ETH ZURICH et al.

Patent Trials and Appeals Board

Oct 19, 2021

2021000361 (P.T.A.B. Oct. 19, 2021)

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.
15/427,952 02/08/2017 Simon M. Ametamey KSC0009US 1060
23413 7590 10/19/2021
CANTOR COLBURN LLP
20 Church Street
22nd Floor
Hartford, CT 06103
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
10/19/2021 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):
usptopatentmail@cantorcolburn.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte SIMON M. AMETAMEY, STEFANIE KRAEMER,
AHMED HAIDER, LINJING MU, and BERNHARD WUENSCH
__________

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Technology Center 1600
__________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and
DAVID COTTA, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a method
for the diagnosis of NMDA-receptor-associated diseases or disorders. The
Examiner rejected the claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b). We affirm in part.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as ETH Zurich,
University of Zurich, and Westfaelische Wilhelms - Universitaet (see
Appeal Br. 3). An oral hearing was held on Oct. 7, 2021.
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Statement of the Case
Background
“Positron emission tomography (PET) is a nuclear medicine,
functional imaging technique that produces a three-dimensional image of
functional processes in the body” by detection of a PET ligand, specifically
“a positron-emitting radionuclide (tracer), which is introduced into the body
on a biologically active molecule” (Spec. ¶ 6). “Depending on the target
specificity of the PET ligand an abnormal biodistribution of targets can be
indicative of diseases and disorders” (id. ¶ 7). “[A]t present there are no
NMDA[N-methyl-D-aspartate]-specific PET ligands with an in vivo
specificity that is sufficiently high, i.e. much higher than 30%, to correctly
reflect the NMDA receptor biodistribution in patients with NMDA receptor-
associated diseases or disorders” (id. ¶ 9) (emphasis omitted).
The Specification teaches “new PET ligands with high NMDA
receptor affinity and high NMDA receptor selectivity that are suitable for
use in the diagnosis of NMDA receptor-associated diseases or disorders by
positron emission tomography (PET) with good biodistribution, high signal
to noise ratio and little artifact generation” (Spec. ¶ 10).
The Claims
Claims 1–18 are on appeal. Claim 1 is an independent claim, is
representative, and reads as follows:
1. A method for the diagnosis of NMDA-receptor-
associated diseases or disorders, the method comprising:
(d) administering to a patient in need of such diagnosis a
radioactively labelled compound in an amount effective for
PET imaging of NMDA receptors,
(e) recording at least one PET scan, and
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(f) diagnosing the patient as having an NMDA-receptor-
associated disease or disorder from an abnormal NMDA
receptor expression pattern on the PET scan,
wherein the radioactively labelled compound has formula (I)

wherein:
at least one atom of formula (I) is a radiolabeled atom,
selected from the group of 11C-, 18F-, 13N-, or 15O-
atom, suitable for positron emission tomography
detection (PET);
one of R1, R2, R3 and R4 is independently selected from
the group consisting of hydrogen, fluorine, -(C1-
C4)alkyl, fluorinated -(C1-C4)alkyl, -CH2F, -CD2F,
FCH2CH2-, FCH2CH2CH2-, -O(C1-C4)alkyl,
fluorinated -O(C1-C4)alkyl, OCH2F, -OCD2F,
FCH2CH2O-, and FCH2CH2CH2O-,
and the other of R1 to R4 are hydrogen or fluorine;
R5 is selected from the group consisting of hydrogen, -(C1-
C6)alkyl, fluorinated -( C1-C6)alkyl, -CH2F, -CD2F,
FCH2CH2-, and FCH2CH2CH2-;
Y is selected from the group consisting of:
(C1-C6)alkyl,
(C1-C6)alkoxyalkyl, (C1-C6)polyethyleneglycoyl,
-(CH2) 2-O-(CH2) 2-R6, -(CH2)3-O-R6, -(CH2)4-O-R6,
(C1-C6)heteroalkyl, -(CH2)3-X-R6 and -(CH2)4-X-R6,
wherein X is sulfur or SO2,

