Ex Parte Hauske

Patent Trial and Appeal Board

May 26, 2016

12310142 (P.T.A.B. May. 26, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/310,142 11109/2009 James R. Hauske
35437 7590 05/31/2016
Mintz Levin/New York Office
One Financial Center
Boston, MA 02111
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.
35231-504N01US 9039
EXAMINER
0 DELL, DAVID K
ART UNIT PAPER NUMBER
1625
NOTIFICATION DATE DELIVERY MODE
05/31/2016 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):
IPDocketingBOS@mintz.com
IPFileroombos@mintz.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JAMES R. HAUSKE
Appeal2013-009879
Application 12/310, 142
Technology Center 1600
Before JEFFREY N. FREDMAN, JOHN G. NEW, and
ROBERT A. POLLOCK, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to
transporter inhibitor compounds. The Examiner rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellants identify the Real Party in Interest as Prexa
Pharmaceuticals, Inc. (App. Br. 2).
Appeal2013-009879
Application 12/310, 142
Statement of the Case
"If neurotransmitters such as serotonin, norepinephrine, or dopamine
are not made and released in effective amounts or are cleared from the
synaptic cleft too quickly, then cell-to-cell communication can be affected.
Clinical manifestations of such imbalances include depression and related
anxiety disorders and movement disorders" (Spec. 1, 11. 24--28). "Inhibiting
neurotransmitter reuptake can increase the amount of neurotransmitter
present in the synapse, thus helping to normalize the transmission of
neuronal signals" (Spec. 2, 11. 1-3).
"The present invention relates to the discovery of certain transporter
inhibitors ... and the use of those inhibitors in methods of treatment" (Spec.
6, 11. 16-18).
The Claims
Claims 1, 2, 25, and 68-81 are on appeal. 2 Claims 2, 25, and 68-81
have not been argued separately and therefore stand or fall with claim 1. 37
C.F.R. § 41.37(c)(l)(vii). Claim 1 reads as follows:
1. A compound represented by Formula Ila or IIb, or a
pharmaceutically acceptable salt thereof:
R1
!
/ . ,....-Jt.t
~· .· At
' 17
x (Hh!
2 Appellants elected structure 21 in a species election (see Resp.
Restriction Req. 12/7/2011 15).
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Appeal2013-009879
Application 12/310, 142
wherein, as valence and stability permit,
Ar, independently for each occurrence, represents a
substituted or unsubstituted aryl or heteroaryl ring;
X represents-Hor -OR;
Y represents -0-, -S-, -C(R)2-, or-N(R)-;
R, independently for each occurrence, represents-Hor
lower alkyl;
Ri, independently for each occurrence, represents
halogen, amino, acylamino, amidino, cyano, nitro, azido, ether,
thioether, sulfoxido, -J-OH, -J-lower alkyl, -J-lower alkenyl,
-J-SH, -J-NH2, or substituted or unsubstituted lower alkyl,
lower alkenyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,
heterocyclylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
R2, independently for each occurrence, represents H or
substituted or unsubstituted lower alkyl, cycloalkyl,
heterocyclyl, aralkyl, heteroaralkyl, aryl, or heteroaryl;
J represents, independently for each occurrence, a chain
having from 0-8 units selected from -C(R)2-, -N(R)-, -0-, and
-S-·
'
The issue
n is an integer from 0 to 2; and
pis 0 or 1.
The Examiner rejected claims 1, 2, 25, and 68-81under35 U.S.C. §
103(a) as obvious over Aquila3 (Final Act. 2-10).
