Ex Parte Watson et al

Board of Patent Appeals and Interferences

Jun 19, 2008

09975317 (B.P.A.I. Jun. 19, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte ALAN DAVID WATSON, MICHAEL WENDLAND, PER
JYNGE, JAN OLOF KARLSSON, HEIDI BRUROK, PAL RONGVED,
and MAYTHEM SAEED
____________

Appeal 2008-0142
Application 09/975,317
Technology Center 1600
____________

Decided: June 19, 2008
____________

Before ERIC GRIMES, RICHARD M. LEBOVITZ, and JEFFREY N.
FREDMAN, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal from the final rejection of claims 76-81,
84-86, 88-93, and 96. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm.

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Application 09/975,317

STATEMENT OF THE CASE
The claims are directed to a method of distinguishing viable
myocardial tissue from necrotic (infarcted tissue) comprising administering
a manganese chelate complex of a formula I comprising subjecting the tissue
to magnetic resonance imaging (MRI).
According to the Specification, manganese chelates have been
suggested in the prior art for myocardial imaging (Spec. 2-3). The
Specification states that the inventors “surprisingly” found “that
substantially lower, clinically acceptable, dosages of manganese may be
used in fast or ultra-fast imaging techniques to provide an effective method
of myocardial imaging, in particular to provide important information about
myocardial viability during or following a severe heart attack or coronary
occlusion” (Spec. 3-4).
Claims 76-81, 84-86, 88-93, and 96 are on appeal (App. Br. 2).
Appellants appeal from the Final Rejection of:
1) Claims 76, 77, 79-81, 84-86, 88-93, and 96 under 35 U.S.C.
§ 103(a) as obvious over Rocklage ‘744 (U.S. Pat. No. 5,190,744, Mar. 2,
1993) in view of Rocklage ‘931 (U.S. Pat. No. 4,889,931, Dec. 26, 1989)
(Ans. 3); and
2) Claims 77, 78, and 96 under 35 U.S.C. § 103(a) as obvious over
Rocklage ‘744 in view of Goldenberg (U.S. Pat. No. 5,632,968, May 27,
1997) (Ans. 7).
Claims 96, 77, and 78 are representative and read as follows:
96. A method of distinguishing viable myocardial tissue from necrotic
(infarcted) tissue in a human or nonhuman body, said method comprising
administering to said body a physiologically acceptable manganese complex
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wherein said manganese complex is a manganese chelate complex having a
Ka value of from 107 to 1025 and a formula I:

or a salt thereof
(wherein in formula I
each R1 independently represents hydrogen or –CH2COR5;
R5 represents hydroxy, optionally hydroxylated alkoxy, amino or
alkylamido;
each R2 independently represents a group XYR6;
X represents a bond, or a C1-3 alkylene or oxoalkylene group
optionally substituted by a group R7;
Y represents a bond, an oxygen atom or a group NR6;
R6 is a hydrogen atom, a group COOR8, an alkyl, alkenyl, cycloalkyl,
aryl or aralkyl group optionally substituted by one or more groups selected
from COOR8, CONR82, NR82, OR8, =NR8, =O, OP(O)(OR8) R7 and OSO3M;
R7 is hydroxy, an optionally hydroxylated, optionally alkoxylated
alkyl or aminoalkyl group;
R8 is a hydrogen atom or an optionally hydroxylated, optionally
alkoxylated alkyl group;
M is a hydrogen atom or one equivalent of a physiologically tolerable
cation;
R3 represents a C1-8 alkylene group, a 1,2-cycloalkylene group, or a
1,2-arylene group; and
each R4 independently represents hydrogen or C1-3, alkyl);
at a dosage of 0.001 to 0.2 mmol/kg bodyweight, within a period of from 3
to 6 hours following administration of said complex or salt thereof
subjecting said body to a magnetic resonance imaging procedure capable of
generating images with time intervals of less than 0.5 seconds and thereafter
providing a series of images of the myocardium of said body and
distinguishing viable myocardial tissue from infarcted tissue;
with the proviso that said manganese complex or salt thereof is the only
contrast agent administered in said method.
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77. A method as claimed in claim 96 wherein said imaging procedure is a
gradient echo or echo planar imaging procedure.

78. A method as claimed in claim 77 wherein said imaging procedure is an
inversion recovery echo planar imaging procedure.