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-(CH2)3-CO-R6, -(CH2)2-CO-N(CH3)-CH2-R6, and –CO-(CH2)3-
R6, wherein R8 is one or more hydrogen or fluorine;
R6 is selected from the group consisting of:
substituted or non-substituted (C5-C6)aryl, substituted or
non-substituted (C5-C6)heteroaryl, substituted or non-
substituted phenyl or pyridyl, and

wherein Z is selected from the
group consisting of hydrogen, fluorine and nitrile, wherein
R7 is selected from the group consisting of hydrogen,
fluorine, -(C1-C6)alkyl, fluorinated -(C1-C6)alkyl, -CH2F,
-CD2F, FCH2CH2-, FCH2CH2-, and FCH2CH2CH2-;
and pharmaceutically acceptable salts or solvates thereof.

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The Rejections
A. The Examiner rejected claims 1–6, 8–10, 12, 13, and 17 under 35
U.S.C. § 103(a) as obvious over Tewes,2 Arstad,3 and Zhang4 (Non-Final
Act. 4–6).
B. The Examiner rejected claims 1–17 under 35 U.S.C. § 103(a) as
obvious over Tewes, Arstad, Zhang, and Wick5 (Non-Final Act. 6–7).
C. The Examiner rejected claim 18 under 35 U.S.C. § 103(a) as obvious
over Tewes, Arstad, Zhang, and Halldin6 (Final Act. 7–8).

A. 35 U.S.C. § 103(a) over Tewes, Arstad, and Zhang
The Examiner finds Tewes teaches “evaluation of 3-benzazapin-1-ols
as NR2B-selective NMDA receptor antagonists” including a compound 13
that falls within the scope of the compounds of claim 1 (Non-Final Act. 4–
5). The Examiner acknowledges Tewes does not “teach a method for
diagnosing NMDA-receptor associated diseases or disorders” (id.).
The Examiner finds Arstad teaches “a method for in vivo imaging,
suitably SPECT or PET, and preferably for imaging a disease in which the

2 Bastian Tewes et al., Design, Synthesis, and Biological Evaluation of 3-
Benzazepin-1-ols as NR2B-Selective NMDA Receptor Antagonists, 5
ChemMedChem 687–95 (2010).
3 Arstad et al., US 2009/0155168 A1, published June 18, 2009.
4 Ming-Rong Zhang & Kazutoshi Suzuki, [18F]Fluoroalkyl Agents:
Synthesis, Reactivity and Application for Development of PET Ligands in
Molecular Imaging, 7 Current Topics in Medicinal Chemistry 1817–28
(2007).
5 Wick et al., US 4,690,931, issued Sept. 1, 1987.
6 C. Halldin et al., Brain radioligands – State of the art and new trends, 45
Quarterly J. Nuclear Medicine 139–52 (2001).
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NMDA receptor is implicated” and “diagnosing a disease in which NMDA
receptor is implicated” (Non-Final Act. 5). The Examiner finds Zhang
teaches “PET is being more frequently used to detect disease-related
biochemical changes before anatomical changes caused by the disease could
be visualized by standard medical imaging modalities” (id.). The Examiner
finds it obvious to
modify the compound and method of Tewes et al. (compound
13 discussed above and method of its use) by substituting its -
OMe group with -O[11C]Me or -OEt[18F]F and by administering
one of those derivatives to a patient in need of diagnosis in an
effective amount for PET, recording a PET imaging, and by
diagnosing the patient with a disorder such as AD as taught by
Arstad et al. and Zhang et al. because it would advantageously
enable highly selective PET imaging of the NR2B site and non-
invasive diagnosis of disorders such as AD.
(Id. at 6).
Appellant contends “Tewes merely describes certain compounds but
is completely silent on their application or suitability for diagnostic methods,
much less the instantly claimed method of diagnosing NMDA receptor
related diseases or disorders. The absence of sufficient teachings in Tewes
is not supplied by the general teachings in Arstad and/or Zhang” (Appeal Br.
9). Appellant further contends “Zhang does not provide any motivation to
use the in vitro antagonists of Tewes in an in vivo diagnostic method” (id. at
10) (emphasis omitted).
Appellant also contends
Dr. Ametamey states that even if one were to consider the use
of the radioactive fluoroalkyl agents in PET as taught by Zhang,
the skilled artisan “lacks a reasonable expectation of success in
actual preclinical and clinical in vivo settings.” Ametamey
Declaration at p11-14). Halldin et al. (cited by the Examiner)
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illustrates the inherent difficulties associated with the
development of new brain receptor-targeted imaging ligand
candidate.
(Appeal Br. 12) (emphasis omitted).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that the
combination of Tewes, Arstad, and Zhang render claim 1 obvious?
Findings of Fact
1. Tewes teaches: “With the aim of increasing the selectivity of
[ifenprodil] without losing affinity toward NR2B subunit containing NMDA
receptors (Ki = 10 nM), a new class of NR2B-selective NMDA receptor
antagonists with reduced conformational flexibility was designed” (Tewes
688, col. 1).
2. Tewes teaches that compounds 13 to 27 share a core structure
as reproduced below:

