Ex Parte Krakauer et al

Patent Trial and Appeal Board

Mar 22, 2018

13387299 (P.T.A.B. Mar. 22, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/387,299 06/11/2012 Teresa Krakauer
30951 7590 03/22/2018
NASH & TITUS, LLC
21402 UNISON RD
MIDDLEBURG, VA 20117
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.
071007-0197 9795
EXAMINER
LEE, WILLIAM Y
ART UNIT PAPER NUMBER
1629
MAILDATE DELIVERY MODE
03/22/2018 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 TERESA KRAKAUER and MARILYN BUCKLEY
Appeal2017-005518 1
Application 13/3 87 ,299
Technology Center 1600
Before RICHARD M. LEBOVITZ, FRANCISCO C. PRATS, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims to methods of
preventing or treating toxic shock. The Examiner rejected the claims for
obviousness.
We have jurisdiction under 35 U.S.C. § 6(b)(l). We affirm.
1 Appellants state that the "real party in interest in this appeal is the U.S.
Government as represented by the Secretary of the Army." Appeal Br. 2.
The Appeal Brief does not include page numbers. We cite to the Appeal
Brief as if the first page was numbered as page 1, and the remaining pages
numbered consecutively.
Appeal2017-005518
Application 13/3 87 ,299
STATEMENT OF THE CASE
The sole rejection before us for review is the Examiner's rejection of
claims 1-13 and 22-26 under 35 U.S.C. § 103(a) as being unpatentable over
Krakauer, 2 Halloran, 3 Rapamune Prescribing Information, 4 Mita, 5 and Zhu. 6
Final Act. 7-16.
Claim 1 is representative and reads as follows:
1. A method for preventing or treating toxic shock in a
subject, comprising determining whether a patient has
been exposed to a toxic agent; monitoring the patient for
symptoms of toxic shock, administering to said subject a
therapeutically effective amount of rapamycin until one
or more of said toxic shock symptoms are alleviated.
Appeal Br. 9.
2 Teresa Krakauer and Marilyn Buckley, Dexamethasone Attenuates
Staphylococcal Enterotoxin B-Induced Hypothermic Response and Protects
Mice from Superantigen-Induced Toxic Shock, 50 ANTIMICROBIAL AGENTS
AND CHEMOTHERAPY 391-395 (2006). Despite the 2006 year of publication
indicated on the first page of the Krakauer article, the Examiner cites to
Krakauer as "Krakauer (2005)." See Final Act. 10. The pages cited by the
Examiner, however, and the teachings referred to therein, correspond to the
publication referred to herein, dated 2006.
3 Philip F. Halloran, Immunosuppressive Drugs for Kidney
Transplantation, 351 N. ENGL. J. MED. 2715-2729 (2004).
4 Rapamune® Prescribing Information, Wyeth Laboratories (2002).
5 Atsuyoshi Mita et al., Anti-Pro-Inflammatory Effects of Sirolimus on
Human Islet Preparations, 86 TRANSPLANTATION 46-53 (2008).
6 US 7,282,505 B2 (issued Oct. 16, 2007). The Examiner cited Zhu as
evidence of the obviousness of certain features in claim 8, which depends
from representative claim 1. Because our analysis as to claim 1 is sufficient
to resolve all issues on appeal, we do not discuss the Zhu reference.
2
Appeal2017-005518
Application 13/3 87 ,299
DISCUSSION
The Examiner's Prima Facie Case
In rejecting claim 1 for obviousness, the Examiner cited Krakauer as
teaching the treatment of toxic shock induced by staphylococcal enterotoxin
B (SEB) in mice by administering dexamethasone. Final Act. 8.
The Examiner cited Halloran as evidence that dexamethasone is "a
known glucocorticoid immunosuppressant[] compound; glucocorticoids are
known immunosuppressive therapies for organ transplantation." Id. at 8-9
(citing Halloran 2718-2719, Table 1).
The Examiner conceded, however, that Krakauer's toxic
shock-treating process differs from the process recited in claim 1 in that
Krakauer "does not teach the treatment or prevention of toxic shock
syndrome with rapamycin." Id. at 10.