The Examiner finds that compound 24 of Aquila "differs from the
elected species by a methyl group" (Ans. 2). The Examiner finds that
compound 24 "was one of the most potent compounds used. See the Table
on page 93 where NE and DA uptake were both less than <10 nM for
compound 24. It was so good that the inventors decided to make all 4
3 Aquila et al., WO 02/22572 A2, published Mar. 21, 2002.
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Appeal2013-009879
Application 12/310, 142
stereoisomers" as compounds 124, 125, 126, and 127 (Ans. 3). The
Examiner finds that these "compounds were of such interest that they were
also chosen for experiments with animals" (id.). The Examiner finds that
Aquila teaches the "performance of compounds 124--127 in various animal
assays for depression" (Ans. 5).
The Examiner finds that the "interchangeability of hydrogen and
methyl generally creates a case of prim a facie obviousness" (Ans. 4 ). The
Examiner finds that because Aquila teaches "variables [that] are listed as
alkyl in the genus ... methyl would immediately be envisioned. According
to page 10 lines 11-12, 'preferred alkyl groups are lower alkyls'" (Ans. 5).
The issue with respect to this rejection is:
(i) Does the evidence of record support the Examiner's conclusion
that Aquila renders claim 1 obvious?
(ii) If so, has Appellant presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. The elected species, compound 21, is reproduced below:
(21)
Compound 21 is (S)-1-[ 1-( 4-chlorophenyl)cyclobutyl]-2-{ (2R,5R)-2-methyl-
5-14-(trifluoromethyl)phenoxy] methyl}-piperidin-1-ylethanol (Spec. 32).
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Appeal2013-009879
Application 12/310, 142
2. Aquila teaches compound 24 that is reproduced below:
24
Compound 24 is 1-[1-( 4-Chlorophenyl)cyc lobutyll-2-[3-( 4-
trifluoromethyl-phenoxvmethyl)piperidin-1-yl]ethanol (Aquila 73, 11. 4--7).
3. Aquila teaches that the piperidine ring of the generic compound
may be substituted at the 2-position with Rs and/or R9 that "are selected
independently for each occurrence from the group consisting of H, alkyl,
(CH2)pY, aryl, heteroaryl, F, OR2, and OC(O)R2" (Aquila 18, 1. 1to19, 1. 4).
4. Aquila teaches synthesis of four stereoisomers of compound 24,
compounds 124--127 (see Aquila 137, 1. 10 to 139, 1. 6) reproduced below:
124
f""~'(CF:, . . r9ijCf's
or--o~Jl /Y'o~
N (N)
.
~
... c~
126
+
~
l&l_CI
127
Compounds 124 and 125 are is JR and JS 1-[1-( 4-Chloro-phenyl)-
cyclobutyl]-2-[ (JS)-3-( 4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-
ethanol and compounds 126 and 127 are JR and JS 1-[1-(4-Chloro-phenyl)-
cyclobutyl]-2-[ ( 3 R)-3-( 4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-
ethanol.
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Application 12/310, 142
5. Aquila teaches analyzing the ability of compounds of the
invention to displace norephinephrine, dopamine, and serotonin ligands in
vitro (Aquila 92, 11. 23-26) with the results table reproduced in part below:
!,• <:::@lil(}(1tt·~·~r-- t,J1>~ke l~aflle ! l:'tindfonal As-<>a.,,,~~
l
! flCe:o. nM) ! (antagonism. I~(·~~" nM'!
n:=i:~ i!:l:~mku ~~;;~.,
"1·\z4-· ~---------t·l,000 I NA ! NA NA i
t.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._4.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._J__.............._.._...._.._.._.._.._.._.._.._.._.._.._ .._.._.._.._.._.._...._._..._........._.._.._.._.._.._.._.._.._.._.._.._.._.._,,,_..._.._.._..._.._.._.._,,_,,. .. _.._.._._.._.._.._~.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._.._ "-"-"-"-"-"-"-"-"-"-"-"-"-"-'"" __ .._n~
iJ2S !1,00Q <1,000 i <10 >l.0-00 ~·
~---+-l --- t . :
fi6 l <100 1 30% are considered effective in this in vivo model" and Aquila finds that
"[b]ased on the aforementioned criterion for effectiveness, compounds 124,
126, and 127 were effective at a dose of 2.5 mg/kg; compound 126 was also
effective at a dose of 1.0 mg/kg" (Aquila 197, 1. 12 to 128, 1. 10).
