Ex Parte Valkirs et al

Board of Patent Appeals and Interferences

Apr 17, 2007

10225082 (B.P.A.I. Apr. 17, 2007)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

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

Appeal 2007-0628
Application 10/225,082
Technology Center 1600
__________

Decided: April 17, 2007
__________

Before TONI R. SCHEINER, ERIC GRIMES, and
NANCY J. LINCK, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of diagnosing stroke, which the Examiner has rejected for lack of adequate
description and obviousness. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
BACKGROUND
“Stroke can be categorized into two broad types, ‘ischemic stroke’
and ‘hemorrhagic stroke’” (Specification 1). Ischemic stroke is caused by
Appeal 2007-0628
Application 10/225,082

inadequate blood flow to brain tissue, and hemorrhagic stroke is caused by a
ruptured blood vessel in the brain (id. at 2). The different types of stroke
require different treatments (id. at 3).
The Specification discloses that the two types of stroke can be
distinguished from each other, and from transient ischemic attacks (TIAs),
by assaying for certain proteins in the blood (id. at 4). More precisely, the
Specification states that assaying for at least one specific marker of cerebral
injury and at least one non-specific marker of cerebral injury provides a
“rapid, sensitive and specific diagnostic assay to be used in the diagnosis and
differentiation of various forms of stroke and TIAs” (id.).
Specific markers of cerebral injury are “polypeptides that are
associated with brain tissue and neural cells, and which can be correlated
with a cerebral injury, but are not correlated with other types of injury” (id.
at 8:1-3). They include S100β (id. at 8:6). “[S]pecific markers of cerebral
injury may . . . be found in the blood . . . as well as the CSF of a patient
experiencing stroke or TIAs” (id. at 15:13-15). Non-specific markers of
cerebral injury are “polypeptides that are elevated in the event of cerebral
injury, but may also be elevated due to non-cerebral events,” and include
caspase-3 (id. at 8:10-11, 16).
DISCUSSION
1. CLAIMS
Claims 45, 47, 50, 53-69, 73, 75, 77, 80, 83-99, and 103 are on appeal.
Claims 46, 48, 49, 51, 52, 70-72, 74, 76, 78, 79, 81, 82, 100-102, and 104
are also pending but have been withdrawn from consideration by the
Examiner.
2
Appeal 2007-0628
Application 10/225,082

Claim 45 is representative and reads as follows:
A method of determining a diagnosis of stroke or cerebral injury in a
subject, said method comprising:
analyzing a test sample obtained from a subject for the presence or
amount of one or more markers selected from the group consisting of
adenylate kinase, brain-derived neurotrophic factor, calbindin-D, creatine
kinase-BB, glial fibrillary acidic protein, lactate dehydrogenase, myelin
basic protein, neural cell adhesion molecule, neuron-specific enolase,
neurotrophin-3, one or more isoforms of protein kinase C, proteolipid
protein, S-100β, brain-derived neurotrophic factor, thrombomodulin, and
marker(s) related thereto;
analyzing said test sample for the presence or amount of one or more
markers selected from the group consisting of acute phase reactants, A-type
natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide,
adrenomedullin, endothelin-1, endothelin-2, endothelin-3,
β-thromboglobulin, cardiac troponin I, caspase-3, creatine kinase-MB,
D-dimer, fibrinopeptide A, head activator, hemoglobin a2 chain,
interleukin-8, myoglobin, plasmin-a-2 antiplasmin complex, platelet factor
4, prothrombin fragment 1+2, thrombin-antithrombin III complex, tissue
factor, vascular endothelial growth factor, one or more forms of von
Willebrand factor, and marker(s) related thereto; and
correlating the presence or amount of the analyzed markers to the
occurrence or nonoccurrence of a stroke or cerebral injury in said subject.
Claim 45 is directed to a method of diagnosing stroke or cerebral
injury by analyzing a sample from a patient for at least two markers: one
chosen from a set of specific markers of cerebral injury and one chosen from
a set of non-specific markers of cerebral injury. The claim language reciting
“analyzing a test sample . . . ; analyzing said test sample” indicates that the
same test sample is used in both assays.
The claim also requires correlating the results of the assays to
determine whether the subject has suffered a stroke or cerebral injury. The
specification defines “correlating” to mean “comparing the presence or
3
Appeal 2007-0628
Application 10/225,082

amount of the indicator in a patient to its presence or amount in persons
known to suffer from, or known to be at risk of, a given condition; or in
persons known to be free of a given condition” (Specification 9).
Claim 45 is a “Markush-type” claim (see MPEP § 803.02). Thus, the
Examiner requested an election-of-species. In response to that request,
Appellants elected S100β as the specific marker of cerebral injury and
caspase-3 as the non-specific marker of cerebral injury (Br. 8).1
2. WRITTEN DESCRIPTION
Claims 45, 47, 50, 53-69, and 73 stand rejected under 35 U.S.C.
§ 112, first paragraph, as failing to comply with the written description
requirement. The Examiner focuses on the recitation in the claims, in
addition to the specified protein markers, of “marker(s) related thereto.” The
Examiner notes that the Specification defines “related marker” to mean
“fragments of a particular marker that may be detected as a surrogate for the
marker itself” (Answer 5) but argues that that definition is an inadequate
description because the specification does not define “what the fragments of
S100β and caspase-3 are” (id.).

