Ex Parte Wang et al

Patent Trial and Appeal Board

Aug 21, 2017

12675248 (P.T.A.B. Aug. 21, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/675,248 02/25/2010 Yanming Wang CWR-8745US PCT 2986
68705 7590 08/23/2017
TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP
1300 EAST NINTH STREET
SUITE 1700
CLEVELAND, OH 44114
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
08/23/2017 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 WU1
Appeal 2016-001826
Application 12/675,248
Technology Center 1600
Before ERIC B. GRIMES, ULRIKE W. JENKS, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to a method of detecting myelin in vivo in brain tissue. The Examiner rejects
the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 According to Appellants, the real party in interest is Case Western Reserve
University. Br. 2.
Appeal 2016-001826
Application 12/675,248
STATEMENT OF THE CASE
Claims 8, 10—12, 16, and 54 are on appeal,2 and can be found in the
Claims Appendix of the Appeal Brief. Claim 8 is representative of the
claims on appeal, and reads as follows:
Claim 8. A method of detecting myelin in vivo in brain tissue
of an animal having a myelination disorder, the method
comprising:
(i) administering to the animal a molecular probe
including the general formula:
OCHs
and salts thereof;
(ii) imaging a demyelinated region of interest in the
animal’s brain in vivo using positron emission tomography
(PET) to detect a level of the molecular probe in the region of
interest; and
(iii) comparing the detected level of molecular probe in
the region of interest to a control level, wherein a decrease in
the detected level of molecular probe in the region of interest
compared to the control level is indicative of demyelination of
the region of interest of the animal’s brain.
2 Claims 9, 13—15, 19-43, 53, 55, and 56 are cancelled. Claims 1—7, 17, 18,
and 44—52 are withdrawn. Br. 2.
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Application 12/675,248
Appellants request review of the following grounds of rejection:
I. Claims 8, 11, and 12 under 35 U.S.C. § 103(a) as unpatentable
over Wu,3 Stankoff,4 Halldin,5 Price,6 and Klunk.7
II. Claims 8 and 10-12 under 35 U.S.C. § 103(a) as unpatentable over
Wu, Stankoff, Halldin, Price, Klunk, and Knoess.8
Ill Claims 8 and 16 under 35 U.S.C. § 103(a) as unpatentable over
Wu, Stankoff, Halldin, Price, Klunk, and Kung.9
IV. Claim 54 under 35 U.S.C. § 103(a) as unpatentable over Wu,
Stankoff, Halldin, Price, Klunk, and Barrio.10
I. Obviousness over Wu, Stankoff, Halldin, Price, and Klunk
The Examiner has rejected claims 8, 11, and 12 under 35 U.S.C.
§ 103(a) as being unpatentable over Wu, Stankoff, Halldin, Price, and
Klunk. The issue is: Does the evidence of record support the Examiner’s
3 Wu et al., A Novel Fluorescent Probe That Is Brain Permeable and
Selectively Binds to Myelin, 54 J. Histochemistry & Cytochemistry 997—
1004 (2006) (“Wu”).
4 Stankoff et al., Imaging of CNS myelin by positron-emission tomography,
103 PNAS 9304—9309 (2006) (“Stankoff’).
5 Halldin et al., PET Studies with Carbon-11 Radioligands in
Neuropsychopharmacological Drug Development, 7 Current Pharmaceutical
Design 1907-1929 (2001) (“Halldin”).
6 Price et al., Kinetic modeling of amyloid binding in humans using PET
imaging and Pittsburgh Compound-B, 25 J. Cerebral Blood Flow &
Metabolism 1528—1547 (2005) (“Price”).
7 Klunk et al., US 6,168,776 Bl, issued Jan. 2, 2001 (“Klunk”).
8 Knoess et al., Performance evaluation of the microPET R4 PET scanner
for rodents, 30 Euro. J. Nucl. Med. & Mol. Imag. 737—747 (2003)
(“Knoess”).
