GE Healthcare Limited

Patent Trials and Appeals Board

Dec 11, 2020

2020002996 (P.T.A.B. Dec. 11, 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.
15/199,108 06/30/2016 Lorenzo Williams 037380.00049-243558-
US-15
8151
170688 7590 12/11/2020
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
12/11/2020 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):
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 LORENZO WILLIAMS,
GUNNAR KEILEN, and JARLE ANDRE HAUGAN
____________

Appeal 2020-002996
Application 15/199,108
Technology Center 1600
____________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
FRANCISCO C. PRATS, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims 22–34. We have jurisdiction under
35 U.S.C. § 6(b).
We AFFIRM.

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” (Appellant’s November 11, 2019 Appeal Brief (Appeal
Br.) 2).
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STATEMENT OF THE CASE
Appellant’s disclosure “relates to an improved synthesis of N-
monofluoroalkyl tropanes using fluoroalkyl iodides” (Spec.2 1:12–13).
Claims 22 and 25 are reproduced below:
22. A method for preparing of a composition comprising a
non-radioactive N-monofluoroalkyl tropane compound of
Formula (IIIA):

having less than 1 % of a transesterified impurity compound,
analyzed by HPLC, of Formula (V):

2 Appellant’s September 12, 2016 Specification.
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wherein m is 2, 3, or 4, the method comprising alkylation of an
amine of Formula (III):

with an alkylating agent of formula F-(CH2)mI, in the presence
of a base and a solvent.
(Appeal Br. 19–20.)
25. The method of claim 22, wherein the heating is done at
reflux for about 2 hours.
(Id. at 20.)

Claims 22–34 stand rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Neumeyer, Chesis I, and Chesis II.3

3 Examiner’s July 9, 2019 Final Office Action (“Final Act.”) rejects
Appellant’s claims 22–34 under 35 U.S.C. § 103(a) as being unpatentable
over Neumeyer et al., US 6,537,522 B1, issued Mar. 25, 2003 (“Neumeyer”)
in view of Chesis et al., Comparison of Bromo- and Iodoalkyl Triflates for
18F-Radiolabeling of Amines, 41 Appl. Radiat. Isot. 259–265 (1990)
(“Chesis I”) and Chesis et al., N-(3-[18F]Fluoropropyl)-N-
nordiprenorphine: Synthesis and Characterization of a New Agent for
Imaging Opioid Receptors with Positron Emission Tomography, 33 J. Med.
Chem. 1482–1490 (1990) (“Chesis II”) (see Final Act. 5).
Examiner’s January 10, 2020 Answer (“Ans.”), however, incorrectly
recites a rejection of canceled claims under 35 U.S.C. § 103(a) as being
unpatentable over Neumeyer, Chesis I, and Neumeyer et al., N-ω-
Fluoroalkyl Analogs of (1R)-2β-Carbomethoxy-3β-(4-iodophenyl)-tropane
(β-CIT): Radiotracers for Positron Emission Tomography and Single
Photon Emission Computed Tomography Imaging of Dopamine
Transporters, 37 J. Med. Chem. 1558–1561 (1994) (see Ans. 4). The prior
art cited in the rejection reproduced in the Answer was cited in prior,
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ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Appellant refers to the amine of Formula (III) as “nor-beta-CIT” (see
Spec. 2).
FF 2. Appellant discloses that the alkylation of N-nor-beta-CIT with 1-
bromo-3-fluoropropanol (BFP) or 1-fluoro-3-iodopropane (FIP) yields FP-
CIT (Spec. 2:1–5; see also id. at 4:20; id. at 5:19–21).
FF 3. Neumeyer disclose a method of preparing “2-β-Carbomethoxy-3-β-
(4-iodophenyl)-8-(3-fluoropropyl)-nortropane,” wherein:
A solution of 2-β-carbomethoxy-3-β-(4-iodophenyl) nortropane
(371 mg, 1.0 mmol), 1-bromo-3-fluoropropane (155 mg, 1.1
mmol), and triethylamine (0.5 mL) in dry toluene (20 mL) was

