University of Maryland, Baltimore et al.

Patent Trials and Appeals Board

Apr 16, 2021

2019006852 (P.T.A.B. Apr. 16, 2021)

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.
15/179,696 06/10/2016 J. Marc Simard UOMD.P0016US.C2-11606093 4321
26271 7590 04/16/2021
NORTON ROSE FULBRIGHT US LLP
1301 MCKINNEY
SUITE 5100
HOUSTON, TX 77010-3095
EXAMINER
BASQUILL, SEAN M
ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
04/16/2021 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):
hoipdocket@nortonrosefulbright.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
_____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
_____________

Ex parte J. MARC SIMARD
_____________

Appeal 2019-006852
Application 15/179,696
Technology Center 1600

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL

This is an appeal1,2 under 35 U.S.C. § 134 involving claims to a
method of targeting a target plasma level of glyburide. The Examiner
rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We affirm-in-part.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. Appellant identifies the Real Parties in Interest as the
University of Maryland, Baltimore, the Department of Veterans Affairs, and
Biogen Chesapeake LLC (see Appeal Br. 1).
2 We have considered the Specification of June 10, 2016 (“Spec.”); Final
Office Action of Dec. 20, 2018 (“Final Act.”); Appeal Brief of May 14,
2019 (“Appeal Br.”); Examiner’s Answer of July 22, 2019 (“Ans.”), and
Reply Brief of Sept. 20, 2019 (“Reply Br.”).

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Statement of the Case
Background
“The sulfonylurea receptor-1 (SUR1)-regulated NCca-ATP channel is a
non-selective cation channel that is not constitutively expressed, but is
transcriptionally up-regulated in astrocytes and neurons following an
hypoxic or ischemic insult” (Spec. ¶ 9). “Block of the channel in vitro by
the sulfonylurea, glibenclamide, prevents cell depolarization, cytotoxic
edema and oncotic cell death” (id.). “Thus, depending upon the disease, a
composition (an antagonist, which may also be referred to as an inhibitor) is
administered to block or inhibit at least in part the channel, for example to
prevent cell death and/or to prevent or reduce or modulate depolarization of
the cells” (id. ¶ 26).
The Claims
Claims 49–52, 54, 55, 57–59, 61, 63, and 64 are on appeal. Claims 49
and 64 are representative and read as follows:
49. A method of targeting a target plasma level of from 4.07
ng/ml to 160.2 ng/ml glyburide in an individual, comprising the
step of administering glyburide to the individual as follows:
(a) an intravenous loading dose of glyburide of 15.7 µg
to 665 µg to achieve said target plasma level; and
(b) a maintenance intravenous dose of 0.3 µg/min to 11.8
µg/min glyburide, which is different than the loading dose, to
maintain said target plasma level for 3 days to 7 days.

64. A method of targeting a target plasma level of from 4.07
ng/ml to 160.2 ng/ml glyburide in an individual having from at
least one of traumatic brain injury, cerebral ischemia, central
nervous system (CNS) damage, peripheral nervous system
(PNS) damage, cerebral hypoxia, and cerebral edema,
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comprising the step of administering glyburide to the individual
as follows:
(a) an intravenous loading dose of glyburide of 15.7 µg
to 665 µg to achieve said target plasma level; and
(b) a maintenance intravenous dose of 0.3 µg/min to 11.8
µg/min glyburide, which is different than the loading dose, to
maintain said target plasma level for 3 days to 7 days,
wherein the total daily dose administered to the
individual is 432 µg/day to 17 mg/day, and
wherein the targeted plasma level of glyburide in the
individual is from 4.07 ng/ml to 28.3 ng/ml.

The Rejection
The Examiner rejected claims 49–52, 54, 55, 57–59, 61, 63, and 64
under 35 U.S.C. § 103(a) as obvious over Simard,3 Lindblad,4 and Ansel5
(Final Act. 3–5).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s finding Simard, Lindblad, and
Ansel render the rejected claims obvious?
Findings of Fact
1. The Specification teaches “[t]here is data showing a strong
salutary effect of glibenclamide when treatment is begun immediately after
percussion-TEI. The findings indicate that this drug is useful. Doses of drug
and timing of drug administration is optimized” (Spec. ¶ 478).

