Ex Parte Fox et al

Patent Trial and Appeal Board

Feb 25, 2019

13811568 (P.T.A.B. Feb. 25, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/811,568 06/24/2013
66469 7590 02/27/2019
RATNERPRESTIA
2200 RENAISSANCE BL VD
SUITE 350
KING OF PRUSSIA, PA 19406
FIRST NAMED INVENTOR
Joseph M. Fox
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.
U0D-338US 4859
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
02/27/2019 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):
PCorrespondence@ratnerprestia.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte NICHOLAS LOEBEL and CALE STREET
Appeal2017-004485
Application 13/811,568
Technology Center 1600
Before JEFFREY N. FREDMAN, JOHN G. NEW, and
RICHARD J. SMITH, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1,2 under 35 U.S.C. § 134(a) involving claims to a
radiolabeled Diels-Alder adduct of a trans-cyclooctene with a tetrazine. The
Examiner rejected the claims as obvious. We have jurisdiction under 35
U.S.C. § 6(b). We reverse.
1 Appellants identify the Real Parties in Interest as the University of
Delaware and the University of Southern California (see App. Br. 1 ).
2 We have considered and herein refer to the Specification of Jan. 22, 2013
("Spec."); Final Office Action of Dec. 22, 2015 ("Final Act."); Appeal Brief
of Aug. 22, 2016 ("App. Br."); and Examiner's Answer of Nov. 3, 2016
("Ans.").
Appeal2017-004485
Application 13/811,568
Statement of the Case
Background
"Positron emission tomography (PET) is a non-invasive imaging
modality that utilizes positron-emitting radionuclides .... For example, F-
18 PET has a number of attributes that make it clinically attractive, including
100% positron efficiency, a very high specific radioactivity, and a short half-
life of -110 min" (Spec. 1 :4--7). "The invention provides an extremely fast
and reactive method for generating radionuclide labeled probes based on
TTCO [tetrazine-trans-cyclooctene]-ligation, employing a Diels-Alder
reaction between 3,6-diaryl-s-tetrazines and trans-cyclooctenes, one of
which is labeled with a radionuclide, for example 18F" (Spec. 4:9-12).
The Claims3
Claims 1, 4, 13, 14, and 20 are on appeal. Claims 1 and 20 are
representative and read as follows:
1. A Diels-Alder adduct of a trans-cyclooctene with a
tetrazine, wherein the adduct bears a substituent labeled with
a radionuclide, wherein the substituent is a substituent on the
trans-cyclooctene residue of the Diels-Alder adduct.
20. The compound according to structure 9
1~
Oh~.~ H.
~~""
3 We limit our consideration of the merits of the appealed rejection to the
elected species. See Ex parte Ohs aka, 2 USPQ2d 1460, 1461 (BP AI 1987).
Thus, we read the claims as limited to compound 9 shown in claim 20 (see
Response to Election/Restriction filed on June 29, 2015).
2
Appeal2017-004485
Application 13/811,568
The Issue4
The Examiner rejected claims 1, 4, 13, 14, and 20 under 35 U.S.C.
§ 103(a) as obvious over Blackman, 5 Royzen, 6 Arstad, 7 and Zhang8 (Ans. 2-
6).
The Examiner finds Blackman teaches "strained click reactions that
take advantage of intrinsic reactivity of cylcooctyne towards organic azides"
that "could form the basis of powerful bioorthogonal reaction" (Ans. 2).
The Examiner finds that Royzen teaches "synthesis of trans-cyclooctene
derivative" and functionalization of that derivative with a hydroxy
substituent (see Ans. 3--4).
The Examiner finds Arstad teaches "a need for labelling agents such
as 18F-labelled prosthetic groups and methodologies, which allow rapid,
chemoselective introduction of a label such as a radionuclide" (Ans. 4). The
Examiner finds Zhang teaches a "labeling strategy has been developed for
introducing 18F onto a target molecule by first attaching 18F to a prosthetic
groups" (Ans. 5).
4 We note that claim 10, identified as rejected in the Examiner's Answer,
was cancelled in an Amendment filed Nov. 16, 2015.
5 Blackman et al., Tetrazine Ligation: Fast Bioconjugation Based on
Inverse-Electron-Demand Diels-Alder Reactivity, 130 J. Am. Chem. Soc.
13518-9 (2008).
6 Royzen et al., A Photochemical Synthesis of Functionalized trans-
Cyclooctenes Driven by Metal Complexation, 130 J. Am. Chem. Soc. 3760-
1 (2008).
7 Arstad et al., WO 2006/067376 A2, published June 29, 2006.
8 Zhang et al., {1 8F]Fluoroalkyl Agents: Synthesis, Reactivity and
Application for Development of PET Ligands in Molecular Imaging, 7
Current Topics in Medicinal Chem. 1817-28 (2007).
3
Appeal2017-004485
Application 13/811,568
The Examiner finds:
It would have been obvious to one of ordinary
skill in the art at the time of invention to modify the
compounds taught by Blackman et al. (i.e.,
compounds transcyclooctene discussed above) by
simply incorporating a [18F]fluoroethyl radical as
taught by Royzen et al., because it would
advantageously enable inverse-electron-demand diels-
alder reactivity with appropriate tetrazine bearing
biomolecule in the absence of catalysis and in tum
PET imaging.
(Ans. 6).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner's conclusion that Blackman, Royzen, Arstad, and
Zhang suggest the compound 9 of claim 20?
Findings of Fact
1. Blackman teaches "a bioorthogonal reaction that proceeds with
unusually fast reaction rates without need for catalysis: the cycloaddition of