(Tewes 689, col. 1, Scheme 3).
3. Table 2 of Tewes is reproduced, in part, below:

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“3-Benzazepines 13–27 were synthesized by nucleophilic substitution of
secondary amine 12 with various haloalkanes (Scheme 3 and Table 2)”
(Tewes 689, col. 1).
4. Table 4 is reproduced, in part, below:

“Table 4. Affinities of 3-benzazepin-1-ols for the ifenprodil binding site of
NR2B-containing NMDA receptors, the PCP binding site of the NMDA
receptor, and for σ1 and σ2 receptors” (Tewes 691, col. 1).
5. Figure 2 of Tewes is reproduced below:
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“[T]he 4-phenylbutyl derivative 13, which has the same N–Ph distance as
the lead compound 1 . . . showed the highest affinity in this series (see
Figure 2)” (Tewes 688, col. 2).
6. Tewes teaches:
A new compound class of NR2B-selective NMDA receptor
antagonists has been identified. The most promising compound
is 7-methoxy-3-(4-phenylbutyl)-2,3,4,5,-tetrahydro-1H-3-
benzazepin-1-ol (13) showing high affinity (Ki=5.4 nM) toward
NR2B receptors. In contrast to the lead compound 1,
benzazepine 13 does not interact with α1, NMDA (PCP binding
site), 5-HT1A, 5-HT2, σ1, and σ2 receptors. In an assay using
cells stably expressing only NR1a and NR2B subunits, 13 was
able to inhibit (IC50=360 nM) the excitotoxicity caused by (S)-
glutamate and glycine, indicating the NMDA antagonistic
activity of 13.
3-Benzazepine 13 represents a very promising new
lead[.]
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(Tewes 692, col. 2).
7. Arstad teaches “N-methyl-D-aspartate (NMDA) receptors are
vital to a wide range of biological processes, including neuroprotection,
neurodegeneration, long-term potentiation, memory and cognition . . . NR2B
is expressed predominantly in the forebrain but not in cerebellum,” (Arstad
¶ 2).
8. Arstad teaches “NMDA receptors are implicated in a wide
range of pathological processes, including Alzheimer’s disease, Parkinson’s
disease, Huntington’s Chorea, epilepsy, schizophrenia, diabetes, anxiety,
depression, chronic pain and drug abuse” (Arstad ¶ 2).
9. Arstad teaches “there still exists a need for improved agents
suitable for in vivo imaging of the NR2B receptor subtype of the NMDA
receptor with good affinity for the receptor and favourable metabolic
profile” (Arstad ¶ 6).
10. Arstad teaches
antagonists of the human NMDA receptor, being selective for
those containing the NR2B subunit, and that carry a
radionuclide suitable for PET or SPECT imaging. As such the
compounds will be useful for imaging the NR2B receptor in the
living human brain, and may therefore find use in diagnosis or
therapy monitoring of diseases in which the NMDA receptor is
implicated.
(Arstad ¶ 7).
11. Arstad teaches “selective antagonists of the NR2B receptor
subtype of the NMDA receptor . . . may therefore have utility for diagnostic
purposes or therapy monitoring” (Arstad ¶ 60).
12. Arstad teaches:
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[T]here is provided use of a compound of formula (I) or (Ia) or
a salt or solvate thereof for the manufacture of a
radiopharmaceutical for use in a method of in vivo imaging,
suitably SPECT or PET, and preferably for imaging a disease in
which the NMDA receptor is implicated; involving
administration of said radiopharmaceutical to a human or
animal body and generation of an image of at least part of said
body.
(Arstad ¶ 68).
13. Arstad teaches standard methods for incorporating radiolabels,
for example “[11C]methyl iodide may used to effect [11C]methylation of a
hydroxy-containing precursor” such as compound 13 of Tewes. Arstad also
teaches “[r]adiohalogenation methods are reviewed in detail in Bolton” (see
Arstad ¶¶ 69–75).
14. Arstad teaches a working example using test compounds
including EA10 with an inhibition values of Ki<2 nm (Arstad ¶ 134). Arstad
teaches that EA10 and EA11 were administered to rats for “[i]maging
studies . . . performed using a Focus 120 microPET unit” (Arstad ¶¶ 135–
140). Arstad showed “region/cerebellum uptake ratios of Compound EA10”
(Arstad ¶ 140).
15. Zhang teaches
PET is being used more frequently to detect disease-related
biochemical changes before the anatomical changes caused by
the disease could be visualized by standard medical imaging
modalities. Some positron-emitters (11C, 18F, 13N, 15O, 61Cu,
62Cu, and 124I etc.) can be incorporated into a target molecule to
form a PET ligand for molecular imaging study.
(Zhang 1817, col. 1).
16. Zhang teaches “the preparation, reactivity, and application of
[18F]fluoroalkyl agents for the development of 18F-labeled PET ligands.
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[18F]Fluoroalkyl agents have been prepared through the nucleophilic
substitution of [18F]F with the corresponding alkyl derivatives containing
halogen and sulfonate as leaving groups” (Zhang 1825, col. 1–2).
17. Zhang teaches “[18F]fluoroalkylation is a potential tool for
developing [18F]ligands in molecular imaging study” (Zhang 1825, col. 2).
18. Zhang teaches “[18F]fluoroalkyl visions are generally more
lipophilic and easily reach the target organs or regions. A relatively
lipophilic PET ligand may readily pass through the blood-brain barrier,
which is necessary for a suitable PET ligand over the brain imaging” (Zhang
1818, col. 1).
Principles of Law
A lead compound is a compound in the prior art that would be “a
natural choice for further development efforts.” Bristol-Myers Squibb Co. v.
Teva Pharm. USA, Inc., 752 F.3d 967, 973 (Fed. Cir. 2014). In assessing the
prior art, we “consider[s] whether a PHOSITA would have been motivated