OBVIOUSNESS OVER ROCKLAGE ‘744 AND ROCKLAGE ‘931
Claims 76, 77, 79-81, 84-86, 88-93, and 96 stand rejected under 35
U.S.C. § 103(a) as obvious over Rocklage ‘744 in view of Rocklage ‘931.
Scope and content of the prior art
In making an obviousness determination, the Examiner must first
identity the scope and content of the prior art. Graham v. John Deere Co.,
383 U.S. 1, 17 (1966). Thus, we first turn to the prior art. The following
numbered findings of facts (“FF”) summarize the prior art relied upon by the
Examiner in setting forth the basis of the rejection.

The Rocklage ‘744 patent
1. Rocklage ‘744 describes the use of MRI for detecting blood flow
variations “particularly useful in the determination of the extent and severity
of ischemia” (Rocklage ‘744, at col. 1, ll. 10-12).
2. To accomplish the method, a contrast enhancing amount of paramagnetic
metal is administered to the cardiovascular system (Rocklage ‘744, at col. 1,
ll. 55-65).
3. The method can be carried out using a fast or ultra fast imaging technique
“capable of generating images with time intervals of less than 5 seconds,
especially less than 0.5 seconds and more especially less than 100
milliseconds” (Rocklage ‘744, at col. 2, ll. 10-18).
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4. Manganese (“Mn”) chelates are among a list of “[p]articularly suitable
paramagnetic metal ions” for use as a contrast agent in Rocklage ‘744’s
method (at col. 4, ll. 50-55).
5. “For most MS contrast agents the appropriate dosage will generally lie in
the range 0.02 to 3 mmol paramagnetic metal/kg bodyweight, especially
0.05 to 1.5 mmol/kg, particularly 0.08 to 0.5, and more especially 0.1 to 0.4
mmol/kg. It is well within the skill of the average practitioner in this field to
determine the optimum dosage for any particular MS contrast agent by
simple experiment, either in vivo or in vitro” (Rocklage ‘744, at col. 5, ll.
54-61).
6. In the examples, a cerebral artery (“MCA”) of an adult cat was occluded
to produce cerebral ischemia (Rocklage ‘744, at col. 7, ll. 26-32). After
occlusion, a Dy contrast agent was administered (id. at col. 7, ll. 48-51).
7. Successive MRI images were obtained for up to 12 hours following
occlusion (Rocklage ‘744, at col. 7, ll. 40-42). “Within 3-5 hours after MCA
occlusion, . . . images also demonstrated tissue injury clearly” (id. at col. 9,
ll. 14-16).
8. Rocklage ‘744 states that its method can be utilized in “identifying and
providing an indication of the severity of cerebral or coronary ischemias or
infarcts” and “has a broad range of possible diagnostic and evaluative
applications” (Rocklage ‘744, at col. 2, ll. 33-37).
9. Rocklage ‘744 also states: “It seems likely that the method of the
invention may be able to help identify reversibly ischemic penumbra from
infarcted tissue based on the degree and duration of perfusion deficit to
cerebral tissues” (Rocklage ‘744, at col. 10, ll. 3-6).

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The Rocklage ‘931 patent
10. Rocklage ‘931 describes a contrast agent comprising a chelating agent
chelated with a Mn ion of formula I (Rocklage ‘931, at col. 3, l. 34 to col. 4,
l. 55; Ans. 3-4).
11. Mn chelates as contrast agents “are particularly useful as MRI contrast
agents because manganese is less toxic than many paramagnetic metal ions”
(Rocklage ‘931, at col. 1, ll. 13-16).
The Specification
12. “[S]everal proposals [in the prior art] have been made for the use of
MnDPDP [a manganese chelate] in T1-weighted spin echo imaging for
detection of acute myocardial infarction” (Spec. 3).

