Ex Parte Guilford et al

Patent Trial and Appeal Board

Mar 12, 2015

10289934 (P.T.A.B. Mar. 12, 2015)

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.
10/289,934 11/07/2002 F. Timothy Guilford GLFD-02-004 1624
25175 7590 03/12/2015
Daneker, McIntire, Schumm,
Prince, Manning & Widmann, P.C.
One N. Charles Street
Suite 2450
Baltimore, MD 21201
EXAMINER
PRYOR, ALTON NATHANIEL
ART UNIT PAPER NUMBER
1616
MAIL DATE DELIVERY MODE
03/12/2015 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte F. TIMOTHY GUILFORD and BROOKE SCHUMM III
1

____________

Appeal 2012-006889
Application 10/289,934
Technology Center 1600
____________

Before ERIC B. GRIMES, ULRIKE W. JENKS, and
CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.

JENKS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims directed to
ameliorating or minimizing the effects of a bioterror weapon. The Examiner
rejects the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.

1
Appellants state that the Real Party in Interest is Your Energy Systems,
LLC (“YES”). (App. Br. 3.)
Appeal 2012-006889
Application 10/289,934

2
STATEMENT OF THE CASE
Claims 29, 64, and 65 are on appeal, and can be found in the Claims
Appendix of the Appeal Brief (App. Br. 37–38). Claim 29 is representative
of the claims on appeal, and reads as follows:
29. A method of ameliorating the effects of exposure to a
bacterial bioterror weapon containing such as Bacillus
Anthracis, comprising the following steps:
administering in a pharmaceutically acceptable carrier at
least one therapeutic dose of NAC [N-acetyl cysteine], said
dose being in a range of 14 mg/kg weight of a human being to
14 g/kg weight of said human being; and
administering at least one therapeutic dose of at least one
antibiotic to said human being upon exposure to said bacterial
bioterror weapon containing Bacillus Anthracis.
The Examiner has rejected claims 29, 64, and 65 under 35 U.S.C.
§ 103(a) as unpatentable over Dixon
2
and Hanna
3
.
The issues are: (1) has the Examiner set forth a prima facie case of
obviousness and, if so, (2) have Appellants provided sufficient evidence of
unexpected results from the combination of an N-acetyl cysteine [NAC] and
antibiotic for showing amelioration of the effects of anthrax infection, as
claimed?
Findings of Fact (FF)
1. Dixon discloses that “[p]enicillin and doxycycline are used for
the treatment of anthrax. . . . Chloramphenicol, erythromycin, tetracycline,
or ciprofloxacin can be administered to patients who are allergic to
penicillin.” (Dixon, 822.) Dixon also discloses a summary of various

2
Terry C. Dixon et al., ANTHRAX, 341 The New England J. of Medicine,
No. 11, 815–826 (1999).
3
Philip C. Hanna et al., Role of Macrophage Oxidative Burst in the Action of
Anthrax Lethal Toxin” 1 Molecular Medicine, 7–18 (1994).
Appeal 2012-006889
Application 10/289,934

3
pharmacologic therapies for the treatment of anthrax. (Dixon, 823, see
Table 2.) Additionally, Dixon provides that “[p]rophylaxis for
asymptomatic patients with suspected exposure to anthrax spores can be
achieved with a six-week course of doxycycline or ciprofloxacin. If the
suspected dose of spores is high, a longer course of antibiotics is warranted.”
(Dixon, 822.)
2. Hanna discloses
[A]ntioxidants that are relatively nontoxic to animals were also
tested in vivo. Six month-old BALB/c mice were injected with
N-acetyl-L-cysteine [NAC], mepacrine or vitamin C
simultaneously to LeTx [anthrax lethal toxin] challenge.
Although none of these compounds fully protected mice from
high toxin doses, a significant reduction in mortality, both in
terms of increased survival and increased time to death, was
observed in mice receiving N-acetyl-L-cysteine or mepacrine at
intermediate and low toxin doses (Table 3).
(Hanna, 14 (emphasis added).)
3. Hanna discloses treating mice with antioxidants.

Table 3, reproduced above, shows:
Appeal 2012-006889
Application 10/289,934

4
Anthrax lethal toxin was administered to anesthetized animals
in 300 μl sterile PBS via the tail vein. Antioxidants or mock
were administered to animals in 200 μl sterile PBS at the same
time as toxin at a second tail vein site.
a
LeTx = 100 μg PA + 20 μg LF per animal.
b
LeTx = 50 μg PA + 10 μg LF per animal.
c
LeTx = 50 μg PA + 5 μg LF per animal.
d
Antioxidant dose = 800 mg per animal.
e
No deaths after day 14.
(Hanna, 15.)
4. Tan’s thesis
4
provides a study that looks at the “[p]rotective
effect of NAC liposome in combination with ciprofloxacin in
DBA2 mice infected with B. anthracis sterne spores.” (Tan, 84.)