to combine the prior art to achieve the claimed invention and whether there
would have been a reasonable expectation of success in doing so.” BTG
Int’l Ltd. v. Amneal Pharm. LLC., 923 F.3d 1063, 1073 (Fed. Cir. 2019)
(citing In re Warsaw Orthopedic, Inc., 832 F.3d 1327, 1333) (Fed. Cir.
2016).
Analysis
We adopt the Examiner’s findings of fact and conclusion of law (see
Non-Final Act. 4–6, FF 1–18) and agree that the combination of Tewes,
Arstad, and Zhang renders the claims obvious. We address Appellant’s
arguments below.
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Appellant contends:
Absent the application of impermissible hindsight reasoning,
there is nothing in Tewes alone or in combination with Arstad
and Zhang that teaches or suggests every element recited in the
claims or that enables the claimed invention. As such, the
present rejection amounts to no more than the application of
impermissible hindsight.
(Appeal Br. 9).
While we are fully aware that hindsight bias may plague
determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36
(1966), we are also mindful that the Supreme Court has clearly stated that
the “combination of familiar elements according to known methods is likely
to be obvious when it does no more than yield predictable results.” KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). In the present case,
Arstad teaches “there still exists a need for improved agents suitable for in
vivo imaging of the NR2B receptor subtype of the NMDA receptor” (FF 9)
and teaches a “radiopharmaceutical for use in a method of in vivo imaging,
suitably SPECT or PET, and preferably for imaging a disease in which the
NMDA receptor is implicated” (FF 12).
The ordinary artisan, interested in an improved ligand for NR2B
receptor subtypes of the NMDA receptor, would reasonably look to
compound 13 of Tewes, because Tewes teaches a “new compound class of
NR2B-selective NMDA receptor antagonists has been identified. The most
promising compound is [compound] (13) showing high affinity (Ki=5.4 nM)
toward NR2B receptors . . . [compound] 13 represents a very promising new
lead” (FF 6).
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The Examiner cites Zhang to establish that “PET is being used more
frequently to detect disease-related biochemical changes before the
anatomical changes caused by the disease could be visualized by standard
medical imaging modalities” (FF 15) and that “[18F]fluoroalkylation is a
potential tool for developing [18F]ligands” (FF 17).
Thus, the evidence reasonably supports the Examiner’s position that
the ordinary artisan would perform Arstad’s PET scan for NR2B receptor
subtypes using the promising lead compound 13 of Tewes because
compound 13 has high affinity for NR2B receptors, increased selectivity
without non-specific binding to other receptors, and was functional in cells
in culture (FF 2, 6).
Appellant contends “Zhang does not provide any motivation to use the
in vitro antagonists of Tewes in an in vivo diagnostic method as is presently
claimed” (Appeal Br. 10) (emphasis omitted).
We find this argument unpersuasive because it fails to address the
combination of references, which includes Arstad as well as Zhang and
Tewes. “Non-obviousness cannot be established by attacking references
individually where the rejection is based upon the teachings of a
combination of references. . . . [The reference] must be read, not in
isolation, but for what it fairly teaches in combination with the prior art as a
whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
Moreover, Zhang reasonably suggests that fluoroalkylation of ligands
results in compounds that are more lipophilic and more readily pass through
the blood-brain barrier and are therefore more suitable for brain imaging
using PET (FF 18). Consequently, Zhang provides reasons for
fluoroalkylation of ligands, such as the promising lead compound 13 of
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Tewes, in order to improve its ability to pass through the blood brain barrier
and bind to the target ligand as needed for the PET diagnostic assay of
Arstad.
Appellant contends “the cited combination of references provides
insufficient guidance to the skilled artisan to make the likelihood of success
anything more than remote or desired” (Appeal Br. 12). Appellant contends
agents for receptor inhibition impose completely different
requirements on chemical compounds as compared to agents for
use in receptor-related diagnosis, and the suitability of a
compound for inhibition does not necessarily, and not with a
reasonable expectation of success in what the courts have
indicated is an inherently unpredictable art, translate into the
suitability for diagnosis with PET methods.
(Id.) Appellant contends “Dr. Ametamey states that even if one were to
consider the use of the radioactive fluoroalkyl agents in PET as taught by
Zhang, the skilled artisan ‘lacks a reasonable expectation of success in actual
preclinical and clinical in vivo settings.’ Ametamey Declaration7 at p11-14)”
(id.) (emphasis omitted).
As to the underlying issue of a reasonable expectation of success, an
obviousness finding is “appropriate where the prior art ‘contained detailed
enabling methodology for practicing the claimed invention, a suggestion to
modify the prior art to practice the claimed invention, and evidence
suggesting that it would be successful.”’ In re Kubin, 561 F.3d 1351, 1360
(Fed. Cir. 2009) (citing In re O’Farrell, 853 F.2d 894, 902 (Fed. Cir. 1988)
(emphasis omitted). “Obviousness does not require absolute predictability

