Ex Parte Schibli et al

Patent Trial and Appeal Board

Dec 11, 2017

14239275 (P.T.A.B. Dec. 11, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/239,275 02/18/2014 Roger Schibli MERCK-4433 1379
23599 7590 12/18/2017
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON, VA 22201
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
12/18/2017 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 ROGER SCHIBLI, RUDOLF MOSER, CRISTINA
MAGDALENA MULLER, SIMON MENSAH AMETAMEY,
CINDY RAMONA FISCHER, and VIOLA GROEHN
Appeal 2017-002146
Application 14/239,275
Technology Center 1600
Before DEBORAH KATZ, ROBERT A. POLLOCK, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appeal 2017-002146
Application 14/239,275
Appellants1 seek our review, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 3—10, 13, 15, 16, 18, 20 and 29-30.2
(App. Br. 1.) We have jurisdiction under 35 U.S.C. § 6(b).
The Examiner rejected claims 1—4, 7, 13, and 18 under 35 U.S.C.
§112, second paragraph. (See Ans. 4.) We do not affirm this rejection.
The Examiner also rejected claims 3—10, 13, 15, 16, 18, 20 and 29-
303 under 35 U.S.C. § 103 over Ametamey,4 Maschauer,5 and Bettio.6 In
addition, the Examiner rejected these claims under the doctrine of obvious-
type double-patenting over Patent 8,344,140 (“the ’140 patent”), claims 1—
23, in view of Maschauer and Bettio. We affirm these rejections.
Appellants do not provide separate arguments against the individual
claims recited in the Examiner’s rejections. Accordingly, we focus on claim
3 in our analysis. See 37 C.F.R. § 41.37(c)(l)(iv).
1 The real party in interest is reported to be Merck Patent GmbH. (App. Br.
1.)
2 Claims 1, 2, 21, and 22 were canceled, while claims 11, 12, 14, 17, 19 and
23—28 were withdrawn. (See App. Br. 1.)
3 In the Answer, the Examiner referred to claims 1—10, 13, 15—16, 18, and 20
(see, e.g., Ans. 4), but claims 1 and 2 have been canceled. (See App. Br. 1.)
Accordingly, our decision is directed only to claims 3—10, 13, 15, 16, 18, 20
and 29—30. In addition, the Examiner discussed the rejections of claims 29
and 30 separately. (See, e.g., Ans. 7—8.) We consider all of the rejected
claims together, focusing on claim 3.
4 Ametamey et al., WO 2008/125615 Al; published October 23, 2008.
5 Maschauer and Prante, A series of 2-0-trifluoromethylsulfonyl-o-
mannopyranosides as precursors for concomitant 18F-labeling and
glycosylation by click chemistry, 344 Carbohydrate Res. 753—761 (2009).
6 Bettio et al., Synthesis and Preclinical Evaluation of a Folic Acid
Derivative Labeled with 18F for PET Imaging of Folate Receptor—Positive
Tumors, 47 J. Nucl. Med. 1153-1160 (2006).
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Appellants’ Specification is directed to 18F-folate
radiopharmaceuticals that can be used as diagnostic, monitoring, and
therapeutic agents for certain cancers and inflammatory diseases because of
the overexpression of folate receptors on cells implicated in those
conditions. (Spec. 1—2.) Appellants’Specification reports that 18F-labeled
folic acid derivatives were known in the art. (Spec. 6.) Many of those,
especially having the 18F isotope directly linked or linked through a
prosthetic group to the folate molecule, were time-consuming to synthesize,
had low radiochemical yields, or had unfavorable pharmacokinetics. (Spec.
6.)
To address these problems, Appellants assert that they invented
efficient and versatile methods of producing new 18F-labeled folate
radiopharmaceuticals, wherein the 18F isotope is introduced via a prosthetic
group having a saccharide moiety, such as a cyclic mono- or oligosaccharide
preferably based on a pyranoside or furanoside. (Spec. 6.)
