GE HEALTHCARE LIMITED

Patent Trials and Appeals Board

Jul 6, 2020

15742512 - (D) (P.T.A.B. Jul. 6, 2020)

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.
15/742,512 01/07/2018 Christopher John Buckley 037380.00070 9734
157683 7590 07/06/2020
Arent Fox LLP and GE Healthcare
1717 K Street, NW
Washington, DC 20006-5344
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
07/06/2020 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):
patentdocket@arentfox.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte CHRISTOPHER JOHN BUCKLEY and ADRIAN SMITH
__________

Appeal 2020-001210
Application 15/742,5121
Technology Center 1600
__________

Before ERIC B. GRIMES, TAWEN CHANG, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of staging beta amyloid pathology in a living human subject’s brain, which
have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
Appellant’s Specification states that “[a]myloid is an abnormal
deposit of insoluble protein fibrils in a body tissue or organ.” (Spec. 1) Beta
amyloid (Aβ) is a specific type of amyloid involved in Alzheimer’s disease

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 GE
Healthcare Limited. (Appeal Br. 2.)
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(AD). (Id.) “Aβ is one of the two neuropathological hallmarks of AD that
can be seen microscopically in brain tissue specimens stained with certain
dyes.” (Id.) “A number of positron emission tomography (PET) imaging
agents that bind to Aβ are commercially-available.” (Id.) They “enable
detection in living subjects of Aβ build up in plaques and in the blood
vessels supplying the brain.” (Id. at 1–2.) “Thal . . . propose[d] five phases
of Aβ amyloidosis (‘Thal phases’) based on histopathological assessment of
post-mortem brain tissue.” (Id. at 2.) Appellant’s invention relates to in
vivo imaging of Aβ plaques in the brain of a subject.
Claims 1 and 4–19 are on appeal. Claims 1 and 17 are representative
and read as follows:
1. A method for staging beta amyloid (Aβ) pathology in a
living human subject’s brain wherein said method comprises:
(i) administering an Aβ imaging agent to said subject
such that the Aβ imaging agent is delivered to said subject’s
brain;
(ii) obtaining an in vivo image of said subject’s brain
using a Aβ imaging agent;
(iii) determining from said in vivo image the uptake of
said Aβ imaging agent in a cortical region of said brain; and,
(iv) determining from said in vivo image the uptake of
said Aβ imaging agent in a striatal region of said brain;
wherein positive uptake of said Aβ imaging agent in said
cortical region and negative uptake of said Aβ imaging agent in
said striatal region indicates Thal Phase 3 Aβ pathology
and wherein positive uptake of said Aβ imaging agent in
said cortical region and positive uptake of said Aβ imaging
agent in said striatal region indicates Thal Phase 4 or 5 Aβ
pathology.

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17. A method for treatment of Alzheimer’s disease (AD)
wherein said method comprises the method as defined in Claim
1 and the further steps of:
(v) selecting those subjects in whom Thal Phase 3 Aβ
pathology or greater has been indicated;
(vi) treating those subjects selected in step (v) with an
AD therapy.
(Appeal Br. Claims Appendix 1, 4.)
The prior art relied upon by the Examiner is:
Name Reference Date
Shanka Vallabhajosula, Positron Emission Tomography
Radiopharmaceuticals for Imaging Brain Beta-Amyloid, 41 Semin Nucl.
Med. 283–99 (2011)
Irina Alafuzoff et al., Assessment of β-amyloid deposits in human brain: a
study of the BrainNet Europe Consortium, 117 Acta Neuropathol. 309–20
(2009)
John C. Mazziotta, Mapping Human Brain Activity In Vivo, 161(3) West
J. Med. 273–78 (1994)

