Deepak Ramesh. Thakker et al.

Patent Trials and Appeals Board

Oct 15, 2019

13267243 - (D) (P.T.A.B. Oct. 15, 2019)

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.
13/267,243 10/06/2011 Deepak Ramesh Thakker 134.05290101 2558
64619 7590 10/15/2019
MEDTRONIC, INC. (NEURO/MRG)
710 MEDTRONIC PARKWAY NE
MS-LC340
MINNEAPOLIS, MN 55432-5604
EXAMINER
DICKINSON, PAUL W
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
10/15/2019 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):
ptodocketing@mrgs.com
rs.patents.five@medtronic.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte DEEPAK RAMESH THAKKER,
LISA L. SHAFER, and GREG STEWART
__________

Appeal 2018-007767
Application 13/267,243
Technology Center 1600
__________

Before RICHARD M. LEBOVITZ, 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 intrathecal molecule delivery to cerebrospinal fluid. The
Examiner rejected the claims as obvious. We have jurisdiction under 35
U.S.C. § 6(b). We reverse.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identify the Real Parties in Interest as Medtronic,
Inc. and Medtronic, plc (see App. Br. 2).
2 We have considered and refer to the Specification of Oct. 6, 2011
(“Spec.”); Final Action of Sept. 21, 2017 (“Final Act.”); Appeal Brief of
Feb. 15, 2018 (“App. Br.”); Examiner’s Answer of May 29, 2018 (“Ans.”);
Reply Brief of July 24, 2018 (“Reply Br.”); Prior Decision in Appeal 2015-
004335 of Nov. 30, 2016 (“Dec.”).
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Statement of the Case
Background
“A variety of agents have been administered to the cerebrospinal fluid
(CSF), such as through intracerebroventricular (ICV) or intrathecal (IT)
bolus infusion. Typically, these agents are administered acutely through a
single, bolus infusion at flow rates in the range of about 0.5 to 12 ml/min.”
(Spec. ¶ 3). “However, at lower flow rates, such as less than 1 ml/day,
studies report that the distribution of the agent in the CSF is limited” (Spec.
¶ 4). “[I]t would be desirable to administer an agent at a low flow rate to a
subject’s CSF; e.g. when using a chronically implanted infusion device, but
achieve broad distribution of the agent in the subject’s CNS” (Spec. ¶ 5).
The Claims
Claims 1–6, 8–15, 17, 18, and 23–25 are on appeal. Claim 1 is
representative and reads as follows:
1. A method comprising:
selecting a subject for which delivery of a therapeutic or
diagnostic molecule to cerebrospinal fluid (CSF) of a
brain is desired; and
administering a liquid formulation comprising the molecule
to an CSP-containing intrathecal space of the subject
at a flow rate of less than 500 microliters per hour,
wherein the liquid formulation is administered for a
period of time sufficient to reach a steady state
concentration in CSF of the brain, and wherein the
molecular weight of the molecule is less than 5 kDa,
between 15 kDa and 200 kDa, greater than 200 kDa,
or a polypeptide or anti sense DNA having a
molecular weight of between 5 kDa and 15 kDa, and
wherein the molecule is generally distributed
throughout at least most of the CSF of the brain at
therapeutically or diagnostically effective
concentrations.
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The Issue
The Examiner rejected claims 1–6, 8–15, 17, 18, and 23–25 under 35
U.S.C. § 103(a) as obvious over Heruth3 (Ans. 3–5).
The Examiner finds:
Heruth discloses a method for delivering a therapeutic molecule
to the cerebrospinal fluid of a brain of a subject, comprising
administering a liquid formulation comprising the molecule to
an CSF-containing intrathecal space, such as the lumbar space
(paragraph 180), the thoracic space (paragraph 123), or the
cervical space (paragraph 180), of the subject at a flow rate of
less than 50 milliliters (50,000 microliters) per hour, wherein
the liquid formulation is administered for 5 minutes or more
(paragraph 37).

(Ans. 3). The Examiner finds “[l]ower flow rates yield more equitable drug
distribution radially for both hypobaric and hyperbaric drugs (paragraph
136)” (Ans. 3). The Examiner finds:
Regarding the limitation, “wherein the molecule is generally
distributed throughout at least most of the CSF of the brain at
therapeutically or diagnostically effective concentrations,” the
drug (molecule) of Heruth is administered to the spinal cord so
as to reach the reach the CSF of the brain at therapeutically
effective concentrations (paragraph 180). This is a teaching
that the drug is distributed in the CSF of the brain at
therapeutically effective concentrations. Although Heruth does
not use the word “generally distributed,” it would be
understood that as the drug is solubilized in the CFS fluid of the
brain in a therapeutically effective amount, and as it solubilized
in the CFS fluid of the brain in a therapeutically effective
amount, it would be generally distributed throughout at least
most of the CSF of the brain.
(Ans. 4–5).

