itself, acknowledges that “[f]urther studies will need to delineate

6 Andrea I. Guaricci et al., Incremental value and safety of oral ivabradine
for heart rate reduction in computed tomography coronary angiography,
156 Int’l J. Cardio. 28–33 (2012), available online Nov. 23, 2010.
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optimal beta-blocker dosing strategies.” (Shapiro 40 (rt. col.).) The
foregoing indicates that a higher dosage of metoprolol in Shapiro might have
reduced heart rate even lower.
Similarly, regarding the study results comparing atenolol and
ivabradine reported in Guaricci, Guaricci “admits that in their methods, only
a highly selected patient population was studied, and the amount of beta-
blocker employed was not the maximum tolerated but the standard dose.”
(Non-Final 3; Ans. 5; Guaricci § 4.1.) As with Shapiro, a higher dosage of
atenolol might have eliminated the variation in patient population efficacy.
Consequently, while the Declarant contends the ivabradine results are
unexpected, the evidence relied upon does not establish that there is an
unexpectedly better percentage of patients reaching the target heart rate of
65 bpm using ivabradine.
Furthermore, the Declarant does not indicate how the “reduction of
heart rate” and “percentage of patients reaching the target heart rate of 65
bpm” was unpredictably superior (Declaration 2, 3) in light of Sorbera’s
teaching that ivabradine was known to “specifically and selectively interact[]
with f-channels on the intracellular side of the plasma membrane of
pacemaker cells blocking If [,] [t]he consequence [of which] is a reduction in
the speed of diastolic depolarization and a decrease in heart rate; (Sorbera
654 (col. 1); see also 655 (col. 2 (noting “The effects of ivabradine were also
compared to the β-blocker atenolol” and while both reduced heart rate “by
about 30%”, ivabradine did not have negative lusitropic effects”)), and that
“[s]ignificant reductions in exercise heart rate were observed after single . . .
and repeated . . . oral dosing” of ivabradine, (Sorbera 656 (col. 1)). Thus,
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given ivabradine’s characteristics, it would have been expected that it would
be effective in reducing heart rate. Notably, Guaricci, even after performing
a head-to-head comparison between atenolol and ivabradine, did not identify
ivabradine as unexpectedly superior or as providing unexpected results given
its known characteristics, but simply noted that it is a “suitable” safe and
effective drug for use in achieving a target heart rate of <65 bpm. (Guaricci
§§ 4 (rt. col.), 4.2.) And, for the reasons already discussed, there is
insufficient information that ivabradine would be unexpectedly better than
other beta-blockers since the differences in heart rate suppression were
mentioned in the studies as related to dosages and failure to titrate and find
the best dosages.
Consequently, we do not find the Declaration’s conclusion of
unexpected superiority with respect to IV and/or oral administration is
supported by the data; that is particularly true in light of the teachings of
Sorbera concerning the properties ivabradine is known to have. Cf. In re
Soni, 54 F.3d 746, 751 (Fed. Cir. 1995) (“[W]hen an applicant demonstrates
substantially improved results . . . and states that the results were
unexpected, this should suffice to establish unexpected results in the
absence of evidence to the contrary.” (Emphasis in the original)).
Moreover, to the extent that the Declarant suggests it is unexpected
that achieving the heart rate lowering with a single IV bolus of ivabradine is
unexpected (Declaration 3), we note that such an assertion is not
commensurate in scope with claim 1. As already noted, claim 1 is not
limited to administration of a single dose of ivabradine to reduce heart rate.
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Claim 1 simply requires that ivabradine be administered in an effective
amount.
In light of the foregoing, we affirm the Examiner’s rejection of claim
1 as obvious in view of Schlosser and Sorbera.
Claims 2–4 have not been argued separately and therefore fall with
claim 1. 37 C.F.R. § 41.37(c)(1)(iv).
SUMMARY
We affirm the rejection of claims 1–4 under 35 U.S.C. § 103(a).
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