As evidence that the process in claim 1 would nonetheless have been
obvious, the Examiner cited the Rapamune Prescribing Information as
teaching the administration of rapamycin as an immunosuppressant to
prevent organ transplant rejection. Id. at 10-11. The Examiner found that,
although the Rapamune Prescribing Information did not describe
administering rapamycin to treat toxic shock, "said [claimed] property to
prevent toxic shock is deemed to be present during the administration of
rapamycin in a subject." Id. at 10.
As to using rapamycin to treat toxic shock, the Examiner found that
an ordinary artisan would have been motivated to "substitute one known
immunosuppressant, dexamethasone, for another, rapamycin, to arrive at the
claimed invention of claims 1-5 and 25-26. This substitution is based on
3
Appeal2017-005518
Application 13/3 87 ,299
the suggestion and teaching of Halloran that these compounds are
immunosuppressants for a common indication." Id. at 11.
As further evidence that it would have been obvious to use rapamycin
in Krakauer' s toxic shock treating process, the Examiner cited Krakauer as
teaching that gamma-interferon "from activated T-cells acts synergistically
with IL-1 and TNF-alpha to enhance immune reactions and tissue injury, see
page 391" and noted Mita's teaching that rapamycin "has anti-
proinflammatory effects with regard to cytokines and chemokines, more
specifically, rapamycin significantly decreased TNF-a, IL-B, MCP-1 and
MIP-lB production in cells, see abstract and Results section, pages 4-6." Id.
at 11-12.
The Examiner summarized the rationale for the rejection as follows:
[T]he rationale to support a finding of obviousness for
the embodiment of applicant's claims drawn to treating toxic
shock with rapamycin are the prior art elements (the role
rapamycin plays with regulating T-cell, chemokine and
cytokine response during an immune response of a subject, the
teaching that a glucocorticoid ( dexamethasone) and rapamycin
have similar functions as immunosuppressants (see Halloran))
combined with Krakauer' s teaching that dexamethasone was
used to treat toxic shock syndrome (and that treatment of said
syndrome was measured in terms of serum levels of
inflammatory markers and body temperature) to predictably
arrive at applicant's claimed invention. A further rationale to
support a finding of obviousness is the replacement of art
recognized equivalent immunosuppressants (rapamycin for
dexamethasone as suggested by Halloran).
Id. at 16.
4
Appeal2017-005518
Application 13/3 87 ,299
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
primafacie case ofunpatentability ....
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In the present case, Appellants do not persuade us that the
preponderance of the evidence fails to support the Examiner's conclusion of
obviousness.
Appellants contend that "[ o ]ther immunosuppressant drugs are not
effective in treating SEB induced shock" and "strongly dispute[], with
respect, any immunosuppressant used in the treatment for organ transplants
would be effective for treating toxic shock. There was no evidence of this in
the art." Appeal Br. 5 (citing Venkataraman); 7 see also id. at 6 (contending
that glucocorticoids were recognized in the art as being "harmful"); id. at 6-
7 (contending that skilled artisan "would have known that dexamethasone as
well as other immunosuppressants can be harmful or useless which
ultimately teaches away from using rapamycin for toxic shock treatment or
prevention").
We acknowledge the following statement in Venkataraman: "High-
dose corticosteroid therapy has not been shown to be beneficial; Stress dose
steroids (hydrocortisone 50 mg IV every 6 hours) should be considered in
7 Ramesh Venkataraman, Toxic Shock Syndrome Treatment & Management,
http://emedicine.medscape.com/article/169177-treatment (2012 ).
5
Appeal2017-005518
Application 13/3 87 ,299
patients with refractory shock despite adequate antimicrobial theory and
source control." Venkataraman 3.
The fact that a high-dose corticosteroid therapy might not have been
shown to be beneficial to a patient with toxic shock syndrome does not
demonstrate that immunosuppressants categorically had been shown to be of
no use for treating toxic shock. Indeed, as seen above, immediately after the
statement regarding high dose corticosteroids, V enkataraman states that
hydrocortisone therapy, another immunosuppressant, should be considered
as a therapeutic alternative.