1 Appellants have requested that, in the event that the rejections on appeal
are reversed, the Board direct the Examiner to apply the procedures of the
MPEP relating to restriction/election of Markush claims in future
prosecution (Br. 4-5). We decline to do so. Restriction practice is a
procedural matter that is normally reviewed by way of petition, not appeal.
It is true that, in some cases, a restriction amounts to a de facto rejection and
is properly appealable (see, e.g., In re Haas, 486 F.2d 1053, 179 USPQ 623
(CCPA 1973)), but it would be premature to decide whether this case is in
that category.
4
Appeal 2007-0628
Application 10/225,082

Appellants argue that “the ‘related markers’ [are] all characterized by
their structural relationship to a parent marker, the structure of which is well
known” (Br. 12) and that “[a]s the proteins recited in the claims are all
known proteins having known sequences, the identity of various ‘related’
polypeptides (e.g., the corresponding ‘precursor’ and ‘NT-pro’ forms) may
be easily ascertained from . . . a standard database” (id. at 13-14).
We agree with Appellants that the Examiner has not shown that the
“related markers” recited in the claims are not adequately described. The
Examiner argues that the Specification’s definition of related markers is
“inclusive and nonlimiting and thus is not limited to fragments” (Answer 9).
We disagree. “Related marker” is expressly defined to mean “fragments of a
particular marker that may be detected as a surrogate for the marker itself”
(Specification 5).
Appellants have asserted that all the proteins recited in the claims are
known in the art, and the Examiner has not disputed that assertion. Thus, the
“related markers” recited in the claims are merely fragments of known
proteins. We agree with Appellants that the sequences of known proteins,
and fragments of them, are readily available to those skilled in the art.
“[T]here is no per se rule that an adequate written description of an
invention that involves a biological macromolecule must contain a recitation
of known structure.” Falkner v. Inglis, 448 F.3d 1357, 1366, 79 USPQ2d
1001, 1007 (Fed. Cir. 2006). “Indeed, [such a requirement], if one existed,
would serve no goal of the written description requirement.” Id. at 1368,
79 USPQ2d at 1008.
5
Appeal 2007-0628
Application 10/225,082

The Examiner has not established that the claims are unpatentable
under 35 U.S.C. § 112, first paragraph. The rejection of claims 45, 47, 50,
53-69, and 73 for lack of adequate written description is reversed.
3. OBVIOUSNESS
All of the claims on appeal stand rejected under 35 U.S.C. § 103, as
follows:
• Claims 45, 47, 50, 73, 75, 77, 80, and 103 as obvious in view of
Martens2 and Phanithi;3
• Claims 53-68 and 83-98 as obvious in view of Martens, Phanithi,
and “further in view of appellants[’] own disclosure;” and
• Claims 69 and 99 as obvious in view of Martens, Phanithi, and
Jackowski.4
Since all of these rejections rely on the combination of Martens and
Phanithi, we can consider them together.
The Examiner relies on Martens for its disclosure of assaying for
S100β in cerebrospinal fluid (CSF) and its teaching that “S100β is elevated
in CSF due to cerebral ischemia” (Answer 5). The Examiner also notes that
Martens teaches that a second marker is elevated in CSF during cerebral
ischemia, but does not teach assaying for caspase-3 (id.).

2 Martens et al., “Serum S-100 and neuron-specific enolase for prediction of
regaining consciousness after global cerebral ischemia,” Stroke, Vol. 29, pp.
2363-2366 (1998).
3 Phanithi et al., “Mild hypothermia mitigates post-ischemic neuronal death
following focal cerebral ischemia in rat brain: Immunohistochemical study
of Fas, caspase-3, and TUNEL,” Neuropathology, Vol. 20, pp. 273-282
(2000).
4 Jackowski, US 6,235,489, May 22, 2001.
6
Appeal 2007-0628
Application 10/225,082

The Examiner characterizes Phanithi as “teach[ing] that caspase-3 is
elevated in cerebral ischemia” (id.), and concludes that
[i]t would have been obvious . . . to also analyze the test sample
of Martens et al for caspase-3 because Phanithi et al teaches
that caspase-3 is elevated in cerebral ischemia and it would
have been obvious to combine the two markers for the detection
of cerebral ischemia because both markers are known to be
elevated in cerebral ischemia and thus the detection of a second
marker provides further confirmation of cerebral ischemia.
(Id. at 6.)
Appellants argue that
the primary Martens et al. publication examines S100β levels in
serum and cerebrospinal fluid samples, while the secondary
Phanithi et al. publication detects cytoplasmic expression of
caspase-3, an intracellular protein, in histological sections of
brain tissue. . . . Nothing in either publication discloses or
suggests that, in the case of stroke or cerebral injury, it is
possible for S100β and caspase-3 to be measured in the same
type of sample.
(Br. 17.) Appellants cite the second declaration of Kenneth F. Buechler,
submitted May 11, 2005, as supporting their position.
We agree with Appellants that the Examiner has not made out a prima
facie case of obviousness. As Appellants point out, Martens discloses that
levels of S100β in serum or CSF were significantly higher in patients who
never regained consciousness (Martens, p. 2364, col. 2) while Phanithi
discloses that caspase-3 is expressed in brain cells after ischemia (p. 276,
col. 2 (“Staining was cytoplasmic . . .”)). Phanithi does not state that
caspase-3 was found in CSF or serum. Nor does Phanithi provide any other
basis for concluding that the caspase-3 detected by immunostaining would
7
Appeal 2007-0628
Application 10/225,082