subsequently withdrawn, rejections appearing in the April, 7, 2017 and June
26, 2018 Final Office Actions (see April 7, 2017 Final Office Action 5; June
26, 2018 Final Office Action 4).
Examiner subsequently corrected the recitation of claims rejected in
Examiner’s Answer, but did not correct the prior art relied upon (see
Examiner’s January 21, 2020 Communication).
Examiner’s Answer, however, correctly responded to Appellant’s
contentions, as set forth in the Appeal Brief, with respect to the correct
ground of rejection as set forth in Examiner’s July 9, 2019 from which this
Appeal was taken (see Appellant’s September 9, 2019 Notice of Appeal
(“Applicant hereby appeals to the Patent Trial and Appeal Board from the
last decision of the examiner” (emphasis omitted))). As Appellant
recognizes, Examiner’s July 9, 2019 was Examiner’s last decision prior to
Appellant’s Appeal on this record (see Appellant’s March 10, 2020 Reply
Brief (“Reply Br.”) 2). Therefore, we find Examiner’s reproduction of the
wrong rejection in the Answer to represent a harmless typographical error.
Therefore, Appellant’s contentions relating to a rejection not properly before
this Panel, will not be considered (see Reply Br. 2–6).
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stirred under an atmosphere of dry nitrogen and heated to
reflux. After four hours, the reaction mixture was cooled to
room temperature and filtered. The filtrate was concentrated
under reduced pressure, and the residue chromatographed on a
silica column (eluant: diethyl ether). Concentration of product-
containing fractions gave 2-β-carbomethoxy-3-β-(4-iodopheny
1)-8-(3-fluoropropyl) nortropane as a white solid, m.p. 78.5-
79.5° C. C18H23NO2FI, Calculated: C, 50.13; H,5.34; N, 3.25;
Found: C, 50.27; H, 5.26; N,3.15.
(Neumeyer 10:26–38; see also Final Act. 5.)
FF 4. Neumeyer discloses the use of “flash chroma-tography” to purify a
chemical residue after synthesis (see Neumeyer 10:17–18; see also Final
Act. 5).
FF 5. Examiner finds that Neumeyer fails to disclose a method wherein:
[T]he alkylating agent is of formula F-(CH2)m-I . . .[,] done at
reflux for about 2 h . . .[,] the triethyl amine is at 1.1 mol
equivalents . . .[, the composition produced] is at least 90% of
the compound of formula (IIIA) . . .[, and] flash
chromatography [is used to purify] . . . the N-monofluoroalkyl
tropane compound of formula (IIIA).
(Final Act. 5.)
FF 6. Chesis I discloses that “[b]oth bromo and iodinated compounds are
effective for alkylating amines when time constraints are not paramount.
We have found, however, that radiochemical yields are significantly
improved by using 1-[18F]fluoro-3-iodopropane compared with 1-bromo-3-
[18F]fluoropropane. This ~75% increase is apparent over the entire range of
amine concentrations studied” (Chesis I 264; see Final Act. 5).
FF 7. Examiner finds that Chesis I discloses the dependence of N-
alkylation reaction on amine concentration, time, and temperature (Final
Act. 5 (citing Chesis I, Figs. 4–5); see also Ans. 9 (Examiner finds that
Chesis I discloses the use of HPLC to “monitor alkylation reactions using
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FIP and BFP,” wherein, for example, an “alkylation reaction at 130ºC using
FIP reached a peak yield of 30% at 30 min and then drops to about 25%
at . . . 60 min”); see Chesis I 264 (“The highest possible amine concentration
which doesn’t interfere with either the final HPLC purification or other
considerations is desirable”)).
FF 8. Examiner finds that Chesis II discloses the reflux of N-
nordiprenorphine 1-fluoro-3-iodopropane and NaHCO3 in MeCN synthesize
3-hydroxy-4,5α-epoxy-6-methoxy-7α-(1-hydroxy-1-methylethyl)-6,14-
endo-ethano-17-(3-fluoropropyl)morphinan, wherein flash chromatography
was used to separate the product from free amine (see Final Act. 6 (citing
Chesis II 1487)).
ANALYSIS
Examiner finds that Neumeyer’s method “comprises alkylation of an
amine of instant formula (III) in the presence of a base, trimethylamine, and
solvent, toluene, and results in a compound of instant formula (IIIA) having
less than 1% of a trans-esterified impurity compound, analyzed by HPLC, of
Formula (V)” (Ans. 8–9). In this regard, Examiner explains that
Neumeyer’s “method of preparing 2-β-carbomethoxy-3-β-(4-iodophenyl)-8-
(3-fluoropropyl)-nortropane . . . meets all of the limitations of [Appellant’s]
claim 1 except . . . [the requirement for] an alkylating agent of formula [F-
(CH2)m-I], such as 1-fluoro-3-iodopropane (FIP), instead of the 1-bromo-3-
fluoropropane (BFP) used by Neumeyer” (Ans. 8; see FF 3–5).
Examiner finds, however, that “Chesis I directly compares BFP and
FIP as alkylating agents for the alkylation of a secondary amine,” wherein
“FIP is preferred over BFP for the alkylation of amines because yields can
advantageously be significantly improved when using FIP” (Ans. 9; see FF
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6–7). Thus, based on the combination of Neumeyer, Chesis I, and Chesis II,
Examiner concludes that, at the time Appellant’s invention was made, it
would have been prima facie obvious to modify Neumeyer’s
method of synthesizing a composition of 2-β-carbomethoxy-3-
β-(4-iodophenyl)-8-(3-fluoropropyl)-nortropane having less
than 1% of transesterified impurity compound comprising
reacting a compound of instant formula III with F(CH2)3-Br[]
by substituting the Br with I as taught by Chesis [I] . . . because
it would have been expected to provide a functionally
equivalent alkylating agent
and to have further purified the synthesis product using flash
chromatography as disclosed by Neumeyer and Chesis II (Final Act. 6). In
this regard, Examiner finds that because “[r]eaction times and mol
equivalents of base are result effective variables . . . a person of ordinary
skill in the art would have been motivated to optimize [these variables] at the
time of [Appellant’s] invention” (id. (citing In re Aller, 220 F.2d 454, 456
(CCPA 1955)); see also FF 6). Therefore, Examiner concludes that “[a]
person of ordinary skill in the art would have arrived at a reaction time of 2
[hour] through routine experimentation because Chesis [I] . . . teach
optimization of reaction time when using 1-fluoro-3-iodopropane as an
alkylating agent” (Final Act. 6; see also Ans. 9 (Examiner finds that based
on the combination of Neumeyer, Chesis, I and Chesis II “a person of
ordinary skill in the art would have been . . . motivated to monitor chemical
reaction of FIP with nor-beta CIT (formula III) over time in order [to]
advantageously arrive at the optimal yield of FP-CIT”); see FF 3–8).

