Ex Parte BINDER et al

Patent Trial and Appeal Board

Dec 29, 2015

11568445 (P.T.A.B. Dec. 29, 2015)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111568,445 0612912007
32425 7590 12/31/2015
NORTON ROSE FULBRIGHT US LLP
98 SAN JACINTO BOULEVARD
SUITE 1100
AUSTIN, TX 78701-4255
FIRST NAMED INVENTOR
Dieter BINDER
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.
SONN: 101 US/10613721 4576
EXAMINER
CORNET, JEAN P
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
12/31/2015 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):
aoipdocket@nortonrosefulbright.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DIETER BINDER, EV A BINDER, and MICHAEL PYERIN
Appeal2013-006015
Application 11/568,445
Technology Center 1600
Before ULRIKE W. JENKS, RICHARD J. SMITH, and TA WEN CHANG,
Administrative Patent Judges.
SMITH, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
compound and pharmaceutical preparation of central nicotine receptor
subtype agonists, which may be used for conditions or treatments such as
Alzheimer's disease and smoke substitution therapy. (Spec., 9-10.) We
have jurisdiction under 35 U.S.C. § 6(b ).
We affirm.
Appeal2013-006015
Application 11/568,445
STATEivIENT OF THE CASE
Claims on Appeal
Claims 20, 26, and 27 are on appeal. Claim 20 is illustrative and
reads as follows:
20. (-)-[3aR-(3aa, 8ba)]-1,2,3,3a,4,8b-Hexahydropyrrolo-
[3',2':4,5]cyclopenta[l,2-c ]pyridine dihydrochloride or a
pharmaceutically usable salt thereof.
(Br. 7, Claims Appendix.)
Examiner's Rejections
A. Claims 20 and 26 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over Zhai, 1 Patani, 2 and Ullrich. 3 (Ans. 5.)
B. Claim 27 stands rejected under 35 U.S.C. § 103(a) as unpatentable
over Zhai, Patani, Ullrich, and Le. 4 (Ans. 9.)
Appellants have presented arguments for the patentability of claims
20 and 26 as a group. (Br. 1-5.) Therefore, we limit our discussion to claim
20 as representative of both claims 20 and 26.
FINDINGS OF FACT
FF 1. The Examiner finds that Zhai teaches a compound named cis-l-
methyl-1,2 ,3 ,3a,8b-hexahydroxypyrro lo [3 ,2-fJpyridine, with a conformation
rigidified by a methylene bridge, and the following structure:
1 Zhai et al., A Facile Synthesis of cis-l-Methyl-l,2,3,3a,4,8b-
hexashydropyrrolo[3,21Jpyrindine, an Annulated Nicotine Analog, 4
ORGANIC LETTERS 4385-86 (2002).
2 G.A. Patani & E.J. LaVoie, Bioisosterism: A Rational Approach in Drug
Design, 96 CHEM. REV. 3147-76 (1996).
3 Ullrich et al., Conformationally Constrained Nicotines: Polycyclic,
Bridged, and Spiro-Annulated Analogues as Novel Ligands for the Nicotinic
Acetylcholine Receptor, 45 J. MED. CHEM. 4047-54 (2002).
4 Le et al., US 2002/0119193 Al, published Aug. 29, 2002.
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(Ans. 6, citing Zhai, pp. 4385-86.)
FF 2. The Examiner finds that Zhai's teachings show that its compound
(FF 1) has the ability to target and activate nicotinic acetylcholine receptors
(nAChRs) and has favorable effects on patients with Alzheimer's disease.
(Id.)
FF 3. The Examiner finds that the structure of the elected compound (claim
20) is as follows:
(Ans. 6-7.)
FF 4. The Examiner finds that a difference between the Zhai compound and
the claimed compound is that the pyrrolo group has a methyl group (Me) on
the Zhai compound (FF 1) whereas the claimed compound contains
hydrogen in place of the methyl group (FF 3). (Id.)
FF 5. Patani states that "[b ]ioisosterism represents one approach used by the
medicinal chemist for the rational modification of lead compounds into safer
and more clinically effective agents." (Patani, p. 3147.)
FF 6. The Examiner finds, based on the teachings of Patani, that the Zhai
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compound and the elected compound (claim 20) are bioisosteres of each
other, and that "[h]ydrogen is a bioisostere replacement for methyl (Grimm's
Hydride Displacement Law)." (Ans. 7; Patani p. 3152.)
FF 7. The Examiner finds that Ullrich teaches that conformation restraint of
nicotine-related compounds can lead to high affinity ligands, which are
stereochemically discriminated by nAChRs. (Ans. 8.)
FF 8. Ullrich states that nAChRs are "a potential target for the treatment of
Alzheimer's and other neurodegenerative diseases." (Ullrich, p. 4047.)
FF 9. Le states that compositions of its invention can be used for treatment
of Alzheimer's disease, and "can be used in combination therapies with
opioids and other analgesics," including numerous ones listed in Le. (Le,
iii! 73, 80.)
ISSUE
Whether a preponderance of evidence of record supports the
Examiner's conclusion of obviousness with respect to claim 20.
Analysis
The Examiner determined that claim 20 would have been obvious to a
person of ordinary skill in the art. (Ans. 5-9.) This determination was
based, in part, on the finding that the structural difference between the
compound of claim 20 and the Zhai compound is the replacement of the
methyl group on the Zhai compound with hydrogen, and the teaching of
Patani that hydrogen is a bioisostere replacement for methyl. (FF 4, 6.)
Furthermore, the Examiner found that Ullrich teaches that conformation
restraint of nicotine-related compounds can lead to high affinity ligands.
(FF 7 .) Finally, the Examiner set forth motivation from the prior art to
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combine the teachings of Zhai, Patani, and Ullrich, with a reasonable
expectation of success. (Ans. 8-9.)
We find that the Examiner has established a prima facie case of
obviousness. See Aventis Pharma Deutsch/and GmbH v. Lupin, Ltd., 499
F.3d 1293, 1301 (Fed. Cir. 2007) ("In the chemical arts, ... '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"') (citing cases). Furthermore, as discussed below, we find that
Appellants' arguments do not overcome or rebut that prima facie case.
Bioisosterism in Nicotine-Like Compounds
Appellants contend that N-methyl is not bioisosteric with N-hydrogen
in nicotine-like compounds, and set forth several arguments in support of
that contention. (Br. 2--4.)
First, Appellants argue that Patani shows that N-methyl and N-
hydrogen are not bioisosteric in the context of nicotine-like compounds,
citing a statement in Patani that, according to Appellants, indicates that N-
methyl and N-hydrogen are not bioisosteric in every context. (Id. at 2.)
Appellants also point to data in Patani (Table 12) as showing that a
"hydrogen substituted compound was about 6 times less active" than a
methyl substituted compound. (Id. at 2-3.) According to Appellants, Patani
thus demonstrates that methyl and hydrogen cannot be exchanged "without
significantly changing the activity of the compound." (Id. at 2.)
Second, Appellants cite to Ullrich for the proposition that
"[i]ntroduction of the N-methyl substituent resulted in a significant
improvement" and "[i]n the case of [compound ( + )-5b] ... the beneficial
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effects oi an N-methyi group ... were demonstrated." (Id. at 3, c1tmg
Ullrich, p. 4050.)
Appellants buttress their first and second arguments with the Ullrich
Declaration, 5 which states that "in compounds such as 5b, an N-methyl
group is superior to the N-unsubstituted analog in terms of binding affinity"
and "in the context of nicotine-like compounds, the N-methyl group is not
bioisosteric with N-hydrogen." (Id., citing Ullrich Dec. i-f 4.) Appellants
conclude by stating that Patani and Ullrich "generally indicate that replacing
the N-methyl with N-hydrogen is detrimental to a nicotine-like compound's
activity" and, as such, those references teach away from the claimed
compounds. (Id. at 4.)
We are not persuaded by Appellants' arguments. Patani teaches
hydrogen and methyl are bioisosteres, thereby suggesting that their
substitution would result in the same type of biological activity. (FF 6.) See
In re Merck & Co., Inc., 800 F.2d 1091, 1096 (Fed. Cir. 1986) (describing
bioisosterism). Furthermore, while Table 12 of Patani shows that a
hydrogen substituted compound was less active than a methyl substituted
compound in inhibiting a particular enzyme, Patani also shows that
hydrogen and methyl are bioisosteres and that the hydrogen substituted
compound retained activity. (Patani, p. 3153.)
Appellants essentially argue that Patani shows that substituting
hydrogen in place of a methyl group may result in a compound that is less
active. (Br. 2-3.) However, "obviousness cannot be avoided simply by a
showing of some degree of unpredictability in the art so long as there was a
5 Declaration of Dr. Thomas Ullrich under 37 C.F.R. § 1.132, dated Sept. 26,
2011.
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reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364 (Fed. Cir. 2007). As such, the mere difference in the degree of
activity, resulting from substitution of the bioisosteres hydrogen and methyl
in certain contexts, does not overcome the prima facie case of obviousness.
Appellants' argument regarding the Ullrich reference, as buttressed by
the Ullrich Declaration, is unpersuasive for several reasons. Appellants'
argument is that the N-hydrogen substitution is inferior to N-methyl. (Br. 3.)
However, as pointed out by the Examiner, the Ullrich compounds referenced
by Appellants ( 5a, 5b) are structurally dissimilar from the Zhai compound
and the claimed compound. (Ans. 15-16.) Moreover, simply because
Ullrich may describe an N-hydrogen compound as somewhat inferior to an
N-methyl compound does not make an N-hydrogen compound patentable.
See In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
Appellants' argument that Patani and Ullrich teach away from the
claimed compound is likewise unpersuasive. Ullrich shows that an N-
hydrogen compound can have better activity than an N-methyl compound.
(Ans. 16; Ullrich, p. 4050.) Patani shows that hydrogen and methyl are
bioisosteres (FF 6), and that hydrogen substitution retains enzyme inhibition
activity. (Patani, pp. 3152-53.) Thus, neither Ullrich nor Patani can be said
to teach away because they do not "criticize, discredit, or otherwise
discourage" the claimed solution of substituting the N-methyl in Zhai with
hydrogen. See In re Fulton, 391F.3d1195, 1201 (Fed. Cir. 2004).
Separation of Enantiomers
Appellants contend that, based on the teachings of Ullrich, a person of
ordinary skill in the art would not have been motivated to separate the
enantiomers of Zhai's compound. (Br. 4.) Furthermore, according to
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Appellants, there would have been no "reasonable expectation of success
that the enantiomers would have any 'remarkable enantioselectivity,' as this
was not observed with all of the compounds Ullrich tested." (Id., citing
Ullrich, p. 4050.) Appellants also cite to the Ullrich Declaration and the
statements therein that the Ullrich reference shows that "conformational
restriction ... does not necessarily lead to an increase of enantioselectivity"
and that the Ullrich reference "does not teach any predictivity of receptor
stereoselectivity based on conformational restriction." (Br. 4--5; Ullrich
Dec., i17.)
We are not persuaded by Appellants' argument that enantioselectivity
cannot be predicted. As stated above, obviousness is not overcome by
merely showing some degree of unpredictability in the art. Pfizer, 480 F.3d
at 1364. Moreover, Ullrich shows, and the Ullrich Declaration confirms, the
enantioselectivity of certain compounds ( 5a, 5b ), and that one enantiomer is
generally expected to have better activity in a given assay compared to the
other enantiomer. (Ans. 18-19; Ullrich, p. 4050; Ullrich Dec., i17.)
Unexpected Results
Appellants also argue that, even if the Examiner established a prima
facie case of obviousness, the claimed compound "possesses unexpectedly
advantageous or superior properties." (Br. 5.) Appellants point to Example
9 in the Specification as demonstrating "a remarkable difference" in the
properties between the claimed compound and its enantiomer. (Id.) This
argument is also buttressed with the statement in the Ullrich Declaration that
he "would not have expected such high enantioselectivity as reported in
Example 9." (Id.; Ullrich Dec. i18.)
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We are not persuaded by Appellants' argument. Unexpected results
must be shown to be unexpected compared with the closest prior art. In re
Baxter Travenol Labs, 952 F.2d 388, 392 (Fed. Cir. 1991) (citing In re De
Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984)). In this case, the closest prior
art is the Zhai compound. Moreover, a difference in properties between the
enantiomers of Example 9 would not have been unexpected or surprising to
a person of ordinary skill in the art given the teachings of the Ullrich
reference. See In re Soni, 54 F.3d 746, 750-751 (Fed. Cir. 1995).
CONCLUSION OF LAW
A preponderance of evidence of record supports the Examiner's
conclusion that claim 20 is obvious under 35 U.S.C. § 103(a). Furthermore,
Appellants have not provided sufficient evidence of unexpected results that,
when weighed with the evidence favoring obviousness, shows that the
claimed compound would have been nonobvious.
Claim 26 was not argued separately and therefore falls with claim 20.
37 C.F.R. § 41.37(c)(l)(iv).
ISSUE
Whether a preponderance of evidence of record supports the
Examiner's conclusion of obviousness with respect to claim 27.
Analysis
Claim 27 recites "[t]he pharmaceutical preparation of claim 26,
further comprising an additional therapeutically valuable compound."
(Br. 7 .) The Examiner found that it would have been obvious to combine
the additional therapeutically valuable compound of Le, in view of the prior
art, with the expectation of a better action for improving Alzheimer's
disease, and to test and check such action. (Ans. 10.) Appellants argue that
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"there is no teaching or suggestion of the expectation that such additional
compounds may be successfully employed with the currently claimed
compound, nor could there be." (Br. 6.)
We are not persuaded by Appellants' argument. "It is prima facie
obvious to combine two compositions each of which is taught by the prior
art to be useful for the same purpose, in order to form a third composition
which is to be used for the very same purpose." In re Kerkhoven, 626 F.2d
846, 850 (CCP A 1980) (citing cases). Here, the Le composition is useful for
treating Alzheimer's (FF 9), and it would have been obvious to combine it
with a pharmaceutical preparation for treating Alzheimer's as taught by the
prior art (e.g. claim 26). See id. Accordingly, we find that the Examiner has
established a prima facie case of obviousness as to claim 27, and Appellants
have not presented sufficient evidence and argument in rebuttal to overcome
that prima facie case.
CONCLUSION OF LAW
A preponderance of evidence of record supports the Examiner's
conclusion that claim 27 is obvious under 35 U.S.C. § 103(a).
SUMMARY
We affirm the rejection of all appealed claims.
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
KRH
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