7 Declaration of Dr. Simon Mensah Ametamey, dated Oct. 17, 2019.
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of success . . . all that is required is a reasonable expectation of success.”
Kubin, 561 F.3d at 1360 (emphasis omitted).
That is the situation at hand. Arstad teaches a need for improved
agents for in vivo imaging of the NR2B receptor subtype of NMDA with
good affinity (FF 9). Arstad teaches a detailed methodology for performing
PET imaging including radiolabeling of ligands (FF 11–13). Lastly, Arstad
teaches a working PET imaging example using compound EA10 with a Ki of
less than 2 nm (FF 14). Tewes teaches a compound 13 that binds the NR2B
selective NMDA receptor and is a potent lead compound with a Ki of 5.4 nm
(FF 6). Zhang evidences known methods of fluoroalkylation that assist
compounds in passing the blood brain barrier (FF 15–18).
We agree with the Examiner that the detailed suggestion of a single
specific preferred compound 13 in Tewes for binding the NR2B subtype
NMDA receptor and the detailed enabling methodology in Arstad provides a
reasonable expectation of success.
The Specification acknowledges that:
PET imaging of NMDA receptors in the human body, in
particular the living human brain is a modern but already
standard procedure in medical science and diagnosis. The
average skilled person can routinely select an effective dosage,
an effective formulation, the route and site of administration as
well as all further parameters that are necessary to provide a
meaningful PET scan[.]
(Spec. ¶ 41). The Specification recognizes that compounds useful in PET
scanning “have an affinity to the NMDA receptor in the nanomolar range,
preferably at least 100 nM, more preferably at least 10 nM, most preferably
at least less than 5 nM” (id. ¶ 20). Compound 13 of Tewes has an affinity of
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5.4 nm, well within the range identified as preferred by the Specification and
therefore reasonably expected to succeed (FF 6).
Appellant cites the Ametamey Declaration for the proposition that
“the skilled artisan ‘lacks a reasonable expectation of success in actual
preclinical and clinical in vivo settings.’ Ametamey Declaration at p11-14).
According to Appellant, Halldin et al. (cited by the Examiner) illustrates the
inherent difficulties associated with the development of new brain receptor-
targeted imaging ligand candidate” (Appeal Br. 12; Ametamey Decl. at 9)
(emphasis omitted). Appellant quotes Halldin as teaching:
It has to be emphasized that any data extracted from in vitro
experiments can only give a rough estimate of the situation to
be encountered in vivo. . . . It has to be kept in mind that
neurotransmission systems in the intact body constitute part of a
dynamic and communicating environment and that neural
interaction may actually alter in vivo receptor binding.
(Appeal Br. 12; italics omitted).
We find this argument unpersuasive because the ellipsis interposed by
Appellant and Dr. Ametamey elides a true understanding of Halldin’s
comparison of in vivo and in vitro detection. The omitted portion includes
the statement that “[m]ost in vitro assays use homogenized tissue, which
does not reflect the tissue heterogeneity in the intact organ in vivo” (Halldin
144, col. 1) (emphasis omitted). Thus, Halldin isn’t addressing any
difficulties with in vivo or in vitro use of radiotracers such as a labeled
compound 13, but rather is only pointing out that when radiotracers are used
in homogenized tissue, tissue that has been removed from its native source,
in vivo results may differ from in vitro results. This quote by Halldin
therefore does not support a finding that there is a lack of a reasonable
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expectation of success in using a labeled compound 13 as a radiotracer in
PET analysis of living brains, only that the resultant data might differ in
some way from an in vitro homogenized sample.
Appellant cites the Ametamey Declaration for the proposition that
“Addy8 and her co-authors teach the single-dose administration of an NR2B-
selective NMDA antagonist MK0657 and the failure of a clinically
meaningful improvement in motor function in patients with moderate
Parkinson’s disease” (Appeal Br. 22; Ametamey Decl. at 9–10).
We reviewed Addy, which did not test compound 13 of Tewes but
rather tested a different compound, MK-0657 for treatment of Parkinson’s
disease. Indeed, this argument is irrelevant because whether compound 13
of Tewes would treat Parkinson’s disease lacks any relationship with the
instant claims, which simply require a compound that can be used in
diagnostic PET assays. The claims do not require any therapeutic efficacy.
“[A]ppellant’s arguments fail from the outset because . . . they are not based
on limitations appearing in the claims.” In re Self, 671 F.2d 1344, 1348
(CCPA 1982).
And while Addy did not find that MK-0657 treated the particular
condition of Parkinson’s disease, Addy did state that an expectation that the
drug would enter the brain, with “MK-0657 plasma concentration that was
predicted to achieve 50% brain receptor occupancy was estimated at
approximately 400 nM based on intrinsic binding affinity of MK-0657 in