be expected to be released from the cells in which it was expressed and be
detectable in CSF or serum.
The Examiner argues that CSF is “a sample of the same type as brain
tissue because CSF and brain tissues are within the same system in the body
and one of ordinary skill in the art would expect markers which are known
to be within the brain tissue would also . . . be contained within CSF”
(Answer 12). The Examiner cites Vander,5 Webster’s,6 and Jackowski as
show[ing] that CSF and brain tissue clearly are within the same
system in the body and particularly Jackowski shows that
proteins that are released by brain cells during a cerebral event
can be detected in cerebrospinal fluid. Thus, since the prior art
teaches the equivalence of brain tissue and CSF as samples for
markers related to cerebral ischemia. It would have been
obvious to one of ordinary skill in the art at the time the
invention was made to expect the markers which are known to
be within the brain tissue to also be in CSF.
(Id. at 13.)
We do not agree with the Examiner’s reading of the cited references.
Webster’s merely defines “tissue” as an “aggregation of morphologically
and functionally similar cells”; it does not provide any basis for concluding
that brain cells and CSF meet that definition. Vander teaches that CSF
surrounds the brain, but does not teach that the contents of brain cells are
found in CSF.
Jackowski is more relevant to the Examiner’s argument, in that it
teaches that myelin basic protein, S100, and neuron-specific enolase are
“released by the specific brain cells as the cells become damaged during a

5 Vander et al., Human Physiology, 6th ed., pp. 214-215, 230 (1994).
6 Webster’s II, New Riverside University Dictionary, p. 1212 (1994).
8
Appeal 2007-0628
Application 10/225,082

cerebral event” (col. 5, ll. 12-14). Jackowski teaches that all three proteins
are found in CSF after release from brain cells (col. 5, ll. 34-37, 64-66; col.
6, ll. 19-22).
However, Jackowski teaches that S100β has about a two-hour half-life
when released in serum (col. 5, ll. 61-62) and that its level in “fluid collected
from brain,” presumably CSF, peaked about 180 minutes after an ischemic
event (col. 7, ll. 8-20). Phanithi, by contrast, teaches that caspase-3 was not
detectable, even intracellularly, until three hours after reperfusion (p. 280,
left-hand column).
If caspase-3 were detectable in CSF at all, it would only be after the
cells expressing it had completed the apoptotic process, died, and released
their cellular contents into the extracellular space. Phanithi teaches that the
TUNEL detects cells undergoing apoptosis, that no TUNEL-positive cells
were detected until five hours after reperfusion, and that the number of
TUNEL-positive cells peaked twenty-four hours after reperfusion (page 280,
paragraph bridging the columns). Phanithi does not suggest whether the
apoptotic cells would release their contents into the CSF, or whether they
would do so in a detectable amount, but it does suggest that, if they did, the
release would be unlikely to coincide with the presence of S100β in CSF.
Finally, Härter7 teaches that “the presence of active caspase-3 is a
good indicator of apoptosis. To date it is unknown whether active caspase-3
can be released from cells dying by apoptosis into CSF” following traumatic

7 Härter et al., “Caspase-3 activity is present in cerebrospinal fluid from
patients with traumatic brain injury,” Journal of Neuroimmunology, Vol.
121, pp. 76-78 (2001). Härter was cited on the Form PTO-892 mailed July
25, 2005.
9
Appeal 2007-0628
Application 10/225,082

brain injury. Härter, supra, at 76. Härter was published in December 2001,
and therefore provides further evidence that those skilled in the art did not
have an expectation of detecting caspase-3 in CSF as of the instant
application’s claimed effective filing date of August 20, 2001 (Specification
1).8
Thus, we conclude that the evidence of record does not adequately
support the Examiner’s position that the cited references would have made it
obvious to obtain a single sample from a subject who may have suffered a
stroke, and assay the same sample for both S100β and caspase-3. The
rejection for obviousness is reversed.
SUMMARY
The Examiner has not shown that the claims on appeal are not
adequately described in the specification or that the claimed method would
have been obvious to a person of ordinary skill in the art. The rejections
under 35 U.S.C. §§ 112, first paragraph, and 103 are reversed.

REVERSED

lbg

8 The Examiner has provided no basis on which to conclude that the present
claims are not entitled to priority based on provisional application
60/313,775, filed August 20, 2001.
10
Appeal 2007-0628
Application 10/225,082

FOLEY & LARDNER LLP
P.O. BOX 80278
SAN DIEGO CA 92138-0278
11