Ex Parte Wang et al

Patent Trial and Appeal Board

Aug 18, 2016

13284288 (P.T.A.B. Aug. 18, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/284,288 10/28/2011 Y ANMING WANG
68705 7590 08/22/2016
TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP
1300 EAST NINTH STREET
SUITE 1700
CLEVELAND, OH 44114
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.
CWR-019330US ORD 1688
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
08/22/2016 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):
rkline@tarolli.com
docketing@tarolli.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte YANMING WANG and CHUNYING WU
Appeal2014-009299
Application 13/284,288 1
Technology Center 1600
Before LORA M. GREEN, JEFFREY N. FREDMAN and
DAVID COTTA, Administrative Patent Judges.
COTTA, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of labeling myelinated regions in an animal's peripheral nervous system.
The Examiner rejected the claims on appeal as obvious under 35 U.S.C.
§ 103(a).
We reverse.
1 According to Appellants, the real party in interest is Case W estem Reserve
University. App. Br. 2.
Appeal2014-009299
Application 13/284,288
STATEMENT OF THE CASE
Claims 1, 2, 5, 8-11, 14, 17-18, 22, and 25-29 are on appeal. Claim
1 is illustrative and reads as follows:
1. A method of labeling myelinated regions in an
animal's peripheral nervous system in vivo, the method
compnsmg:
administering to the animal's peripheral nervous
system tissue a molecular probe including the general
formula:
wherein Ri and R2 are each independently selected
from the group consisting ofH, N02, NH2, NHCH3,
N(CH3)2, OH, OCH3, COOCH3, SH, SCH3, or alkyl
derivatives thereof, or derivatives thereof that include a
radiolabel, a chelating group, a near infrared imaging
group, or a salt; and
detecting the molecular probe bound to myelin of
the peripheral nervous system to determine myelinated
regions of the animal's peripheral nervous system.
The following grounds of rejection by the examiner are before us on
review:
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Appeal2014-009299
Application 13/284,288
Claims 1-2, 9, and 11under35 U.S.C. § 103 as being unpatentable
over the combination of Wu,2 Stankoff,3 Bhushan,4 Frangioni,5 and/or
Quarles; 6
Claims 1, 2, 5, 8-11, 14, and 17 under 35 U.S.C. § 103 as being
unpatentable over the combination of Wu, Stankoff, Bhushan, Frangioni,
Halldin, 7 Frangioni II, 8 and/or Quarles.
The Examiner found that Wu disclosed (E, E)-l,4-bis(4'-aminostyryl)-
2-dimethoxy-benzene ("BDB"), a fluorescent compound of the formula:
2 \Vu et al., A 1'·.fovel Fluorescent Probe that is Brain Permeable and
Selectively Binds to Myelin, Journal of Histochemistry & Cytochemistry,
Vol. 54(9), 997-1004 (2006) ("Wu").
3 Stankoff et al., Imaging of CNS Myelin by Positron-Emission Tomography,
Proceedings of the National Academy of Sciences, Vol 103 (24 ), June 13,
2006 ("Stankoff').
4 Bhushan et al., Synthesis of Conjugatable Biosphosphonates for Molecular
Imaging of Large Animals, Angew. Chem. Int. Ed. 46, 7969-7971 (2007)
("Bhushan").
5 Frangioni, WO 2008/042486 A2, published Apr. 10, 2008 ("Frangioni").
6 Quarles et al., Myelin Formation, Structure and Biochemistry, Basic
Neurochemistry: Molecular, Cellular and Medical Aspects (2006)
("Quarles").
7 Halldin et. al., PET Studies with Carbon 11 Radioligands in
Neuropsychopharmacological Drug Development, Current Pharmaceutical
Design, 7, 1907-1929 (2001) ("Halldin").
8 Frangioni et al., U.S. Patent Publication No. 2006/0108509 Al, published
May 25, 2006 ("Frangioni II").
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Appeal2014-009299
Application 13/284,288
Ans. 3--4; Wu, 997-998. The Examiner found Wu to disclose BDB labeling
in the central nervous system, including that BDB was "selectively retained
in white matter" and that BDB "stain[ ed] intact myelin sheaths in vitro and
in vivo." Id. at 4. In addition, the Examiner found that Wu teaches that
previous studies have shown that compounds like BDB "bind preferentially
to amyloid-like proteins possessing aggregated B-sheets instead of
monomeric B-sheets" and that "[ s ]imilar structures have been shown in
myelin basic protein (MBP)." Id. at 13. The Examiner concluded that,
based on these teachings, "one of ordinary skill would have considered Wu
to suggest that at least one cause of BDB binding to myelin is MBP." Id.
The Examiner found that Wu did not "expressly teach detecting the
molecular probe bound to myelin in the peripheral nervous system to
determine myelinated regions of the animal peripheral nervous system." Id.
at 5. The Examiner found that Stankoff taught that a BDB-related
compound, l ,4-bis(p-aminostyryl)-2-methoxy benzene ("BMB"), binds at
low levels to the sciatic nerve (which is part of the peripheral nervous
system) and that this binding was compatible with BMB binding to myelin
basic protein ("MBP"). Id. at 6.