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Application 12/310, 142
8. Aquila teaches compounds 82, 131, and 132 as reproduced
below:
:RZ (:rn"t.mfilc); and
131 andl32
femm!:K-u.ne:rn}
Compounds 82, 131, and 132 are the racemate and enantiomers of cis-1-[1-
( 4-Chloro-phenyl)-cyclobuty lmethyl ]-3-( 4-trifluoromethyl-phenoxvmethyl )-
piperidin-2-yl ]-methanol (Aquila 143, 11. 5-10).
Principles of Law
This court, in reconsidering this case in bane,
reaffirms that structural similarity between claimed and prior
art subject matter, proved by combining references or
otherwise, where the prior art gives reason or motivation to
make the claimed compositions, creates a prima facie case
of obviousness, and that the burden (and opportunity) then
falls on an applicant to rebut that prima facie case.
In re Dillon, 919 F.2d 688, 693 (Fed. Cir. 1990).
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Analysis
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. 2-10; FF 1-7) and agree that
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Appeal2013-009879
Application 12/310, 142
the claims are rendered obvious by Aquila. We address Appellant's
arguments below.
Prima F acie Obviousness
Appellant contends that "[i]t is clear that the Federal Circuit requires
modification [sic motivation] to modify in order to establish prima facie
obviousness" (Br. 4). Appellant contends that the "'lead compound'
analysis does apply in the instant case. Such application compels a
conclusion that the Examiner has failed to fulfill the initial burden of
establishing a prima facie case of obviousness for at least the reason that
there is no motivation to select and modify the compounds" (Br. 6).
We agree that Takeda requires "some reason that would have led a
chemist to modify a known compound in a particular manner to establish
prima facie obviousness." Takeda Chem. Industries, Ltd. v. Alphapharm
Pty., Ltd. 492 F.3d 1350, 1357 (Fed. Cir. 2007). However, the claim in
Takeda was limited to a specific molecular species, not a genus of chemical
compounds. See Id. at 1353. While Daiichi and Otsuka also require reasons
"to select and then to modify a prior art compound (e.g., a lead compound)
to arrive at a claimed compound," both of these cases are also drawn to
claims to specific molecular species, not large genera of chemical
compounds. Daiichi Sankyo Co., Ltd. v. Matrix Laboratories, Ltd., 619 F.3d
1346, 1353 (Fed. Cir. 2010) (Claim 13 of US 5,616,599 at issue was drawn
to a specific compound); Otsuka Pharm. Co., Ltd., v. Sandoz, Inc., 678 F.3d
1280, 1291 (Fed. Cir. 2012) (Claims 12, 17, and 23 of US 5,006,528 at issue
were drawn to specific compounds).
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Application 12/310, 142
Thus, the instant case differs substantially from these Federal Circuit
decisions because claim 1 is drawn to a substantial genus of compounds, not
a single species. Even if we treat the species election as limiting our
consideration to compound 21, the Examiner has provided significant
reasoning to select compound 24 of Aquila as the lead compound.
As the Examiner points out, compound 24 is one of only two
compounds shown in the tables on pages 93 to 96 of Aquila that have uptake
profiles for both NE and DA uptake with values of "<10", with compound
193 as the other compound (see Ans. 3--4; FF 5). Aquila is reasonably
interpreted as suggesting that compounds 24 and 193 were "lead"
compounds because Aquila chose to synthesize all four stereoisomers of
these compounds (FF 4; cf Ans. 3--4). Aquila further motivates selection of
compound 24 as a "lead" compound by demonstrating that the synthesized
stereoisomers 124 and 126 treated locomotor activity in animals (FF 6) and
functioned as antidepressants in rats (FF 7).