Difference between the prior art and the claimed invention
Once the scope and content of the prior art have been determined, the
next step is to identify the differences between the prior art and the claimed
invention. Graham, 383 U.S. at 17. The following numbered findings of
fact are pertinent to this issue:
13. Claim 96 is directed to a “method of distinguishing viable myocardial
tissue from necrotic (infarcted) tissue in a human or nonhuman body.”
14. The claimed method involves subjecting the body to an MRI procedure
which is “capable of generating images with time intervals of less than 0.5
seconds.”
15. A manganese complex is administered in the claimed method “having a
Ka of from 107 to 1025 of formula I”,
16. “at a dosage of 0.001 to 0.2 mmol/kg bodyweight”, and
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17. MRI is carried out “within a period of from 3 to 6 hours following
administration” of the manganese complex.
18. Rocklage ‘744 describes an MRI imaging method that preferably
generates time intervals “especially less than 0.5 seconds and more
especially less than 100 milliseconds” (FF 3), meeting the limitation of
claim 96 of “capable of generating images with time intervals of less than
0.5 seconds” (FF 14; Ans. 3).
19. A complex is administered by Rocklage ‘744 in its imaging method in
an amount of “0.05 to 1.5 mmol/kg” (FF 5) which overlaps with the claimed
range of “0.001 to 0.2 mmol/kg” (FF 16; Ans. 3).
20. Rocklage ‘744 also describes imaging within “3-5 hours after”
administration of the contrast agent (FF 6, 7) – which overlaps with the
claimed range of 3 to 6 hours (FF 17).
21. Rocklage ‘744 describes its method as useful for “identifying and
providing an indication of the severity of . . . coronary ischemias or infarcts”
(FF 8) and states that it “may be able to help identify reversibly ischemic
penumbra from infarcted tissue based on the degree and duration of
perfusion deficit to cerebral tissues” (FF 9), but does not expressly state that
it is a “method of distinguishing viable myocardial tissue from necrotic
(infarcted) tissue” as in claim 96 (FF 13) (emphasis added).
22. Mn contrast agents are described as useful by Rocklage ‘744 (FF 4), but
Rocklage ‘744 does not describe the specific complex recited in claim 96
(Ans. 3).
23. However, Rocklage ‘931 describes a contrast agent comprising a
chelating agent chelated with a Mn ion of formula I (FF 10) which is the
same as the claimed formula I complex (FF 15; Ans. 3-4).
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24. Appellants also admit in the Specification that Mn chelates had been
proposed in the prior art for myocardial imaging (FF 12).
25. Since the claimed complex has the same formula as in Rocklage ‘931, it
is reasonable to believe that it would also have the same Ka as in claim 96
(FF 15) since compounds of the same formula would be expected to have the
same properties (Ans. 6).

Reason to combine the prior art
Once the differences between the prior art and the claimed invention
have been ascertained, the next step is to identify a reason why persons of
ordinary skill in the art would have been prompted to combine the prior art
to have made the claimed invention. KSR Int’l Co. v. Teleflex Inc., 127 S.
Ct. 1727, 1741 (2007). The following findings are relevant to this
determination:
26. Rocklage ‘744 states that its method “may be able to help identify
reversibly ischemic penumbra from infarcted tissue based on the degree and
duration of perfusion deficit to cerebral tissues” (FF 9). In other words, the
method can be used to distinguish “reversibly ischemic” or viable tissue
from “infarcted” or necrotic tissue.
27. Thus, Rocklage ‘744’s explicit goal is the same as in claim 96 (FF 13),
but for “cerebral” tissue rather than “myocardial” tissue.
28. While Rocklage ‘744’s stated goal (FF 9, 26) is in the context of
cerebral tissues, Rocklage ‘744 also states that its method is applicable to
“coronary . . . infarcts” (FF 8).
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29. An “infarct” is defined as a “necrotic area of tissue resulting from
failure of local blood supply.”1
30. Since a coronary artery supplies blood to the heart (App. Br. 6), persons
of ordinary skill in the art would have recognized that “coronary . . .
infarcts” are a result of blockage to the coronary artery that lead to ischemia
and subsequent necrosis in the heart, i.e., myocardial tissue.
31. Because Rocklage ‘744 states its method is applicable to coronary
infarct, i.e., necrosis of heart tissue (FF 28) and “has a broad range of
possible diagnostic and evaluative applications” (FF 8), Rocklage ‘744
would have reasonably suggested to persons of ordinary skill in the art that
its method be used to distinguish “reversibly ischemic” or viable tissue from
“infarcted” or necrotic tissue in the heart (FF 28, 29) as required by claim
96.
32. With regard to the specific Mn agent which is claimed, Rocklage ‘931
teaches a list of suitable contrast agents which would be expected to be
equivalent for the purposes of MRI (FF 10; Ans. 7).
33. Persons of ordinary skill in the art would have had reason to have
utilized the particular Mn contrast agent of Rocklage ‘931 for its low
toxicity (FF 11) and would have expected it to work based on Rocklage
‘744’s teaching that Mn is suitable for MRI imaging (Ans. 7).
34. It also admitted in the Specification that the prior art had suggested
manganese chelates for myocardial imaging (FF 12), providing further
reason to have utilized an Mn contrast agent of Rocklage ‘931.