9 Kung et al., US 2003/0149250 Al, published Aug. 7, 2003 (“Kung”).
10 Barrio et al., US 2007/0218002 Al, published Sept. 20, 2007 (“Barrio”).
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Application 12/675,248
conclusion that the prior art renders a method of using a compound having
the following structure
prima facie obvious?
Findings of Fact
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art as set out in the Answer and Final Office
Action mailed May 9, 2014 (“Final Act.”). For emphasis only we highlight
the following:
FF1. Stankoff teaches a fluorescent label that binds myelin. The structure
of Stankoff s compound is reproduced below:
Compound iv, shown above, is called l,4-bis(4-aminostyryl)-2-
methoxy-benzene (BMB). Stankoff 9308.
FF2. Stankoff teaches radiolabeling the BMB compound with nC. “BMB
was labeled with carbon-11 (Ty2 = 20.38 min) in the 2-position of the
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Application 12/675,248
central benzene ring by using . . . the highly efficient methylation
reagent [nC]methyl triflate.” Stankoff 9308.
For radiolabeling, the methoxy group of [the
precursor of BMB] compound iii was first converted to a
hydroxyl group to give (E,E)~l,4-bis(4’ -nitro-styryl)- 2-
methoxy-benzene and subsequent reduction of the nitro
groups yielded (E,E)~l,4-bis(4’ -amino-styryl)-2-
hydroxy-benzene.
Stankoff 9308.
FF3. Stankoff teaches that “BMB is a Congo red derivative, [and] it should
share some binding properties with other structurally related
compounds.” Stankoff 9307.
[T]here was a profound, but not total, decrease in BMB
binding in shiverer mice, which totally lack MBP
[(myelin binding protein)]. ... In quaking mice, . . .
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. These
findings, and the lower level of binding in the sciatic
nerve, which contains less MBP in myelin, are
compatible with a predominant binding of BMB to MBP.
However, because BMB staining on myelin, although
largely reduced, is still present in shiverer mice, other
putative targets have to be considered.
Stankoff 9307.
FF4. Wu teaches a fluorescent stilbenzene derivative that binds myelin.
“Myelin is a specialized membrane that ensheathes neuronal axons,
promoting efficient nerve impulse transmission.” Wu 997. The
structure of Wu’s compound is reproduced below:
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Application 12/675,248
Wu’s compound, shown above, is called (E,E)~l,4-bis(4’-
aminostyryl)-2-dimethoxy-benzene (BDB). Wu 998, Fig. 1.
FF5. Wu teaches that “BDB selectively stains intact myelin sheaths in
normal mice in situ following IV injection.” Wu 998. “BDB readily
penetrated the BBB [(blood brain barrier)] and accumulated in the
brain following IV injection.” Wu 1002. “In the absence of myelin
sheaths, as occurs in the quaking mouse brain, BDB binding was
virtually undetectable.” Wu 998.
FF6. Wu teaches that “BDB is a fluorescent compound and is soluble in
CH2CI2, DMSO, and in most other organic solvents.” Wu 1000.
FF7. Wu suggests that, based on the ability of BDB to cross the BBB, there
is “the possibility that properly labeled, brain-permeable myelin
probes like BDB could potentially be used for in vivo imaging
modalities like positron emission tomography and single photon
emission computed tomography to detect and quantify myelin
contents in vivo.” Wu 1004.
FF8. Halldin teaches that “C-l 1 is being used in the widest variety of PET
[(positron emission tomography)] radiochemistry applications.”
Halldin 1908.
The most widely used approach for labelling
ligands using carbon-11 is [nC]methylation of alcohols,
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phenols, amines, carboxylic acids, amides and thiols ....
These reactions usually employ [nC]methyl iodide.
Recently, the more reactive 1 ^-labelled precursor
[nC]methyl triflate has been utili[z]ed.
Halldin 1909. Halldin teaches the need to maintain chemical
properties after labeling. “The substitution of naturally occurring
carbon-12 with carbon-11 does not change the biochemistry or the
pharmacology of the drug molecule.” Halldin 1909.
FF9. The Examiner finds that Price teaches creating a 1 ^-labeled PET
radiotracer Pittsburgh Compound-B (PIB) having the following
structure:
See Ans. 6. Price teaches that PIB is created by labeling the
nucleophilic nitrogen atom of 2-(4’-aminophenyl)-6-hydroxy-
benzothiazole using [nC]methyl triflate. Price 1530, Radiochemical
Synthesis.
FF10. The Examiner finds that Klunk teaches Congo Red derivatives having
the following formula:
See Final Act. 7. “[W] herein R5 is N(R’)2 (wherein R’ is a lower
alkyl group).” See Klunk 53: 15—38, see 52:35—55. Klunk also
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teaches that “[rjadiolabeling with nC can be readily done via N-
methylation, O-methylation . . . substituting [nC]methyl iodide,
[nC]alkylation, or [nC] carboxylation of suitable alkyl, alkenyl, or
alkynyl Chrysamine G analogues.” Klunk 30:23—27.
Principle of Law
“An obviousness rejection based on similarity in chemical structure
and function entails the motivation of one skilled in the art to make a
claimed compound, in the expectation that compounds similar in structure
will have similar properties.” In re Payne, 606 F.2d 303, 313 (CCPA 1979).
If an Examiner
considers that he has found prior art close enough to the
claimed invention to give one skilled in the relevant chemical
art the motivation to make close relatives (homologs, analogs,
isomers, etc.) of the prior art compound(s), then there arises
what has been called a presumption of obviousness or a prima
facie case of obviousness.
In re Dillon, 919 F.2d 688, 696 (Fed. Cir. 1990), citing In re Henze, 181
F.2d 196 (CCPA 1950); In re Hass, 141 F.2d 122, 127, 130 (CCPA 1944).
Analysis
We have reviewed Appellants’ contentions that the Examiner erred in
rejecting claims 8, 11, and 12 under 35 U.S.C. § 103(a) as being
unpatentable over Wu, Stankoff, Halldin, Price, and Klunk. We disagree
with Appellants’ contentions and adopt the findings concerning the scope
and content of the prior art set forth in the Examiner’s Answer and the Final
Office Action. For emphasis, we highlight and address the following:
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Appellants contend that there is no expectation that the cited BDB of
Wu “could be modified to provide nCH3 group on the amine group of the
terminal benzene for imaging, and if so modified, the compound could be
used for PET detection of myelin in vivo in brain tissue of an animal with a
demyelination disorder.” Br. 8, see also 10 (Wu suggests labeling the BDB
compound but “provide [s] no teaching of how or where BDB can or would
be labeled”).
We are not persuaded. The Examiner has identified a close structural
homologue of the presently claimed compound (see claim 8 above) that
differs from the compound BDB disclosed in Wu by the addition of a methyl
group to the nucleophilic nitrogen on either of the outer benzene rings of the
BDB compound. Final Act. 7; FF4. As noted by the Examiner, Wu’s
compound binds myelin in vivo and in vitro. Final Act. 7; see FF4—FF6.
The compound of Wu is also structurally related to the compound of
Stankoff, the two compounds differing solely by the addition of a methoxy
group onto Stankoff s central benzene ring. Compare FF1 and FF4; Final
Act. 7 (“BMB is a derivative of BDB where one methoxy group in BDB is
replace[d] by a hydrogen atom”). Stankoff teaches that the BMB compound
is a Congo Red derivative and is expected to have similar binding properties
to Congo Red. FF3. Stankoff also teaches that the BMB compound binds
myelin in vitro and in vivo. FF1—FF3.
Stankoff teaches that radiolabeling the BMB compound with carbon-
11 allows for the use of the compound in PET analysis. FF2. Wu does not
create a radiolabeled BDB compound but suggests that, based on the
properties of BDB, there is “the possibility that properly labeled, brain-
permeable myelin probes like BDB could potentially be used for in vivo
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imaging modalities like positron emission tomography and single photon
emission computed tomography to detect and quantify myelin contents in
vivo.” FF7. Thus, Wu suggests radiolabeling the BDB compound in order
to use the compound in PET imaging.