Table 3.2, reproduced above, shows:
Protective effect of NAC liposome in combination with
ciprofloxacin in DBA2 mice infected with B. anthracis
sterne spores. The treatments were administered for 10 days

4
Yian Kim Tan, Novel Function of Anthrax Lethal Toxin, Thesis, George
Mason University (2009).
Appeal 2012-006889
Application 10/289,934

5
and observed for mortality up to 24 days. NAC-liposome was
administered in the morning, and ciprofloxacin was
administered in the evening starting from day 2 to day 10.
NAC-liposome was administered simultaneously with
ciprofloxacin on day 1 (24 hour post spore challenge).
(Tan, 84)
5. The Specification provides that “NAC will be the collective
reference for glutathione pathway enhancing compounds in this description.
Those compounds include N-acetyl-cysteine which is normally referred to as
NAC, but in this invention, the term NAC, and the term glutathione
precursor” can encompass many other compounds. (Spec. 20, l. 2 to 21, l.
8.)

Principle of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“[W]here the general conditions of a claim are disclosed in the prior
art, it is not inventive to discover the optimum or workable ranges by routine
experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955).

Analysis
The Examiner relies on Dixon for disclosing methods of “treating
anthrax with the antibiotic ciprofloxacin . . . . [The Examiner, however,
acknowledges that] Dixon et al. do[es] not teach treating anthrax with N-
acetyl cysteine (NAC).” (Ans. 5; see also FF1.) The Examiner finds that
Hanna teaches treating anthrax lethal toxin exposure in mice with NAC.
Appeal 2012-006889
Application 10/289,934

6
(Ans. 4–5; see also FF 2–3.) The Examiner concludes that “[i]t would have
been obvious to develop a treatment [method] by combining ciprofloxacin
with NAC to treat anthrax. One would have been motivated to do this
because Dixon et al. and Hanna et al. individually teach treating anthrax.”
(Ans. 5.)
We conclude that the Examiner has met the burden of presenting a
prima facie case of obviousness for a method of ameliorating or minimizing
the effects of anthrax exposure by administering a combination of antibiotic
and NAC. Because the Examiner presents a prima facie case, we consider
whether Appellants submit sufficient evidence or argument in rebuttal. In re
Rijckaert, 9 F.3d 1531, 1532 (Fed. Cir. 1993). Evidence rebutting a prima
face case of obviousness may include “[e]vidence of unexpected results.”
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1369 (Fed. Cir. 2007).
We find there has to be a nexus established between the alleged
unexpected property and the claimed invention. See In re Kao, 639 F.3d
1057, 1068 (Fed. Cir. 2011) (“Where the offered secondary consideration
actually results from something other than what is both claimed and novel in
the claim, there is no nexus to the merits of the claimed invention.”). In
addition, “when unexpected results are used as evidence of nonobviousness,
the results must be shown to be unexpected compared with the closest prior
art.” In re Baxter-Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991).
Appellants rely on Tan’s thesis
5
as support for the presently claimed
dosages. (App. Br. 10.) Appellants contend that “for mice, Tan observed,

5
Appellants are relying on post-filing date experimental results provided in
the form of a thesis as evidence of unexpected results (see App. Br. 10), as
opposed to using the more traditional route of presenting such evidence in
Appeal 2012-006889
Application 10/289,934

7
‘There were 60% survivors in 100mg/kg NAC liposome treated group [i.e.
no ciprofloxacin] as compared to 30% survivors in ciprofloxacin only
group. All mice in the untreated group expired by day 7. [emphasis added]’
. . . Thus, as to high dose anthrax, Tan achieved with a low dose of NAC the
opposite of what Hanna’s data had shown.” (App. Br. 29, (brackets in
original), citing Tan, 82.)
We are not persuaded by Appellants’ contention that Tan provides a
sufficient evidentiary basis for finding unexpected results. Tan explains that
“[a]ll mice including NAC-liposome treated started to show signs of
hemorrhages and accumulation of fluid within the peritoneal cavity (ascites)
on day 2 after challenge. All animals had ruffled fur by day 3. Mice
survival count was recorded (Table 3.2 [see FF4]) and survival curve was
graphed. . . . We observed a delayed death in NAC-liposome treated group
especially in 100mg/kg group.” (Tan, 82) Contrary to the Appellants’
assertions, the Examiner finds that Tan’s table 3.2 does not show results for
animals treated with NAC-liposomes alone. (FF 4; see also Ans. 5.)
Specifically, “Tan does not provide data on the activity of using NAC alone
to treat Anthrax. Tan shows the activity of Ciprofloxacin alone as well as
synergistic activity for a combination of Ciprofloxacin plus N-acetylcystiene
[sic] (NAC). While the combination appears to be synergistic, no activity
data are provided for NAC alone.” (Ans. 5.) We agree with the Examiner’s

the form of a Declaration. See MPEP 2145. Regardless of how the evidence
is presented, the comparative showing must be made to the closest prior art.
In re Merchant, 575 F.2d 865, 869 (CCPA 1978) (“An applicant relying
upon a comparative showing to rebut a prima facie case must compare his
claimed invention with the closest prior art.”).
Appeal 2012-006889
Application 10/289,934

