Ex Parte Thakker et al

Patent Trial and Appeal Board

Nov 28, 2016

13267243 (P.T.A.B. Nov. 28, 2016)

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 11/30/2016
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
11/30/2016 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):
medtronic_neuro_docketing @ cardinal-ip.com
ptodocketing @ mrgs .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 2015-004335
Application 13/267,243
Technology Center 1600
Before MELANIE L. McCOLLUM, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35U.S.C. § 134 involving claims to a method
of molecule delivery to cerebrospinal fluid. The Examiner rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
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
1 Appellants identify the Real Party in Interest as Medtronic, Inc. (see App.
Br. 3).
Appeal 2015-004335
Application 13/267,243
single, bolus infusion at flow rates in the range of about 0.5 to 12 ml/min.”
(Spec. 13). “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.
14). “[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 [central nervous
system]” (Spec. 1 5).
The Claims
Claims 1—23 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 antisense DNA having a molecular
weight of between 5 kDa and 15 kDa.
The Issues
A. The Examiner rejected claims 1—23 under 35 U.S.C. § 103(a) as
obvious over Heruth* 2 (Final Act. 2-4).
2 Heruth et al., US 2004/0220546 Al, published Nov. 4, 2004 (“Heruth”).
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Application 13/267,243
B. The Examiner rejected claims 1—3, 5, 7—12, 14—18, and 23 under 35
U.S.C. § 103(a) as obvious over Oldfield* 3 (Final Act. 5—6).
A. 35 U.S.C. § 103(a) over Heruth
The Examiner finds:
Heruth discloses a method for delivering a therapeutic molecule
to 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 181), the thoracic space (paragraph 123), or the
cervical space (paragraph 180), of the subject at a flow rate of
less than 50 milliliters per hour (paragraph 37) (which overlaps
with “less than 500 microliters per hour”) wherein the liquid
formulation is administered for 5 minutes or more (paragraph
37).
(Final Act. 3).
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 microl[i]ters per hour
through routine experimentation” (Ans. 3).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that Heruth renders claim 1 obvious?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
3 Oldfield et al., US 2006/0073101 Al, published Apr. 6, 2006 (“Oldfield”).
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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 1180).
2. Heruth teaches
a method for reducing the amount of a drug that reaches a
subject’s brain when introduced intrathecally. The method
comprises infusing a hyperbaric drug into the subject’s spine.
The method may be advantageous because it may be desirable
to keep certain drugs from reaching the brain, where the drug
may act to produce side effects. To maximize the amount of
drug kept out of the brain, the drug may be infused at a low
spinal location, such as the lumbar region.
(Heruth 1181; emphasis added).
3. Heruth teaches
infusing 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 ull 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 137; emphasis added).
4. Heruth teaches “[ejxemplary opioid agonists include morphine
and hydromorphone. Ranges of effective daily doses of such drugs are
known by physicians” (Heruth 1172).
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5. The Examiner finds that morphine has “a molecular weight of
less than 5 kDa” (Ans. 2).
Principles of Law
“In cases involving overlapping ranges, we and our predecessor court
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).
“[WJhere 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 Alter, 220 F.2d 454, 456 (CCPA 1955). This rule is
limited to cases in which the optimized variable is a “result-effective
variable.” In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir.
2012) (citing In re Antonie, 559 F.2d 618, 620 (CCPA 1977)).
Analysis
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. 2-4; FF 1—5) and agree that the
claims are rendered obvious by Heruth. We address Appellants’ arguments
below.
Appellants contend that “one of skill in the art would not read Heruth
as teaching or suggesting that even lower flow rates (less than 500
microliters per hour) would be of any use for achieving broad distribution of
the drug in CSF, or to achieve distribution in the CSF of the brain via
intrathecal administration” (App. Br. 10). Appellants further contend that
“Heruth teaches that the higher the flow rate, the broader the distribution . . .
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For a drug to reach the brain via intrathecal infusion (infusion into the CSF
in the spinal canal) broad distribution would be desired” (App. Br. 11).
