Ex Parte Moser et al

Patent Trial and Appeal Board

Sep 21, 2016

12595147 (P.T.A.B. Sep. 21, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/595,147 01/26/2010
23599 7590 09/23/2016
MILLEN, WHITE, ZELANO & BRANIGAN, P,C
2200 CLARENDON BL VD.
SUITE 1400
ARLINGTON, VA 22201
Rudolf Moser
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.
EPROV-0030 1916
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
09/23/2016 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):
docketing@mwzb.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte RUDOLF MOSER, ROGER SCHIBLI,
CRISTINA MAGADELANA MULLER, VIOLA GROEHN,
URS FELIX MICHEL, CHRISTOF SPARR, and
THOMAS LEIGHTON MINDT 1
Appeal2014-008436
Application 12/595,147
Technology Center 1600
Before DEMETRA J. MILLS, ERIC B. GRIMES, and
JOHN G. NEW, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1Appellants state the real party-in-interest is MERCK & CIE. App. Br. 1.
Appeal2014-008436
Application 12/595,147
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 9, 10, 12, 15-18, 20, 21, 23, 24, 26-
28, 33, 40, 41, 44, 45, and 47 which stand rejected as unpatentable under 35
U.S.C. § 103(a) as being obvious over the combination of Christopher P.
Leamon et al., Folate-mediated Drug Delivery: Effect of Alternative
Conjugation Chemistry, 7(3) J. DRUG TARGETING 157-69 (1999)
("Leamon"), Green et al. (US 2005/0227985 A9, October 13, 2005)
("Green"), Thomas L. Mindt et al., Click to Chelate: Synthesis and
Installation of Metal Chelates into Biomolecules in a Single Step, 128 J. AM.
CHEM. Soc. 15096-97 (2006) ("Mindt"), and Jae Kyoung Pak et al., NE:
Functionalization of Metal and Organic Protected L-Histidine for a Highly
Efficient, Direct Labeling of Biomolecules with [Te(OH2)3(C0)3], 9 CHEM.
EUR. J. 2053-61 ("Pak").
\Ve have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to novel folate-conjugates and the
corresponding metal-chelate complexes as well as pharmaceutical
compositions thereof, their method of production and their use in diagnostic
and therapeutic medical applications, such as diagnostic imaging and
radiotherapy. Spec., 1, 11. 6-10.
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Application 12/595,147
REPRESENTATIVE CLAIM
Appellants argue all of the claims on appeal together. Independent
claim 9 is representative and recites:
9. A compound according to formula III,
III
wherein
X1, X2, X3, X4 and Xs are independently of each other C or N;
Y1, Y2 are independently of each other C, 0 or N,
Rl and R2 are independently of each other H, Hal, -OR', -NHR',
C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C1-C12 alkenyl, C1-
C 12 alkynyl, ( C 1-C 12 alkoxy )carbonyl, and ( C 1-C 12 alkylamino)
carbonyl,
R' is Hor C1-C6 alkyl,
R3 and R4 are independently of each other H, formyl,
iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12
alkanoyl, halosubstituted C1-C12 alkanoyl,
Rs is H, CN, Hal, N02, C1-C12 alkyl, C1-C12 alkoxy, C1-C12
alkanoyl, C12 alkenyl, C1-C12 alkynyl, (C1-C12 alkoxy) carbonyl,
and (C1-C12 alkylamino) carbonyl,
p has a value of 0, 1 or 2,
q has a value of 1 to 7,
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Application 12/595,147
r is 0 or 1,
R6 and R7 are independently of each other H, straight chain or
branched C1-C12 alkyl, which is unsubstituted or substituted by
at least one CN, Hal or N02, or a group of formula IV,
IV
wherein
Z1, Z2, are, independently of each other, CH or N,
Z3 is C orN,
S2, S3, S4 are independently of each other a single bond or a
spacer group,
Ra, Ra', Rb are independently of each other H, -OR', -COOR', -
NHR', -CONHR', -SR', a phosphine or a heterocyclic group, or
a folate or derivative thereof, and
wherein of groups Ra, Ra' and Rb at least two adjacent groups are
a donor group -OH, -COOH, -NHR', -CONH2, -SH, a phosphine
or a heterocyclic group,
Re is H, C02R', COR', -S03R', -NHR', or straight-chain or
branched C1-C12 alkyl, which is unsubstituted or substituted by
at least one CN, Hal, or N02, or a folate or derivative thereof,
mis 0, 1, 2, 3, or 4, and
n is 1 or 2,
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Application 12/595,147
with the proviso that at least one of R6 and R7 is a group of
formula IV.