Finally, the Examiner found that Quarles taught that in the peripheral
nervous system, MBP varies from approximately 5% to 18% of total protein.
Id. at 5.
Based on the teachings of Wu, Stankoff, and Quarles, the Examiner
concluded that it would have been obvious to use BDB to bind myelin in the
peripheral nervous system. The Examiner explained:
Wu teaches BDB, a compound of instant formula I
wherein Ri and R2 equal NH2. Wu teaches that previous
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Appeal2014-009299
Application 13/284,288
Id. at 13-14.
studies have shown that these types of compound bind
preferentially to amyloid-like proteins possessing
aggregated B-sheets instead of monomeric B-sheets.
Similar structures have been shown in myelin basic
protein (MBP), which are only preserved in intact myelin
sheaths. Once myelin sheaths degenerate, aggregation of
B-sheet conformation of MBP would be lost, thereby
reducing the binding affinity for BDB .. . Together these
findings are consistent with BDB binding to a structural
feature only in compact myelin (see paragraph starting on
pg. 1003 and ending on pg. 1004 at the left column). In
view of these teachings, one of ordinary skill would have
considered Wu to suggest that at least one cause of BDB
binding to myelin is MBP.
Stankoff teaches BMB, which is substantially
similar in structure to BDB. BMB only differs from
BDB by a mere hydrogen-methoxy exchange at the
central phenyl group. Stankoff expressly states that these
findings, and the lower level of binding in the sciatic
nerve, which contains MBP in myelin, are compatible
with the predominant binding ofBMB to MBP (see pg.
9307, right col., first complete paragraph). Therefore,
two of cited references independently suggest that the
aminostyryl benzene compounds, such as BMB or BDB,
bind to MBP in myelin. The fact pattern is clear. As
noted Office action filed 13 Aug. 2013, Quarles teaches
MBPs are present in the PNS (see pg. 64, col. 2). In
addition, as noted above, Stankoff expressly teaches that
the sciatic nerve contains MBP in myelin.
Appellants contend that Wu teaches BDB's binding is dependent on
the structure of myelin. App. Br. 10. Appellants further contend that
Quarles teaches that the composition of myelin in the central nervous system
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Application 13/284,288
is different from the composition of myelin in the peripheral nervous system.
Id. at 12-15. Appellants thus conclude:
[S]ince BDB binding, unlike BMB binding, is dependent
on CNS myelin structure and PNS and CNS myelin have
significant chemical and structural differences, Wu et al.,
Stankoff et al., and Quarles et al. do not teach or suggest
to one skilled in the art that BDB would bind to PNS
myelin.
Reply Br. 7. Appellants further contend that BDB and BMB are different
and that the differences between them lead to different binding behavior, as
reflected by the fact that BDB was unable to bind myelin of quaking mice
while BMB was able to bind myelin of quaking mice. App. Br. at 19-20.
FINDINGS OF FACT
1. Wu teaches:
The requirement for intact myelin is also evident in the
staining patterns observed (see Figures 2F and 5C), where
one can see IHC staining for MBP outside of the white
matter tracts to which BDB staining is restricted.
Similarly, in frontal cortex deficient in myelin sheaths, no
BDB staining was observed, whereas IHC staining for
MBP was still positive due to staining of free MBP
localized in the OL cytoplasm in the absence of myelin
sheaths (Figure 5B). Together these findings are
consistent with BDB binding to a structural feature
present only in compact myelin and not to either individual
myelin protein or to a lipid component.
Wu 1004 (emphasis added).
2. Wu teaches that "[t]he reason why BDB binds only myelin
sheaths and not components of degenerating myelin fragments also remains
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Application 13/284,288
to be determined." Id. at 1003.
3. Wu teaches:
Id. at 1000.
Specificity of BDB for myelin was tested by comparing
staining in myelin-deficient quaking mice compared with
age-matched control littermates. The quaking mouse is a
mutant model of dysmyelination (Sidman et al. 1964 ),
resulting in complete CNS demyelination shown by a lack
of myelin staining of the corpus callosum with BDB
(Figure 3B) and MBP (Figure 3D) compared with intense
labeling in age-matched littermate controls (BDB, Figure
3A and MBP, Figure 3C).
4. Stankoff teaches:
[T]here was a profound, but not total, decrease in BMB
binding in shiverer mice, which totally lack MBP (26, 27).
In quaking mice, whereas the primitive mutation of the Qk
RNA binding protein also affects to some extent MBP
expression (28), there is not a complete disappearance of
MBP. Interestingly, the decrease in BMB staining is less
pronounced in the Qk than in the shiverer mouse.
Stankoff 9307.