Therefore, we agree with the Examiner that "there is ample
motivation to select the requisite compound to arrive at the elected species"
(Ans. 2).
Appellant contends that because "the 1,3-di-substituted compounds
(e.g., compounds 24, 164, and 165) are superior to the two 1,2,3-tri-
substituted piperidine compounds ... the skilled artisan would not be
motivated to modify the di-substituted compounds" (Br. 4). Appellant
contends that the "skilled artisan would readily recognize that the claimed
1,3, 6-trisubstituted compounds (having Formula Ila) are not encompassed
by the broad genus of WO 2002022572" (Br. 5).
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Application 12/310, 142
We are not persuaded. Aquila teaches that the piperidine ring may be
substituted with an alkyl group (FF 3) and exemplifies substitution of the
piperidine ring with a CH20H group in compounds 82, 131, and 132 (FF 8).
We agree with the Examiner that the ordinary artisan, after selecting
compound 24 as the lead compound, would have found simple homologs
comprising methyl modifications of the piperidine ring obvious (see Ans. 4).
See Dillon, 919 F.2d at 696 ("[T]he cases establish that if an examiner
considers that he has found prior art close enough to the claimed invention to
give one skilled in the relevant chemical art the motivation to make close
relatives (homo logs, analogs, isomers, etc.) of the prior art compound(s),
then there arises what has been called a presumption of obviousness or a
primafacie case of obviousness ... The cases of Hass and Henze
established the rule that, unless an applicant showed that the prior art
compound lacked the property or advantage asserted for the claimed
compound, the presumption of unpatentability was not overcome").
This reasoning is particularly apt here, where claim 1 is not limited to
the particular species of compound 21, but broadly encompasses virtually
any possible substituent at two of the four possible positions on the
piperidine ring (the 4 and 6 positions), suggesting that any of a variety of
substituents are obvious variations. Moreover, claim 1 encompasses Ar
substituents on the compounds, where Ar "represents a substituted or
unsubstituted aryl or heteroaryl ring." Thus, claim 1 explicitly recognizes
that the ordinary artisan would have had reason to incorporate any
substituent onto any position of a ring as desired, with no indication that
such a substitution would require any more than ordinary skill. This fact
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Application 12/310, 142
pattern is very different than that in Takeda, Daiichi, and Otsuka which were
limited to specific chemical entities, not generic claims.
Here, the change from compound 24 to the elected species of
compound 21 is the conservative modification of the piperidine ring to
include a methyl substituent (Ans. 2), not the much broader range of
possibilities envisioned by instant claim 1. "After selecting a lead
compound, both experts ... agreed that a chemist in drug development
would seek to make small, conservative changes to that structure. In drug
development, it is common to modify a lead compound in an effort to
'obtain a compound with better activity.'" Bristol-Myers Squibb Co. v. Teva
Pharms. USA, Inc., 752 F.3d 967, 974 (Fed. Cir. 2014) (citing Otsuka, 678
F.3dat 1291).
Secondary Considerations
Appellant contends that
as demonstrated by Table I of the instant application (at
pages 77-78), 1,3,4- or 1,3,6-tri-substituted compounds (1)
and (3) exhibit an ECso of 1 nM against dopamine uptake.
In comparison, 1,2,3-tri-substituted compound (5) exhibits
an EC so of 5 nM, 5 times greater than that of compound ( 1)
or (3)
(Br. 6). Appellant contends that "the 1,3,4- or 1,3,6-tri-substituted
compounds of claim 1 possess unexpectedly superior properties"
(Br. 6).
We are not persuaded. The Specification does not teach that
compounds 1 and 3 are unexpectedly better than compound 5, but rather
that:
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Application 12/310, 142
It is evident, based on these results, that the select
subject compounds are quite selective inhibitors of DAT
uptake. For example, (3) is a 200-fold and 825-fold more
selective inhibitor for DAT than for NET and 5-HT,
respectively. The selectivity for (1) is 1000-fold (NET) and
5000-fold (5-HT), respectively. The selectivity for (5) is
1000-fold (NET) and 1000-fold (5-HT), respectively.