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Claim 22:
Appellant contends that “[a] problem that arises with the fluoro
alkylation of nor-beta-CIT is the trans-esterification by nucleophilic
substitution at the primary amine and carbomethoxy to produce the
byproduct of Formula (V),” which “cannot be separated from the FP-CIT
final product using existing chromatographic processes” (Appeal Br. 8).
Haugan explains that Neumeyer discloses one such alkylation method,
wherein a compound of Appellant’s formula (IIIA) is prepared “by
alkylation using . . . [BFP]” (Haugan III Decl.4 ¶ 8). “The transesterified by-
product [of Appellant’s Formula (V)] has not been detected in the process
[of alkylating nor-beta-CIT] that utilizes BFP with KI” (Haugan I Decl.5 ¶ 2;
see also Appeal Br. 8 (“The use of BFP avoids formation of this byproduct
in detectable amounts.”)). BFP, however, “is an ozone depleting agent, and
is not commercially available. There is therefore a need for alternative
viable syntheses of drugs and imaging agents which comprise N-fluoroalkyl
substituents” (Spec. 4:20–22).
Chesis I discloses another known alkylation method (see FF 6–7; see
also Haugan III Decl. ¶ 13 (Chesis I “is supportive of the fact that fluoro-
iodoalkanes were known at the time of [Appellant’s] invention”); see also
Spec. 5:19–21 (“The alternative alkylating agent, 1-fluoro-3-iodopropane
(FIP), is not ozone depleting, is commercially available, and can
replace . . . [BFP] in the synthesis of FP-CIT.”)). Haugan states, however,
that although “a person having ordinary skill in the art would have expected
the alkylation reaction used to create compound IIIA would work with an