The following grounds of rejection by the Examiner are before us on
review:
Claims 1 and 4–17 under 35 U.S.C. § 103(a) as unpatentable over
Alafuzoff and Vallabhajosula.
Claims 1 and 4–19 under 35 U.S.C. § 103(a) as unpatentable over
Alafuzoff, Vallabhajosula, and Mazziotta.
DISCUSSION
Claims 1 and 4–17
The Examiner finds that Alafuzoff teaches in vitro assessment of Aβ
deposits in the human brain by staining brain samples with a monoclonal
antibody directed against Aβ and obtaining images thereof. (See, e.g., Ans.
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7.) The Examiner further finds that Alafuzoff teaches that one can image
regional involvement of amyloid in the brain in 10 anatomical regions
(including cortical and striatal region) and determine the Aβ phase based on
the regional binding. (Id. at 3, 7.) The Examiner finds that Alafuzoff
teaches that 5 phases are known where phase 1 involves detection of Aβ
binding to the monoclonal antibody in the neocortex; phase 2 involves
binding detection in the neocortex and the allocortex; phase 3 involves
binding detection in the neocortex, allocortex, and diencephalon as well as
striatum; phase 4 involves binding detection in the neocortex, allocortex,
diencephalon, striatum, and brainstem; and phase 5 involves binding
detection in the neocortex, allocortex, diencephalon, striatum, brainstem, and
cerebellum. (Id. at 3, 7.) The Examiner further finds that Alafuzoff teaches
“that one may consider the rating of Aβ phases as a diagnostic tool while
analyzing subjects with suspected Alzheimer’s disease (AD) (see pg. 310,
col. 1).” (Id. at 3.)
The Examiner finds that Vallabhajosula teaches PET
radiopharmaceuticals for imaging Aβ in the brain, including 11C labeled PiB,
and that such Aβ tracers “have the potential to become first-line imaging
biomarker for diagnosis and staging of AD.” (Id. at 3–4.) The Examiner
further finds that Vallabhajosula teaches the use of 11C labeled PiB-PET “to
monitor treatment response to anti-Aβ immunotherapy with bapineuzumab
(see pg. 296, Fig 15).” (Id. at 4.) Moreover, the Examiner finds that
Vallabhajosula teaches that recent AD “Neuroimaging Initiative data
indicate that FDG-PET [(18F-fluorodeoxyglucose-PET)] increased statistical
power over traditional cognitive measures, might aid subject selection, and
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could substantially reduce sample size in clinical trials (see pg. 286, col. 2).”
(Id.)
In light of these teachings, the Examiner concludes that one of
ordinary skill in the art would have found it obvious to modify the Alafuzoff
method of staging Aβ to an in vivo method by using the PET imaging agents
described in Vallabhajosula, obtain in vivo images of a subject’s brain, and
determine from the images if there were uptake in the cortical and striatal
regions. (Id. at 4–5.) The Examiner concludes such would have been
obvious to “advantageously enable non-invasive staging of Aβ pathology in
[a] living subject.” (Id. at 5.) The Examiner further concludes that it would
have been obvious to select subjects with phase 3 Aβ pathology and treat
them with an AD therapy “because it would advantageously enable halting
downstream damage cause[d] by cerebral Aβ loads.” (Id.)
We agree with the Examiner that the prior art relied upon supports
finding claims 1 and 17 obvious. Claims 4–16 have not been argued
separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv).
Appellant argues the Examiner’s rejection is in error because neither
reference teaches both in vivo imaging and phase determination based
thereon. (Appeal Br. 4–5; Reply Br. 2.) In particular, Appellant argues that
Alafuzoff does not discuss how to conduct a phase “analysis on a living
patient, or how one might adapt its teachings to an in vivo imaging
technique.” (Appeal Br. 5.) Appellant then argues, even while
acknowledging that Vallabhajosula “states ‘AB tracers for imaging have the
potential to become a first-line imaging biomarker for diagnosing, and
staging of AD.[’] See Vallabhajosula, p. 296,” that Vallabhajosula does not
“teach[] comparing uptake of an imaging agent in different regions of the
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brain.” (Id.) Thus, according to Appellant, “because of the different and
uncorrelated approaches of Alafuzoff and Vallabhajosula, the combined
teachings do not suggest Applicant’s claimed solution.” (Id.) Appellant
states “neither reference hints at examining uptake of an amyloid beta
imaging agent in the cortex and the striatum to determine a subject’s specific
Thal phase.” (Id.)
We do not find Appellant’s arguments persuasive. One cannot defeat
non-obviousness “by attacking the references individually[,] where the
rejection is based upon the teachings of a combination of references.” In re
Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (citation omitted).
We agree with Appellant that Alafuzoff teaches assessment of Aβ
pathology in post-mortem brain specimens and that Vallabhajosula teaches
PET imaging in vivo using Aβ imaging agents. (Appeal Br. 4–5.) However,
that does not end the obviousness inquiry. “In determining whether
obviousness is established by combining the teachings of the prior art, the
test is what the combined teachings of the references would have suggested
to those of ordinary skill in the art.” In re GPAC Inc., 57 F.3d 1573, 1581
(Fed. Cir. 1995) (internal quotations omitted). We agree with the Examiner
that the teachings of Alafuzoff and Vallabhajosula taken together would