8 Carol Addy et al., Single-Dose Administration of MK-0657, an NR2B-
Selective NMDA Antagonist, Does Not Result in Clinically Meaningful
Improvement in Motor Function in Patients With Moderate Parkinson’s
Disease, 49 J. Clin. Pharmacol. 856–64 (2009).
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human temporal cortex” (Addy 862, col. 2). Thus, to the extent that Addy is
relevant, Addy is reasonably interpreted as evidencing that the ordinary
artisan would expect NR2B selective NMDA binding drugs to bind to brain
receptors in vivo, providing a reasonable expectation that compound 13
would also bind brain receptors in vivo.
We have also considered the entire Declaration of Dr. Ametamey,
including statements that
a speculative option based on preliminary data in an
unpredictable field is no more than an invitation to try, which is
insufficient for demonstrating prima facie obviousness. I am
therefore of the opinion that the skilled artisan in the field of
radioligand imaging would find that the new diagnostic utility
of the compounds recited in the present claims is non-obvious
in view of Tewes et al.
(Ametamey Decl. at 12).
We find this argument unpersuasive for several reasons. First, we
disagree with Dr. Ametamey’s characterization of the cited art as providing
“no more than an invitation to try.” For the reasons discussed above, we
agree with the Examiner that the cited art provides not just an invitation to
try, but also a reasonable expectation that compound 13 of Tewes could
successfully be used for PET imaging of NMDA receptors. Second, as
discussed above, Tewes’s disclosures regarding the binding affinity and
specificity of compound 13 call it out as an extremely promising (“lead”)
compound.9 Third, “an affidavit by an applicant or co-applicant as to the