3 Simard et al., WO 2006/036278 A1, published Apr. 6, 2006.
4 Lindblad et al., Sulphonylurea dose-response relationships: relation to
clinical practice, 2 Diabetes, Obesity and Metabolism 25–31 (2000).
5 Ansel et al., PHARMACEUTICAL DOSAGE FORMS AND DRUG
DELIVERY SYSTEMS 48–53 (1999).
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2. The Specification teaches:
An effective amount of an inhibitor of NCca-ATP channel that
may be administered to an individual or a cell in a tissue or
organ thereof includes a dose of about 0.0001 nM to about 2000
μM, for example. More specifically, doses of an antagonist to
be administered are from about 0.01 nM to about 2000μM;
about 0.01 μM to about 0.05 μM; about 0.05 μM to about 1.0
μM; about 1.0 μM to about 1.5 μM; about 1.5 μM to about 2.0
μM; about 2.0 μM to about 3.0 μM; about 3.0 μM to about 4.0
μM; about 4.0 μM to about 5.0 μM; about 5.0 μM to about 10
μM; about 10 μM to about 50 μM; about 50 μM to about 100
μM; about 100 μM to about 200 μM; about 200 μM to about
300 μM; about 300 μM to about 500μM; about 500 μM to about
1000 μM; about 1000 μM to about 1500 μM and about 1500
μM to about 2000 μM, for example. Of course, all of these
amounts are exemplary, and any amount in-between these
dosages is also expected to be of use in the invention.
(Spec. ¶ 51; emphasis added).
3. Simard teaches:
An effective amount of an agonist or antagonist of NCca-ATP
channel that may be administered to a cell includes a dose of
about 0.0001 nM to about 2000μM. . . . Of course, all of these
amounts are exemplary, and any amount in-between these
points is also expected to be of use in the invention.
(Simard ¶ 20). The Examiner finds that “0.05–1 micromoles which for
glibenclamide (molecular weight of 494 g/mol) defines a dosage range of
between 24.7–495 micrograms falling within the instantly claimed ranges”
(Ans. 4).
4. Simard teaches a “rodent model of thromboembolic stroke was
used . . . After stroke, animals were given glucose-free normal saline”
(Simard ¶¶ 352, 354). Simard then teaches: “At the time designated for
treatment, saline, or a loading dose of glibenclamide (1.5 μg/kg, i.v., Sigma,
St. Louis) was first administered . . . Then, using a dorsal thoracic incision, a
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mini-osmotic pump . . . was implanted subcutaneously that delivered either
saline or glibenclamide (300 μM or 148μg/ml, 0.5 μ1/hr s.q.)” (Simard
¶ 355). Simard finds “[a]ll animals (5/5) co-treated with saline showed large
regions of hemorrhagic conversion in cortical and subcortical parenchymal
areas of infarction” but finds “only 1/5 animals co-treated with
glibenclamide had hemorrhagic conversion, with 4/5 showing no evidence
of hemorrhage” (Simard ¶ 357).
5. Simard teaches
the treatment may comprise the amount of the SURI antagonist
or the dose of the SUR1 antagonist that is administered per day
(1, 2, 3, 4, etc.), week (1, 2, 3, 4, 5, etc.), month (1, 2, 3, 4, 5,
etc.), etc. Treatments may be administered such that the
amount of SUR1 antagonist administered to the subject is in the
range of about 0.0001 μ g/kg/treatment to about 20
mg/kg/treatment.
(Simard ¶ 35).
6. Simard teaches an “effective amount of an antagonist of the
NCca-ATP channel or related-compounds thereof as a treatment varies
depending upon the host treated and the particular mode of administration.
. . . those of skill will recognize that a variety of different dosage levels will
be of use” (Simard ¶ 216).
7. Simard teaches: “Some variation in dosage will necessarily
occur depending on the condition of the subject being treated. The person
responsible for administration will, in any event, determine the appropriate
dose for the individual subject, and such individual determinations are
within the skill of those of ordinary skill in the art” (Simard ¶ 220).
8. Lindblad teaches the “most natural way to determine the
appropriate individual dosage of a drug in clinical practice is dose titration
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against a clinically relevant target. In the case of diabetes mellitus, the
obvious target is the level of blood or plasma glucose” (Lindblad 25, col. 1).
9. Lindblad teaches sulphonylureas including “high-potency, low-
dose (second generation) compounds . . . [including] glibenclamide
(glyburide in the USA . . . routinely given in doses of 2.5-20mg/day
(glibenclamide)” (Lindblad 26, col. 1).
10. Ansel teaches the “dose of a drug may be described as an
amount that is ‘enough but not too much’; the idea being to achieve the
drug’s optimum therapeutic effect with safety but at the lowest possible
dose. The effective dose of a drug may be different for different patients”
(Ansel 48, col. 1).
Principles of Law
“[D]iscovery of an optimum value of a result effective variable in a
known process is ordinarily within the skill of the art.” In re Boesch, 617
F.2d 272, 276 (CCPA 1980).
Analysis
Claim 49
We adopt the Examiner’s findings of fact and conclusion of law (see
Ans. 3–5, FF 1–10). We agree that the cited prior art renders the claims
obvious. We address Appellant’s arguments below.
Appellant contends