App. Br. 12-13.
ISSUES AND ANALYSES
We agree with, and adopt, the Examiner's findings and conclusion
that the appealed claims are prima facie obvious over the cited prior art
references. We address the arguments raised by Appellants below.
Issue
Appellants argue the Examiner erred in finding that the compounds of
claim 9 are obvious over the prior art. App. Br. 4.
Analysis
Appellants dispute the Examiner's conclusion that the claims on
appeal are prima facie obvious over the combined cited prior art. App. Br.
4. Specifically, Appellants argue that the references relied upon by the
Examiner do not support a finding that combining pteroates, pteroate
dipeptides, or "non-peptide" folic acid analogs with the histidine-like portion
of a histidine/bombesin conjugate would have been obvious to one of
ordinary skill in the art at the time the claimed invention was made. Id.
Appellants also contend that none of the references provide any suggestion
of a linker structure in accordance with Formula III of claim 9. Id.
Appellants also dispute the Examiner's finding that Leamon teaches
the parent structure Pte-Glu (i.e., folic acid), and that this structure is "a
compound of instant formula III." App. Br. 5 (citing Leamon 159, Fig. 1 ).
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Application 12/595,147
Appellants contend Pte-Glu is not a compound of claim 9's formula Ill since
it does not meet claim 9's requirement that at least one of R6 and R7 is a
group of formula IV.
Appellants assert that Green teaches the use of linkers that do not
contain peptide bonds, i.e., "non-peptide" folic acid analogs. App. Br. 6.
Appellants contend that, rather than proposing an alternative to a Pte-Glu
linkage, Green is specifically teaching a replacement of the Pte-Glu linkage
and therefore teaches away from Leamon.
Moreover, Appellants argue, Green teaches a very broad genus of
"non-peptide" folic acid analogs and, as defined by Green's formula I,
teaches a further very large number of possible linkers. Id. at 7 (citing
Green, Formula I ,-i,-i 37--48). Appellants point to the two exemplary
embodiments explicitly taught by Green, CYK4-013 and CY 4-036, and to
their intermediates, and argue that these do not suggest the linker of formula
III. Id. at 7-8 (citing Green, Figs. 2, 3).
Appellants argue Pak teaches compounds (viz., Pak's compounds 7a
and 7b ), which can be coupled to a free amino group of a biomolecule via
the acetyl group to form an amide bond (e.g., the acetyl group can be reacted
with an NH2 group of a peptide as shown in scheme 1 ). App. Br. 9.
Appellants contend Pak teaches that the Na can be deprotected and the ester
subjected to hydrolysis, thereby freeing all three of the coordination sites for
chelation (i.e., Na, N8, and COO} Id. (citing Pak schemes 1, 2; 2055).
Appellants argue that a person of ordinary skill in the art would not
have been motivated to modify the pteroate dipeptide Pte-Gly-Cys of
Leamon by replacing the cysteine moiety with a histidine moiety. App. Br.
9. According to Appellants, even though Mindt teaches histidine-like
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structures, i.e., 1, 2, 3-triazole-4-yl alanines, a person of ordinary skill would
find no reason to look to the disclosures of Mindt or Pak to modify the
dipeptide folate ligands taught by Leamon, i.e., Pte-yGlu-Cys, Pte-aGlu-Cys,
and Pte-Gly-Cys. Id. Appellants further argue a person of ordinary skill
would modify the resultant compound to "optionally include a linker as
taught by Green," because Green teaches linkers that represent many
thousands of possible compounds. Id. (citing, e.g., Green ,-i,-i 84-89).