Appellants' contentions, moreover, are directly contradicted by the
Krakauer reference, which discloses that, "[b ]ased on the anti-inflammatory
effects of dexamethasone and because it is used clinically for treating a
variety of inflammatory diseases, we tested its effectiveness in a well-
established model of SEB [staphylococcal enterotoxin BJ-induced shock in
BALB/c mice." Krakauer 392. Thus, not only did Krakauer treat toxic
shock in mice, but the rationale for selecting dexamethasone as the treating
agent was because of its known immunosuppressant properties and clinical
use in treating other inflammatory disorders.
And Krakauer disclosed its treatment as being effective:
"Dexamethasone, an anti-inflammatory agent, attenuated staphylococcal
enterotoxin B (SEB)-induced hypothermia and serum proinflammatory
cytokines and improved survival from 0% to 86% in a lethal mouse model of
SEE-mediated shock." Id. at 391 (abstract).
As the Examiner found, Krakauer found that dexamethasone reduced
serum concentrations of a number of cytokines associated with toxic shock:
6
Appeal2017-005518
Application 13/3 87 ,299
Previous reports show that superantigens trigger a
cascade of proinflammatory cytokines resulting in toxic shock. .
. . We therefore analyzed the effects of dexamethasone on
cytokine levels in mice. Dexamethasone significantly (P <
0.05) reduced serum concentrations of TNF-a, IFN-y, IL-la,
IL-2, and IL-6 levels by 86%, 63%, 52%, 83%, and 90%,
respectively, at 8 h after SEB administration, with further
reduction of most cytokines 24 h after SEB treatment (Fig. 3).
We found that dexamethasone prevented the hypothermic
response to SEB, reduced serum proinflammatory cytokine
levels, and ultimately improved survival.
Id. at 393.
Although Krakauer does not disclose using rapamycin to treat toxic
shock, the Rapamune Prescribing Information discloses that rapamycin (also
undisputedly known as sirolimus) was an immunosuppressive drug
(Rapamycin Prescribing Information 1) used "for the prophylaxis of organ
rejection in patients receiving renal transplants" (id. at 9).
The Rapamune Prescribing Information explains that rapamycin
"inhibits T lymphocyte activation and proliferation that occurs in response to
antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation ...
. " Id. at 2 (brackets in original).
Similar to the Rapamune Prescribing Information, Mita discloses that,
in cell culture, rapamycin exhibited the "anti-pro-inflammatory" effect (Mita
1) of inhibiting the production of a number of cytokines, including TNF-a,
IL-1 B, MCP-1 and MIP-1 B (id. at 2).
Halloran, moreover, discloses that both rapamycin and
glucocorticoids, a category of drug that undisputedly includes
dexamethasone, were immune-suppressing drugs useful for treating organ
transplant patients. Halloran 2719 (Table 1 ).
7
Appeal2017-005518
Application 13/3 87 ,299
Thus, as seen above, Krakauer successfully used dexamethasone to
treat toxic shock, and taught that its use of dexamethasone in that treatment
was based on dexamethasone' s anti-inflammatory properties and clinical use
in treating inflammatory diseases. We, therefore, agree with the Examiner
that an ordinary artisan had a good reason for, and a reasonable expectation
of success in, using other anti-inflammatory drugs, i.e. immunosuppressant
drugs, such as rapamycin, to treat toxic shock, particularly given Halloran's
teaching that rapamycin was useful as an immunosuppressant in treating
transplant rejection, a condition that also responded to treatment with
glucocorticoids, the type of drug used by Krakauer.
As also discussed above, Krakauer discloses that dexamethasone' s
therapeutic effect against toxic shock involved reduced serum levels of
inflammatory cytokines like TNF -a, and both the Rapamune Prescribing
Information and Mita teach that rapamycin inhibits production of pro-
inflammatory cytokines like TNF-a. Accordingly, for this additional reason,
we agree with the Examiner that an ordinary artisan had a good reason for,
and a reasonable expectation of success in, using rapamycin as the
therapeutic agent in Krakauer' s process.
