David J. Yang et al.

Patent Trials and Appeals Board

Feb 19, 2020

13562879 - (D) (P.T.A.B. Feb. 19, 2020)

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.
13/562,879 07/31/2012 David J. Yang UTSC.P0963US.D1 6605
108197 7590 02/19/2020
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
Austin, TX 78746
EXAMINER
SCHLIENTZ, LEAH H
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
02/19/2020 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):
docket@phiplaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DAVID J. YANG, DONGFANG YU,
ANDREW S. THOMPSON, and F. DAVID ROLLO1
Appeal 2019-001183
Application 13/562,879
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of imaging the heart, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.
STATEMENT OF THE CASE
“Embodiments of the present invention . . . pertain to methods of
diagnosis, assessing efficacy of treatment, or imaging in a subject with
known or suspected cardiovascular disease.” Spec. 27:20–22. “Imaging . . .

1 Appellant identifies the real parties in interest as Cell>Point LLC and The
Board of Regents of the University of Texas System. Appeal Br. 3. We use
the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a).
Appeal 2009-001183
Application 13/562,879

2
may involve administering to the subject a pharmaceutically effective
amount of a metal ion labeled chelator-targeting ligand conjugate.” Id. at
28:6–9. “In particular embodiments, the metal ion-labeled radionuclide-
targeting ligand conjugate is 99m-Tc-EC-glucosamine.” Id. at 28:12–13.
Ethylenedicysteine-glucosamine (a.k.a. EC-glucosamine, EC-G, or
EC-DG2) has the following structure:

Spec. 41:27–28, Fig. 13.
Claims 86, 87, 93, 95–99, and 113–116 are on appeal. Claim 95,
reproduced below, is illustrative:
95. A method of imaging the heart of a subject with a
cardiovascular disease comprising:
(a) obtaining a metal ion-labeled-chelator targeting ligand
conjugate, the conjugate being between about 90% and
about 99.9% pure as measured by HPLC using ELSD
detection, wherein the conjugate has been previously
prepared by a synthetic method comprising:
(1) conjugating, in an organic medium, a protected
ethylenedicysteine of the following formula:

2 See Declaration under 37 C.F.R. § 1.132 of Andrew Thompson, filed
October 3, 2016, ¶ 4 (“ethylenedicysteine-glucosamine (EC-DG or EC-G)”).
Appeal 2009-001183
Application 13/562,879

3
to a glucosamine, wherein:
A and D are each a protected thiol;
B and C are each a protected tertiary amine;
and the conjugation is via an amide bond formed
between a -COOH group of the protected
ethylenedicysteine and the amino group of the
glucosamine to form a protected
ethylenedicysteine glucosamine;
(2) removing each protecting group, in one or more
steps, from the protected ethylenedicysteine
glucosamine to form ethylenedicysteine
glucosamine (EC-G); and
(3) chelating a metal ion to the EC-G to form a metal
ion labeled-chelator-targeting ligand conjugate;
(b) administering to the subject a pharmaceutically or
diagnostically effective amount of the conjugate; and
(c) imaging the heart of the subject to detect a signal from
the metal ion of the conjugate.
The claims stand rejected as follows:
Claims 86, 87, 93, 95–99, and 113–116 under 35 U.S.C. § 103(a) as
obvious based on Verbeke3 and Yang4 (Final Action5 3) and
Claims 86, 87, 93, 95–99, and 113–116 under 35 U.S.C. § 103(a) as
obvious based on Oh,6 Yang, and Tidmarsh7 (Final Action 17).

3 Verbeke et al., Development of a Conjugate of 99mTc-EC with
Aminomethylenediphosphonate in the Search for a Bone Tracer with Fast
Clearance from Soft Tissue, Bioconjugate Chem. 13:16–22 (2002).
4 Yang et al., US 2005/0079133 A1, pub. Apr. 14, 2005.
5 Office Action mailed February 8, 2018.
6 Oh et al., Organic and aqueous synthesis of EC-DG for tumor glycolytic
activity assessment, J. Nucl. Med. 47(suppl. 1):502P (2005).
7 Tidmarsh et al., US 2004/0029815 A1, pub. Feb. 12, 2004.
Appeal 2009-001183
Application 13/562,879