1 The American Heritage Dictionary of the English Language, Houghton
Mifflin Co., 673 (1976).
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Analysis
The “examiner bears the initial burden, on review of the prior art . . ,
of presenting a prima facie case of unpatentability.” In re Oetiker, 977 F.2d
1443, 1445 (Fed. Cir. 1992). In making an obviousness determination, a
reason must be provided as to why persons of ordinary skill in the art would
have combined the prior art to have arrived at the claimed invention. See
KSR, 127 S. Ct. at 1741.
After reviewing the scope and content of the prior art and the reason
for combining it, it is our opinion that prima facie obviousness of the subject
matter of claim 1 has been established.
While there is no explicit statement in Rocklage ‘744 that its method
could be used to distinguish between viable and necrotic myocardial tissue,
the patent does make this statement for cerebral tissue (FF 9), describes the
broad applicability of its method (FF 8), and specifically refers to coronary
infarct (FF 8). From these teachings, we agree with the Examiner that
Rocklage ‘744 reasonably suggests that its method could be utilized with
success to distinguish between viable and necrotic myocardial tissue that
would arise during a coronary infarct (FF 28-31) – a condition explicitly
disclosed in Rocklage ‘744 (FF 8). We also agree that an ordinary artisan
applying the method of Rocklage ’744 would have found the Mn chelating
agent in Rocklage ‘931 reasonably suggested for its expected advantages
(lower toxicity) in MRI imaging (FF 11, 33). Appellants admit the
manganese contrast agents had been proposed for myocardial imaging (FF
12, 34).
Appellants argue that Rocklage ‘744 describes its method for
“cerebral or coronary ischemia and not myocardial ischemia” (App. Br. 5).
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They assert that although
Rocklage ‘744 also teaches that the same method would be
useful in the detection of coronary ischemia, the myocardium
and coronary arteries are different parts of the heart – the
myocardium is the middle muscular layer of the heart wall, and
coronary arteries surround the heart and branch out from the
aorta to supply blood to the heart as would be appreciated by
one of ordinary skill in the art. There is no motivation in
Rocklage ‘744 which suggests the claimed invention nor is
there a suggestion of the likelihood of success in arriving at the
presently claimed invention.
(App. Br. 6).
This argument is not persuasive. First, Rocklage ‘744, in addition to
coronary ischemia, also refers to coronary infarct which would have
reasonably suggested application of its method to myocardial tissue that
would be deprived of blood during a coronary infarct (FF 8, 29-31).
Appellants have not addressed this specific disclosure of Rocklage ‘744.
Secondly, we disagree that there would be “no motivation . . . of the
likelihood of success” to arrive “at the presently claimed invention” (App.
Br. 6). As discussed above, Rocklage ‘744 teaches that its method can be
used to distinguish necrotic from viable tissue, albeit cerebral tissue (FF 26).
However, Rocklage ‘744 teaches that its method can be used to assess the
severity of coronary infarct and describes it as having a broad range of
diagnostic application (FF 8). Thus, Rocklage ‘744 does not express any
reservations about the broad applicability of its method; consequently,
persons of ordinary skill in the art would have reasonably expected that the
method could be applied with success to other tissues, including myocardial
tissue.
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Appellants also argue that “Rocklage ‘744 can only be used to
identify and/or monitor abnormal or modified blood flow. The method does
not involve or allow for the detection of damaged tissue in accordance with
the claims on appeal” (App. Br. 7). We do not agree. Rocklage ‘744
expressly states that its method “may be able to help identify reversibly
ischemic penumbra from infarcted tissue based on the degree and duration of
perfusion deficit to cerebral tissues” (FF 9). Rocklage ‘744 also states that
its method is “particularly useful in the determination of the extent and
severity of ischemia” (FF 1). Thus, Rocklage ‘744, in fact, teaches that its
method can be used to assess damaged versus viable or “reversibly
ischemic” tissues – the same purpose recited in claim 96.
Appellants state that the differential uptake of manganese by viable
myocardial cells, but not “irreversibly damaged” myocardial cells is not
suggested by the prior art (App. Br. 7, 10). However, merely recognizing
the mechanism for a process which is suggested by the prior art does not
alone impart patentability to it. See In re Woodruff, 919 F.2d 1575 (Fed. Cir.
1990); In re Cruciferous Sprout Litig., 301 F.3d 1343, 1351 (Fed. Cir.
2002); In re Omeprazole Patent Litig., 483 F.3d 1364, 1373 (Fed. Cir.
2007). Moreover, it is acknowledged in the Specification that manganese
chelates had been suggested in the prior for myocardial imaging (FF 12).
Appellants contend that various claim limitations have been ignored,
including dosage (App. Br. 7, 9) and administration times (App. Br. 8). We
do not agree with Appellants that the Examiner ignored these limitations.
To the contrary, the claimed limitations overlap with those in the prior art
(FF 19, 20). Appellants have not identified any deficiency in Rocklage
‘744’s disclosure regarding these limitations.
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In regard to the dosage limitation, we note that the Specification states
that it was “surprising” that lower dosages of a manganese chelate could be
utilized (Spec. 3-4); however, the claimed range overlaps with the prior art.
It is well-established that even a slight overlap in ranges establishes prima
facie obviousness. In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). In
such cases, it must be shown “that the particular range is critical, generally
by showing that the claimed range achieves unexpected results relative to the
prior art range.” In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990).
Appellants have not provided rebuttal evidence of unexpected results.
Appellants also argue that Rocklage ‘744 prefers other ions for its
contrast agents, not manganese, and thus would have led persons of ordinary
skill in the art away from the subject matter of claim 96 (App. Br. 8-9).
A reference teaches away only when a person of ordinary skill, upon
examining the reference, would be discouraged from following the path set
out in the reference, or would be led in a direction different from the path
that was taken by the applicant. In re Gurley, 27 F.3d 551, 553 (Fed. Cir.
1994). In this case, manganese ions are stated by Rocklage ‘744 to be
“suitable” for MRI (FF 4), were suggested in the prior art for myocardial
imaging (FF 12), and thus the prior art would not have discouraged persons
of ordinary skill in the art from using them. Furthermore, Rocklage ‘931
states that Mn chelates “are particularly useful as MRI contrast agents
because manganese is less toxic than many paramagnetic metal ions” (FF
11; Rocklage ‘931, at col. 1, ll. 13-16) – thus, providing an additional
explicit reason to have used them in the claimed method.
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For the foregoing reasons, we affirm the rejection of claim 96. Claims
76, 77, 79-81, 84-86, and 88-93 fall with claim 96 because separate reasons
for their patentability were not provided. See 37 C.F.R. § 41.37(c)(1)(vii).