4 Declaration of Jarle André Haugan, Ph.D., signed Apr. 29, 2019.
5 Declaration of Jarle André Haugan, Ph.D., signed Feb. 24, 2017.
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iodofluroalkane, he would have expected the reaction to result in a
composition including significant undesirable transesterified impurities due
to the reactivity of iodine compared with bromine” (Haugan III Decl. ¶ 19;
see Appeal Br. 8 (citing Haugan III Decl. ¶ 19)). Thus, at the time of
Appellant’s claimed invention, those of ordinary skill in this art were aware
of the trans-esterification problem associated with the use of FIP as an
alkylating agent in a method of producing Appellant’s compound IIIA (see
Haugan II Decl.6 ¶ 14; see also Haugan III Decl. ¶ 19 (“While a person
having ordinary skill in the art would have expected the alkylation reaction
used to create compound IIIA would work with an iodofluroalkane, he
would have expected the reaction to result in a composition including
significant undesirable transesterified impurities due to the reactivity of
iodine”)).
Appellant contends that because Neumeyer “does not discuss the
problem of trans-esterification” and Chesis I and Chesis II disclose the
alkylation of “a compound that is incapable of transesterification” a person
of ordinary skill in this art would not have found it prima facie obvious to
optimize, as Appellant did, the process suggested by the combination of
Neumeyer, Chesis I, and Chesis II (see Appeal Br. 9; see id. 10 (citing
Haugan III Decl. ¶¶ 13, 14, 16, and 18 (“Chesis I did not deal with
modifying an amine that was susceptible to trans[e]sterified byproducts,”
“Chesis II does not address the problem of overalkylation and creation of
undesirable byproducts,” and “No advantage was demonstrate[ed] for using

