Ex Parte Toledano

Patent Trial and Appeal Board

Aug 31, 2017

12824367 (P.T.A.B. Aug. 31, 2017)

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.
12/824,367 06/28/2010 Annette C. Toledano 550503: ADI-001 9793
12779 7590
Lathrop & Gage LLP
28 State Street
7 th Floor
Boston, MA 02109
09/05/2017 EXAMINER
WEST, THEODORE R
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
09/05/2017 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):
bostonpatent @ lathropgage. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ANNETTE CHANNA TOLEDANO1
Appeal 2015-007226
Application 12/824,367
Technology Center 1600
Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
RYAN H. FLAX, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to a method of treating pain with a combination of naltrexone and clonidine.
The Examiner rejects the claims as obvious and on the grounds of non-
statutory obviousness-type double patenting. We have jurisdiction under
35 U.S.C. § 6(b).
We AFFIRM.
1 According to Appellant, the Real Party in Interest is Allodynic
Therapeutics, LLC. App. Br. 3.
Appeal 2015-007226
Application 12/824,367
STATEMENT OF THE CASE
Claims 13 and 34—38 are on appeal,2 and can be found in the Claims
Appendix of the Appeal Brief. Claim 13 is representative of the claims on
appeal, and reads as follows:
13. A method for treating pain in a mammal in need thereof
comprising administering to said mammal a combination of:
(a) a first compound comprising naltrexone or a
pharmaceutically acceptable salt thereof and
(b) a second compound comprising clonidine or a
pharmaceutically acceptable salt thereof,
wherein the naltrexone or a pharmaceutically acceptable
salt thereof is administered to the mammal at between about
0.25 mg to 15 mg per day, and wherein the clonidine or a
pharmaceutically acceptable salt thereof is administered to the
mammal at between about 0.0125 mg to 0.25 mg per day.
The Examiner has rejected the claims as follows:
I. claims 13, 34—36, and 38 under 35 U.S.C. § 103(a) as
unpatentable over Vining;3
II. claims 13 and 37 under 35 U.S.C. § 103(a) as unpatentable over
Vining and DeMarinis;4 and
III claims 13 and 34—38 are provisionally rejected on the grounds
on non-statutory obviousness-type double patenting over co-pending U.S.
Application No. 13/799,287.5
2 Claims 1—12, 14—33 are cancelled. See Appeal Br. 3.
3 Vining et al., Clinical Utility of Raid Clonidine-naltrexone Detoxification
for Opioid Abusers, 83 British J. Addiction 567-575 (1988) (“Vining”).
4 De Marinis et al., Headache in the use and withdrawal of opiates and other
associated substances of abuse, 31 Headache 159—163 (1991)
(“DeMarinis”).
5 The U.S. Patent and Trademark Office mailed a notice of abandonment on
March 4, 2016, for U.S. Application No. 13/799,287, the application upon
2
Appeal 2015-007226
Application 12/824,367
I. Obviousness over Vining
The Examiner finds that Vining teaches the administration of
combination therapy including “0.3 mg/day clonidine and 12.5 mg/day
naltrexone.” Ans. 2. Vining also teaches that the therapy reduces symptoms
of joint and muscle aches. See id. The Examiner acknowledges that Vining
does not “disclose the claimed dosage amount of clonidine” and naltrexone
but finds that the reference as a whole suggests minimizing the amount of
clonidine when administering combination therapy with naltrexone. See
Ans. 2—3. The Examiner concludes:
It would have been prima facie obvious to one of skill in the art
at the time of invention to reduce the amount of clonidine from
0.3 mg/day to 0.1 mg/day as suggested by Vining et al. and
thereby arrive at the claimed invention. One would have been
motivated to reduce the dosage amount to mitigate the side
effects of clonidine. One would have had a reasonable
expectation of success because reducing dosage amount to
mitigate side effects is routine in clinical medicine. The
disclosure in the reference that the clonidine dosage amount
may be tapered without withdrawal symptoms is further
evidence that one could successfully treat the pain symptoms
associated with withdrawal by using a clonidine dosage amount
of less than 0.3 mg/day, such as 0.1 mg/day.
Ans. 3.
Appellant contends that Vining does not teach treating patients with
doses of “clonidine less than 0.3 mg/day and more than zero.” Reply Br. 4.
“Appellant submits that Vining teaches that pain is a possible symptom of
which this provisional non-statutory obviousness-type double patent
rejection is based. As the application that forms the basis of this rejection
has been abandoned, the contentions presented by Appellant and the
Examiner regarding this rejection are moot. Accordingly, we dismiss the
appeal with respect to this rejection.