OBVIOUSNESS OVER ROCKLAGE ‘744 AND GOLDENBERG
Claims 77, 78, and 96 stand rejected under 35 U.S.C. § 103(a) as
obvious over Rocklage ‘744 in view of Goldenberg (Ans. 7).
Claim 77 is directed to the method of claim 96 where the “imaging
procedure is a gradient echo or echo planar imaging procedure.” Claim 78
depends on claim 77 and further requires that the “imaging procedure is an
inversion recovery echo planar imaging procedure.” The Examiner finds
that the inversion recovery echo MRI is well known in the art – as evidenced
by Goldenberg –and thus concludes it would have been obvious to use the
prior art method as a “useful and an equivalent method” to those described
in Rocklage ‘744 (Ans. 8).
Appellants do not challenge the Examiner’s findings (App. Br. 12),
but instead argue that Rocklage ‘744 does not suggest the subject matter of
claim 96 (App. Br. 13-14). As we have addressed these arguments already,
we affirm the rejections of claims 77, 78, and 96 for the reasons discussed
above.
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CONCLUSION
We affirm the rejections of claims 76-81, 84-86, 88-93, and 96 over
prior art.
TIME PERIOD
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

lp

Richard E. Fichter
BACON & THOMAS, PLLC
Fourth Floor
625 Slaters Lane
Alexandria VA 22314-11

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