6 Declaration of Jarle André Haugan, Ph.D., signed Nov. 22, 2018.
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the iodoalkyl triflate rather than the bromoalkyl triflate with this substrate”
(internal quotations omitted)))). We are not persuaded.
As discussed above, the combination of Neumeyer, Chesis I, and
Chesis II suggests the alkylation of nor-beta-CIT with FIP to produce FP-
CIT, the compound of Appellant’s Formula (IIIA) (see FF 1–8). Stated
differently, the combination of Neumeyer, Chesis I, and Chesis II suggests
the general conditions of Appellant’s claimed method. In addition, the prior
art discloses that “yields are significantly improved using . . . [FIP]
compared to . . . [BFP]” and that the N-alkylation reaction is dependent on
“amine concentration, time, and temperature” (FF 3–8). Further still,
Examiner explains that Chesis I discloses the use of HPLC to monitor the
alkylation reaction and, thus, “[b]ased on the teachings of Chesis I a person
of ordinary skill in the art would have been further motivated to monitor
chemical reaction of FIP with nor-beta-CIT (formula III) over time in order
advantageously arrive at the optimal yield of FP-CIT.” (Ans. 9; FF 7 (Chesis
I discloses that “[t]he highest possible amine concentration which doesn’t
interfere with either the final HPLC purification or other considerations is
desirable”)).
For the foregoing reasons, we find no error in Examiner’s conclusion
that, at the time of Appellant’s claimed invention, it would have been prima
obvious to optimize, as Appellant did, prior art reaction conditions, such as
those suggested by the combination of Neumeyer, Chesis I, and Chesis II to
prepare the compound of Appellant’s Formula (IIIA), having less than 1% of
a trans-esterified impurity compound, analyzed by HPLC, of Formula (V)
(see Final Act. 6; see also Ans. 9; cf. Haugan I ¶ 2 (Acknowledging that
Appellant optimized prior art reaction conditions)). See In re Aller, 220 F.2d
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454, 456 (CCPA 1955) (“[W]here the general conditions of a claim are
disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.”).
As discussed above, a person of ordinary skill in this art would have
arrived at Appellant’s claimed invention by routine optimization of the
method suggested by the combination of Neumeyer, Chesis I, and Chesis II.
Therefore, we are not persuaded by Appellant’s contention that a person of
ordinary skill in this art would not have substituted one alkylating agent,
FIP, for another, BFP, for fear of “creating trans-esterified byproducts that
are difficult to separate from the end product” (Appeal Br. 9 (citing Haugan
I Decl. ¶ 3 and Haugan III Decl. ¶ 13); see Appeal Br. 9–10 (“Given the
inability to separate the trans-esterified byproduct using conventional
chromatography processes, a person having ordinary skill in the art would
have been dissuaded from using iodo-fluoroalkylating agents.”)). For the
same reasons, we are not persuaded by Appellant’s contention that
“conventional wisdom strongly suggest[ed] there would have been no reason
to make the claimed modification” (Appeal Br. 11; see id. at 10–11 (citing
Haugan III Decl. ¶¶ 9–11)).
In KSR [Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007)],
the Supreme Court stated that an invention may be found
obvious if it would have been obvious to a person having
ordinary skill to try a course of conduct:
When there is a design need or market pressure to
solve a problem and there are a finite number of
identified, predictable solutions, a person of
ordinary skill has good reason to pursue the known
options within his or her technical grasp. If this
leads to the anticipated success, it is likely the
product not of innovation but of ordinary skill and
common sense. In that instance the fact that a
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combination was obvious to try might show that it
was obvious under § 103.
550 U.S. at 421. . . . This approach is consistent with our
methodology in In re O’Farrell, 853 F.2d 894 (Fed. Cir. 1988).
See Proctor & Gamble Co. v. Teva Pharms. USA, Inc., 566
F.3d 989, 996–97 (Fed. Cir. 2009); In re Kubin, 561 F.3d 1351,
1359, (Fed. Cir. 2009). O'Farrell observed that most
inventions that are obvious were also obvious to try, but found
two classes where that rule of thumb did not obtain.
Bayer Schering Pharma AG v. Barr Laboratories, Inc., 575 F.3d 1341, 1347
(Fed. Cir. 2009).
The evidence on this record establishes that a method of alkylating an
amine of Appellant’s Formula (III) to produce a non-radioactive N-
monofluoroalkyl tropane compound of Formula (IIIA) was known in this art
(see Ans. 10; see also FF 3–4). The evidence on this record also establishes
a preference for alkylating amines with the non-ozone depleting FIP
alkylating agent over the ozone depleting BFP alkylating agent (see Ans. 10;
see also FF 6–7). Further, as Examiner explains, at the time of Appellant’s
claimed invention, it was “conventional practice to monitor chemical
reactions by chromatography” (Ans. 10; see FF 7).
Thus, taken together, the evidence on this record, supports a
conclusion that a person of ordinary skill in this art would have found it
prima facie obvious to replace the ozone depleting BFP alkylating agent
used in Neumeyer’s method with the non-ozone depleting FIP alkylating
agent, which the evidence of record discloses as a preferred compound for
alkylating amines (see FF 3–7). Stated differently, the evidence of record
establishes a design need or market pressure to solve the problem of
avoiding the use of an ozone depeleting alkylating agent and provides a
finite number of identified, predictable solutions, specifically the use of the
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preferred compound, FIP, for alkylating amines. See Bayer, 575 F.3d at
1347.
As discussed above, given that the general conditions of Appellant’s
claimed method were “disclosed in the prior art, it is not inventive to
discover the optimum or workable ranges by routine experimentation.” See
In re Aller, 220 F.2d at 456. In this regard, the evidence of record
establishes that it was “conventional practice to monitor chemical reactions
by chromatography,” i.e., HPLC (Ans. 10; see FF 7). Thus, it would have
been prima facie obvious, at the time of Appellant’s claimed invention, to
monitor the alkylation reaction suggested by the combination of Neumeyer,
Chesis I, and Chesis II to optimize the preparation of a composition
comprising a non-radioactive N-monofluoroalkyl tropane compound of
Appellant’s Formula (IIIA) with a low level of impurities or contaminants,
e.g., less than 1% of a transesterified impurity compound, analyzed by
HPLC, of Formula (V). As our reviewing court explained:
[A] person of ordinary skill has good reason to pursue the
known options within his or her technical grasp. If this leads to
the anticipated success, it is likely the product not of innovation
but of ordinary skill and common sense. In that instance the
fact that a combination was obvious to try might show that it
was obvious under § 103.
Bayer, 575 F.3d at 1347.
Therefore, we are not persuaded by Appellant’s contention that there
would have been no reasonable expectation that the alkylation of nor-beta-
CIT with an iodo-fluoro alkylating agent would yield a product with less
than 1% trans-esterified impurity (see Appeal Br. 11–13 (citing Haugan II
Decl. ¶ 21; Haugan III Decl. ¶¶ 19–20; and Spec. 18:1–4)).