none of the following claim limitations is described by the
Simard reference: the loading dose:maintenance dose ratio of
claims 49-52; the loading doses of claims 54 or 55; the
maintenance dose rate of claim 57; the total daily doses of
claims 58 and 59; the targeted plasma levels of claim 61; and
the treatment durations of claim 63. Nowhere in the Office
Action does the Examiner cite evidence that Lindblad and
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Pharmaceutical Dosage Forms provide those missing
disclosures.
(Appeal Br. 11). Appellant similarly contends the “Examiner fails to
provide any explanation for why a person of ordinary skill in the art would
have been motivated to use a 244- to about 9593-fold higher dose than in the
Simard reference for a period of time that is 12 to 28 times longer than in the
Simard reference” (Appeal Br. 14).
We find these arguments unpersuasive because the Examiner is not
asserting that Simard anticipates the claims, but rather that Simard teaches
the use of loading and maintenance doses of glyburide (FF 4) and teaches
general dose ranges that overlap those recited by the claims (FF 3) (see, e.g.,
Ans. 9). In “cases involving overlapping ranges, [courts] have consistently
held that even a slight overlap in range establishes a prima facie case of
obviousness.” In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003).
Appellant provides no evidence of any secondary consideration regarding
the specific doses for the loading and maintenance doses to rebut this prima
facie case.
We also note that claim 49, recites no specific disease or condition for
treatment. Thus, to the extent that Appellant argues details regarding “a
patient having at least one of traumatic brain injury, cerebral ischemia,
central nervous system (CNS) damage, peripheral nervous system (PNS)
damage, cerebral hypoxia, and cerebral edema” (Appeal Br. 14), these are
not limitations of claim 49. See In re Self, 671 F.2d 1344, 1348 (CCPA
1982) (“[A]ppellant’s arguments fail from the outset because . . . they are
not based on limitations appearing in the claims.”)
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Appellant contends
The Examiner provides insufficient evidence that a person of
ordinary skill in the art would have had a reasonable
expectation of success in arriving at the claimed method as a
whole. Accordingly, the Examiner has committed reversible
error in “resort[ing] to speculation, unfounded assumptions or
hindsight reconstruction to supply deficiencies” in the cited
references. In re Warner, 379 F.2d 1011, 1017 (CCPA 1967).
(Appeal Br. 12).
We find this argument unpersuasive because Simard expressly teaches
efficacy in reducing hemorrhagic conversion in a working example (FF 4).
Specifically, Simard shows that saline resulted in 5/5 animals having
hemorrhagic conversion but “only 1/5 animals co-treated with glibenclamide
[glyburide] had hemorrhagic conversion, with 4/5 showing no evidence of
hemorrhage” (FF 4). “Obviousness does not require absolute predictability
of success . . . all that is required is a reasonable expectation of success.” In
re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009). Here, experimental
evidence of efficacy provides at least a reasonable expectation of success in
using optimized doses of glyburide in treatments.
As to hindsight, we are fully aware that hindsight bias may plague
determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36
(1966), and we are also mindful that the Supreme Court has clearly stated
that the “combination of familiar elements according to known methods is
likely to be obvious when it does no more than yield predictable results.”
KSR, 550 U.S. at 416. Simard provides the reasonable expectation that
treatment with glyburide will have efficacy (FF 3–6).
Appellant contends:
The Examiner has not adequately shown that a skilled worker
would have recognized that each of the claimed target plasma
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levels, the claimed loading dose, the claimed maintenance dose,
the claimed dosage rates, the claimed dosage ratios, and the
claimed dosage durations, were within the general conditions
disclosed in the prior art.
(Appeal Br. 26–27). Appellant further contends Simard “contrastingly
relates to the administration frequency, e.g., 1–4 times per day or 1–5
times per week, rather than maintaining a target plasma level for 3 days to 7
days as recited by the claims” (id. at 15).
We are not persuaded because every ordinary artisan in medicine
performs “merely routine optimization of drug dosage to maximize
therapeutic effect.” Ariosa Diagnostics, Inc. v. Sequenom, Inc., 809 F.3d
1282, 1293 (Fed. Cir. 2015). Not only are Appellant’s arguments
inconsistent with the knowledge of the ordinary artisan, they are inconsistent
with the teachings of the instant prior art and Specification.
Simard teaches methods of medical treatment of patients in which a
loading levels and maintenance levels of glyburide are used (FF 3–4) and
teaches optimization of doses and treatment periods (FF 5–6). Simard
specifically teaches the need to “determine the appropriate dose for the