Moreover, argue Appellants, the linkers of Green do not contain peptide
bonds, i.e., they form "non-peptide" folic acid analogs. Appellants contend
the compound proposed in the rejection is explicitly a dipeptide compound
(Pte-Gly-His). Consequently, Appellants argue, Green either teaches away
from the proposed modification, by suggesting linkers that contain no amino
acids, or provides no suggestion to modify the ligands taught by Leamon in
such a manner that the resultant compound retains a dipeptide structure, let
alone has the proposed structure of Pte-Gly-His. Id. at 9-10.
The Examiner responds that Leamon teaches Pte-G lu, a compound
that reads in part on Appellants' claimed formula III. Ans. 9. The Examiner
finds Leamon also teaches dipeptide conjugate 1251-BSA-Cys-Glu-Pte
exhibits substantially increased binding to HeLa cells relative to controls and
1251-BSA-Glu-Pte; consequently Leamon would have motivated a person of
ordinary skill to attach an additional spacer moiety, such as an amino acid, to
the distal end of the glutamyl moiety. Id. The Examiner finds Leamon
expressly teaches that carbodiimide-activated Pte-Glu or any of the pteroate-
dipeptide derivatives afforded equipotent delivery of functionally active
cytotoxic enzyme into treated cells. Id. at 9-10 (citing Leamon 168).
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Application 12/595,147
The Examiner relies upon Green as teaching diagnostic imaging of
folate receptor-positive cells using Pte-linker-diagnostic agent conjugates.
The Examiner finds Green teaches that folate-binding proteins involved in
endocytosis are less sensitive to modification of the folate molecule than the
membrane transport proteins, and often recognize folate conjugates. Ans.
10. The Examiner finds that both targeting and uptake of the Pte-linker-
conjugated diagnostic and therapeutic agents are enhanced and that Green
suggests a wide range of chelators and metals may be attached to folate
derivatives. Id.
The Examiner next finds Pak teaches derivatizing biologically active
molecules for radiopharmaceutical purposes. Ans. 10. Specifically, the
Examiner finds Pak teaches that the targeting vector has to be ( 1) derivatized
with appropriate chelator for 99mTc; (2) should be labeled with high specific
activity; and (3) retain its physiochemical properties and its affinity for the
corresponding receptor. Id. The Examiner finds Pak teaches histidine
derivatized at the £-nitrogen as an efficient chelator of [99mTc(OH2)3(C0)3t.
The Examiner finds that histidine derivatized at the £-nitrogen reads on
formula IV of claim 9. Id. at 10-11.
In summary, the Examiner concludes that a person of ordinary skill in
the art would have combined the prior art teachings with a reasonable
expectation of success because Leamon and Green teach the Pte-Glu (folate)
compound confers binding to high affinity folate recognition sites, such as
sites on tumor cells. See Final Act. 9. Green suggests incorporation of a
linker and diagnostic moiety, such as a chelating agent suitable for binding
99mTc, into folate derivatives to enable visualization with SPECT. Id. Pak
teaches that the introduction of tripodal NE-derivatized histidine into a
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Application 12/595,147
biomolecule enables labeling with 99mTc to yield a single
radiopharmaceutical compound of very high specific activity without further
purification. Id.
We are not persuaded by Appellants' arguments. We agree with the
Examiner that Leamon teaches folic acid derivatives comprising pteroic acid
and dipeptides that can bind macromolecules and still be capable of binding
to folic acid receptor species linked to endocytosis. See Leamon 167.
Furthermore, we agree with the Examiner that Green teaches a folic acid
mimetic conjugated to a diagnostic or therapeutic agent to enable selective
delivery of the agent to the targeted cell population. See Green Abstr.
Green also teaches chelation of metals to these linkers, including 99mTc. See,
e.g., Green ,-i 106. We also agree with the Examiner that Pak teaches
histidine (an amino acid) linker complexes that can chelate 99mTc and are
capable of being bound to biomolecules with pendant amines. See Pak
Abs tr.