The Examiner relies on Price and Halldin to establish that carbon-11
can be added onto nucleophilic nitrogen atoms with a reaction that uses
[nC]methyl triflate. See FF8, FF9. Both Price and Halldin establish that
there are various known methods to attach a radioactive tracer onto a
compound. The various compounds disclosed in the art including the
suggested addition of the radioactive methyl group onto either the BMB or
BDB using the [nC]methyl triflate reaction results in a congener of Congo
red. See Ans. 17. Stankoff teaches that there is an expectation that “Congo
red derivative[s] . . . should share some binding properties with other
structurally related compounds.” FF3; see Final Act. 8. Here, Wu already
suggests making radiolabeled compounds of BDB. FF7. Halldin and Price
teach two ways to introduce a radiolabel into a compound: 1) by
substituting a molecule in a compound; and 2) by adding a molecule to a
compound. See FF8—FF9. Here, the addition of the radioactive methyl
group onto the nucleophilic nitrogen of the BDB compound of Wu results in
a close structural homolog that raises a presumption of obviousness or, at a
minimum, a prima facie case of obviousness. In re Dillon, 919 F.2d at 696,
citing In re Henze', In re Hass, 141 F.2d at 127, 130. We find no error with
the Examiner’s rationale that the combination of references suggests adding
a radioactive moiety to the BDB compound. See Ans. 7—8; see FF1—FF10.
Furthermore, the use of such a radiolabeled compound as a PET imaging
agent, is something that is already suggested by Wu. See FF7.
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Appellants contend that Halldin teaches substitution but “neither
disclose[s] nor suggests] it desirable to alter the structure of the molecule so
as to change the biochemistry and pharmacology of the molecule by adding
a nCH3 group.” Br. 12.
We are not persuaded. Wu suggests creating a radiolabeled BDB
compound to be used in PET analysis. FF7. The Examiner explains that:
Halldin et al. teach that the most widely used approach for
labelling ligands using carbon-11 is [nC]methylation of
alcohols, phenols, amines, carboxylic acids, amides, and thiols.
Similarly, Klunk et al. teach that radiolabeling with nC can
readily be done by with N-methylation, O-methylation as
described above with [nC]methyl iodide. Thus a person of
ordinary skill contemplating a 1 ^-labeled congener of BDB
would to look at both the nitrogen moiety and oxygen moieties
for placement of the [nC]methyl group.
Ans. 17. The Examiner explains that the radioactive label can reasonably be
placed in one of two positions on the BDB compound. “Halldin et al. teach
placement of a single [nC]methyl group at the nucleophilic nitrogen because
it would enable fast and efficient labeling with [nC]methyl triflate.” Ans.
17-18 ; see FF8 and FF9. We agree with the Examiner that Wu’s teaching
that it is desirable to radiolabel the BDB compound in conjunction with
adding the label to a nucleophilic nitrogen, as known to be straightforward,
provides sufficient motivation to create the compound with the radiolabel at
that position. See FF7—FF10. Because the resulting compound has a Congo
red related structure, one of skill would have expected that it has similar
binding properties as well. FF3.
Appellants contend that Halldin “teaches away from modifying the
structure of BDB by teaching that adding a radiolabel to a drug molecule, as
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opposed to substitution of an atom, could impair pharmacology and
biochemistry of the molecule.” Br. 13.
We are not persuaded. Halldin explains that substitution is desirable
because it does not alter the structure and thereby change the biochemistry
and pharmacological aspect of the drug. FF8. A recognition of the
desirability of that type of labeling does not take away from the broader
teaching that other labeling can also be successful. We agree with the
Examiner, that:
The substitution of naturally occurring carbon-12 with carbon-
11 does not change the biochemistry or pharmacology of the
drug molecule. However, this cannot reasonably be construed
as teaching away from the placement of a single [nC]methyl
group at the terminal nitrogen of BDB because one of ordinary
skill would not expect a change in its myelin/p-sheet binding
properties.
Ans. 17.
Appellants contend that removal of the methoxy from BDB changes
the properties of the compound. “BDB selectively stains intact myelin
sheaths” whereas BMB “can bind to myelin without intact sheaths.” Br. 14.
We are not persuaded. “Stankoff expressly states BMB allows the
visualization of demyelinated lesions.” Ans. \9; see¥¥3. The same is true
for Wu, which teaches that the absence of myelin results in virtually
undetectable staining. See FF5. In other words, both compounds can be
used to detect demyelination. Wu teaches that “myelin is lipid rich and
consists of nearly 80% lipid and 20% protein. . . . [T]he presence of high
amounts of low-molecular-mass proteins, proteolipid protein (PLP) and
MBP” distinguish myelin sheaths from other types of cell membranes. Wu
1002. In the absence of myelin sheaths, as seen in the quaking mouse brain,
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Wu shows that BDB staining is virtually undetected. FF5. Virtually
undetected does not mean that there is no staining of the brain structure. In
the same quaking mouse, Stankoff shows that staining with BMB was less
pronounced than in shiverer mice that have a total lack of MBP. FF3.
Based on these qualitative descriptors, it is not clear how the staining is
assessed. What is the real difference is between a profound decrease,
something less profound, and something virtually undetected? We are not
persuaded that the qualitative descriptors used in the two different references
in two different experiments establishes that the staining attributes between
the BDB and BMB compounds are as vastly different as argued by
Appellants. See FF3, FF5. A side by side comparison of these compounds
under similar conditions might be able to allow quantification of any
differences; however, this data was not provided.
Appellants contend that “[cjompounds used for diagnostic imaging
are often unique and even simple modifications, such as providing a methyl
group attached to an amine can adversely affect the binding and imaging
properties of the compound.” Br. 15—16, citing Wang Decl.11 in support.
We are not persuaded. Here, both Stankoff and Wu show that the
BMB and BDB compounds can detect areas that are not myelinated. See
FF3, FF5. We agree with the Examiner’s assessment:
To be of probative value, any objective evidence should be
supported by actual proof. Instead, Applicant [in the Wang
Decl.] merely point[s] to a section of [a] published article
[Wang12] that states CIC shares the same pharmacophore as
11 Declaration under 37 C.F.R. § 1.132 by Yanming Wang, signed Feb. 10,
2014 (“Wang Decl.”).
12 Wang et al., In Vivo Quantification of Myelin Changes in the Vertebrate
Nervous System, 29 J. Neurosci. 14663—14669 (2009) (“Wang”).
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BDB and BMB, CIC can dissolve ... in many conventional
solvents used] for tissue staining.
Final Act. 2. The claims do not require a particular solubility, and the art
has shown that the BMB and BDB compounds can be administered to
animals in vivo, indicating that at least for the purpose of administering and
detection, the demonstrated solubility of these compounds is sufficient. See
FF3, FF5.
We conclude that the evidence cited by the Examiner supports a prima
facie case of obviousness with respect to claim 8. Appellants have not
provided sufficient rebuttal evidence or evidence of secondary
considerations that outweighs the evidence supporting the Examiner’s
conclusion of obviousness. As Appellants do not argue the claims
separately, claims 11 and 12 fall with claim 8. 37 C.F.R. § 41.37 (c)(l)(iv).
II-IV. Obviousness over Wu, Stankoff, Halldin, Price, and Klunk
The Examiner has rejected claims 8 and 10-12 as unpatentable under
35 U.S.C. § 103(a) over Wu, Stankoff, Halldin, Price, Klunk, and further
including Knoess; claims 8 and 16 as unpatentable over Wu, Stankoff,
Halldin, Price, Klunk, and further including Kung; and claim 54 as
unpatentable over Wu, Stankoff, Halldin, Price, Klunk, and further including
Barrio.
With respect to these rejections Appellants contend that neither
Knoess (Br. 24), Kung (Br. 25), nor Barrio (Br. 26) overcome the
deficiencies with respect to Wu, Stankoff, Halldin, Price, Klunk. Having
found no deficiency with the combination of Wu, Stankoff, Halldin, Price,
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Klunk with respect to claim 8 (see above), we likewise affirm the rejections
with respect the additional references of Knoess, Kung, and Barrio as well.
SUMMARY
We affirm the rejection of all claims.
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
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