9 We note that the binding affinity and specificity of compound 13 fall well
within the best part of the range preferred by the Specification for functional
ligands (see Spec. ¶ 20).
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advantages of his invention is less persuasive than one made by a
disinterested person.” In re Bulina, 362 F.2d 555, 559 (CCPA 1966).
We also note the inconsistency between Appellant’s argument that a
particular, identified, promising lead candidate compound 13 with an affinity
of 5.4 nm for the NR2B subtype of the NMDA receptor lacks a reasonable
expectation of success in a PET imaging assay of Arstad as labeled by
Zhang while implicitly asserting that the full scope of the instant claims,
which encompass hundreds of millions of compounds as listed on pages 14–
17 of the Appeal Brief, are enabled without undue experimentation.
Conclusion of Law
A preponderance of the evidence of record supports the Examiner’s
conclusion that the combination of Tewes, Arstad, and Zhang render claim 1
obvious.

B. 35 U.S.C. § 103(a) over Tewes, Arstad, Zhang, and Wick
Appellant contends:
Wick teaches l-phenyl-2-piperidoalkanol derivatives in the
context of vigilance disorders. The compounds of Wick have
no chemical resemblance to the claimed compounds of formula
(I). Wick is silent as to NMDA receptor interactions or
diseases. Thus, Wick not only fails to cure the deficiencies of
Tewes, Arstad, and Zhang but also fails to provide any
motivation to: (a) use compounds such as those disclosed in
Tewes in diagnostic methods with PET; or (b) to modify the
compounds of Tewes to arrive at the presently claimed
invention.
(Appeal Br. 18). Appellant also contends “Wick similarly fails to establish
that a reasonable expectation of success existed at the time of the invention.
The skilled artisan in chemistry would never assume that modifications to
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structurally unrelated bioactive molecules lead to the same (advantageous)
effects” (id.).
The Examiner responds
Tewes teaches further structural modification of compound 13
based on the structure of ifenprodil, a related compound that is
structurally different. Tewes teaches the methyl group of
ifenprodyl, which has been omitted in the first series of NR2B
ligands, will be added at position 8 of the 3-benzazepine
system. Wick teaches structural modification of ifenprodil.
Wick was used to teach position isomers. However, position
isomers (compounds having the same radicals in physically
different positions on the same nucleus) are generally of
sufficiently close structural similarity that there is a presumed
expectation that such compounds possess similar properties.
(Ans. 9).
We agree with Appellant. We recognize that Tewes teaches that
“ifenprodil . . . was developed as an α1 adrenoceptor antagonist. However,
[ifenprodil] has been found to interact with several other receptors and ion
channels including . . . NMDA receptors. Subsequently, [ifenprodil] was
shown to be a selective NR2B antagonist” (Tewes 687, col. 2). Tewes
teaches the “aim of increasing the selectivity of [ifenprodil] without losing
affinity toward NR2B subunit containing NMDA receptors” (FF 1). We
also recognize that Wick teaches compounds that are modified forms of
ifenprodil, including compounds 21 and 24 and that satisfy the requirements
of the rejected claims (see Wick, Table).
We are persuaded by Dr. Ametamey that
the skilled artisan would not conclude that the compounds of
Wick et al. are structurally related to the compounds of the
present invention simply because the compounds of Wick are
derivatives of ifenprodil, and Tewes et al. teaches that 3-
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benzazepine compounds were derived from ifenprodil. It is my
professional understanding as an organic and medicinal chemist
that a structural relationship between organic compounds is
solely based on chemical structure and not on the origin of
precursor materials.
(Ametamey Decl. 13). For this reason, the Examiner’s reliance on positional
isomerism is unpersuasive. Moreover, unlike the compound 13 of Tewes,
where there was evidence of a very high Ki value in a binding assay, Wick
lacks any direct evidence that the further modified compounds would bind to
the NR2B subtype of the NMDA receptor or would otherwise function in a
PET assay for that receptor. We do not find the Examiner persuasively
demonstrated that these specific compounds would have been obvious. We
therefore reverse this rejection.