individual subject, and such individual determinations are within the skill of
those of ordinary skill in the art” (FF 7). Lindblad also gives a dose range
for glyburide (FF 10) and teaches the “most natural way to determine the
appropriate individual dosage of a drug in clinical practice is dose titration
against a clinically relevant target” (FF 9). Ansel is a textbook teaching “to
achieve the drug’s optimum therapeutic effect with safety but at the lowest
possible dose. The effective dose of a drug may be different for different
patients” (FF 11).
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Appellant’s own Specification recognizes that drug administration is
routinely optimized by the ordinary artisan, teaching “[d]oses of drug and
timing of drug administration is optimized” (FF 1). The Specification
teaches a wide range of dosages and explains “any amount in-between these
dosages is also expected to be of use in the invention” (FF 2).
Thus, unlike the situations recited in the cases cited by Appellant (see
Appeal Br. 27), the ordinary artisan, the prior art, and the Specification all
recognize that drug dosages for glyburide are ordinarily optimized for dose
and delivery. See In re Aller, 220 F.2d 454, 456 (CCPA 1955) (“[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.”) Appellant provides no evidence that the selected ranges
are anything other than optimized doses.
Appellant contends “the Examiner has not shown that those of
ordinary skill in the art would have modified the Simard reference in a way
that would result in the claimed method” (Appeal Br. 27).
We find this argument unpersuasive because it misunderstands the
allocations of burden in a prima facie case of obviousness. Brandt explains
that “it is important for the examiner to have a few procedural tools to aid
her efforts to issue as patents only those claims that meet the requirements of
the Patent Act . . . One of these procedural tools is the prima facie case, an
evidentiary burden-shifting device available to the examiner.” In re Brandt,
86 F.3d 1171, 1176 (Fed. Cir. 2018). As applied here, the Examiner has
provided a reasonable prima facie case of obviousness, showing Simard
teaches treatment of patients with loading doses of glyburide, maintenance
doses of glyburide, where the treatment extends over multiple days, and
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where the patient specific dosage is routinely optimized (FF 3–7). We note
that plasma levels are simply a marker of the optimized glyburide loading
and maintenance doses. Appellant does not provide any evidence to shift the
burden back to the Examiner.
Claim 64
Appellant contends
the Examiner fails to provide any explanation for why a person
of ordinary skill in the art would have expected to provide a
safe and effective therapy by targeting a target plasma level of
from 4.07 ng/ml to 160.2 ng/ml glyburide in a patient, e.g., a
patient having at least one of traumatic brain injury, cerebral
ischemia, central nervous system (CNS) damage, peripheral
nervous system (PNS) damage, cerebral hypoxia, and cerebral
edema.
(Appeal Br. 14).
We recognize the Examiner finds that Simard teaches regulation “of
the NCca-ATP channel in patients acute neuronal insults such as stroke and
ischemic/hypoxic injury by the administration of an activator or agonist or
antagonist or inhibitor of the channel” (see Final Act. 3–4). However, the
Examiner does not establish that “stroke, an ischemic/hypoxic insult”
(Simard ¶ 18), falls into the categories recited by claim 64. A stroke may
result from a “traumatic brain injury,” but the Examiner failed to establish an
evidentiary basis on this record to conclude that stroke itself is a traumatic
brain injury caused by an external insult to the head and/or brain, or that it
would necessarily result in cerebral ischemia, hypoxia, or edema, and/or
central or peripheral nervous system damage. Nor has the Examiner
explained why this would have been obvious over the disclosure of Simard.
We therefore reverse the rejection of claim 64 because the Examiner
has not established that Simard, Lindblad or Ansel teach or suggest patients
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with the specific recited conditions. “An examiner bears the initial burden
of presenting a prima facie case of obviousness.” In re Huai-Hung Kao, 639
F.3d 1057, 1066 (Fed. Cir. 2011).
Dependent Claims
Appellant contends that the dependent claims reciting particular time-
periods of dosing, loading doses, maintenance doses, and target plasma
levels were not disclosed (Appeal Br. 29–30).
We remain unpersuaded by these arguments because, as Simard
evidences, dosages (and the inherently resulting plasma levels) and dosage
time periods are known optimizable variables for glyburide as discussed
above (see FF 3–7). Appellant provides no evidence of any secondary
consideration regarding these claims.
Conclusion of Law
DECISION SUMMARY
In summary:
Claims
Rejected
35
U.S.C. §
Basis Affirmed Reversed
49–52, 54, 55,
57–59, 61, 63, 64
103 Simard,
Lindblad, Ansel
49–52, 54, 55,
57–59, 61, 63
64

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-IN-PART