GE HEALTHCARE LIMITED et al.

Patent Trials and Appeals Board

Apr 16, 2021

2021001535 (P.T.A.B. Apr. 16, 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.
14/373,413 07/21/2014 Rajiv Bhalla 037380.00029 5733
170688 7590 04/16/2021
Culhane Meadows PLLC
Jeff B. Vockrodt
130 7th Avenue #308
New York, NY 10011
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
04/16/2021 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):
eOfficeAction@AppColl.com
jvockrodt@cm.law
patentdocket@cm.law
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD

Ex parte RAJIV BHALLA, SAJINDER KAUR LUTHRA,
GILL REID I, and WILLIAM LEVASON

Appeal 2021-001535
Application 14/373,413
Technology Center 1600
Before DONALD E. ADAMS, FRANCISCO C. PRATS, and
TAWEN CHANG, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
STATEMENT OF THE CASE
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1–4, 6, 10–13, 15–22, 24, and 25. Oral

1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R.
§ 1.42(a). Appellant identifies the real party in interest as GE Healthcare
Limited and University of Southampton. Appeal Br. 1.
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argument was presented on April 7, 2021. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.
CLAIMED SUBJECT MATTER
The claims are directed to imaging agents, and methods of making
using those imaging agents. Claim 1 is illustrative and reads as follows:
1. An imaging agent which comprises an 18F-labelled
compound of Formula I:

where:
Y1 and Y2 are independently O or NR1, where R1 is C1-3 alkyl or
-CH2-Ar1, wherein Ar1 is C5-12 aryl or C3-12 heteroaryl;
X1, X2 and X3 are independently 19F or 18F, with the proviso that
at least one of X1, X2 and X3 is 18F and at least one of the
remaining X1, X2, and X3 is 19F;
M is Al3+, GA3+, In3+, Se3+, Y3+, Ho3+, Er3+, Tm3+, Yb3+ or Lu3+;
x, y and z are 1;
R2 is R1 or Q;
Q is -L-[BTM], and may be present or absent; when present it is
either R2 or is attached at one of the carbon atoms of
the -(CH2)(CH2)x-, -(CH2)(CH2)y- or -(CH2)(CH2)z- groups,
where BTM is a biological targeting moiety;
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wherein L is a synthetic linker group of formula -(A)m-
wherein each A is independently -CR32-, -CR3=CR3-, -C=C-,
-CR32CO2-, -CO2CR32-, -NR3CO-, -CONR3-, -CR3=N-O-,
-NR3(C=O)NR3-, -NR3(C=S)NR3-, -SO2NR3-, -NR3SO2,
-CR 32OCR32,-CR32SCR32, -CR32NR3CR32-, a C4-8
cycloheteroalkylene group, a C4-8 cycloalkylene
group, -Ar2-, -NR3-Ar2-, -O-Ar2-, -Ar2-CO)-, an amino
acid, a sugar or a monodisperse polyethyleneglycol (PEG)
building block,
wherein each R3 is independently chosen from H,
C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxyalkyl or C1-4
hydroxyalkyl;
m is an integer of value 1 to 20; and
each Ar2 is independently a C5-12 arylene group, or a C3-12
heteroarylene group.
Appeal Br.; Claims Appendix.
REFERENCE(S)
The prior art relied upon by the Examiner is:
Name Reference Date
Michel Gacek et al.
(“Gacek”)
US 2008/0305042 A1 Dec. 11, 2008
William J. McBride et al.
(“McBride”)
US 2011/0110854 A1 May 12, 2011
Wiley J. Youngs et al.
(“Youngs”)
WO 2006/138357 A1 Dec. 28, 2006
Dinesh Shetty et al., Stable aluminium fluoride chelates with
triazacyclononane derivatives proved by X-ray crystallography and
18F-labeling study, 47 CHEM. COMMUN. 9732–9734 (2011) (“Shetty”).
REJECTION(S)
The following rejections are before us for review:
(1) Claims 1–4, 6, 10–13, 15, 19–22, 24 and 25, under pre-AIA
35 U.S.C. § 103(a) as being unpatentable over McBride, Youngs, and Shetty
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(Ans. 3); and
(2) Claims 1–4, 6, 10–13, 15–22, 24, and 25, under pre-AIA
35 U.S.C. § 103 as being unpatentable over McBride, Youngs, Shetty, and
Gacek (Ans. 3).
DISCUSSION
The Examiner’s Prima Facie Case
The rationale for the appealed obviousness rejections appears in the
Non-Final Office Action entered March 3, 2020 (“Non-Final Act.”).
The Examiner found that McBride discloses an 18F-labelled
compound useful as an imaging agent, IMP-479, that differs from the
