Ex Parte Nakanishi et al

Patent Trial and Appeal Board

Sep 15, 2016

13254152 (P.T.A.B. Sep. 15, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/254, 152 10/20/2011
74384 7590
Cheng Law Group, PLLC
1133 13th St. N.W.
Suite C2
Washington, DC 20005
09/15/2016
FIRST NAMED INVENTOR
Hiroaki Nakanishi
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.
NOG-0354 6631
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
MAILDATE DELIVERY MODE
09/15/2016 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte HIROAKI NAKANISHI, HIDEKAZU SAIKI, HIDEO SAJI,
HIROYUKI KIMURA, HIDEKAZU KAWASHIMA, KENJI TOMATSU,
and YUJI KUGE 1
Appeal2015-003895
Application 13/254, 152
Technology Center 1600
Before ERIC B. GRIMES, ULRIKE W. JENKS and DAVID COTTA,
Administrative Patent Judges.
COTTA, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for synthesizing [18F]SFB. 2 The Examiner rejected the claims on appeal as
obvious under 35 U.S.C. § 103(a).
We affirm-in-part, reverse-in-part and enter a NEW GROUND OF
REJECTION pursuant to our authority under 37 C.F .R. § 4 l .50(b ).
1 Appellants identify the Real Party in Interest as Shimadzu Corporation and
Kyoto University of Kyoto. App. Br. 2.
2
[
18F]SFB is N-succinimidyl 4-[ 18F] fluorobenzoate, which is used to label
compounds to synthesize diagnostic probes for Positron Emission
Tomography. Spec. 1:9--15.
Appeal2015-003895
Application 13/254, 152
STATEMENT OF THE CASE
Claims 1---6 are on appeal. Claims 1 and 4 are the only independent
claims. Claims 1 and 4 read as follows:
1. A method for synthesizing [18F]SFB comprising:
continuously performing the following three-step
reaction in a microreactor including a substrate having one
channel formed therein so as to have a cross-sectional width
of 1 mm or less and a cross-sectional depth of 1 mm or less,
the channel being connected to a raw material injection port
and a first reagent injection port at one end thereof, and
connected to a second reagent injection port at a position
spaced apart from the one end thereof, and connected to a
third reagent injection port at a position spaced apart from
the second reagent injection port in a direction toward other
end thereof, and connected to a liquid discharge port at the
other end thereof, by allowing a reaction solution to flow
through the channel serving as a reaction channel from the
one end to the other end thereof without taking out the
reaction solution from anywhere between the one end and
the other end of the channel:
a first-step reaction in \~1hich a solution of a labeled
precursor of [18F]SFB and a solution containing 18F ions as
a first reagent are continuously supplied from the raw
material injection port and the first reagent injection port,
respectively to fluorinate the labeled precursor in the
channel between the one end and the second reagent
injection port;
a second-step reaction in which a TP AH
( tetrapropylammonium hydroxide) solution as a second
reagent is continuously supplied from the second reagent
injection port to saponify a reaction product of the first-step
reaction in the channel between the second reagent injection
port and the third reagent injection port so that a [18F]SFB
intermediate is produced; and
a third-step reaction in which a TSTU (0-(N-
succinimidyl)-N,N,N',N' -tetramethyluronium
tetrafluoroborate) solution as a third reagent is continuously
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Application 13/254, 152
supplied from the third reagent injection port to produce
[
18F]SFB in the channel between the third reagent injection
port and the other end.
4. A method for synthesizing [18F]SFB comprising:
continuously performing the following three-step
reaction in a reactor without taking out a reaction solution
from the reactor:
a first-step reaction in which a solution of a labeled
precursor of [18F]SFB and a solution containing 18F ions as
a first reagent are supplied in the reactor to fluorinate the
labeled precursor;
a second-step reaction in which a TPAH solution as a
second reagent is supplied in the reactor to saponify a
reaction product of the first-step reaction so that a [18F]SFB
intermediate is produced; and
a third-step reaction in which a TSTU solution as a
third reagent is supplied in the reaction solution after the
second step reaction in the reactor to produce [18F]SFB, the
reaction solution not being subjected to purification nor
dehydration.