We do not find these arguments persuasive because Heruth
specifically teaches flow rates of no more than 2 ml [i.e. 2,000 pi] per hour
(FF 3), a range overlapping the “less than 500 microliters per hour” range of
claim 1. Heruth further evidences that the flow rate is an optimizable
variable, as is the delivery dose of dugs (FF 3—4), rendering it obvious to
routinely optimize the flow rate.
Moreover, Appellants’ baseline assumption regarding “broad
distribution of the drug in CSF” is not a limitation of claim 1, which does
not require any degree of distribution in the CSF, nor does claim 1 require
any specific concentration to be obtained in the brain. Moreover, Heruth
also does not require a broad distribution as evidenced by Heruth’s teaching
of “reducing the amount of a drug that reaches a subject’s brain when
introduced intrathecally” by administering to the lumbar region (FF 2).
Therefore, the ordinary artisan, interested in reducing the amount of drug
reaching a subject’s brain, would have reasonably considered optimizing
Heruth to reduce the flow rate as expressly suggested by Heruth (FF 3).
Heruth does teach administering for periods of more than 24 hours (FF 2), a
time period reasonably sufficient to satisfy the “steady state” requirement of
claim 1 consistent with Specification’s teaching that administration for 1 day
was sufficient to cause wide distribution (see Spec. 1 50) in the absence of
any contrary evidence presented by Appellants.
Appellants contend
the inventors have surprisingly and unpredictably demonstrated
that broad distribution within the CSF may be achieved by
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infusing liquid formulations that include therapeutic or
diagnostic agents to the CSF at low flow rates over prolonged
periods of time, particularly for a duration that allows steady
state levels of the agents in the CSF. See Tflf06-07 of the present
application.
(App. Br. 11-12).
We do not find this argument persuasive because neither paragraph 6
nor 7 of the Specification identifies the breadth of distribution as
“surprising” or unexpected (see Spec. Tflf 6—7). “It is not enough to show
that results are obtained which differ from those obtained in the prior art:
that difference must be shown to be an unexpected difference” In re Klosak,
455 F .2d 1077, 1080 (CCPA 1972).
Appellants do not identify any other evidence such as a Declaration
which suggests that the distribution is surprising or unexpected. See In re
Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (“It is well settled that unexpected
results must be established by factual evidence. Mere argument or
conclusory statements... [does] not suffice.”); also see In re Pearson, 494
F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take
the place of evidence.”).
Appellants contend that “Heruth teaches away from [distributions as
recited in the claims]. Accordingly, one would not have administered
molecules at the claimed rates for the claimed period of times to patients for
which the claimed distributions were desired based on the teachings of
Heruth” (App. Br. 12).
We find the teaching away argument unpersuasive. A teaching away
requires a reference to actually criticize, discredit, or otherwise discourage
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Application 13/267,243
the claimed solution. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004)
(“The prior art’s mere disclosure of more than one alternative does not
constitute a teaching away from any of these alternatives because such
disclosure does not criticize, discredit, or otherwise discourage the solution
claimed”). Appellants do not identify, and we do not find, any teaching in
Heruth that administration of less than 500 microliters for periods of time
necessary to reach steady state concentrations in the CSF as undesirable in
any way. In fact, Heruth directly suggests administration of 2,000
microliters or less for periods up to 24 hours (FF 3). Likewise, although
Heruth teaches that reducing the amount of a drug that reaches the brain may
be desirable under some circumstances (FF 2), claim 1 does not require any
specific concentration of the molecule to be obtained in the brain, as
discussed above.
Conclusion of Law
(i) The evidence of record supports the Examiner’s conclusion that
Heruth renders claim 1 obvious.
(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
B. 35 U.S.C. § 103(a) over Oldfield
The Examiner finds Oldfield teaches
administering a liquid formulation comprising the molecule to
an CSF-containing intrathecal space of the subject at a flow rate
of 1.9 ml in 32 hours (0.059 ml/hour, or 59 microliters/hour)
(paragraph 124), wherein the therapeutic agent may be
aminoglutethimide (molecular weight = 232 Da) (paragraph
71). Although Oldfield does not appreciate that 7 hours is a
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Application 13/267,243
period of time sufficient to reach a steady state concentration in
CSF of the brain, the specification states that over 1 day is an
exemplified time period
(Ans. 5). The Examiner acknowledges that “Oldfield fails to teach a specific
example wherein aminoglutethimide is administered at 59 microliters/hour”
but finds it obvious to “administer aminoglutethimide at a flow rate of 59
microliters/hour, as this is one embodiment taught by Oldfield to provide
efficacious administration of aminoglutethimide to the CSF of a brain” (Id.).
