Ex Parte AMETAMEY et al

Patent Trials and Appeals Board

Mar 26, 2019

14797640 - (D) (P.T.A.B. Mar. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/797,640 07/13/2015 Simon Mensah AMETAMEY
23599 7590 03/28/2019
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BL VD.
SUITE 1400
ARLINGTON, VA 22201
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
EPROV-0029-DOl 9057
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
03/28/2019 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):
docketing@mwzb.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SIMON MENSAH AMETAMEY, RUDOLF MOSER,
TOBIAS LUDWIG ROSS, PHOEBE LAM, and VIOLA GROEHN
Appeal2018-004544
Application 14/797 ,640
Technology Center 1600
Before JEFFREY N. FREDMAN, JOHN G. NEW, and JAMIE T. WISZ,
Administrative Patent Judges.
WISZ, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellants 1 seek review of claims 28-
30, 32, 34--36, 38, 39, and 45--49. The Examiner rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b ). For the reasons set
forth below, we reverse.
STATEMENT OF THE CASE
Background
The Specification describes a "method of synthesis of 18F-labeled
pteroate or folate radiopharmaceuticals, wherein fluorine-18 is attached to a
1 Appellants identify the Real Party in Interest as Merck & Cie. App. Br. 1.
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Application 14/797 ,640
pteroate ( or folate) or derivative thereof, through direct radio labeling with
18[F]fluoride." Spec. 1.
The Claims
Claims 28-30, 32, 34--36, 38, 39, and 45--49 are on appeal. Claim 28,
the only independent claim, is illustrative:
28. A method of direct radio labeling of the glutamate moiety
of a folate compound with 18F comprising:
reacting a compound of formulae VII or VIIa with 18F,
vu
VUa
wherein
X1 to Xs are N,
X6, X7 are independently of each other O or NH,
R1, R2 are independently of each other H, Hal, -OR', -NHR',
Cl-C12 alkyl, Cl---C12 alkoxy, Cl---C12 alkanoyl,
C2---C12 alkenyl, C2---C12 alkynyl, (Cl---C12
alkoxy )carbonyl, or ( C 1---C 12 alkyl amino )carbonyl,
R' is Hor Cl---C6 alkyl,
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R3, Ri are independently of each other H, formyl,
iminomethyl, nitroso, Cl-C12 alkyl, Cl-C12 alkoxy,
Cl-C12 alkanoyl or halosubstituted Cl-C12 alkanoyl,
Rs is H, CN, Hal, N02, Cl---C12 alkyl, Cl---C12 alkoxy,
Cl---C12 alkanoyl, C2---C12 alkenyl, C2---C12 alkynyl,
( C 1---C 12 alkoxy )carbonyl, or ( C 1---C 12
alkylamino )carbonyl,
R6, R7 are independently of each other H or straight chain or
branched C 1---C 12 alkyl, which is unsubstituted or
substituted by at least one CN, Hal, or N02,
S2 is straight chain or branched C 1---C6 alkyl, which is
unsubstituted or substituted by at least one CN, Hal,
orN02,
m is 1,
p is 0, 1 or 2,
q has a value of 1 to 7,
Z is a leaving group, and
wherein 18F is activated by phase transfer catalyst in
combination with potassium carbonate or oxalate,
to obtain a 18F-labeled compound of formulae VI or VIa,
VI
Vfa
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Application 14/797 ,640
The Rejections
The Examiner rejected claims 28-30, 32, 34--36, 38, 39, and 45--47
under 35 U.S.C. § 103(a) as being obvious over Bettio2, in view of
Kiesewetter. 3
The Examiner rejected claims 28-30, 32, 34--36, 38, 39, and 45--48
under 35 U.S.C. § 103(a) as being obvious over Bettio, in view of
Kiesewetter, in further view ofLow. 4
The Examiner rejected claim 49 under 35 U.S.C. § 103(a) as being
obvious over Bettio, in view of Kiesewetter and Wedeking. 5
The issue is: Does a preponderance of the evidence of
record support the Examiner's conclusion that the prior art
renders the claims obvious?
ISSUES AND ANALYSIS
We reverse the Examiner's obviousness rejections. We address the
arguments below.
Obviousness
The Examiner finds that Bettio teaches the synthesis and preclinical
evaluation of a folic acid derivative labeled with 18F for PET imaging of
2 Andrea Bettio et al., Synthesis and Preclinical Evaluation of a Folic Acid
Derivative Labeled with 18F for PET Imaging of Folate Receptor-Positive
Tumors, 47 J. NUCL. MED. 1153-1160 (2006) ("Bettio").
3 Dale 0. Kiesewetter et al., Syntheses and D2 Receptor Affinities of
Derivatives of Spiperone Containing Aliphatic Halogens, 37(12) APPL.
RADIAT. ISOT. 1181-1188 (1986) ("Kiesewetter").
4 Low et al., U.S. Patent No. 8,586,595 B2, issued Nov. 19, 2013 ("Low").
5 Wedeking et al., U.S. Patent No. 6,093,382, issued July 25, 2000
("Wedeking").
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Application 14/797 ,640
folate receptor-positive tumors. Ans. 3. The Examiner also finds that Bettio
teaches that "[ t ]he structure of folic acid does not lend itself to direct
radiolabeling with 18F; therefore we sought to functionalize folic acid using a
4-fluorobenzylamine prosthetic group (see pg. 1153, col. 2)." Id. at 3.
According to the Examiner, Bettio teaches a "method for the radiosynthesis
of 4-[ 18F]fluorobenzylamine functionalized folic acid derivatives as
represented by
(see pg. 1156, Fig. 2)." Id. at 3--4. The Examiner further finds that Bettio
teaches the use of kryptofix, K2C03 together with 18F. Id. at 4 (citing Bettio
1154).
The Examiner concedes that Bettio does not teach a method of direct
radio labeling comprising reacting a compound of formula VII or VIIa,
wherein Xis a straight chain or branched C1---C6 alkyl, and Z is a leaving
group, such as mesylate, tosylate, pentafluorobenzoate, or triflate. Ans. 4.
However, the Examiner finds that this deficiency is taught by Kiesewetter,
which discloses "direct radiofluorination of a spiperone derivative as
represented by
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:;;