have rendered obvious the claimed invention to one of ordinary skill in the
art.
Alafuzoff teaches that “[i]n 2002, Thal and colleagues reported . . . a
distinct pattern of involvement of brain regions with Aβ aggregates could be
observed” in postmortem brains. (Alafuzoff 310.) Phase 3 involved the
neocortex, allocortex, diencephalon and striatum, whereas phases prior to
phase 3 did not involve diencephalon or striatum. (Id.) Phase 4 additionally
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involved the brainstem, and phase 5 additionally involved the cerebellum.
(Id.) In other words, Alafuzoff teaches that it was known that there is a
distinct pattern of regional brain involvement of Aβ aggregates in different
phases of AD, and that there is “stepwise involvement” of the regions. (Id.;
see also id. at 311 (“[T]he assessment of the distribution of Aβ aggregates in
a subject with AD related tauopathy might be more than relevant since any
alteration from the expected pattern may reflect a genetic alteration or the
existence of a significant concomitant disease process”).)
Vallabhajosula states “[d]ifferential diagnosis of dementia is very
important.” (Vallabhajosula 296.) Vallabhajosula teaches several PET
imaging agents that can be used as Aβ tracers in in vivo imaging of the
brain. (See, e.g., id. at 288 (Table 1).) It is suggested that 11CPiB can be
used in vivo to evaluate Aβ plaque burden in the cortex and striatum and that
18F-3’-F-PiB and 18F-AV-1 would perform similarly. (Id. at 289, 291–92;
see also 294 (“[I]t was reported that significantly higher PiB retention was
seen in the frontal, temporal, parietal, and occipital cortices; and the striatum
of AD subjects compared with healthy controls.”).) In addition,
Vallabhajosula states:
In a proof-of-concept clinical study, 18F-BAY94-9172 PET
scans showed potential utility in differential diagnosis of AD
and FTLD [(frontotemporal lobar degeneration)] or healthy
controls and might facilitate integration of Aβ imaging into
clinical practice.
(Id. at 292.) Vallabhajosula further states that:
Florbetapir-PET imaging was correlated with the presence and
density of Aβ, and the data provide evidence that a molecular
imaging procedure can identify Aβ pathology in the brains of
individuals during life.
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(Id.) This reference also states that, “[a]fter three decades, we have
successfully developed several PET radiopharmaceuticals to image in vivo
brain Aβ burden and regional distribution in patients with AD.” (Id. at 293
(emphasis added).) In short, Vallabhajosula provides evidence that PET Aβ
tracers are known that can be imaged in various parts of the brain in vivo if
there are Aβ plaques present.
Furthermore, Vallabhajosula provides a reason that one would
reasonably expect to be able to use the phase differentiation identified in
Alafuzoff in conjunction with in vivo PET radiopharmaceuticals specific for
Aβ because it suggests in vivo and post mortem staining are correlated. In
particular, it is stated:
The main brain regions showing PiB retention were the ventral
prefrontal and posterior cingulate/precuneus cortices, following
the known pattern of Aβ deposition as described in postmortem
studies. The histologic and biochemical specificity of PiB
binding across different regions of the AD brain was
demonstrated by showing a direct correlation between Aβ-
containing amyloid plaques and in vivo [11C]PiB retention
measured by PET imaging.
(Id. at 294 (emphasis added).) A similar study and finding was made with
respect to 18F Florbetapir-PET. (Id. at 295.)
Thus, for the foregoing reasons we find the Examiner has established
the combined teachings suggest Appellant’s claimed invention, including
comparing uptake in striatal regions and cortical regions.
The only remaining question is whether the “wherein” clauses of the
claim, which state certain determinations are indicative of certain Thal phase
pathologies, distinguish the claimed method. “A ‘whereby’ clause that
merely states the result of the limitations in the claim adds nothing to the
patentability or substance of the claim.” Texas Instruments, Inc. v. United
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States Int’l Trade Comm’n, 988 F.2d 1165, 1172 (Fed. Cir. 1993) (citation
omitted); Minton v. Nat’l Ass’n of Sec. Dealers, Inc., 336 F.3d 1373, 1381
(Fed. Cir. 2003) (“A whereby clause in a method claim is not given weight
when it simply expresses the intended result of a process step positively
recited.”) Here, the “wherein” clauses similarly merely state a possible
observational outcome of the determination step, they do not state a
condition of the process. Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329
(Fed. Cir. 2005) (“[W]hen the ‘whereby’ clause states a condition that is
material to patentability, it cannot be ignored in order to change the
substance of the invention.”).2 Consequently, we conclude these “wherein”
clauses do not further limit the process set forth in steps (i)–(iv).
Appellant separately argues claim 17, asserting that the references fail
to teach the additional steps (v) and (vi) because they fail to teach
performing steps (iii)–(iv) of claim 1. (Appeal Br. 7; Reply Br. 2–3.)
However, for the reasons discussed above, we find that the combined
references suggest steps (iii) and (iv). And in any event, we note that
Vallabhajosula states “Aβ imaging can have a significant role in identifying