8
position that neither Tan’s table 3.2 nor any of the surrounding text in Tan’s
thesis discusses results of treating mice with NAC-liposomes alone.
There are notable differences between the experimental conditions in
Tan and Hanna. Although both test NAC, the tested compositions differ in
that Tan used a NAC-liposome formulation for treating the animals (FF4),
while Hanna used NAC in saline (FF3). The route of administration also
differs. Tan infects the animals with anthrax spores followed by the
antibiotic and NAC treatment. Specifically, Tan’s protocol requires
“[f]ollowing challenge with B. anthracis 34F2 spores per mouse by
intraperitoneal injection, the mice were treated after 24 hours with 50 mg/kg
ciprofloxacin alone or in combination with different dosages of NAC-
liposome (40, 70 and 100 mg/kg) through intraperitoneal injection.” (Tan,
82.) Hanna’s protocol, on the other hand, differs in that “anthrax lethal toxin
was administered to anesthetized animals in 300 μl sterile PBS via the tail
vein. Antioxidants or mock were administered to animals in 200 μl sterile
PBS at the same time as toxin at a second tail vein site.” (FF 3.) In addition
to using different routes for administering the different NAC formulations,
Tan and Hanna also differ in that Tan infects mice with anthrax spores while
Hanna administers lethal toxin to the animals. (FF 2–4.) “Lethal toxin
(LeTx)[] [is] the central effector of shock and death during systemic anthrax
[infection].” (Hanna, 8.)
Tan infects animals with anthrax (FF 4), and during the course of
infection the organism will produce lethal toxin. What is not known is how
much lethal toxin is produced in each animal. Thus, Tan’s results cannot be
directly compared to Hanna’s because we have no knowledge with respect to
the amount of lethal toxin produced in an animal upon infection by the
Appeal 2012-006889
Application 10/289,934

9
spores. Additionally, as noted by the Examiner, without data directed to the
effect of NAC-liposome alone, Tan’s results cannot readily be compared to
Hanna, the closest prior art, because Hanna shows administration of NAC
contemporaneously with the administration of lethal toxin. (Ans. 5; see also
FF 3–4.) We note that NAC treated mice in Hanna at day 14 show a 60%
and 30% survival rate at low and medium toxin doses respectively, while
Tan’s animals at 14 days shows a 30–40% survival rate for animals
receiving ciproflaxin treatment and a 60–70% survival rate for animals
receiving NAC-liposome plus ciproflaxin in combination. (FF 4.)
The burden of demonstrating unexpected results rests on the party
asserting them. In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972). That
burden has not been carried here because Appellants have not established
that the results achieved by treating animals with a combination of NAC and
antibiotic compounds were unexpectedly superior compared to the closest
prior art, which in this case is Hanna (FF 2–3). See In re Baxter Travenol
Labs., 952 F.2d 388, 392 (Fed. Cir. 1991).
We are equally unpersuaded by Appellants’ contention that Hanna’s
dose of NAC is “completely impractical for humans.” (App. Br. 21–22.)
We agree with the Examiner that “[w]ith respect to dose amounts it is well
within the skill of an artisan in the field to determine the optimum dose
range to administer to the patient in order to get the best results without
damaging the patient’s health.” (Ans. 6.)
We recognize, but are not persuaded, by Appellants’ arguments of
“long felt need” or “lack of expectation of success.” For both arguments,
Appellants contend that “[a]t high doses of anthrax, none of the
experimental mice treated by Hanna with NAC had survived, so that would
Appeal 2012-006889
Application 10/289,934

10
not be a natural direction to proceed.” (App. Br. 34; see also 32.) Hanna’s
test animals receiving the highest dose of lethal toxin did not survive at the
end of the study, however, animals treated with antioxidants fared
significantly better early in the study, i.e. during the first 24–72 hours.
(FF3.) We note that Hanna’s tests were directed at looking at the effects of
lethal toxin given in a bolus injection at day zero and administered
contemporaneously with NAC. Appellants have not pointed to adequate
persuasive evidence to show that the highest dose of lethal toxin used in
Hanna’s studies is comparable to the amount of toxin released in an animal
infected with anthrax spores as the starting point as used in Tan. As
discussed above, the differences in Tan’s and Hanna’s protocols are
sufficiently large to make an assessment with respect to any unexpected
results unreasonable.
On the record before us, we conclude the Examiner did not err in
rejecting claims 29, 64, and 65 under 35 U.S.C. § 103(a) as being
unpatentable over Dixon and Hanna, and Appellants have not provided
sufficient evidence of secondary considerations that outweighs the evidence
supporting the prima facie case.

SUMMARY
We affirm the rejection of all claims.
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
Lp