We conclude that a person of ordinary skill would be motivated to
combine the teachings of the cited prior art references. All of the references
are analogous art from the same highly-specialized field of endeavor and
would be within the scope of the knowledge of a person of ordinary skill.
We agree with the Examiner that such an artisan would realize that
combining the references would provide a desirable means by which a
radioactive marker such as 99mTc can be targeted specifically at cells
expressing the appropriate folic acid receptors.
Appellants contend that Leamon does not teach the entire claimed
molecule because it does not teach that a moiety of formula IV must be
attached to either R6 or R7. However, Leamon does teach (and Appellants
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do not dispute) formula Ill of claim 9, and it is not necessary that a single
reference teach the entire composition when the rejection is based on
obviousness over a combination of references. See In re Keller, 642 F.2d
413, 426 (C.C.P.A. 1981). Moreover, Pak explicitly teaches histidine, which
corresponds to formula IV and is an amino acid capable of forming a peptide
linkage to the glutamate moiety of folate. Indeed, the Pte-Glu-His dipeptide
folate derivative is explicitly depicted as a specific embodiment in Figure 1
of Appellants' Specification.
Appellants also argue that their claimed folate-conjugate compounds
of the present application show an unexpected high tumor-to-blood value,
which proves the high potency of the compounds for applications in
diagnostic imaging and treatment of tumors. App. Br. 4 (citing Spec. Tables
la and 2a). Although it may well be true that the claimed compounds do
show excellent results, Appellants do not demonstrate that the results are
unexpectedly different when compared with the closest prior art. See In re
Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) ("[W]hen
unexpected results are used as evidence of nonobviousness, the results must
be shown to be unexpected compared with the closest prior art"). Indeed,
the prior art cited by the Examiner directly suggests that a number of
different folate-dipeptide compounds are capable of being internalized into
the cytosol via endocytosis. See, e.g., Leamon 167; Green ,-i 21.
Nor are we persuaded by Appellants' argument that Green teaches
away from the teachings of Leamon and their claimed invention because
Green specifically teaches a replacement of the Pte-Glu linkage. See App.
Br. 6. Green explicitly acknowledges the Pte-Glu linkage, as well as other
Pte-amino acid linkages, and teaches non-peptide linkages as an alternative.
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See Green iJ 22 ("A folic acid analog capable of expanding the number or
diversity of agents, via the conjugates of such agents and these folic acid
analogs, presentable to target cells would be advantageous"). However, a
reference teaches away when "a person of ordinary skill, upon reading the
reference, would be discouraged from following the path set out in the
reference, or would be led in a direction divergent from the path that was
taken by the applicant." In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
Appellants point to no teachings of Green that would necessarily discourage
or divert a person of ordinary skill from either the teachings of Leamon or
their claimed invention. Furthermore, merely teaching an alternative or
equivalent method does not teach away from the use of a claimed method.
See, e.g., In re Dunn, 349 F.2d 433, 438 (C.C.P.A. 1965).
Finally, we are not convinced by Appellants' implicit allegation that
the Examiner impermissibly employed hindsight reasoning in combining the
references. See App. Br. 10. We have related supra our reasoning as to why
a person of ordinary skill in this sophisticated art would be motivated to
combine the analogous art references cited by the Examiner. Moreover,
Appellant point to no finding of the Examiner's that could have been
gleaned only from Appellants' Specification or was not within the scope of
knowledge of a person of ordinary skill in the art at the time Appellants'
application was filed. See In re McLaughlin, 443 F.2d 1392, 1395 (C.C.P.A.
1971).
Consequently, and for the reasons we have set forth, we affirm the
Examiner's rejection of the claims on appeal.
DECISION
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Application 12/595,147
The Examiner's rejection of claims 9, 10, 12, 15-18, 20, 21, 23, 24,
26-28, 33, 40, 41, 44, 45, and 47 as unpatentable under 35 U.S.C. § 103(a)
is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § l.136(a)(l). See 37 C.F.R.
§ l.136(a)(l )(iv).
AFFIRMED
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