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Appeal 2015-007226
Application 12/824,367
opiate withdrawal, but not a very prevalent or important symptom.” Reply
Br. 5. “Because Vining does not teach the treatment of pain with any dose
of clonidine and/or naltrexone, it cannot suggest lowering the dose of either
drug for treatment of pain.” Appeal Br. 8.
The issue is: Does the preponderance of evidence of record suggest
reducing clonidine levels to below 0.25 mg daily when co-administering
with naltrexone based on the teachings of Vining?
Findings of Fact
FF1. Vining teaches that the combination of “[cjlonidine hydrochloride (an
alpha-2 adrenergic agonist) and naltrexone hydrochloride (an opioid
antagonist), given in combination, provide a safe and effective
treatment of abrupt opioid withdrawal over 4 or 5 days in an
outpatient/day setting.” Vining 567, Abstract (formatting removed).
FF2. Vining table 1, reproduced below, shows the study treatment protocol:
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4
Appeal 2015-007226
Application 12/824,367
Vining 569.
FF3. Vining teaches that “commonly reported side effects from clonidine
were dry mouth and sedation.” Vining 572; see Ans. 3. Additionally,
Vining teaches that “hypotension and sedation, [are] both potentially
dangerous side effects of clonidine.” Vining 574; Ans. 3.
FF4. Vining teaches that other therapy combinations with lower clonidine
dosages were known in the art, see excerpt of table 3 below:
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Vining 573, see Table 3. The excerpt of Table 3 shows clonidine
administration from day 1—6 of the study period, and the combination
with naltrexone therapy starts on day 2 “using 1 mg doses which were
increased every 4 h by 1 mg increments.” Vining 573. Column C, of
table 3 shows a reduction in clonidine dosage from day 3 to day 6
over the course of the study during the period of the combination
therapy with naltrexone. Vining 573.
FF5. Vining teaches that aches are associated with opioid withdrawal.
Specifically, Vining teaches using a withdrawal symptom checklist to
assess patient comfort. The “opiate withdrawal symptom checklist is
a self-rated analogue scale containing 3 8 statements pertaining to
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Appeal 2015-007226
Application 12/824,367
symptoms of opiate withdrawal (e.g. ‘My bones and joints have been
aching’).” Vining 569. “The treatment regimen effectively
suppressed signs and symptoms of withdrawal. . . . Persistent
symptoms were anxiety, restlessness, insomnia, muscle aches, and
‘yen’ for sleep.” Vining 570.
FF6. The Examiner finds that the pain relieving effect of naltrexone alone
was known to one of ordinary skill in the art. See Ans. 8 (“the prior
art suggests that very low dosage amounts of naltrexone are expected
to be effective in treating pain” citing Stebbing6 in support).
FF7. Stebbing teaches “a method to alleviate or reduce pain in a human or
animal patient comprising a daily administration of low dose
naltrexone. A naltrexone dose of between about 0.5 and 5 milligrams
may be used. . . . Because naltrexone stimulates an endorphin
increase, naltrexone therapy may reduce aches and pains.” Stebbing
111.
Principle of Law
In determining whether the subject matter of a patent claim is obvious,
neither the particular motivation nor the avowed purpose of the patentee
controls.... [A]ny need or problem known in the field of endeavor at the
time of invention and addressed by the patent can provide a reason for
combining the elements in the manner claimed. KSR Int’l Co. v. Teleflex
Inc., 550 U.S. 398, 418, 419-420 (2007).
6 Stebbing, US Patent Publication No. 2007/0259939, published Nov. 8,
2007, having a filing date of Oct. 18, 2006, claiming benefit to the
provisional Application No. 60/797,587, filed May 4, 2006.
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Application 12/824,367
Analysis
Vining teaches the co-administration of clonidine and naltrexone for
the purpose of detoxification of opioid addicts. FF1. The daily dosage
range taught in Vining’s study protocol is from 0.3-0.9 mg of oral clonidine
and from 12.5-100 mg naltrexone, with the lowest amount of clonidine
administered at a dosage of 0.8 mg given intra-muscularly. FF2. Vining
discloses that clonidine is known to produce side effect in patients. FF3.
Vining teaches that other combination therapies using clonidine and
naltrexone are also known in the art and the clonidine concentrations in
these therapies ranges as low as 0.1 mg clonidine per day. FF4. Vining
teaches that opiate withdrawal is associated with certain pains and aches that
are assessed throughout treatment protocol disclosed. FF5.