(Spec. 78, 11. 8-11). Thus, the Specification does not recognize that
compound 5 was unexpectedly better than compounds 1 and 3. Nor is there
other evidence, such as a Declaration, contending that this result was
unexpected. See In re Geisler, 116 F.3d 1465, 1471 (Fed. Cir. 1997) ("[T]he
only reference to unexpected results was a statement by [Appellant's]
counsel, in response to the examiner's first rejection, that [Appellant's]
results were 'surprising.' And, as the Soni court itself noted, naked attorney
argument is 'insufficient to establish unexpected results."').
Even if we treated the improved DAT values in Table 1 as showing an
"unexpected" result, the data was not compared to the closest prior art of
compound 24 of Aquila. See In re Baxter Travenol Labs., 952 F.2d 388,
392 (Fed. Cir. 1991) ("when unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.").
Appellant contends that "the other 1,3,4-tri-substituted or 1,3,6-tri-
substituted compounds tested in the instant application (see Table I) are in
agreement with this trend. Appellant therefore submits that the amended
claims are commensurate in scope with the data presented in the
specification" (Br. 8).
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Application 12/310, 142
We are not persuaded. Table 1 is limited to compounds 1, 3, 5, 6',
and 13-21, where compounds 5 and 6' are not within the scope of claim 1
and compounds 1, 3, and 13-21 are stereo isomers that differ from compound
24 of Aquila in having a methyl substituent on the piperidine ring at either
the 4 or 6 position (where the N is the 1 position) (see Spec. 27, 31-32).
Claim 1 broadly encompasses substituents on the piperidine ring including
halogen, amino, acylamino, amidino, cyano, nitro, azido, ether, thioether,
sulfoxido, -J-OH, -J-lower alkyl, -J-lower alkenyl, -J-SH, -J-NH2, or
substituted or unsubstituted lower alkyl, lower alkenyl, cycloalkyl,
heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, or
heteroaralky 1.
Therefore, the results are not commensurate in scope with the great
breadth of claim 1, and Appellant argues the full scope of claim 1, not solely
the species of compound 21. (See Br. 4 "The instant claims are directed to
1,3,6- or 1,3,4-tri-substituted piperidine compounds.") See In re Harris,
409 F.3d 1339, 1344 (Fed. Cir. 2005) (Unexpected results must be
"commensurate in scope with the degree of protection sought by the claimed
subject matter.")
Appellant contends that
it can be inferred that if any of the IC so values were 1 nM or
less, it would have been presented as 1 nM or < 1 nM. Yet,
none of the 26 compounds that were tested for their
functional dopamine update activity in [Aquila] is presented
in that way. It at least indicates that those 26 compounds
have the ECso value higher than 1 nM.
(Br. 7).
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Application 12/310, 142
We are not persuaded. The inferences of Appellant are not evidence.
See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) ("Attorney's
argument in a brief cannot take the place of evidence.") The inference is
also not sound because Aquila does not show values as specific numbers or
by using the "=" sign but rather either the "<" or ">" signs. Therefore,
values of 1 nm would be shown as "< 1 O" because they would not be less
than 1 ("< 1 ") as argued by Appellant. Indeed, if the data regarding
compounds 1, 3, and 5 were added to the table of Aquila, the reasonable
interpretation would suggest that these compounds would show values of"<
10" consistent with the other data in Aquila's table.
Conclusion of Law
(i) The evidence of record supports the Examiner's conclusion that
Aquila renders claim 1 obvious.
(ii) Appellant has not presented evidence of secondary considerations,
that when weighed with the evidence of obviousness, is sufficient to support
a conclusion of non-obviousness.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
103(a) as obvious over Aquila. Claims 2, 25, and 68-81 fall with claim 1.
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
14