compound of Formula I of Appellant’s claim 1 in that the substituents at the
positions corresponding to positions Y1 and Y2 of Appellant’s Formula I are
not methyl groups encompassed by claim 1. See Non-Final Act. 7
(“McBride et al. do not disclose a compound of instant formula (I) or (IA)
wherein Y1=Y2=NR1, and R1=Me.”).
The Examiner cited Youngs as disclosing a macrocyclic metal-
chelating compound similar in structure to McBride’s compound, useful as
an anticancer agent, with methyl groups at the positions corresponding to
positions Y1 and Y2 of Appellant’s Formula I. Non-Final Act. 7. The
Examiner noted Youngs’s disclosure that one of the metals chelated by its
compound was gallium, as recited in Appellant’s claims, and that one
embodiment of Youngs’s compounds induced no toxicity in a test animal.
See id. (citing Youngs 6, 10–11).
The Examiner cited Shetty as disclosing 18F-labelled compounds
useful as an imaging agents, similar to those disclosed by McBride. Non-
Final Act. 8. The Examiner noted Shetty’s disclosure that, when the
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substituent at the secondary amine position of the macrocyclic compound
was capable of forming a five or six membered ring with the aluminum used
in the chelated complex, fluoride binding to the aluminum decreased,
whereas, when the secondary amine substituent was incapable of either
forming a ring, or formed a greater than six-membered ring, fluoride binding
was unaffected. Id. (citing Shetty 9734).
Based on the combined teachings of the cited references, the
Examiner concluded that it would have been obvious to modify McBride’s
compounds
by substituting their acetate pendent arms with Me and
optionally substituting Al3+ with Ga3+ . . . because it would have
been expected to provide functionally equivalent ligands and
complex thereof suitable for in vivo PET imaging and/or
advantageously enable high labeling efficiency since Me cannot
form 5- or 6-membered ring with Al3+.
Non-Final Act. 8.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant in
response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007), although the
Supreme Court emphasized “an expansive and flexible approach” when
evaluating claims for obviousness, id. at 415, the Court nonetheless also
reaffirmed the importance of determining “whether there was an apparent
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reason to combine the known elements in the fashion claimed by the patent
at issue.” Id. at 418.
Consistent with the flexible approach emphasized in KSR, our
reviewing court has explained that, in cases involving claims to new
chemical compounds, “it remains necessary to identify some reason that
would have led a chemist to modify a known compound in a particular
manner to establish prima facie obviousness of a new claimed compound.”
Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357
(Fed. Cir. 2007).
In other words, establishing that a chemical compound would have
been obvious requires “a showing that the prior art would have suggested
making the specific molecular modifications necessary to achieve the
claimed invention.” Takeda, 492 F.3d at 1356 (emphasis added; internal
quotations omitted); see also In re GPAC Inc., 57 F.3d 1573, 1581 (Fed. Cir.
1995) (“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.”)
(internal quotations omitted).
In the present case, having carefully considered all of the arguments
and evidence advanced by the Examiner and Appellant, we agree with
Appellant that the cited references would not have suggested modifying
McBride’s IMP-479 compound by replacing the acetate substituents with the
methyl groups of Youngs’s compounds, to produce a compound
encompassed by Appellant’s Formula I.
McBride discloses compounds useful in PET imaging, in which an 18F
or 19F is attached to the compounds as a conjugate complex with aluminum
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or another metal via a chelating moiety, as recited in Appellant’s Formula I.
McBride, abstract.
Figure 11 of McBride is reproduced below:

Figure 11 of McBride shows the structure of IMP-479, the compound
cited in the Examiner’s rejection as having a structure similar to that recited
in Appellant’s claim 1. As is evident, IMP-479 differs from the compound
recited in Appellant’s claim 1 in that the cyclic triamine portion of the
compound, i.e. the metal chelating portion, has acetate substituents at the
positions corresponding to the Y1 and Y2 moieties of Appellant’s Formula I,
rather than the C1-3 alkyl or alkaryl required by claim 1.
As Appellant points out, McBride explains that, as to suitable
substituents for its chelating compounds, “hard base chelating functions such
as carboxylate or amine groups, are most effective for chelating hard acid
cations, especially Group IIa and Group IIIa metal cations.” McBride ¶ 53.
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Indeed, McBride expressly discloses using hydrophilic chelating compounds
for its in vivo PET imaging applications. See id. ¶ 51 (“In some
embodiments, an 18F-labeled molecule may comprise one or more
hydrophilic chelate moieties, which can bind metal ions and also help to
ensure rapid in vivo clearance.”).
The structure of the compound in Youngs, cited by the Examiner as
providing motivation for substituting methyl groups for McBride’s acetate
groups is shown by the following formula:

“wherein M comprises a metal ion selected from the group consisting of
iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium,
platinum, copper, chromium, gallium, molybdenum, manganese, and
tungsten.” Youngs 6. Youngs explains that its metal-complexed
compounds are useful in cancer chemotherapy. See id. at 1–3.
As the Examiner found, and is evident, Youngs’s compound has
methyl groups encompassed by Appellant’s Formula I at the Y1 and Y2
positions, rather than the acetate groups of McBride’s IMP-479.
As the Examiner found, Youngs discloses an embodiment in which a
compound encompassed by Youngs’s formula, Me3TacnRhCl3, was tested for
toxicity in rats, and found to have “no complex-related toxicity or side
effects.” Youngs 11. Youngs explains, however, that the “LD50 of this
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complex was not determined because of the limited solubility in the 0.7%
saline solution used.” Id. at 10.
Thus, on the current record, McBride teaches generally that
hydrophilic compounds are useful in its PET imaging methods, and
specifically that carboxylate moieties are the most effective substituents for
chelating Group IIa and Group IIIa metal cations to its compounds.
McBride ¶¶ 51, 53. Youngs, in contrast, teachings that its methyl-bearing
chelating compounds have limited aqueous solubility. Youngs 10. Given
the importance of carboxylate groups to McBride’s compounds, as well as
the low aqueous solubility of Youngs’s methyl-bearing compounds, we are
not persuaded that the cited references would have suggested replacing the
acetate substituents of McBride’s IMP-479 with the methyl groups of
Youngs’s compounds, to produce a compound encompassed by Appellant’s
Formula I.
We are not persuaded that Shetty remedies the lack of motivation
provided by the cited references. Shetty describes a study of various
18F-bearing cyclic triamine compounds useful in PET imaging. Shetty 9732.
Figure 1 of Shetty is reproduced below:

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Figure 1 of Shetty shows derivatives of NOTA (1,4,7-
triazacyclononane-1,4,7-triacetic acid) and NODA (l ,4,7-triazacyclononane-
1,4-diiacetic acid) used in Shetty’s study.
We acknowledge, as the Examiner found, that Shetty discloses that
when the secondary amine of NODA is substituted with a moiety capable of
forming a five or six membered ring that complexes with aluminum, fluoride
binding to the aluminum decreased, whereas, when the secondary amine
substituent was incapable of either forming a ring, or formed a greater than
six-membered ring, fluoride binding was unaffected. Shetty 9734. It might
therefore be true, as the Examiner posits, that a methyl group would be a
useful substituent of the secondary amine of the Shetty’s NODA compound,
because a methyl group cannot form a six membered ring.
As is evident, however, all of Shetty’s PET imaging compounds have
at least two acetate moieties on the cyclic triamine structure, regardless of
the substituent at the secondary amine. See Shetty 9732 (Figure 1). In
contrast, Formula I of Appellant’s claim 1 excludes acetate moieties from
those positions. See Appeal Br., Claims Appendix (Y1 and Y2 are either C1-3
alkyl or alkaryl). Thus, even if Shetty was viewed as suggesting placement
of a methyl group at the secondary amine of NODA, we are not persuaded
that Shetty would have suggested replacing all acetate groups of NODA with
methyl groups, as required to arrive at a compound encompassed by
Appellant’s claim 1. Moreover, as discussed above, we are not persuaded
that the combined teachings of McBride and Youngs would have suggested
modifying McBride’s IMP-479 compound to have only methyl groups, as
posited by the Examiner.
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In sum, for the reasons discussed, we are not persuaded that McBride,
Youngs, and Shetty would have suggested preparing a compound
encompassed by Formula I of Appellant’s claim 1. We, therefore, reverse
the Examiner’s obviousness rejection of claim 1, as well as the rejection of
claims 2–4, 6, 10–13, 15, 19, and 20, which depend directly or ultimately
from claim 1, over McBride, Youngs, and Shetty.
Appellant’s independent claim 21, like claim 1 discussed above,
requires moieties Y1 and Y2 to be either C1-3 alkyl or alkaryl. See Appeal
Br., Claims Appendix. Accordingly, for essentially the same reasons as
applied to claim 1, we also reverse the Examiner’s obviousness rejection of
claim 21, and its dependent claims 22, 24, and 25 over McBride, Youngs,
and Shetty.
Lastly, in rejecting claims 1–4, 6, 10–13, 15–22, 24, and 25 over
McBride, Youngs, Shetty, and Gacek, the Examiner relied on the teachings
in McBride, Youngs, and Shetty discussed above, and cited Gacek only as
evidence of the obviousness of preparing the claimed compounds by using
an automated synthesizer apparatus comprising a cassette. See Non-Final
Act. 9. Because the teachings in Gacek identified by the Examiner do not
remedy the deficiency in the combination of McBride, Youngs, and Shetty
discussed above, we also reverse the Examiner’s rejection of claims 1–4, 6,
10–13, 15–22, 24, and 25 over McBride, Youngs, Shetty, and Gacek,
CONCLUSION
For the reasons discussed, we reverse both of the Examiner’s
rejections.
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DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–4, 6, 10–
13, 15, 19–
22, 24, 25
103(a) McBride, Youngs,
Shetty
1–4, 6, 10–
13, 15, 19–
22, 24, 25
1–4, 6, 10–
13, 15–22,
24, 25
103(a) McBride, Youngs,
Shetty, Gacek
1–4, 6, 10–
13, 15–22,
24, 25
Overall
Outcome
1–4, 6, 10–
13, 15–22,
24, 25

REVERSED