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Application 13/254, 152
The claims stand rejected as follows:
Claims 1-3 under 35 U.S.C. §103(a) as unpatentable over the combination
of Tang, 3 Miller, 4 Bannwarth, 5 Katadokoro, 6 Marik, 7 and Brady. 8
Claims 4---6 under 35 U.S.C. § 103(a) as unpatentable over the
combination of Tang, Miller, Katadokoro, Marik, Elizarov, 9 and Brady.
With respect to claims 1-3, the Examiner found that Tang disclosed a
method of preparing [18F]SFB using a "three-step, one-pot procedure,
consisting of [18F]fluorination of the precursor ethyl 4-(triemethylamonium
[sic] triflate )benzoate, saponifications to generate the [ 18F]FBA salt with
tetrapropylammonium hydroxide, and [reacting the [18F]FBA salt with HSTU
to achieve] conversion of the [18F]FBA salt to [18F]SFB." Ans. 4. Following
the second step of the reaction described in Tang (i.e., saponification to
generate the [18F]FBA salt), the reaction product is "azeotropically dried."
3 Tang et al., Facile Synthesis of N-succinimidyl 4-[18F}jluorobenzoate
([18F}SFB) for Protein Labeling, 51 Journal of Labelled Compounds and
Radiopharmaceuticals 68-71 (2008) ("Tang").
4 Miller, Radiolabelling with Short-Lived PET (Positron Emission
Tomography) Isotopes Using Microfluidic Reactors, 84 Journal of Chemical
Technology and Biotechnology 309-315 (2009) ("Miller").
5 Bannwarth et al., Formation of Carboxamides with N,N,N',N' -Tetramethyl
(Succinimido) Uranium Tetrafluoroborate in Aqueous/Organic Solvent
Systems, 32 Tetrahedron Letters, 9, 1157-1160 (1991) ("Bannwarth").
6 Katadokoro et al., Japanese Pat. Pub. No. 2004-313867, published Nov. 11,
2004 ("Katadokoro").
7 Marik et al., Fully Automated Preparation of a n.c.a. 4-[1 8F}jluorobenzoic
Acid and N-succinimidyl 4-[18F}jluorobenzoate Using a Siemens/CTI
Chemistry Process Control Unit (CPCU), 65 Applied Radiation and Isotopes
199-203 (2007) ("Marik").
8 Brady et al., US 2005/0026776 Al, published Oct. 13, 2005 ("Brady").
9 Elizarov, US 2009/0036668 Al, puolished Feb. 5, 2009 ("Elizarov''J.
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Appeal2015-003895
Application 13/254, 152
Tang 70. The Examiner found that Bannwarth taught that TSTU 10 "acts as an
effective condensing agent to yield carboxamides from carboxy compounds
with amino components ... even in the presence of water." Ans. 7. Based on
this disclosure, the Examiner found that a person of ordinary skill in the art
would expect that TS TU could be substituted for HS TU and the reaction
described in Tang could then proceed without azetropic drying. Ans. 15. The
Examiner acknowledged that Tang did not teach performing the reaction in a
microreactor configured as described in claim 1, but found that the
combination of Miller, Katadokoro, Marik, and Brady made conducting the
reaction in such a microreactor obvious. Ans. 5-8.
With respect to claims 4--6, the Examiner relied on the same art except
that Bannwarth was removed from the combination, and Elizarov was added.
The Examiner found that Elizarov taught "continuous infusion of reagents into
a microreactor." Ans. 16.
Appellants argue that the cited art teaches that azeotropic drying is
required between the second and third steps of the reaction disclosed in Tang.
Based on the premise that azeotropic drying is required, Appellants contend
that the cited art does not teach "continuously" preforming the three reaction
steps recited in claim 1. App. Br. 10. Appellants further contend that the three
step reaction of Tang cannot be performed in the microreactors of Miller and
Katadokoro because the reaction solution cannot be taken out of a microreactor
in order to remove "unreacted reactants" and "side products." App. Br. 11-12.
10 The Examiner refers to "N,N,N',N'-tetramethyl-0-(N-succinimidyl)uranium
hexafluorophosphate (HSTU)" (Ans. 7) but the cited page in Bannwarth refers
to "N,N,N',N'-tetramethyl (succinimido) uronium tetrafluoroborate (TSTU)."
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Appellants also argue that the claimed invention "provides for unexpected and
superior results not achieved in the prior art." App. Br. 15.