Appellants’ claim 3 recites:
A compound of the formula II:
II
wherein
Xi to X5 are, independently of each other: C, N or O,
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Ri, and R2 are, independently of each other: H, halogen, C(l-
12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, -OR5, -COR5, -COOR5, -
NHR5, -CONHR5, or-CONHR5, wherein R5 represents H, halo, C(l-
12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, -OR’, -COR’, -COOR’, or
—NHR’, and wherein R’ is H or C(l-8)alkyl,
R3 and R4 are, independently of each other: H, nitroso, C(l-
12)alkyl, -OR’, -COR’ or halosubstituted -COR’, wherein R’
represents H or C(l-8)alkyl,
Yi and Y2 are independently of each other: O, N or S,
m is 1, 2 or 3,
r has a value of 1 to 7,
p is 0 or 1,
Qi and Q2 are, independently of each other: H, a protecting
group or a group of formula—L-A-L’- 18F.
wherein
L and L’ are independently of each other: a linking group,
which is a covalent bond or a straight-chain or branched C(l-50)alkyl,
which is unsubstituted or substituted by at least one CN, Hal, OH,
NH2, CO2H, or NO2, and wherein one or more of the non-adjacent
CH2 groups may independently be replaced by a group selected from
-0-, -CO-, -C0-,-0-C0-,-NR’ -,-NR’ -CO-,-CO-NR’ -,-NR’ -CO-O-
,-0-, CO-NR’ -,-NR’ -CO-NR’ -,-CH=CH-,-C5C-,-0-C0-0-, -S-R’-,
-SO3R’-, and a five- or six-membered heterocycle, wherein R’
represents H or C(l-8)alkyl, and
A is a saccharide group,
with the proviso that at least one of Qi and Q2 is a group of
formula —L-A-L’-18F.
(App. Br. 14—15, Claims App’x.)
35 U.S.C. § 112, second paragraph
The Examiner rejected claims 1—4, 7, 13 and 18 as being indefinite,
asserting that the term “protecting group” does not define the metes and
bounds of the claims. (Ans. 4.) The Examiner acknowledged that
Appellants’ Specification defines “protecting group” and provide examples
(see Spec. 27—28), but maintains the rejection because of a perception that it
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Application 14/239,275
is unclear which groups are intended to be encompassed by the claim. (See
Ans. 12.) As an example, the Examiner asserts that in some instances a
carboxyl protecting group includes hydrogen and in other instances it
excludes hydrogen.
We are persuaded that this rejection is erroneous because, as
Appellants argue, the Specification provides examples to guide the
ordinarily skilled artisan. (See App. Br. 4; Reply Br. 1.) In addition, as
Appellants argue, the Specification incorporates by reference a publication
that provides further protecting groups and techniques to use them. (See
Spec. 28 (citing "Protective Groups in Organic Synthesis" Third Ed. Greene,
T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York: 1999).)
We do not agree with the Examiner that the claim term is improperly
based on limitations imported from the examples. Instead, Appellants show
that the Specification provides guidance about the choice of an appropriate
protecting group. The Examiner does not explain why this guidance is
unsatisfactory.
35U.S.C.§ 103
The Examiner finds that Ametamey teaches 18F-folate
radiopharmaceuticals with 18F covalently linked through a triazole- or
tetrazole-linker to a folate or derivative thereof for use in PET imaging.
(Ans. 4; see Ametamey 1 and 36.) Ametamey teaches that the 18F can be
added by cycloaddition of an azide with an alkyne, called a “Click-
Reaction.” (Ametamey 14.)
Bettio also teaches folic acid radiopharmaceuticals labelled with 18F.
(Bettio 1153—54; see Ans. 5—6.) Bettio teaches folic acid linked to 18F
through 4-fluorobenzylamine as a prosthetic group. (Id.)
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The Examiner acknowledges that neither Ametamey nor Bettio
teaches the species of Appellants’ claimed compound depicted below,
wherein the 18F label is attached to the folate through a saccharide.
HO'
HQ
1.-sS-VIsf
H
V
1 HNj
K*H>
labeled compound or
19F(reference compound)
(Spec. Fig. 2B (described as a [18F ]- or [19F ]-glucose folate compound at
Spec. 13).)