4
OPINION
Obviousness: Verbeke and Yang
The Examiner finds that “Verbeke teaches conjugation of 99mTc-EC to
aminomethylenediphosphonate for use as a bone tracer.” Final Action 3. The
Examiner acknowledges that Verbeke does not teach the claimed EC-
glucosamine, but finds that “it is well known in the art to conjugate a
targeting moiety to EC . . . , including glucosamine, as shown by Yang, for
site-specific imaging, including of myocardial infarction.” Id. at 6.
Specifically, the Examiner finds that Yang teaches EC-drug
conjugates that “include a radionuclide label chelated with
ethylenedicysteine and a tissue specific ligand.” Id. The Examiner finds that
Yang expressly discloses 99mTc-EC-glucosamine. Id. at 7.
The Examiner concludes that it would have been obvious
to perform imaging of the heart because Yang teaches that the
99mTc-EC-drug conjugates of the invention may be useful to
image not only tumors, but also myocardial infarction (i.e.
heart). One would have had a reasonable expectation of success
in doing so because glucose is known to target tumor as well as
myocardial infarction, for example [18F]fluorodeoxyglucose
(FDG) has been used to diagnose tumors, myocardial
infarction, and neurological disease, as taught by Yang ’133
(paragraph 0007). In addition, Yang teaches imaging of the
heart (paragraph 0021).
Id. at 9. The Examiner also points out that “Yang teaches that ‘previous
experiments have shown that cellular uptake of 99mTc-EC-deoxyglucose is
similar to FDG’ (paragraph 0310),” and reasons that,
[s]ince Yang correlates EC-deoxyglucose uptake with that of
FDG, and teaches that FDG has been used to image myocardial
infarction, as well as teaching that his conjugates may be used
to image myocardial infarction, it is considered that one of
Appeal 2009-001183
Application 13/562,879

5
ordinary skill would have at least a reasonable expectation of
success in using EC-DG for imaging the heart.
Id. at 10–11.
Appellant argues, among other things, that “Yang ’133 neither teaches
imaging of the heart with 99mT[c]-EC-glucosamine nor with any other
targeting ligand conjugate. Instead the Action relies on a very broad
speculative statement in Yang ’133.” Appeal Br. 6, citing Yang ¶ 21.
Regarding the Examiner’s reliance on cellular uptake of FDG and
99mTc-EC-DG, Appellant argues that
Example 7 of Yang ’133 which the Examiner refers to only
tests cellular uptake in breast and lung cancer cells and makes
no mention of uptake in the heart. Thus, the comparison of
similar uptake between EC-DG and FDG does not apply to
cardiac cells and Appellants submit that there is no reason to
choose EC-G for heart imaging based on the disclosure of
Yang ’133.
Id. at 7.
We agree with Appellant that the Examiner has not persuasively
shown that it would have been obvious to use 99mTc-EC-glucosamine in a
method of imaging the heart, as claimed. Verbeke discloses an EC conjugate
for use in imaging bone, not heart tissue. See Verbeke 16, abstract.
Yang discloses a “labeling strategy employing 99mTc chelated with
ethylenedicysteine (EC) . . . conjugated with a variety of ligands . . . for use
as an imaging agent for tissue-specific diseases.” Yang, abstract. The
conjugates disclosed by Yang include “99mTc-EC-aminoglycosides,
(glucosamine, EC-deoxyglucose).” Id. ¶ 16; see also Figs. 49, 59 (“99mTc-
EC-Glucosamine”). Yang teaches that glucosamine is among the “tissue
specific ligands” that act as “an agent that mimics glucose.” Id. ¶¶ 12–13.
Appeal 2009-001183
Application 13/562,879

6
Yang describes “a method of imaging” that includes administering “a
composition comprising a 99mTc labeled ethylenedicysteine-tissue specific
ligand conjugate and detecting a radioactive signal from the 99mTc localized
at the site.” Id. ¶ 20. “In certain preferred embodiments, the site will be an
infection, tumor, heart, lung, brain, liver, spleen, pancreas, intestine or any
other organ.” Id. ¶ 21.
The Examiner has not pointed to a disclosure in Yang identifying
glucosamine, specifically, or agents that mimic glucose, generally, as ligands
that are specific for heart tissue or that are used in imaging the heart. We do
not find that the generic disclosure of 99mTc-EC-glucosamine as a conjugate
useful for imaging some tissue(s), and the generic disclosure that some
conjugate(s) can be used to image heart tissue, would have provided a
skilled artisan with a reason to administer 99mTc-EC-glucosamine to a patient
in need of heart imaging.
The Examiner also cites Yang’s disclosure that “[18F]fluorodeoxy-
glucose (FDG) has been used to diagnose . . . myocardial infarction . . .
(paragraph 0007),” Final Action 9, and its “teach[ing] that ‘previous
experiments have shown that cellular uptake of 99mTc-EC-deoxyglucose is
similar to FDG’ (paragraph 0310),” id. at 10. The Examiner reasons that,
based on these disclosures, “one of ordinary skill would have at least a
reasonable expectation of success in using EC-DG for imaging the heart.”
Id. at 11; see also Ans. 4.8