2 Moreover, the scope of the wherein clause regarding negative uptake of
the Aβ imaging agent in the striatal region being indicative of Thal 3 is
unclear. According to Alafuzoff, Thal phase 3 is defined as involving Aβ
aggregates in the striatum that are detectable. (Alafuzoff at 310.)
Appellant’s Specification indicates that a 50% of peak intensity compared to
the thalamus and frontal white matter is indicative of a negative striatal scan.
(Spec. 9.) This would suggest that uptake of the Aβ binding of the imaging
agent in the striatal region may be present for Thal Phase 3 Aβ pathology.
Such would be consistent with Alafuzoff’s discussion of the Thal Phase
descriptions established in 2002 whereas a completely negative uptake
would not be.
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patients at risk for AD who would be suitable candidates for anti-Aβ
therapies.” (Vallabhajosula 297.) Thus, we conclude that claim 17 is
suggested by the combination of Alafuzoff and Vallabhajosula.
Claims 4–16 have not been argued separately and therefore fall with
claim 1. 37 C.F.R. § 41.37(c)(1)(iv).

Claims 18 and 19
Claim 18 requires evaluation of the effects of an experimental AD
therapy where the method comprises carrying out the method of claim 1 on
subjects that are receiving experimental AD therapy. Vallabhajosula states
“Aβ imaging might have a significant role in monitoring the efficacy of anti-
Aβ therapies.” (Vallabhajosula 297.)
The Examiner relies on Mazziotta for teaching the use of PET in the
monitoring of experimental therapy. Ans. 5. We conclude that this
reference is not even necessary to establish the claimed invention is prima
facie obvious given the teaching of Vallabhajosula just discussed.
Claim 19 recites a method to determine inclusion of subjects into a
clinical trial where the method involves the steps of claim 1 and admission
to clinical trial is based on positive uptake in the cortical region and negative
uptake in the striatal region. As noted above, Vallabhajosula states “Aβ
imaging can have a significant role in identifying patients at risk for AD who
would be suitable candidates for anti-Aβ therapies.” (Vallabhajosula 297.)
Furthermore, Vallabhajosula states that “[r]ecent Alzheimer’s Disease
Neuroimaging Initiative (ADNI) data also indicate that FDG-PET increased
statistical power over traditional cognitive measures, might aid subject
selection, and could substantially reduce the sample size in a clinical trial.”
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(Id. at 286.) In combination with the reference teachings above, this
statement suggests the claimed method for using the imaging and diagnostic
phase determination for selecting a patient to enroll in a clinical study.
Appellant’s only argument against the Examiner’s rejection of claims
18 and 19 is that Mazziotta does not disclose or suggest performing steps
(iii)–(iv). (Appeal Br. 5–6.) However, as we discussed above, those steps
are rendered obvious by the combination of Alafuzoff and Vallabhajosula.
In affirming a multiple reference rejection under 35 U.S.C. § 103, the Board
may rely on fewer than all of the references relied on by the Examiner in an
obviousness rationale without designating it as a new ground of rejection. In
re Bush, 296 F.2d 491, 496 (CCPA 1961).

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 4–17 103 Alafuzoff,
Vallabhajosula
1, 4–17
1, 4–19 103 Alafuzoff,
Vallabhajosula,
Mazziotta
1, 4–19
Overall
Outcome
1, 4–19

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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). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED