Ex Parte Baranowska-Kortylewicz et al

Patent Trial and Appeal Board

Dec 13, 2016

13512966 (P.T.A.B. Dec. 13, 2016)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/512,966 07/09/2012 Janine Baranowska-Kortylewicz 48259 2883
23589 7590 12/15/2016
Hovey Williams LLP
10801 Mastin Blvd., Suite 1000
Overland Park, KS 66210
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
12/15/2016 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):
patents @ hovey williams, com
amalik @hovey williams .com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JANINA BARANOWSKA-KORTYLEWICZ
AND ZBIGNIEW P. KORTYLEWICZ
Appeal 2015-006217
Application 13/512,966
Technology Center 1600
Before JEFFREY N. FREDMAN, ROBERT A. POLLOCK and
JACQUELINE T. HARLOW, Administrative Patent Judges.
POLLOCK, Administrative Patent Judge.
DECISION ON APPEAL
Appellants appeal under 35 U.S.C. § 134(a) from the final rejection of
claims 29-31. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
According to the Specification, the invention relates to
therapeutic and diagnostic applications of radiolabeled
synthetic compounds, which are effective to (1) kill cancer
cells undergoing DNA replication or repair by incorporation
into the growing DNA strand resulting in DNA double strand
breaks, (2) specifically target two membrane proteins
expressed in cancer cells and implicated in tumorogenesis,
butyrylcholinesterase (BChE) and the androgen receptor
Appeal 2015-006217
Application 13/512,966
(AR). The compounds of the invention are taken up
selectively by malignant tumor cells and are incorporated
into the nucleus of such cells, where they produce a cytotoxic
effect and/or are detectable via nuclear medicine imaging
techniques.
Spec. 1.
Appealed Claims
Claims 29-31 are on appeal. Claim 29, the sole independent claim on
appeal, recites:
29. A compound of the formula:
0
wherein X represents H, F, Cl, or a C1-C4 alkyl, or C1-C4
alkoxy group;
Y represents H or a C1-C4 alkyl group;
Z represents H or a C1-C4 alkyl group;
R represents halogen, radiohalogen, or a C1-C4 alkyl, C6-C14
aryl, Ci-Cg alkylthio, Ci-Cg alkoxy, C2-C6 alkenyl, C2-C6
alkynyl, C3-C12 cycloalkyl, or Sn(Ci-C4 alkyl)3 group; any
of said alkyl, alkenyl, alkynyl, alkylthio, alkoxy, and
cycloalkyl group being optionally substituted by at least
one halogen, OH, SH, NH2, C1-C4 monoalkylamino, Ci-
C4 dialkylamino, COOH, CN, NO2, C1-C4 alkyl, C1-C4
alkoxy or phenyl group, any of said aryl and phenyl group
being optionally substituted by at least one halogen, OH,
SH, NH2, C1-C4 monoalkylamino, C1-C4 dialkylamino,
COOH, CN, NO2, C1-C4 alkyl or C1-C4 alkoxy group;
2
Appeal 2015-006217
Application 13/512,966
L is a cleavable bifunctional linking moiety; and said
radiohalogen represents 123I, 124I, 125I, 1311,211At, 18F, 76Br,
77Br, or 80mBr; and stereoisomeric forms and
pharmaceutically acceptable salts of said compound.
Claim 31 recites a kit comprising a compound of claim 29 and a
pharmaceutically acceptable carrier medium. Also depending from claim
29, claim 30 is drawn to a compound of the formula:
O
Grounds of Rejection
I. Claims 29-31 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Baranowska-
Kortylewicz,1 Meier I2, Meier II,3 Dadachova4 and
Kortylewicz.5
1 Baranowska-Kortylewicz et al., US 2005/0069495 Al, published March
31,2005.
2 Meir et al., Interaction of cvcloSal-Pronucleotides with Cholinesterases
from Different Origins. A Structure-Activity Relationship, 47 J. Med. Chem.
2839-2852 (2004).
3 Meier and Balzarini, Application of the cvcloSal-prodrug approach for
improving the biological potential of phosphorylated biomolecules, 71
Antiviral Res. 282—292 (2006).
4 Dadachova et al., US 2006/0018827 Al, published Jan. 26, 2006.
5 Kortylewicz et al., US 2009/0117041 Al, published May 7, 2009.
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Appeal 2015-006217
Application 13/512,966
II. Claims 29—31 stand rejected as unpatentable for obviousness-
type double patenting over claims 1—6 of the ’730 Patent,6,7 in
view of Meier II, and Dadachova.
I
We have reviewed Appellants’ contentions that the Examiner erred in
rejecting claims 29-31 as unpatentable over the cited art. App. Br. 4—8;
Reply 1—2. Except as otherwise discussed in footnote 8, we disagree with
Appellants contentions and adopt as our own the findings and analysis set
forth in the Examiner’s Answer. For emphasis and clarity, we highlight and
address the following:
Findings of Fact
FF1. Baranowska-Kortylewicz discloses “conjugates composed of a
radiolabeled, cell cycle-dependent therapeutic agent chemically coupled
to a ligand that targets androgen receptor (AR). The conjugates of the
invention are taken up selectively by malignant tumor cells that have
androgen receptor and are incorporated into the nucleus of such cells,
where they produce a cytotoxic effect and/or are detectable via
radioimaging techniques.” Baranowska-Kortylewicz 12; see also, 19
(“[T]he radiolabeled conjugates of the present invention [] are capable of
targeting and being selectively taken up and degraded by a tumor cell,
and thereby delivering to the tumor cell nucleus radioisotope capable of
being incorporated into the nuclear material, so as to produce a cytotoxic
6 Baranowska-Kortylewicz et al., US 7,220,730 B2, issued May 22, 2007.
7 The ’730 Patent issued from US 2005/0069495 Al, the application that
published as Baranowska-Kortylewicz.
4
Appeal 2015-006217
Application 13/512,966
effect and/or to render the cell detectable by radioimaging.”). The
reference explains that “[u]pon administration, the conjugate first binds
to the sex hormone binding globulin, which in turn carries it exclusively
to cells that have AR [androgen receptor]. Subsequent to this interaction,
the entire conjugate is transported into the cell. Intracellular enzymes
cleave the linking moiety, thus releasing and trapping within the cell the
portion of the conjugate that is responsible for killing tumor cells.” Id. |
FF2. Baranowska-Kortylewicz discloses a general formula for the
conjugates {id. at || 10-11) and then focuses on the synthesis, chemistry,
and biological properties of a small number of specific examples
designated conjugates 1, 2, 3, 4, 4a, and 5. See id. at || 25—76.
Conjugates 1 and 2, respectively, have the formulas:
FF3. With respect to conjugate 1, Baranowska-Kortylewicz states that,
The release of 125IUdR from the succinate ester appears to be
very effective, both in vitro in cell culture and in vivo in
tumor bearing animals. The half-life in vivo is short and may
be detrimental to the delivery of therapeutic doses to tumor.
On the other hand, because the half-life is short, repeated
injections should be possible without a large radioactive
burden in normal tissue.
13.
Id. 143.
5
Appeal 2015-006217
Application 13/512,966
FF4. Baranowska-Kortylewicz also states that,
Conjugate 2 is the most hydrophilic of the conjugates
described herein (two negative charges on the
monophosphate group). It cannot cross the cell membrane
by itself, i.e., it requires the active transport mechanism from
the systemic circulation into the tumor cells with the aid of
sex hormone binding globulin.
Id. 1 50.
FF5. Baranowska-Kortylewicz describes conjugate 5 as “the most
hydrophobic of all the conjugates described herein. It may be best suited
for local/regional administration (e.g., intra peritoneal in the case of
ovarian cancer) with a slow diffusion from the site of injection.” Id. | 63.
FF6. Meier I discloses that
cycloSal-phosphate triesters represent a particular class of
pronucleotides. These lipophilic derivatives of various
antiviral and antitumor active nucleoside analogues have
been developed as intracellular delivery forms of the
corresponding nucleotide analogues. By releasing the
nucleotide, the metabolic bottleneck of the conversion of the
nucleoside into the nucleotide by cellular or viral enzymes
can be bypassed (chemical trojan horse concept). The
cycloSal approach relies on a chemically driven hydrolysis
reaction. The initial chemical hydrolysis step intrinsically
activates the remaining masking group which is then
spontaneously cleaved to yield the nucleotide (tripartite
prodrug).
Meir I, 2839; see also Figure 2 (disclosing representative
cycloSal-phosphate esters).
FF7. Meier II teaches that the administration of therapeutic nucleotides
such as d4TMP is hindered because “nucleotides are charged molecules
under physiological conditions and do not efficiently penetrate cell
membranes. This difficulty can be surmounted by attaching suitably
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Appeal 2015-006217
Application 13/512,966
degradable lipophilic groups to the phosphate moiety that leads to
neutral, membrane-permeable masked.” Id. at 283. In particular,
Meier II teaches that salicyl alcohol moieties may be used as cyclic
bifimctional masking units for phosphate triesters where the addition of
the lipophilic cycloSal moiety enhances the membrane penetration of
phosphate triesters. See id. at 290-291. Once inside the cell, the
cycloSal moiety dissociates leaving the more polar nucleotide “locked-
in,” i.e., trapped inside the cell. See id. at 290.
FF8. Meier II figure 3 is reproduced below:
Ss s;
_ y'^v’v''oA
...............X"-vr" J O.o*wscm
c«?;«cai afitp-
5 iissiiay: pfesspnaS* dsasssri
* Hjv1
SgFtSvIjd ’iisp b
«
X-
OH
J, A
" 0--B;
rfAod4T
sfsp d
? ptx&ptim dieses;
Ffg, X UvPm. g-UP‘.Y;iof ths L'-Y /,YS:tE-:.i4 ! MF oiootOY 2
Meier II, figure 3 illustrates the hydrolysis pathway of cyc/oSal-dTMP
triesters. Meier II teaches that the hydrolysis pathway is independent of
the nucleoside analog attached to the phosphate moiety. Id. at 285.
FF9. Meier II teaches that cycloSal derivatives may useful for the
intracellular delivery of bioactive nucleotides including antiviral and
antitumor nucleoside analogs, moreover, “the delivery of biologically
active phosphorylated compounds from cycloSal—phosphate triesters
7
Appeal 2015-006217
Application 13/512,966
generally may lead to a strong improvement in [] bioactivity.” Id. at 291,
see id. at Abstract, 286.
FF10. Meier II further discloses a series of cycloSal nucleotide triesters and
their ability to inhibit AChE (acetylcholinesterase), BChE
(butyrylcholinesterase), and HIV replication in cell culture. See e.g., id.
Abstract, Tables 1 and 2.
FF11. Kortylewicz discloses cyc/oSalingenyl pyrimidine nucleoside
monophosphates comprising positron emitters or gamma-emitting
radiohalides having the general formula
which bind to BChE in the brain and are useful for monitoring
Alzheimer's disease progression. Kortylewicz || 3, 13, 20, 22.
FF12. Dadachova teaches kits comprising positron emitters for the treatment
of inflammation, infection, and disease. See Dadachova, Abstract H 39,
Appellants argue that “a chemist of ordinary skill would not have
selected conjugate 1 or conjugate 2 of Baranowska-Kortylewicz as a starting
point for further chemical modification.” App. Br. 4—5 (citing Otsuka
Pharmaceutical Co. Ltd., v. Sandoz, Inc., 678 F.3d 1280, 1291—1292 (Fed.
Cir. 2012). In particular, Appellants suggest that Baranowska-Kortylewicz
teaches away from the selection of those compounds because conjugate 1 is
described “as having a short half-life, which may be detrimental to the
48.
Analysis
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Appeal 2015-006217
Application 13/512,966
delivery of therapeutic doses to tumors, possibly requiring repeated
injections,” whereas Baranowska-Kortylewicz reports that conjugate 2
“cannot cross the membrane by itself, i.e., it requires the active transport
mechanism from the systemic circulation into the tumor cells with the aid of
sex hormone binding globulin.” Id. at 5—6. Rather, Appellants argue, one of
ordinary skill in the art would have selected compound 5 for further
development as Baranowska-Kortylewicz describes it as “best suited for
local/regional administration . . . with a slow diffusion from the site of
injection.’” Id. at 6 (quoting Baranowska-Kortylewicz 163).
We do not find Appellants argument persuasive.
The lead compound analysis begins with the identification of “a
compound in the prior art that would be most promising to modify in order
to improve upon its . . . activity and obtain a compound with better activity.”
Otsuka, 678 F.3d at 1291 (citing Takeda Chem. Indus., Ltd. v. Alphapharm
Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007)). As such, a lead compound
is “a natural choice for further development efforts.” Altana Pharma AG v.
Teva Pharm. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009). Otsuka,
however, expressly acknowledges the possibility that there can be “one or
more lead compounds.” 678 F.3d at 1291; see also Altana, 566 F.3d at 1008
(“to the extent Altana suggests that the prior art must point to only a single
lead compound for further development efforts, that restrictive view of the
lead compound test would present a rigid test similar to the teaching-
suggestion-motivation test that the Supreme Court explicitly rejected in KSR
Inti Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007)”).
In the present case, we agree with the Examiner that one of ordinary
skill in the art would have reasonably looked to any of the small number of
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Appeal 2015-006217
Application 13/512,966
compounds highlighted in the Baranowska-Kortylewicz reference.8 See
Ans. 12. With respect to Appellants argument one of ordinary skill in the art
would not have selected conjugate 1 as a lead compound because its short
half-life “may be detrimental to the delivery of therapeutic doses to tumors”
(App. Br. 5), we note that Baranowska-Kortylewicz teaches that the
conjugates are useful for their “cytotoxic effect and/or . . . radioimaging
techniques.” See FF 1 (emphasis added). With respect to the latter, the
reference clearly teaches the benefit of conjugate 1, stating that “because the
half-life is short, repeated injections should be possible without a large
radioactive burden in normal tissue.” See FF 3. As noted by the Examiner,
Baranowska-Kortylewicz teaches the use of androgen receptor/globulin
complexes in transporting the disclosed conjugates across cell membranes,
whereupon the transported compounds are released and beneficially retained
within the cell. See Ans. 12—13; FF 1. Accordingly, we do not understand
the hydrophilicity of conjugate 2 and its specificity for active transport as a
reason not to select conjugate 2 for further development.
Moreover, to the extent we accept Appellant’s argument regarding the
active transport requirement of conjugate 2, Meier II teaches the addition of
8 Appellants argue that the Examiner errs in referencing compounds claimed
in Baranowska-Kortylewicz “while effectively disregarding other relevant
disclosure which would plainly influence the selectin of a lead compound.”
Reply 1—2. To the extent the Examiner may have improperly looked to the
claims as evidence of the scope and teachings of the prior art, such error is
harmless because, as recognized by the Examiner, the reference clearly
focuses on the chemistry and biology of a small number of representative
compounds. See FF 2—5. We also recognize that the Examiner does not
distinguish between compounds 4 and 4a but do not find this point
determinative.
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Appeal 2015-006217
Application 13/512,966
lipophilic cycloSal moieties to charged nucleotides that do not efficiently
penetrate cell membranes. See FF 7; see also Ans. 13 (“[A] chemist of
ordinary skill would have understood that the substitution of polar phosphate
radical in compound 2 discussed above with nonpolar cyc/oSal radical
advantageously enables intracellular delivery and chemical hydrolysis to
corresponding nucleotide.”).
Finally with respect to Appellants’ position that one of ordinary skill
in the art would have looked exclusively to conjugate 5 for further
development, we note that Baranowska-Kortylewicz’s teaching that
conjugate 5 “may be best suited for local/regional administration” in no way
suggests that it is best suited for ah applications including systemic
administration. See FF 4, 5.
Appellants also argue that “the cited references provide no reason to
modify any compound described therein to arrive at the compounds of
claims 29-31 with a reasonable expectation of success.” App. Br. 5. We do
not find Appellants’ argument persuasive. As explained by the Examiner, it
would have been obvious to modify Baranowska-Kortylewicz compounds 1
and 2 by incorporating a cyc/oSal moiety having substituents at the 3, 5,
and/or 6 positions as taught by Meier I, Meier II, and Kortylewicz, as well as
Dadachova,9 to “advantageously enable improved intracellular delivery of
radiotherapeutic nucleoside conjugate.” Ans. 8. The Examiner further finds
that “[tjhere would have been a reasonable expectation of success because
[Meier I and Meier II] teach that [the] cyc/oSal moiety acts as lipophilic
9 Dadachova is cited with respect to claim 31 as teaching positron emitters in
kit form. See Ans. 7.
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prodrug which undergoes hydrolysis within cells and bypasses the metabolic
bottleneck of converting nucleoside into nucleotide and [Meier II] teach[es]
that the hydrolysis pathway is independent on the nucleoside analog.” Id.',
see id. at 14.
For the above reasons, we affirm.
II
Appellants rely on the same arguments with respect to the rejection
for obviousness-type double patenting over claims 1—6 of the ’730 Patent, in
view of Meier II, and Dadachova. App. Br. 8—9. As indicated above, the
’730 Patent issued from the application that published as Baranowska-
Kortylewicz. Claims 1—6 of the ’730 patent disclose compounds bearing the
cycloSal radical including conjugates 1 and 2, discussed above with respect
to Baranowska-Kortylewicz.
Finding no error in the Examiner’s rejection based on obviousness, we
likewise affirm the rejection for obviousness-type double patenting.
SUMMARY
I. We affirm the rejection of claims 29-31 under § 35 U.S.C. 103(a) as
obvious over the combination of Baranowska-Kortylewicz, Meier I,
Meier II, Dadachova and Kortylewicz.
II. We affirm the rejection of claims 29-31 as unpatentable for
obviousness-type double patenting over claims 1—6 of the ’730 Patent,
in view of Meier II, and Dadachova.
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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
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