r;::::~{1,~.,·,v.rs~:::::}:1\r·~',,M,
.,...-::-,.::.>~
(see pg. 1187, Fig. 5)." Id. The Examiner also finds that Kiesewetter
teaches that "the optimization of radio labeling methodology for the
incorporation of [18F]fluoride into 3-N-methyl spiperone during the
final step should result in a successful new 18F imaging agent for dopamine
receptors in vivo (see pg. 1188, col. 1)." Id. at 5.
Id.
The Examiner concludes that:
It would have been obvious to a person of ordinary skill
in the art at the time of the invention to modify the indirect
radiolabeling method of Bettio et al. (i.e., method for the
indirect 18F-labeling of [18F]fluorobenzylamine functionalized
folic acid) by predictably preparing amidoethyl mesylate
precursor and then reacting that precursor with 18F and krytofix
in the presence of potassium carbonate as taught by Kiesewetter
et al. because it would advantageously enable incorporating of
18F in the last step of the synthesis where the radiosynthesis
advantageously results in a single radiolabeled regioisomer.
Appellants argue that Bettio does not disclose or suggest a process for
direct radiolabeling of a folic acid analogue/derivative. App. Br. 5. Rather,
Bettio uses a synthesis process that provides for direct radiolabeling of a
prosthetic compound with 18F and this prosthetic compound is then coupled
to folic acid. Id. Appellants also argue that Bettio teaches away from the
claimed process because Bettio discloses that the structure of folic acid does
not lend itself to direct radio labeling with 18F. See id. Furthermore,
Appellants argue that Bettio 's direct radio labeling of a relatively small
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Application 14/797 ,640
prosthetic compound with 18F had a very low yield, i.e., 8-13%, which
would discourage the direct radiolabeling of a much larger and more
complex compound such as formulas VII or VIIa as claimed. See id.
Appellants also argue that Kiesewetter does not mention folic acid or
folic acid analogues and that the Examiner's rejection presents no rationale
as to how the reaction procedure shown in Kiesewetter would result in a
compound structure similar to that of Appellants' formula VII or VIIa. Id. at
6-7. Appellants further argue that, like Bettio, Kiesewetter shows
radio labeling of the smaller and less complex spiperone compound and
provides no suggestion for direct radio labeling of a large and complex
structure like folic acid or a folic acid analogue. See id. at 7.
Principles of Law
A prima facie case for obviousness requires "a reason that would have
prompted a person of ordinary skill in the relevant field to combine the
elements in the way the claimed new invention does." KSR Int 'l Co. v.
Teleflex Inc., 550 U.S. 398, 418 (2007).
Analysis
Under the lead compound analysis rubric, we must first "determine[]
whether a chemist of ordinary skill would have selected the asserted prior art
compounds as lead compounds, or starting points, for further development
efforts." Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir.
2012). "The second inquiry in the analysis is whether the prior art would
have supplied one of ordinary skill in the art with a reason or motivation to
modify a lead compound to make the claimed compound with a reasonable
expectation of success." Id. at 1292.
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In this case, even if Bettio provides folic acid derivatives as a starting
point, Bettio would not have supplied the ordinary artisan with reason to
modify these lead compounds with a reasonable expectation of success using
the 18F labeling process described in Kiesewetter because Bettio teaches that
the structure of folic acid does not lend itself to direct radio labeling with 18F.
Bettio 1153. Instead, Bettio directly radio labels a prosthetic compound as
shown in steps i-iii of Figure 2. See id. at 1156. Figure 2 ofBettio is
reproduced below:
4
:,,,,
"FIGURE 2. Radiosynthesis of 18F-labeled a- and y-FBA-folate." Bettio
1156.
We also agree with Appellants that Bettio' s disclosure rises to the
level of a teaching away. "A reference may be said to teach away when a
person of ordinary skill, upon reading the reference, would be discouraged
from following the path set out in the reference, or would be led in a
direction divergent from the path that was taken by the applicant." In re
Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). Bettio discloses that the structure
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Application 14/797 ,640
of folic acid does not lend itself to direct radiolabeling with 18F. Bettio
1153. Furthermore, Bettio 's direct radio labeling of a relative small
prosthetic compound with 18F had a very low yield. Id. at 1156. Therefore,
Bettio discourages the direct radio labeling of folic acid or a folic acid
analogue. We therefore agree with Appellants that Bettio "clearly points
one of ordinary skill in the art in a direction away from a direct radiolabeling
process such as claimed by appellants." App. Br. 5.
The Examiner also rejected claims 28-30, 32, 34--36, 38, 39, and 45-
48 as being obvious over Bettio, in view of Kiesewetter, in further view of
Low and rejected claim 49 as being obvious over Bettio, in view of
Kiesewetter and Wedeking et al. Since Bettio and Kiesewetter are the
primary references for all of these rejections, the same analysis from above
applies.
Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner's conclusion that the prior art renders the claims obvious.
SUMMARY
We reverse the Examiner's obviousness rejections of claims 28-30,
32, 34--36, 38, 39, and 45--49 under 35 U.S.C. § 103(a).
REVERSED
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