Maschauer teaches labeling peptides with 18F using mannoside
saccharides linked through triazoles in a “click chemistry” reaction. (See
Maschauer 753—54 and 756, Scheme 4; Ans. 6.) In the reaction of
Maschauer, an alkyne-functionalized amino acid derivative is glycosylated
to achieve 18F labeling. (See Maschauer abstract.) Maschauer teaches that
glycosylation of peptides enhances the biokinetics and in vivo clearance
properties of peptides. (See id. 753.) Maschauer does not teach 18F labeled
folates or derivatives of folates. The 18F labeled compounds of Maschauer
are useful in PET imaging. (See id. 756.)
The Examiner’s rejection is based on substituting the triazole linkers
of the 18F-labelled folate compounds of Ametamey with the 18F
glucopyranoside labels taught in Maschauer. (See Ans. 7.) The Examiner
finds that one of ordinary skill in the art would have made this substitution
because the prosthetic groups of Maschauer are hydrophilic, durable, and
high-yielding, based on reliable radiochemistry. (See id.)
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According to Appellants, the primary feature of Ametamey is a
linking group containing a triazole- or a tetrazole group. (See App. Br. 7—8
and 11; see also Reply Brief 3.) Appellants argue that neither Ametamey
nor Bettio teach linking an 18F label to a folate with a saccharide-containing
linker, as claimed. (See App. Br. 8—9.) Appellants also argue that
Maschauer provides no teaching or suggestion regarding folates or related
compounds. (See id. 9.) These arguments do not persuade us that the
Examiner erred because “[n]on-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references.” In re Merck & Co., Inc., 800
F.2d 1091, 1097 (Fed. Cir. 1986).
Similarly, we are not persuaded by Appellants’ arguments that the
compounds taught in Bettio are inferior to the claimed compounds. (See
App. Br. 9.) The Examiner’s rejection is not based on Bettio alone.
Appellants cite to Bemard-Gauthier7 to argue that the steps necessary
to synthesize the claimed compounds would not have been standard
synthetic steps known to one of ordinary skill in the art at the time of
Appellants’ filing and could not have been simply carried out with
compounds other than those recited in the cited references. (See App. Br. 6—
7; see Reply Br. 2.) We are not persuaded by Appellants’ argument because
although Bemard-Gauthier discusses “relatively cumbersome and lengthy
labeling procedures” and the need for a final purification, these “obstacles”
7 Bamard-Gauthier et al., 18F-Labeled Silicon-Based Fluoride
Acceptors: Potential Opportunities for Novel Positron Emitting
Radiopharmaceuticals, 2014 BioMed Research Inf1 1—20 (2014).
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do not indicate that before Appellants’ filing date those of skill in the art
considered it to be beyond their knowledge or reasonable ability to
radiolabel with 18F. (See Bemard-Gauthier 2.) Indeed, Bemard-Gauthier
reports that
[i]n principle, almost any organic compound can be
radioactively labeled depending on the nuclide; the acceptable
level of derivatization which is necessary particularly in
radiometal labeling, and of course the position of the label
itself. With the contingent of existing labeling methods, it is
possible to label nearly all compounds in sufficient
radiochemical yields (RCYs)....
(Bemard-Gauthier 1—2.) Because Appellants’ claims recite 18F-labled folate
compound without limitation to amount or concentration, we are not
persuaded that the obstacles discussed in Bemard-Gauthier indicate it would
have been unobvious to make 18F-labeled folate as claimed by modifying the
teachings of Ametamey, Bettio, and Maschauer as proposed by the
Examiner. Bemard-Gauthier is focused on “clinical routine production” of
18F-lablelled compounds (see id.), an element not recited in Appellants’
composition claims on appeal.
Appellants argue further that the Examiner failed to provide
articulated reasoning for making the proposed substitution and that those of
ordinary skill in the art would not have had a reasonable expectation of
success in making it. (See App. Br. 6 and 12.) But Appellants do not
dispute the reasons for combining the teachings of the prior art cited by the
Examiner. For example, Appellants do not dispute that the prosthetic groups
taught in Maschauer are hydrophilic, durable, and high-yielding. (See Ans.