C. 35 U.S.C. § 103(a) over Tewes, Arstad, Zhang, and Halldin
Appellant contends “that Halldin fails to cure the deficiencies of
Tewes, Arstad, and Zhang because of the complex nature of the research
field of diagnostically stable radioligands along with unpredictability
associated with relevant target binding in vivo” (Appeal Br. 23). Appellant
contends “the Examiner has not properly weighed the expert declaration in
contravention of the patent laws” and “Applicant has submitted evidence
that a skilled artisan would not have been able to predict a priori that one
could reasonably expect to successfully employ the claimed compounds in a
diagnostic method” (id.).
We remain unpersuaded by these arguments. Tewes teaches that
compound 17, at issue here, has a Ki value of about 29 nm (see Tewes 691,
Table 4), well within the Ki values desired by the Specification that are at
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least as low as 100 nm (Spec. ¶ 20) and which would reasonably have been
expected to function in the diagnostic PET assay. Halldin teaches known
prior art processes for radiolabeling ligands, including teaching that
selection of radioligands is “often guided by data obtained in vitro using
tritiated or iodinated radioligands” (Halldin 142, col. 2) (emphasis omitted).
We have considered the Declaration, as already discussed, and find it
does not persuasively demonstrate why known ligands for the NR2B
subtype of the NMDA receptor that bind to the receptor with Ki values
below those required by the Specification would not have at least a
reasonable expectation of success. Kubin, 561 F.3d at 1360. Indeed, the
Ametamey Declaration does not point to any specific reason why the
particular prior art ligands would not be expected to succeed, but simply
points to generic arguments that “development of diagnostically suitable
radioligands is a most complex and by no means predictable endeavor”
(Ametamey Decl. at 13). As we balance this general statement by an
inventor against prior art demonstrating in vitro binding efficacy and
Halldin’s teaching that radioligand selection is guided by such in vitro data,
and the particularly good Ki values in Tewes, we find more evidence
supporting obviousness and we find that evidence more persuasive. See In
re Am. Acad. of Sci. Tech Ctr., 367 F.3d 1359, 1370 (Fed. Cir. 2004) (“[T]he
Board is entitled to give such weight to declarations as it deems
appropriate.”)

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DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–6, 8–10,
12, 13, 17
103 Tewes, Arstad, Zhang 1–6, 8–10,
12, 13, 17

1–17 103 Tewes, Arstad,
Zhang, Wick
1–17
18 103 Tewes, Arstad,
Zhang, Halldin
18
Overall
Outcome
1–6, 8–10,
12, 13, 17,
18
7, 11, 14–
16

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 IN PART