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Unexpected Results:
For the foregoing reasons, we are not persuaded by Appellant’s
contention that the claimed process produces unexpected results, specifically
“the low level of trans-esterified impurity obtained when using FIP to
fluoro-alkylate the primary amine of nor-beta-CIT” (Appeal Br. 13; see id. at
13–14–15 (citing Haugan I Decl. ¶ 5; Haugan III Decl. ¶¶ 19–22; Spec.
18:1–4). As Appellant explains, the asserted unexpected result was obtained
by doing no more than what would have been obvious to a person of
ordinary skill in this art, specifically optimizing or “adjusting the process to
‘stop the reaction when the trans-esterified impurity starts forming (after
approximately 2 hours)’ . . . [to obtain FP-CIT having] good yield and a low
amount of trans-esterified byproduct,” as opposed to allowing “the reaction
to continue for more than 2 hours[, which] results in an increase in trans-
esterified byproduct” (Appeal Br. 14 (citing Haugan I Decl. ¶ 5; Spec. 18:1–
4); see also Appeal Br. 14 (“[T]ransesterification actually occurs when the
reflux time is not controlled”)). See In re Freeman, 474 F.2d 1318, 1324
(CCPA 1973) (“In order for a showing of ‘unexpected results’ to be
probative evidence of non-obviousness, it falls upon the applicant to at least
establish . . . that the difference actually obtained would not have been
expected by one skilled in the art at the time of invention”).
In addition, we agree with Examiner’s finding that because
Appellant’s claim 22 is not limited to a particular reaction time, or particular
base, or a particular solvent or a particular mol equivalent,” Appellant’s
asserted unexpected result is not commensurate in scope with Appellant’s
claimed invention (Ans. 10). In re Huai-Hung Kao, 639 F.3d 1057, 1068
(Fed. Cir. 2011) (In order to be persuasive of non-obviousness, “[e]vidence
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of secondary considerations must be reasonably commensurate with the
scope of the claims.”).