FINDINGS OF FACT
1. Tang discloses:
We manually synthesized [ 18F] SFB (Scheme 1) using ethyl 4-
( trimethylammonium triflate )benzoate (1) as a precursor via a
three-step, one-pot procedure. [18F]Fluorination of the ammonium
triflate precursor 1 in the solvent MeCN gave 2, which was
directly used for the hydrolysis reaction. Hydrolysis of 2 with
aqueous tetrapropylammonium hydroxide yielded the [18F]FBA
salt 3, which was azeotropically dried using MeCN. Reaction of 3
with HSTU, followed by purification using a C 18 cartridge, a
SepPak alumina cartridge, and a cation exchange cartridge in
series yielded the purified [18F]SFB. [18F]SFB was produced in a
decay-corrected radiochemical yield of up to 43.8 ± 4.6% (based
on [18F]fluoride; n = 10) in less than 60min (n = 10). This
simplified one-pot procedure should be readily adaptable to
automated radiosynthesis techniques.
Tang 70.
2. Scheme 1 of Tang (referenced in FF 1) discloses:
[KlK22~j 1 $F M~CN ------
9-:l ''C, W m:i;i
2
90"C. 5 miJ<
J
Id.
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3. Tang discloses that "HSTU can also be used in place of TSTU to
achieve similar radiochemical yields." Id.
4. Bannwarth discloses:
In summary we have found that N,N,N',N'-tetramethyl
(succinimido) uronium tetrafluoroborate (TSTU) acts as an
effective condensing agent to yield carboxamides from the
reaction of carboxy compounds with amino components.
These reactions proceed even in the presence of water and
in a fast and clean manner with only a slight excess of
TSTU.
Bannwarth 1160.
5. Miller discloses:
Many chemical reactions, performed in microfluidic
environments, have been improved in terms of reaction
rates, product yields and/or selectivities compared with
their corresponding bulk reaction systems. These
improvements are due directly to the effects of increasing
the surface area-to-volume ratio of the reactor.
Miller 310-311.
REJECTION OF CLAIMS 1-3 OVER THE COMBINATION
OF TANG, MILLER, BANNWARTH, KATADOKORO, MARIK
AND BRADY
Tang teaches a synthesis reaction that includes a step where [18F]FBA
salt was "azeotropically dried using MeCN." FFl. After the azeotropic drying
step, the [18F]FBA salt is reacted with HSTU to produce [18F]SFB. FFl &
FF2. Several of the issues in this case tum on the question of whether the
person of ordinary skill in the art would have expected that the synthesis
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Application 13/254, 152
reaction disclosed in Tang could be carried out without the azeotropic drying
step.
As an initial matter, Appellants and the Examiner disagree on what
azeotropic drying entails. The Examiner contends that "[a ]zeotropic drying
involves adding MeCN to form a MeCN-water azeotrope and evaporating to
remove water at a lower temperature than the boiling point of pure water."
Ans. 14--15. Appellants contend that the reaction mixture after step 2 of the
Tang synthesis reaction contains "unreacted reactants" as well as "side
products" and that "these unreacted reactants and side products are expected to
be removed to a substantive extent by evaporation along with the water during
the azeotropical drying process." Reply Br. 2.
Appellants' argument that azeotropic drying removes "unreacted
reactants" and "side products" relies exclusively on unsupported attorney
argument. Attorney argument is not evidence and cannot take the place of
evidence. In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974); Meitzner v.
Mindick, 549 F.2d 775, 782 (CCPA 1977). In fact, Tang states that "[t]he Sep-
Pak C18 cartridge trapped the [18F]SFB, the Sep-Pak alumina cartridge
removed the free 18P-, and the SCX cartridge removed the impurities." Tang
69, right col. Thus, the evidence does not support Appellants' position that
evaporating a MeCN/water azeotrope during the synthesis process of Tang
would remove any "unreacted reactants" and "side products."