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Oldfield renders claim 1 obvious?
Findings of Fact
6. Oldfield teaches “a method of monitoring the distribution of
therapeutic agents as they move through solid tissue during CED
[convection enhanced delivery]” (Oldfield 12). Oldfield explains that
“CED delivery relies on bulk flow to distribute substances within the
interstitial spaces of the CNS. Unlike intraventricular delivery, which relies
on diffusion, convection is not limited by the infusate’s molecular weight,
concentration, or diffusivity” (Oldfield 1100).
7. Oldfield teaches
Delivery of therapeutic agents to large targeted volumes (and
substantially only to those targeted volumes) of the brain offers
great potential for treatment of many neurological disorders . . .
potential target areas should be completely perfused by infusing
0.4 ml over a 7 hour period, or 1.9 ml over a course of 32 hours,
assuming a flow rate of 1 pgl/min and a volume of distribution
equal to four.
(Oldfield 1124).
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8. The Examiner finds that aminoglutethimide has a molecular
weight of 232 Da (see Ans. 5).
9. Oldfield teaches:
Factors that influence delivery of a therapeutic agent by CED
include the type of tissue infused (for example, white or gray
matter) and the tissue binding properties, metabolism and
microvascular permeability of the agent. In addition, the
volumetric flow rate, duration of infusion, and the size of the
cannula (or catheter) used to deliver an infusate may affect the
distribution of therapeutic agents delivered by CED.
(Oldfield 15).
Principles of Law
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003) and “a reason that would have prompted a person of
ordinary skill in the relevant field to combine the elements in the way the
claimed new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007).
Analysis
Appellants contend
Oldfield relates to CED to infuse substances directly into the
interstitial space of a solid tissue. One of skill in the art at the
time the present application was filed would learn nothing from
Oldfield with regard to infusion rates or times that could be
used for infusing an agent into the fluid filled CSF space of a
subject for broad distribution within the CSF space.
(App. Br. 13).
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The Examiner responds “Oldfield teaches administration of its liquid
formulation to the brain. The brain, even though it is a semi-solid, contains
cerebrospinal fluid (CSF). Therefore administration into the brain is
administration into a CSF-containing intrathecal space” (Ans. 7).
We find that Appellants have the better position. The definition of
“intrathecal” is “[wjithin a sheath, specifically, the spinal canal—in the
subarachnoid or subdural space).”4 Claim 1 specifically requires
administration to a “CSF-containing intrathecal space”. Therefore, even if
the Examiner is correct that Oldfield administers to the CSF in the brain, that
administration does not constitute an “intrathecal space” as required by
claim 1. The Examiner provides no reason why administration to the
intrathecal space in the spine would have been obvious over the teachings of
Oldfield.
Claim 10 requires “administering a liquid formulation comprising the
molecule to the CSF”. We agree with Appellants that Oldfield’s
administration by CED to the brain is not reasonably interpreted as
“administering” the liquid to the CSF, even if some of the liquid may be
transported through the brain tissue to the CSF (see App. Br. 13). The
Examiner does not establish that an ordinary artisan would reasonably
interpret Oldfield’s administration to solid tissue as “administering a liquid”
to the CSF.
4 Intrathecal, (n.d.) McGraw-Hill Concise Dictionary of Modern
Medicine. (2002). Retrieved November 16 2016 from
http://medical-dictionary.theffeedictionary.com/intrathecal
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Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that Oldfield renders claim 1 obvious.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C.
§ 103(a) as obvious over Heruth. Claims 2—23 fall with claim 1.
We reverse the rejection of claims 1 and 10, and of claims 2, 3, 5, 7—9,
11, 12, 14—18, and 23, which directly or indirectly depend from claims 1 or
10, under 35 U.S.C. § 103(a) as obvious over Oldfield.
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
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