s-tetrazine and trans-cyclooctene derivatives" (Blackman 13518, col. 1).
2. Blackman teaches "[b ]ioorthogonal reactions, unnatural
transformations that are unaffected by biological functionality, are broadly
useful tools with applications that span synthesis, chemical biology, and
materials science . . . and the enhanced reactivity enables applications for
dynamic in vivo imaging" (Blackman 13 518, col. 1 ).
3. Scheme 3a of Blackman is reproduced below:
an.· I;
HO· ·. / ,_,..
4
Blackman teaches "trans-Cyclooctene derivative 5 is readily accessible from
4
Appeal2017-004485
Application 13/811,568
cis-cyclooctene 4 by a photochemical protocol" (Blackman 13 518, col. 2).
4. Royzen teaches the "unusual reactivity and well-defined chiral
structure of trans-cyclooctene make it an attractive framework for
stereocontrolled synthesis" (Royzen 3760, col. 1).
5. Royzen teaches compound 2b as reproduced below:
(Royzen 3761, col. 1).
6. Royzen teaches functionalizing compound 2B in Figure 2a as
reproduced below:
a
2b
(mlnor diastereomar)
NaH j l,............_,CO ... fi
THF L
..,..---CQ..,H
H O "
~
H s
"Figure 2. (a) Preparation and X-ray structure of a trans-cyclooctene with an
axial substituent. 1,3-Diaxial interactions are highlighted" (Royzen 3761,
col. 1 ).
7. Arstad teaches "a need for labelling agents such as 18F-labelled
prosthetic groups and methodologies, which allow rapid, chemoselective
introduction of a label such as a radionuclide, for example 18F, particularly
into peptides" (Arstad 1 :32 to 2:2).
8. Zhang teaches "fluorine-18 ... is an important positron emitter
for theimaging study using PET due to its optimal decay characteristics ...
So far, a number of methods for introducing 18F into a taqrget molecule have
5
Appeal2017-004485
Application 13/811,568
been developed" (Zhang 1817, col. 1 ).
Principles of Law
A prima facie case for obviousness requires "a reason that would have
prompted a person of ordinary skill in the relevant field to combine the
elements in the way the claimed new invention does." KSR Int'! Co. v.
Teleflex Inc., 550 U.S. 398,418 (2007).
Analysis
Appellants contend that "Arstad does not discuss trans-cyclooctenes"
and "provides no motivation to instead use an 18F-containing
transcyclooctene, and particularly Appellants' Compound 9" (App. Br. 4--5).
Appellants contend "Zhang does not disclose or suggest making compounds
where the 18F fluoroalkyl group is attached to oxygen, such as Appellants'
claimed compound 9" (id. at 5, emphasis omitted). Appellants contend
"nothing in Zhang suggests substituting a trans-cyclooctene with an
[
18F]fluoroethyl radical" and "motivation cannot come from Zhang, who
does not discuss labeling biomolecules and provides no suggestion to do so.
More particularly, Zhang provides no motivation to label a biomolecule
indirectly via an 18F-containing trans-cyclooctene" (id.).
The Examiner responds that because "Arstad teaches click reactions
that enable applications for in vivo dynamic imaging" and " 18F-labelled
bioactive peptides have great clinical potential because of their utility in PET
to quantitatively detect and characterize a wide range of diseases",
it would have been obvious to a person of ordinary
skill to incorporate 18F-label onto the diels-alder
substrates of Blackman because it would
advantageously enable applications for quantitative
dynamic in vivo imaging and high yield conjugation
without the need for a catalysis in organic solvents,
6
Appeal2017-004485
Application 13/811,568
water, cell media, or cell lysate.
(Ans. 8).
We find that Appellants have the better position because the Examiner
has not established a persuasive "reason that would have prompted a person
of ordinary skill in the relevant field to combine the elements in the way the
claimed new invention does." KSR, 550 U.S. at 418. While Blackman
mentions in vivo imaging (FF 2) and Arstad and Zhang discuss the use of 18F
in labeling agents (FF 78), the Examiner does not persuasively demonstrate
why the ordinary artisan would have found it obvious to incorporate an 18F
into the trans-cyclooctene compound 2b of Royzen. Royzen does not teach
that compound 2b or compound 3 may be used in medical imaging. Royzen
does not even teach that these compounds are used as biological linkers.
Moreover, while Blackman generally discusses bioconjugation and medical
imaging (FF 1-3), Blackman does not discuss labeling any compound, much
less compound 5, with any type of label. Even the single mention of
imaging in Blackman (FF 2) does not identify how the imaging occurs or
provide any suggestion or reason to image using any type of label, much less
a radioactive label such as 18F.
Thus, the Examiner's prima facie case of obviousness is not
persuasive because there is no persuasive evidence linking the 18F labeling
teachings of Arstad and Zhang with the trans-cyclooctene compounds of
Royzen and Blackman, sufficient to provide a reason to label a trans-
cyclooctene compound with 18F.
Conclusion of Law
The evidence of record does not support the Examiner's conclusion
that Blackman, Royzen, Arstad, and Zhang suggest the compound 9 of claim
7
Appeal2017-004485
Application 13/811,568
20.
SUMMARY
In summary, we reverse the rejection of claims 1, 4, 13, 14, and 20
under 35 U.S.C. § 103(a) as obvious over Blackman, Royzen, Arstad, and
Zhang.
REVERSED
8