Long-felt Need:
Appellant contends that “[t]he age of the references relied upon by the
Office and the long-time use of ozone depleting bromo-fluoroalkanes
demonstrates that [Appellant’s] . . . invention satisfies a long felt, yet unmet
need” (Appeal Br. 15 (citing Leo Pharmaceutical Products Ltd. v. Rea, 726
F.3d 1346, 1359 (Fed. Cir. 2013) (“The intervening time between the prior
art’s teaching of the components and the eventual preparation of a successful
composition speaks volumes to the nonobviousness of the ’013 patent”)).
We are not persuaded.
“True enough, Leo Pharmaceutical discusses the number of years that
passed from the time the prior art was invented until the filing of the patent
at issue.” Nike, Inc. v. Adidas AG, 812 F.3d 1326, 1338 (Fed. Cir. 2016),
overruled on other grounds by Aqua Prods., Inc. v. Matal, 872 F.3d 1290
(Fed. Cir. 2017) (en banc). As the Nike Court explained, however,
our reversal of the Patent Board’s obviousness determination
[in Leo Pharmaceutical] hinged on the fact that nothing in the
cited prior art appreciated the problem the invention recognized
and then solved. [Leo Pharmaceutical] . . . at 1353 (“The ’013
patent, however, is not simply a combination of elements found
in the prior art. The inventors . . . recognized and solved a
problem . . . that the prior art did not recognize.”). Because
there was no prior recognition of the problem solved by the
subject invention, there was no reason in the record why one of
skill in the art would attempt to combine the cited prior art to
arrive at the claimed invention. Id. at 1354 (“Only after
recognizing the existence of the problem would an artisan then
turn to the prior art and attempt to develop [the claimed
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invention].”); see also id. at 1356–57 (rejecting an obvious-to-
try argument because “[u]ntil the advancement made by the
inventors . . . [t]he problem was not known, the possible
approaches to solving the problem were not known or finite,
and the solution was not predictable”).
In this way, our decision in Leo Pharmaceutical is
entirely consistent with established precedent that “[t]he mere
age of the references is not persuasive of the unobviousness of
the combination of their teachings, absent evidence that,
notwithstanding knowledge of the references, the art tried and
failed to solve the problem.” In re Wright, 569 F.2d 1124, 1127
(CCPA 1977); see also Iron Grip Barbell Co. v. USA Sports,
Inc., 392 F.3d 1317, 1325 (Fed. Cir. 2004) (“Absent a showing
of long-felt need or the failure of others, the mere passage of
time without the claimed invention is not evidence of
nonobviousness.”). Leo Pharmaceutical recognizes the natural
consequence of this idea: Persons of skill in the art cannot have
tried and failed to solve the problem if they were never aware of
that problem to begin with. Thus, the number of years that
passed between the prior art and the claimed invention may be a
relevant factor to underscore that skilled artisans had long failed
to appreciate the problem solved by that invention. Here, there
is no question that skilled artisans knew of the desire to reduce
waste when producing wearable, knitted shoe uppers because
that problem is expressly recognized in Nishida. Thus, Leo
Pharmaceutical does not control the present case.
Nike v. Adidas, 812 F.3d at 1338.
The evidence on this record establishes that FIP and BFP were both
known as alkylating agents for use in a method, within the scope of
Appellant’s claimed invention, of preparing a non-radioactive N-
monofluoroalkyl tropane compound of Appellant’s Formula (IIIA) (see FF
3–8; cf. Appeal Br. 19–20). The evidence on this record further establishes
that it was known to monitor alkylation reactions to optimize product
recovery by minimizing impurity contamination (see FF 7). The evidence of
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record also establishes BFP was preferred over FIP, because “[t]he
transesterified by-product [of Appellant’s Formula (V)] has not been
detected in the process [of alkylating nor-beta-CIT] that utilizes BFP with
KI” (Haugan I Decl.7 ¶ 2; see also Appeal Br. 8 (“The use of BFP avoids
formation of this byproduct in detectable amounts.”)).
Haugan makes clear that the problem on this record is “[t]he change
of one raw material (FIP for BFP) [that] is required due to the phasing out of
BFP with its ozone depleting characteristics” (Haugan I Decl. ¶ 4; see also
Spec. 4:20–22 (Appellant discloses that BFP “is an ozone depleting agent,
and is not commercially available. There is therefore a need for alternative
viable syntheses of drugs and imaging agents which comprise N-fluoroalkyl
substituents”)). Stated differently, at the time of Appellant’s claimed
invention, the industry moved away from the use of BFP toward the use of
an alternative alkylating agent, such as the art-recognized FIP alkylating
agent.
For the foregoing reason, we are not persuaded by Appellant’s prior
art citations relied upon to support Appellant’s contention that “it took over
17 years from the development of a process using . . . [BFP] agents before
the present inventors found a process that could work with . . . [FIP] agents”
(Appeal Br. 17). Notwithstanding Appellant’s contentions relating to long-
felt need, because BFP was previously available there was no problem that
needed to be solved. The problem, asserted by Appellant, occurred when the
industry decided to move away from the use of BFP (see Ans. 10
(“Establishing a long felt need requires evidence that an art recognized