3 Heruth et al., US 2004/0220546 A1, published Nov. 4, 2004.
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The Examiner found that Heruth describes delivery of morphine, a
therapeutic molecule within the scope of the claim. The Examiner
acknowledges that “Heruth fails to teach an example where morphine is
delivered at a ‘flow rate of less than 500 microliters per hour ... for a period
of time sufficient to reach a steady state concentration in CSF of the brain’”
(Ans. 3–4).
The Examiner finds that during “the course of optimizing the method
for maximum efficacy and equitable drug distribution radially, the artisan
would find the instant flow rate of less than 500 microliters per hour through
routine experimentation” (Ans. 4).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that Heruth renders the claims
obvious?
Findings of Fact
1. Heruth teaches “a method for delivering a drug to a subject’s
brain via the subject’s spinal canal. The method comprises administering
. . . a hypobaric solution comprising the drug to the subject’s cerebrospinal
fluid (CSF) in a spinal location” (Heruth ¶ 180).
2. Heruth teaches
The drug may enter the brain through CSF, as there is
communication between CSF in the brain and in the spine.
Infusing a hybobaric drug into a subject’s spinal CSF may
facilitate delivery of the drug the brain. As people sit and stand
upright, buoyant forces will carry the drug upward towards the
brain
(Heruth ¶ 180).
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3. Heruth teaches “[i]n an embodiment, the drug or solution
carrying the drug is sufficiently hydrophilic that the drug may reach the
brain in a concentration effective to treat a disease” (Heruth ¶ 180).
4. Heruth teaches:
[I]nfusing the drug solution to an internal body location at a
continuous rate of no more than 50 milliliters (ml) per hour for
a period of five minutes or more. In variations on this method,
the maximum infusion rate may be, e.g., no more than 25 ml
per hour, no more than 10 ml per hour, no more than 5 ml per
hour, or even potentially no more than 2 ml [i.e. 2,000 µl] per
hour. Variations may also be found in the time period over
which the infusion is performed. The period of infusion may
alternatively be, e.g., 10 minutes or more, one hour or more,
eight hours or more, or even 24 hours or more.

(Heruth ¶ 37; emphasis added).
5. Heruth teaches “[w]ith respect to the rate of infusion, low rates
of infusion may tend to yield more equitable drug distribution radially for
both hypobaric and hyperbaric drugs. Faster flow rates may lead to broader
drug distribution over more vertebral segments than slower flow rates”
(Heruth ¶ 136).
6. Heruth teaches
if it is desirable to reach a variety of levels of a spinal column
with drug, the flow rate with which the drug is delivered may
be increased. . . . If it is desired to have a drug localized to a
region around a particular level of the spinal column, the flow
rate with which the drug is delivered may be decreased.
(Heruth ¶ 136).
7. Heruth teaches “[e]xemplary opioid agonists include morphine
and hydromorphone. Ranges of effective daily doses of such drugs are
known by physicians” (Heruth ¶ 172).
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8. The Examiner finds that morphine has “a molecular weight of
less than 5 kDa” (Final Act. 6).
Principles of Law
“A reference may be said to teach away when a person of ordinary
skill, upon reading the reference, would be discouraged from following the
path set out in the reference, or would be led in a direction divergent from
the path that was taken by the applicant.” In re Gurley, 27 F.3d 551, 553
(Fed. Cir. 1994).
Analysis
Appellant “does not agree that Heruth reasonably teaches or suggests
that intrathecal administration of a flow rate of less than 500 microliters per
hour would result in the drug being generally distributed throughout at least
most of the CSF of the brain at therapeutically or diagnostically effective
concentrations” (App. Br. 7). Appellant contends instead that the “cited
portions of Heruth teach or suggest that lower infusion rates lead to the drug
tending to remain in a ring at a particular vertebral level (radially
distributed) rather than being distributed more broadly over several vertebral
segments (longitudinally distributed)” (App. Br. 9). Appellant further
explains that “based on the teachings of Heruth, one would expect that a
drug administered at a low flow rate would spread out radially at the
vertebral level at which it was administered, but would not be expected to
spread longitudinally to other vertebral levels” (App. Br. 10).
The Examiner responds that:
Regarding the limitation, “wherein the molecule is generally
distributed throughout at least most of the CSF of the brain at
therapeutically or diagnostically effective concentrations,” the
drug (molecule) of Heruth is administered to the spinal cord so
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as to reach the reach the CSF of the brain at therapeutically
effective concentrations (paragraph 180). This is a teaching
that the drug is distributed in the CSF of the brain at
therapeutically effective concentrations. Although Heruth does
not use the word “generally distributed,” it would be
understood that as the drug is solubilized in the CFS fluid of the
brain in a therapeutically effective amount, and as it solubilized
in the CFS fluid of the brain in a therapeutically effective
amount, it would be generally distributed throughout at least
most of the CSF of the brain.
(Ans. 4–5).
We find that Appellant has the better position. Unlike the previous
appeal, where we noted that “‘broad distribution of the drug in CSF’ is not a
limitation of claim 1” (Dec. 6), the instant claims on appeal all include a
limitation that the therapeutic molecule is “generally distributed throughout
at least most of the CSF of the brain.” And as Appellant notes, Heruth does
not support the idea that lower drug amounts will result in general
distribution in the CSF. Thus, while Heruth discloses amounts less than 2
ml, the skilled worker would not have had reason to use 500 microliters or
less because it would defeat the purpose described by Heruth. Rather, Heruth
teaches that:
if it is desirable to reach a variety of levels of a spinal column
with drug, the flow rate with which the drug is delivered may
be increased. . . . If it is desired to have a drug localized to a
region around a particular level of the spinal column, the flow
rate with which the drug is delivered may be decreased.
(FF 6). Heruth therefore teaches that reduction of the flow rate results in
localization of drug delivery, not a broad distribution in the CSF as taught by
Appellant. This is a teaching away because it leads “in a direction divergent
from the path that was taken by the applicant.” Gurley, 27 F.3d at 553. The
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Examiner provides no evidence, as opposed to argument, that Heruth’s
delivery would necessarily be “generally distributed” in the brain.
Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that Heruth renders the claims obvious.
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
1–6, 8–15, 17,
18, 23–25
103 Heruth 1–6, 8–15, 17,
18, 23–25

REVERSED