Having found that we lack the evidence to conclude that Tang's
azeotropic drying step does anything more than remove water, we tum next to
the Examiner's finding that the azeotropic drying step in Tang was
unnecessary. The Examiner found that Bannwarth taught that N,N,N',N'-
tetramethyl (succinimido) uronium tetrafluoroborate (TSTU) "acts as an
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Application 13/254, 152
effective condensing agent even in the presence of water." Final Act. 5; see
also, FF4. The Examiner further found that TSTU was "a functionally
equivalent HSTU derivative" that could be substituted for the HSTU used in
Tang's synthesis reaction. Ans. 15; see also, FF3. The Examiner then
concluded that one of ordinary skill would have been motivated to substitute
the TSTU taught by Bannwarth for the HSTU used in Tang's synthesis
reaction for "because Bannwarth et al. teach TSTU advantageously enables
coupling even in the presence of water in a fast and clean manner thereby
making [Tang's] dehydration step unnecessary." Ans. 15.
Appellants argue that the teaching of Bannwarth is limited to situations
where only water is present. Appellants assert:
Bannwarth et al. shows a reaction of TSTU with carboxyl
compounds in a solvent including only water. In contrast,
Tang et al. discloses a reaction of the reagent with a
carboxyl compound in a reaction solution including
impurities other than the carboxyl compound, which is a
different chemical condition than that of Bann\~1arth.
Reply Br. 3. Appellants thus contend that Bannwarth "would not lead one of
ordinary skill in the art to expect that the third step reaction of Tang et al. could
proceed in the reaction solution of the second-step reaction without first
performing a purification process." App. Br. 12.
We are not persuaded. As discussed above, there is no evidence of
record that the azeotropic drying step in Tang does anything more than simply
remove water. Bannwarth teaches that the presence of water does not hinder a
reaction of TSTU of carboxy compounds with amino components. FF4. Since
all that occurs between step two and step three of Tang's synthesis reaction is
to remove water, see FF 1, and since water is not an impediment to
TSTU/carboxy reactions, see FF4, we find that a person of ordinary skill in the
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art would have expected that the third step of the synthesis reaction described
in Tang, if carried out using TSTU, could proceed without azeotropic drying
and without performing a purification process. 11
Our finding that a person of ordinary skill would have expected that
azeotropic drying was unnecessary in the reaction of Tang is dispositive with
respect to several of Appellants' arguments. We are thus not persuaded by
Appellants' argument that the cited art does not meet the requirement of claim
1 for "continuously performing" the claimed three-step reaction because Tang
teaches that an azeotropic drying step must occur between steps 2 and 3. App.
Br. 10. We are similarly not persuaded by Appellants' arguments that the
reaction of Tang cannot take place in a microreactor as disclosed in Miller and
Katadokoro because "the reaction solution after the second-step reaction
cannot be taken out from the microreactor in order to remove unreacted
reactants and the side reaction products from the [18F]SFB intermediate." App.
Br. 11, 12.
11 We note that Appellants have not provided any evidence that a person of
skill in the art would expect the "unreacted reactants" or "side products" to
preclude completion of the reaction of Tang. Appellants rely solely on
attorney argument for this proposition.
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Appellants argue that the claimed method provides "unexpected and
superior results not achieved in the prior art." App. Br. 15. Appellants cite
Table 1 of the Specification as evidence of such unexpected results. Table 1 is
reproduced below.
Specification 23. Appellants contend that Table 1 shows that "the present
invention has a significantly reduced synthesis time, as well as significantly
increased decay-corrected yield and non-decay-corrected yield, as compared to
Conventional Method 1." App. Br. 15. Tang is cited as the source of
Conventional Method 1 in Table 1.
While the results reflected in the Example of Table 1 are improved as
compared to the prior art, Appellants do not explain why these results would
have been unexpected. Miller discloses that carrying out chemical reactions in
microfluidic environments increases the surface area-to-volume ratio of the
reactor, leading to improved reaction rates and product yields. FF5.
Accordingly, one of ordinary skill in the art might well expect that carrying out
the claimed reaction in a microfluidic environment would result in improved
reaction rates and yields. Indeed, Appellants themselves attribute the
improved reaction rate achieved by their method at least in part to carrying out
the reaction in a microfluidic environment. App. Br. 9 (noting that it was
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possible to improve reaction time "because the reaction efficiency is improved
by performing a reaction in a microspace provided in a microreactor"). Absent
further explanation or evidence from Appellants on why the improved results
of claim 1 were unexpected, we have no basis on which to find unexpected
results.