7.) Accordingly, we are not persuaded that the Examiner erred in providing
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a reason why those of skill in the art would have considered the claimed
compound to be obvious.
We are also not persuaded that one of ordinary skill in the art would
not have reasonably expected success in combining the teachings of the cited
references. Appellants argue that Maschauer provides no reasonable
expectation that “clickable mannopyranosides,” as taught in Maschauer,
could be used to label folates because Maschauer only teaches labeling
amino acids. (See App. Br. 9.) We are not persuaded by this argument
because the reactions taught in Ametamey rely on similar chemistry.
Maschauer teaches radioflourination of saccharides attached to an
azide by cycloaddition to a triazole. (See Maschauer 756, Scheme 4 (“In
conclusion, a new mannosyl azide precursor was successfully synthesized
for the radiosynthesis of a ‘clickable’ 18F-glycosyl donor as a hydrophilic
prosthetic group. With this precursor ... a simple and reliable click
chemistry-based three-step, two-pot concomitant 18F-labeling and
glycosylation of alkyne-fimctionalized molecules in high radiochemical
yields has been established.”); see Ans. 13—14.) Similarly, Ametamey
teaches radiofluorination of folate by cycloaddition of an azide and alkyne to
produce a triazole linker in a Click Reaction. (See Ametamey 34 (“the
compounds of the invention may be obtained in an effective manner by a
process which comprises a cycloaddition of an azide with an alkyne or
alkyne substitute under thermal conditions or in the presence of a catalyst.
These reactions are known as Huisgen 1,3-dipolar cycloaddition (thermal
conditions) and Click-Reaction (catalytic conditions). . . see Ans. 13—
14.) Thus, both Ametamey and Maschauer teach radiolabeling with 18F
through similar pathways — cycloaddition to produce a triazole. (See Ans.
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14.) Appellants do not dispute this finding. Accordingly, we are not
persuaded that Appellants’ claimed compounds are more than the
substitution of one element for another known in the field (specifically, the
substitution of the saccharide of Maschauer for the spacer of Ametamey),
producing a predictable result. See KSR Int'l Co. v. Teleflex Inc., 550 U.S.
398,416 (2007).
Appellants argue further that Ametamey would lead one of ordinary
skill in the art to linkers distinct from the saccharide linker of the claimed
invention. (See App. Br. 8.) Appellants argue that Ametamey does not
expressly teach saccharide linkers, but that it provides a broad array of other
options. (See id.) Similarly, Appellants argue that Ametamey and Bettio
“direct away” from combining the saccharide linkers of Maschauer because
they teach different linkers (triazole linkers in Ametamey and benzylamine
linkers in Bettio). (See id. 9-10.)
Appellants state that they are not presenting a “teaching away”
argument (see App. Br. 11) and we agree that if the references do not
discredit or discourage a saccharide linker, they do not “teach away” as
defined in the case law. But we are not persuaded that the teachings of
linkers in Ametamey and Bettio indicate Appellants’ claimed compounds
would not have been obvious because the Examiner’s rejection is based on
the modification of the Ametamey compounds, not the linkers taught
therein. According to Appellants, modification of the compounds of
Ametamey to include a saccharide linker “would destroy a primary
characterizing feature of the Ametamey compounds (i.e., use of a triazole- or
a tetrazole linking group). . . .” (Id.) We are not persuaded that the
“primary” feature of Ametamey is the linker and not the radiolabeling of
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folate. Appellants do not explain why modification to add saccharide by
cycloaddition of an azide and alkyne to produce a triazole linker, as taught in
Maschauer (see Maschauer 756, Scheme 4), would destroy this feature.
Furthermore, Appellants do not explain why the production of somewhat
different 18F-folate compounds that exhibit the advantages taught in
Maschauer would destroy the purpose of the 18F-folate compounds taught in
Ametamey.
Appellants cite to Hart8 and George9 as evidence of the non­
obviousness of the claimed compounds. (See App. Br. 10; see Reply Br. 2.)