5. Quarles teaches:
It appears that MBP does not play as critical a role in
myelin structure in the PNS as it does in the CNS. For
example, the shiverer mutant mouse, which expresses no
MBP (Table 4-2), has a greatly reduced amount of CNS
myelin, with no compaction of the major dense line. By
contrast, shiverer PNS has essentially normal myelin, both
in amount and structure, despite the absence ofMBP. This
CNS/PNS difference in the role of MBP is probably
because the cytoplasmic domain of Po has an important
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Application 13/284,288
role in stabilizing the major dense line of PNS myelin.
Quarles 64.
6. Quarles teaches:
Id. at 63.
The principal difference in the overall protein
composition of PNS and CNS myelin is that Po replaces
PLP as the major protein, although myelin-forming
Schwann cells do express very low levels of PLP ....
The relatively large, glycosylated, extracellular lg-like
domain of Po probably accounts for the greater separation
of extracellular surfaces in PNS myelin relative to CNS
myelin where closer apposition of these surfaces is
possible in the presence of the smaller extracellular
domains of PLP.
7. Quarles teaches:
Id. at 55-56.
CNS myelin is a spiral structure similar to PNS myelin: it
has an inner mesaxon and an outer mesaxon that ends in a
loop, or tongue, of glial cytoplasm (Fig. 4-3). Unlike
peripheral nerve, where the sheath is surrounded by
Schwann cell cytoplasm on the inside and outside (Fig. 4-
10), the cytoplasmic tongue in the CNS is restricted to a
small portion of the sheath (Figs 4-3, 4-8). This glial
tongue is continuous with the plasma membrane of the
oligodendroglial cell through slender processes.
ANALYSIS
The arguments presented in this appeal with respect to the Examiner's
first obviousness rejection (claims 1-2, 9, and 11 over the combination of
Wu, Stankoff, Bhushan, Frangioni, and/or Quarles) are the same as those
with respect to the Examiner's second obviousness rejection (claims 1, 2, 5,
8-11, 14, and 17 over the combination of Wu, Stankoff, Bhushan, Frangioni,
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Appeal2014-009299
Application 13/284,288
Halldin, Frangioni II and/or Quarles). Accordingly, we will address both
obviousness rejections together.
The Examiner's obviousness analysis rests principa11y on the findings
that "two of the cited references independently suggest that aminostyryl
benzene compounds, such as BJ\1B or BDB, bind to J\1BP in myelin" and
that "Yv1BPs are present in the PNS." Ans. 13-14. vVe find that the
Examiner's analysis is not adequately supported by the record.
\Vu teaches that BDB binds to '"a structural feature present only in
compact myelin and not to either individual myelin protein or to a lipid
component,'' FFl (emphasis added), and that "'the reason why BDB binds
only to myelin sheaths and not components of degenerating myelin
fragments also remains to be deten11ined." FF2. Because BDB binds to a
"structural feature" that has "yet to be determined" and not to "individual
myelin protein," the presence of YvlBPs in peripheral nervous system myelin
is not, by itself~ sufficient to create a reasonable expectation that BDB wm
bind to myelin in the peripheral nervous system. J\1oreover, Quarles teaches
that the composition and structure of myelin in the central nervous system
differs from that in the peripheral nervous system. See, FF5----7. The
Examiner does not address how these differences might affect the "stn1ctural
feature" to which BDB binds or othenvise explain what impact these
differences might have on the ability of BDB to bind myelin in the
peripheral nervous system.
vVu and Stankoff also teach that BMB will stain myelin of quaking
mice while BDB will not. Compare FF3 with FF4. Appellants argue that
this shows that BDB and BivlB "do not bind to CNS myelin in the same
fashion." App. Br. 20. The Examiner dismisses this argument stating:
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Application 13/284,288
'"Appellant has not presented any statistically significant or quantifiable
difference in binding between BDB and BMB to myelin in order to support
the assertion that BMB and BDB bind to myelin in a different fashion."
Ans. 15. But the evidence ofBDB and BMB binding in quaking mice
cannot be so easily dismissed. Although the evidence is not "quantifiable"
because Stankoff does not quantify how much BMB bound to myelin in
quaking mice, the difference between no binding (BDB in quaking mice)
and some binding (BMB in quaking mice) is sufficient evidence to suggest
that BDB and BMB bind myelin differently. The Examiner does not present
any evidence or offer any scientific explanation that would support a
contrary conclusion. Ans. 15.
In view of the above, we find that the Examiner's articulated rationale
for finding the claims on appeal obvious is insufficiently supported by the
evidence of record. Accordingly, we reverse the Examiner's rejection of
claims 1-2, 9, and 11under35 U.S.C. § 103 as being unpatentable over the
combination of Wu, Stanko ff, Bhushan, Frangioni, and/or Quarles and the
Examiner's rejection of claims 1-2, 5, 8-11, 14, and 17 under 35 U.S.C. §
103 as being unpatentable over the combination of Wu, Stanko ff, Bhushan,
Frangioni, Halldin, Frangioni II, and/or Quarles.
SUMMARY
For the reasons set forth herein, the Examiner's final decision to reject
claims 1, 2, 5, 8-11, 14, and 17 is reversed.
REVERSED
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