Applying the KSR standard of obviousness in view of the findings of
fact, we agree with the Examiner that it would have been obvious to one of
skill in the art at the time of invention to reduce the “amount of clonidine
from 0.3 mg/day to 0.1 mg/day as suggested by Vining. . . . One would have
been motivated to reduce the dosage amount to mitigate the side effects of
clonidine.” Ans. 3. Here, the motivation for reducing clonidine identified
by the Examiner was for the purpose of reducing side effects in patients
receiving the combination therapy. A rejection for obviousness must include
“articulated reasoning with some rational underpinning to support the legal
conclusion.” KSR, 550 U.S. at 418, quoting In re Kahn, 441 F.3d 977, 988
(Fed. Cir. 2006). The Examiner relies on the teachings in Vining to
establish that clonidine was known to have serious side effects and cites
these side effects as a reason to further reduce the clonidine concentration
when applying combination therapy to patients. FF3. Thus, the Examiner
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Appeal 2015-007226
Application 12/824,367
has articulate a sufficient reason, in this case the reduction of serious side
effects, to support a conclusion of obviousness.
Appellant contends that Vining does not teach treating patients with
doses of “clonidine less than 0.3 mg/day and more than zero.” Reply Br. 4.
“Appellant submits that Vining teaches that pain is a possible symptom of
opiate withdrawal, but not a very prevalent or important symptom.” Reply
Br. 5.
“[DJuring examination proceedings, claims are given their broadest
reasonable interpretation consistent with the specification.” In re Hyatt, 211
F.3d 1367, 1372 (Fed. Cir. 2000). Here, the body of the claim recites
applying combination therapy comprising clonidine and naltrexone at
particular concentrations. At best, the preamble disclosure of “treating pain”
identifies a particular patient population. It is, however, not clear based on
the body of the claim whether the treatment with clonidine and naltrexone is
required to show any efficacy, i.e. and actual reduction of pain in the patient
population. See In re Montgomery, 677 F.3d 1375, 1380 (2012).
Vining teaches that “[t]he treatment regimen effectively suppressed
signs and symptoms of withdrawal. On no day was the mean number of
signs and symptoms greater than 5 out of the 17 [symptoms] included in the
abstinence rating scale. Persistent symptoms were anxiety, restlessness,
insomnia, muscle aches, and ‘yen’ for sleep.” Vining 570; FF5. Here,
Vining teaches that muscle aches (i.e. pain, see Ans. 2) is a known symptom
experienced during opioid withdrawal in addicts and the goal of Vining is to
reduce all the symptoms associated with opioid withdrawal including any
pain associated with withdrawal. The fact that the prior art discloses treating
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Application 12/824,367
multiple symptoms associated with opioid withdrawal does not make the
treatment of any one symptom less obvious.
Appellant contends that Vining provides “statements showing that
clonidine and naltrexone are ineffective in treating pain.” Appeal Br. 7.
“Because Vining does not teach the treatment of pain with any dose of
clonidine and/or naltrexone, it cannot suggest lowering the dose of either
drug for treatment of pain.” Appeal Br. 8.
We are not persuaded by Appellant’s argument that the reason for
lowering the dosage of clonidine or naltrexone needs to be the same as those
contemplated by the patent application. “In determining whether the subject
matter of a patent claim is obvious, neither the particular motivation nor the
avowed purpose of the patentee controls. . . . [A]ny need or problem known
in the field of endeavor at the time of invention and addressed by the patent
can provide a reason for combining the elements in the manner claimed.”
KSR, 550 U.S. at 418, 419-420. Here, the Examiner articulated the reason
for lowering the dosage of clonidine was to reduce the side effects
associated with that drug. See Ans. 3 (“[o]ne would have been motivated to
reduce the dosage amount to mitigate the side effects of clonidine”). We
find that the Examiner has articulated a sufficient reason to lower the
concentration of clonidine in the combination therapy taught by Vining, in
this case the articulated desire is to lower the associated side effects of
clonidine.
Additionally, we note that the Examiner in responding to Appellant’s
arguments has cited Stebbing to establish that naltrexone is a known pain
reliever. FF6. We are not persuaded by Appellant’s contention that
“Stebbing provides no evidence that naltrexone is effective in the treatment
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Appeal 2015-007226
Application 12/824,367
of pain.” Reply Br. 6. Stebbing discloses “a method to alleviate or reduce
pain in a human or animal patient comprising a daily administration of low
dose naltrexone.” FF7. “The use of patents as references is not limited to
what the patentees describe as their own inventions or to the problems with
which they are concerned. They are part of the literature of the art, relevant
for all they contain.” In re Lemelson, 397 F.2d 1006, 1009 (CCPA 1968).