Appellants do not persuade us (see Appeal Br. 5---6; Reply Br. 3) that,
because rapamycin and dexamethasone might target different physiological
pathways, an ordinary artisan would not have used rapamycin in a treatment
method that had previously used dexamethasone. Nor do Appellants
persuade us (see Appeal Br. 7; Reply Br. 2-3) that, because rapamycin and
dexamethasone might have different chemical structures, an ordinary artisan
would not have used rapamycin in a treatment method that had previously
used dexamethasone.
8
Appeal2017-005518
Application 13/3 87 ,299
As noted above, despite the alleged different pathways targeted, and
despite the alleged different chemical structures, Halloran discloses that both
rapamycin and glucocorticoids, a category of drug that undisputedly
includes dexamethasone, were immune-suppressing drugs useful for treating
organ transplant patients. Thus, the evidence of record does not support
Appellants' contention that an ordinary artisan would not have used drugs
targeting different pathways, or having different structures, to treat the same
immune system-related disorder.
Appellants contend, as to the alleged unsuitability of using organ
transplant immunosuppressant drugs in treating toxic shock, that they "have
provided examples of two other FDA-approved organ transplant compounds,
cyclosporine A and tacrolimus. These two immunosuppressant compounds
showed no effectiveness against SE-induced shock. Please see response
filed July 15, 2015." Appeal Br. 6; see also Reply Br. 2 ("Appellant has
provided evidence that other immunosuppressants are not effective in
treating toxic shock.").
Other than the reference to the prior response, however, Appellants do
not identify the specific evidence alleged to support their contentions
regarding cyclosporine A and tacrolimus. MPEP § 1205.02 explains
(emphasis added):
It is essential that the Board be provided with a brief fully
stating the position of the appellant with respect to each ground
of rejection presented for review in the appeal so that no search
of the Record is required in order to determine that position.
Thus, the brief should not incorporate or reference previous
responses.
Thus, on the current record, the Appeal Brief improperly incorporates
a previous response, and fails to identify the specific evidentiary support for
9
Appeal2017-005518
Application 13/3 87 ,299
the assertions regarding cyclosporine A and tacrolimus. Appellants do not
persuade us, therefore, that their assertions regarding cyclosporine A and
tacrolimus provide a sufficient evidentiary basis for rebutting the Examiner's
prima facie case.
Appellants contend:
Table 1 on page 15 of the specification shows a side by
side comparison of mice treated with SEB+rapamycin and
SEB+dexamethasone. Table 1 shows that mice infected with
SEB and treated with dexamethasone begin to die at 3 hours
and continue to die off over time. These results would have
suggested to the artisan that dexamethasone was not very useful
because mice ultimately die. This evidence supports that one of
ordinary skill in the art would not have been motivated to use
rampamycin for treatment of SEB simply because
dexamethasone is a known immunosuppressant.
Appeal Br. 6.
Appellants, however, do not identify any specific evidence suggesting
that an ordinary artisan, "at the time the invention was made[,]" 35 U.S.C.
§ 103(a), would have been aware of the experimental evidence presented in
Appellants' Specification, such that the experimental evidence could or
would have dissuaded the artisan from following the teachings in the cited
references, discussed above, suggesting the use of rapamycin to treat toxic
shock.
Appellants contend that their invention "does not merely boil down to
substituting one immunosuppressant for another. It is focused on the use of
rapamycin to save lives by treating toxic shock, even at up to 24 hours post
exposure. This is a result never shown before and not suggested in the prior
art." Appeal Br. 7.
10
Appeal2017-005518
Application 13/3 87 ,299
We are not persuaded. Claim 1 does not recite that the administered
rapamycin prevents death, but instead encompasses results in which as few
as one symptom of toxic shock is alleviated. See Appeal Br. 9. Claim 1,
moreover, does not include any specific limitation at to the timing of
rapamycin administration in relation. See id. Because Appellants'
arguments, therefore, are not directed to elements of representative claim 1,
we do not find those arguments persuasive.
In sum, for the reasons discussed, we are not persuaded that the
preponderance of the evidence fails to support the Examiner's conclusion of
obviousness as to claim 1. We, therefore affirm the Examiner's rejection of
claim 1 over the cited references. The remaining claims fall with claim 1.
37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
For the reasons discussed, we affirm the Examiner's obviousness
rejection.
TIME PERIOD
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
11