8 It is unclear from the record what, if any, difference there is between “EC-
deoxyglucose” and “EC-glucosamine.” For example, both compounds are
referred to as “EC-DG.” See Yang ¶ 300; Thompson Decl. ¶ 4. And Yang
states that its Figure 59 shows a synthetic scheme of “99m-Tc-EC
deoxyglucose,” but in Figure 59, the product is labeled “99m-Tc-EC-
Appeal 2009-001183
Application 13/562,879

7
We do not agree that the cited disclosures support the Examiner’s
conclusion. As Appellant has pointed out, Yang’s Example 7 (¶¶ 300–318)
“refers to only . . . cellular uptake in breast and lung cancer cells and makes
no mention of uptake in the heart.” Appeal Br. 7.
Specifically, Yang’s Example 7 includes an experiment testing the
“Effect of D- and L-Glucose on Cellular Uptake of 99mTc-EC-Deoxyglucose
and 18F-FDG.” Yang ¶ 306. The experiment used “breast or lung cancer
cells.” Id. ¶ 307. Yang reports that “a decreased uptake of 99mTc-EC-
deoxyglucose and 18F-FDG by d-glucose in breast and lung cancer cells was
observed. However, there was no influence on both agents by l-glucose. . . .
The findings suggest that the cellular uptake of 99mTc-EC-deoxyglucose is
mediated via d-glucose mechanism.” Id. ¶ 308.
This experiment provides the context for Yang’s statement that
“[p]revious experiments have shown that cellular uptake of 99mTc-EC-
deoxyglucose is similar to FDG. . . . The uptake of 99mTc-EC-deoxyglucose
is mediated via d-glucose mechanism.” Id. ¶ 310.
Read in context, therefore, Yang’s statement applies only to its
findings relating to uptake of EC-deoxyglucose by breast and lung cancer
cells. The Examiner has not provided adequate evidence or sound technical
reasoning to show that a skilled artisan would have read Yang’s statement
regarding cellular uptake of EC- deoxyglucose and FDG to apply to all cells,
or specifically to heart cells. Nor has the Examiner explained why Yang’s
finding that cellular uptake of EC-deoxyglucose is mediated via d-glucose

Glucosamine.” Yang ¶ 91, Fig. 59. However, both Appellant and the
Examiner treat Yang’s Example 7, regarding EC-deoxyglucose, as relevant
to the EC-G recited in the claims.
Appeal 2009-001183
Application 13/562,879

8
metabolism would have provided a reason to use EC-glucosamine for
imaging the heart.
The Examiner relies, rather, on Yang’s statement that EC-deoxyglucose
and FDG have similar cellular uptake, in combination with its statement that
FDG “has been used to diagnose tumors, myocardial infarction, and
neurological disease.” Yang ¶ 7. This statement, however, does not relate
FDG’s use in diagnosing myocardial infarction, in the heart, to the breast or
lung cancer cells used by Yang to test cellular uptake, or to uptake mediated
via d-glucose metabolism, or to glucosamine or EC-glucosamine specifically.
In summary, we do not find that Yang’s disclosure that 18F-FDG has
been used to diagnose myocardial infarction, and that 99mTc-EC-
deoxyglucose and 18F-FDG have similar cellular uptake in breast and lung
cancer cells, would have provided a person of ordinary skill in the art with
sufficient reason to use 99mTc-EC-glucosamine in a method of imaging the
heart with a reasonable expectation of success. We therefore reverse the
rejection of claims 86, 87, 93, 95–99, and 113–116 under 35 U.S.C. § 103(a)
based on Verbeke and Yang.
Obviousness: Oh, Yang, and Tidmarsh
Claims 86, 87, 93, 95–99, and 113–116 stand rejected under 35 U.S.C.
§ 103(a) based on Oh, Yang, and Tidmarsh. Final Action 17. With regard to
this rejection, the Examiner relies on the same disclosures in Yang,
discussed above, as a basis for concluding that it would have been obvious
to use 99mTc-EC-G to image a patient’s heart. Id. at 18–19, 20–21, 23;
Ans. 4. Appellant argues that “there is no reason to choose EC-G for heart
imaging based on the disclosure of Yang ’133” for the same reasons
previously set out. Appeal Br. 21–22.
Appeal 2009-001183
Application 13/562,879

9
We therefore reverse this rejection for the same reason discussed
above: the Examiner has not identified an adequate reason for a skilled
artisan to use 99mTc-EC-G in a method of heart imaging.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
86, 87, 93,
95–99, 113–
116
103(a) Verbeke, Yang 86, 87, 93,
95–99,
113–116
86, 87, 93,
95–99, 113–
116
103(a) Oh, Yang, Tidmarsh 86, 87, 93,
95–99,
113–116
Overall
Outcome
86, 87, 93,
95–99,
113–116

REVERSED