According to Appellants, these articles teach that modification of the
glutamic acid portion of folate could have adverse effects on its biological
activity, indicating that there would not have been a reasonable expectation
of success in such modification. (See App. Br. 10.) We are not persuaded
by Appellants’ arguments because they do not explain that the site of
attachment in Hart or George is different from that in Ametamey. (See
Ametamey 12:4—8 (“The present invention is in a first aspect directed to new
18F-folate radiopharmaceuticals . . . , wherein fluorine-18 is linked through a
triazole or a tetrazole linker to a folate or derivative thereof, such as to the
glutamate functionality of folic acid.”) Thus, we are not persuaded that any
effect of the modification of the glutamic acid portion on the biological
8 Hart et al., Synthesis and Biological Activity of Folic Acid and
Methotrexate Analogues Containing L-threo-(2S,4S)-4-Fluoroglutamic Acid
and DL-3,3-Difluoroglutamic Acid, 39 J. Med. Chem. 56—65 (1996).
9 George et al., Mammalian Folylpoly-y-glutamate Synthetase. 3. Specificity
for Folate Analogues, 26 Biochemistry 522—529 (1987).
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activity of folate would necessarily discourage those in the art from linking
18F there.
Furthermore, although Appellants discuss the “serious drawbacks” of
modifying the glutamic acid portion of folate taught in Hart and George,
Appellants’ claimed compounds are not limited to any specific level of
biological activity. In view of the all of the cited references, we are not
persuaded that one of ordinary skill in the art would have expected glutamic
acid-modified folate to be inoperable.
Double-Patenting
The Examiner rejected all of Appellants’ pending claims under the
doctrine of obviousness-type double-patenting over the ’140 patent, Bettio,
and Maschauer. (See Ans. 9—10.) The Examiner finds that claims 1—12 of
the ’ 140 patent recite 18F-folate derivatives bearing a triazolyl linker moiety
and that those of ordinary skill in the art would have substituted the 18F-
glucopyranoside label as taught in at least Maschauer for the generic linker
recited in claims 1—23 of the ’014 patent to achieve the advantages of
hydrophilicity, durability, and high-yield, as well as reliability. (Ans. 9 and
14.)
Appellants argue that the Examiner erred for the same reasons argued
against the rejections under 35 U.S.C. § 103. (App. Br. 12.) As discussed
above, we are not persuaded by these arguments.
Appellants also argue that claim 1 of the ’140 patent excludes
compounds with saccharide-containing linking group recited in Appellants’
pending claims. According to Appellants there is not “generic overlapping
scope” between Appellants’ pending claims and the claims of the ’140
patent. (App. Br. 12—13.) Appellants argue that claims 1—23 of the ’140
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patent specifically exclude the subject matter of Appellants’ currently
pending claims.
We are not persuaded by Appellants’ arguments because even if the
currently claimed compounds are not overlapping in scope with or exclude
the subject matter claimed in the ’140 patent, if the current claims are
rendered obvious by the claims of the ’140 patent, they are unpatentable
over those claims. “A double-patenting rejection precludes one person from
obtaining more than one valid patent for either (a) the ‘same invention’ or
(b) an ‘obvious’ modification of the same invention.” In reLongi, 759 F.2d
887, 892 (Fed. Cir. 1985) (explaining that overlapping and conflicting
claims are considerations more significant in a § 101 “same invention”
double patenting analysis, but are not significant or controlling factors in an
obviousness type double patenting analysis where a rejection may be applied
to clearly distinct inventions.).
Like the compounds of Ametamey, the compounds recited in claims
1—23 of the ’140 patent have a triazole linker. For the reasons discussed
above, we are not persuaded that the Examiner erred in concluding the
currently claimed subject matter to be obvious over such compounds.
Conclusion
Upon consideration of the record and for the reasons given, the
rejection of Appellants’ claims under 35U.S.C. § 112, second paragraph, is
not sustained.
The rejection of Appellants’ claims under 35 U.S.C. § 103(a) over
Ametamey, Bettio, and Maschauer is sustained. The rejection of Appellants’
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claims under the doctrine of obvious-type double-patenting over the ’140
patent, Bettio, and Maschauer is also sustained.
Therefore, we affirm the decision of the Examiner.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136.
AFFIRMED
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