We are not persuaded by Appellant’s argument that the art fails to
recognize that naltrexone and clonidine have both have side effects and it is
only through the combination that the side effects are alleviate. See Reply
Br. 6—7. This argument is not persuasive because as stated by our reviewing
court in In re Hiniker Co., 150 F.3d 1362, 1369 (Fed. Cir. 1998), “the name
of the game is the claim.” It is well established that limitations not
appearing in the claims cannot be relied upon for patentability. In re Self,
671 F.2d 1344, 1348 (CCPA 1982). Here, the claims do not require that
combination therapy alleviates symptoms of side effects of both drugs.
Appellant contends that “the Examiner has impermissibly failed to
consider Appellant’s evidence of unexpected results,” specifically, those
results presented in the Toledano Declaration7 showing that “naltrexone and
clonidine are independently and synergistically effective at treating back
pain.” Appeal Br. 8—9.
We are not persuaded that the Examiner failed to consider the
Toledano Declaration. A review of the record shows that the Examiner
considered the Toledano Declaration, but found it unpersuasive. See Ans. 8.
The Examiner explains that the pain relief shown in the Declaration is
7 Declaration by Dr. Toledano filed on September 23, 2013.
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Application 12/824,367
unpersuasive because it was known in the art that low doses of naltrexone
are effective at relieving pain. See Ans. 8; FF6 and FF7. With respect to the
reduction in side effects, the Examiner explains that the Declaration “is not
persuasive because it is typical and expected in the pharmaceutical arts that
when a dosage amount is reduced, side effects will likewise be reduced.”
Ans. 8. We do not disagree with the Examiner’s reason for finding the
Declaration unpersuasive, and also note that it not clear from the Declaration
that the comparison provided in the Declaration shows a comparison to the
closest prior art.
“[W]hen 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-TravenolLabs., 952 F.2d 388, 392 (Fed. Cir. 1991).
Here, the closest prior art identified by the Examiner is Vining and that
reference treats a patient population undergoing opioid withdrawal (see, e.g.,
FF 4, where patients were treated with 1 mg naltrexone and clonidine doses
ranging from 0.1 to 1.1 mg). Table 1 of the Toledano Declaration shows
pain level reduction based on various clonidine and naltrexone combination,
however, the Declaration does not set forth the underlying cause of the pain
in the tested patient population. See Toledano Deck 1 6. In other words, the
results cannot be compared to Vining because there is insufficient evidence
to establish that the patient populations are the same, nor was a comparison
made with the data shown in Vining by the Declarant. Table 2 of the
Toledano Deck shows the reduction of side effects based on the drug
combination tested. See Toledano Deck | 8. What is not clear from the
Declaration, however, is how many patients were actually involved in the
study. See Toledano Deck 13 (“evaluated [the drugs] alone and in
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Application 12/824,367
combination on a human subject”). Testing of an effect of a drug on a single
subject is not necessarily indicative the effect on a larger patient population.
For these additional reason, we agree with the Examiner that the evidence
presented it the Declaration is insufficient to persuade us that the results are
unexpected.
In summary, we agree with the Examiner that the cited reference
supports a prima facie case of obviousness, but Appellant’s showing of
unexpected results when balanced with the prima facie case, does not render
the claims nonobvious. We affirm the rejection of claim 13 under 35 U.S.C.
§ 103(a) over Vining. Claims 34—36, and 38 were not separately argued and
fall with claim 13.
II. Obviousness over Vining and DeMarnis
The Examiner has rejected claims 13 and 37 as obvious based Vining
and DeMarinis. Ans. 4—5. DeMarinis teaches that a higher “incidence of
headache was found in the opiate addicts (60%), particularly those with a
longer history of addiction, than in the control subjects.” DeMarinis,
Abstract.
Appellant’s sole argument with respect to this rejection is that “De
Marinis cannot cure the deficiencies of Vining because De Marinis only
teaches headaches as a symptom of opiate withdrawal.” Appeal Br. 13.
This argument is not persuasive because, as discussed above, we conclude
that Vining would have made obvious a method of treating pain by
providing combination therapy to a patient population that is routinely
experiences pain. Accordingly, we affirm the rejection of claims 13 and 37
for the reasons given by the Examiner.
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Application 12/824,367
SUMMARY
We affirm the rejection of claim 13 under 35 U.S.C. § 103(a) over
Vining, claims 34—36, and 38 were not separately argued and fall with claim
13.
We affirm the rejection of claims 13 and 37 under 35 U.S.C. § 103(a)
over Vining and DeMarinis.
TIME PERIOD FOR RESPONSE
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
13