7 Declaration of Jarle André Haugan, Ph.D., signed Feb. 24, 2017.
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problem existed in the art for a long period of time without a solution. The
need must have been a persistent one that was not recognized by those of
ordinary skill in the art.”)). Texas Instruments, Inc. v. International Trade
Comm., 988 F.2d 1165, 1178 (Fed. Cir. 1993) (“[L]ong-felt need is analyzed
as of the date of an articulated identified problem and evidence of efforts to
solve that problem.”). The prior art, however, already had a solution, i.e. a
FIP alkylating agent, to accommodate the phasing out of BFP, with its ozone
depleting characteristics. Stated differently, Appellant’s asserted long-felt
need was already satisfied by another before the date of Appellant’s
invention (see FF 3–8; see also Ans. 11). See Newell Companies v. Kenney
Mfg. Co., 864 F.2d 757, 768 (Fed. Cir. 1988) (“[O]nce another supplied the
key element, there was no long-felt need or, indeed, a problem to be
solved.”).
For the foregoing reasons, we are not persuaded by Appellant’s
contentions regarding long-felt need (see Appeal Br. 15–17).
Claim 25:
Claim 25, reproduced above, depends from and further limits claim 22
to require “the heating is done at reflux for about 2 hours” (Appeal Br. 17).
Appellant contends that “[n]one of the prior art provides any reason or
motivation to conduct the reflux for 2 hours when forming FP-CIT from nor-
beta-CIT using an iodo-flouroalkyating agent” (Appeal Br. 18). We are not
persuaded.
As Examiner explains, the evidence of record establishes that an N-
alkylation reaction depends on amine concentration, time, and temperature
(see FF 7; see also Ans. 11 (Chesis I recognized that time was a result
effective variable when using FIP as an alkylating agent)). Thus, we find no
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error in Examiner’s conclusion that at the time of Appellant’s claimed
invention, “[a] person of ordinary skill in the art would have arrived at a 2
h[our] reaction time through routine experimentation by monitoring the
reaction with chromatography in order to arrive at the optimal yield in the
shortest reaction time at the optimal temperature” (Ans. 11). Appellant’s
contentions supports Examiner’s conclusion “the present inventors found
that one could lower the amount of transesterified impurity to less than 1 %
while achieving adequate yield by conducting the reflux for about 2 hours.
When the reflux time was increased, the amount of transesterified impurity
increased” (Appeal Br. 18).
For the reasons set forth above, we are not persuaded by Appellant’s
contentions regarding unexpected results (see id.). Thus, we are not
persuaded by Appellant’s contention that “it would not have been obvious as
a matter of routine optimization to conduct the reflux for 2 hours when
forming FP-CIT from nor-beta-CIT using an iodo-flouroalkyating agent as
claimed” (id.).
CONCLUSION
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness.
The rejection of claims 22 and 25 under 35 U.S.C. § 103(a) as
unpatentable over the combination of Neumeyer, Chesis I, and Chesis II is
affirmed/reversed. Claims 23, 24, and 26–34 are not separately argued and
fall with claim 22.

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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
22–34 103 Neumeyer, Chesis
I, Chesis II
22–34

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