In sum, for the reasons discussed, Appellants' arguments do not
persuade us that a preponderance of the evidence fails to support the
Examiner's rejection of claim 1 as obvious under 35 U.S.C. § 103(a). Because
they were not argued separately, claims 2 and 3 fall with claim 1. See, 37
C.F.R. § 41.37(c)(l)(iv).
REJECTION OF CLAIMS 4---6 OVER THE COMBINATION
OF TANG, MILLER, ELIZAROV, KATADOKORO, MARIK
AND BRADY
The Examiner applied the same art with respect to claims 4--6 as was
applied with respect to claims 1-3 with the exception that the Examiner
substituted Elizarov for Bannwarth.
Claim 4 and the claims depending therefrom require "the reaction
solution not being subjected to purification nor dehydration." The azeotropic
drying step disclosed in Tang is a dehydration step. Elizarov does not teach
that the azeotropic dying step of Tang is unnecessary. Because the Examiner
relied on Bannwarth for the teaching that azeotropic drying was unnecessary,
and because Bannwarth was not cited in connection with this ground of
rejection, we reverse the Examiner's rejection of claims 4---6.
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Application 13/254, 152
NEW GROUND OF REJECTION UNDER 37 C.F.R. § 41.50(b)
Claims 4--6 are rejected on a new ground of rejection under 35 U.S.C.
§ 103(a) as being unpatentable over the combination of Tang, Miller, Elizarov,
Katadokoro, Marik, Brady and Bannwarth.
We conclude that claim 4 is obvious over the cited art for the same
reasons that claim 1 is obvious. We note that claim 4 is substantially identical
to claim 1 except that it omits limitations requiring the reaction to be
performed in a microreactor having the claimed configuration and adds
language requiring: "the reaction solution not being subjected to purification
nor dehydration." The absence of limitations requiring the reaction to be
performed in a microreactor broadens the claim, and thus, does not change the
application of the art discussed with respect to claim 1. The addition of
language requiring "the reaction solution not being subjected to purification
nor dehydration," also does not change the application of the art discussed with
respect to claim 1 given our conclusion that, based on Bannwarth, a person of
ordinary skill in the art would expect that the third step of the synthesis
reaction described in Tang could proceed without azeotropic drying and
without performing a purification process.
We also conclude that claims 5 and 6 would have been obvious over the
combination of Tang, Miller, Elizarov, Katadokoro, Marik, Brady and
Bannwarth for the reasons discussed with respect to claim 4 and for the reasons
provided by the Examiner. See Final Act. 8, Ans. 8-11. We note that claims 5
and 6 are substantially identical to claims 2 and 3, respectively, except that
they depend from claim 4 rather than claim 1
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Application 13/254, 152
SUMMARY
For the reasons set forth herein, the Examiner's final decision to reject
claims 1-3 is affirmed, the Examiner's final decision to reject claims 4---6 is
reversed, and a new ground of rejection is entered with respect to claims 4---6
pursuant to 37 C.F.R. § 41.50(b).
TIME PERIOD FOR RESPONSE
This decision contains a new ground of rejection pursuant to 3 7 C.F .R.
§ 41.50(b). 37 C.F.R. § 41.50(b) provides "[a] new ground of rejection
pursuant to this paragraph shall not be considered final for judicial review."
Section 41.50(b) also provides:
When the Board enters such a non-final decision, the
appellant, within two months from the date of the decision,
must exercise one of the following two options with respect
to the new ground of rejection to avoid termination of the
appeal as to the rejected claims:
( 1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence
relating to the claims so rejected, or both, and have the
matter reconsidered by the examiner, in which event the
prosecution will be remanded to the examiner. The new
ground of rejection is binding upon the examiner unless an
amendment or new Evidence not previously of Record is
made which, in the opinion of the examiner, overcomes the
new ground of rejection designated in the decision. Should
the examiner reject the claims, appellant may again appeal
to the Board pursuant to this subpart.
(2) Request rehearing. Request that the proceeding
be reheard under§ 41.52 by the Board upon the same
Record. The request for rehearing must address any new
ground of rejection and state with particularity the points
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Application 13/254, 152
believed to have been misapprehended or overlooked in
entering the new ground of rejection and also state all other
grounds upon which rehearing is sought.
Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure§ 1214.01.
No time period for taking any subsequent action in connection with this
appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED-IN-PART, 37 C.F.R. § 41.50(b).
15