Ex Parte Dubach-Powell et al

Patent Trial and Appeal Board

Jul 14, 2017

12375586 (P.T.A.B. Jul. 14, 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.
12/375,586 03/03/2009 Judith Dubach-Powell 3075-014-01 8963
33432 7590 08/01/2017
KTT YK fr ROWF.R.SOY P T T C
EXAMINER
400 HOLIDAY COURT SCHLIENTZ, NATHAN W
SUITE 102
WARRENTON, VA 20186 ART UNIT PAPER NUMBER
1616
MAIL DATE DELIVERY MODE
08/01/2017 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 JUDITH DUB ACH-PO WELL,
RUDOLF HAUSMANN, and PIERRE VANKAN1
Appeal 2015-004770
Application 12/375,586
Technology Center 1600
Before JOHN G. NEW, CHRISTOPHER G. PAULRAJ, and
KRISTI L. R. SAWERT, Administrative Patent Judges.
NEW, Administrative Patent Judge.
1 Appellants state the real party-in-interest is Santhera Pharmaceuticals
(Schweiz) AG. App. Br. 3.
Appeal 2015-004770
Application 12/375,586
DECISION ON APPEAL
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Non-Final Rejection of claims 2, 13, 14, 16, and 17 as
unpatentable under 35 U.S.C. § 103(a) as being obvious over the
combination of the Tagaki Group, Research on the pathology and treatment
of muscular dystrophy and related diseases,” Ministry of Welfare, Japan
1995 (“Takagi”), Sassover (US 2004/0067986 Al, April 8, 2004)
(“Sassover”), Hedner et al. (WO 00/25821, May 11, 2000) (“Hedner”),
Akinobu et al. (JP 2503571 B2, June 5, 1996) (“Akinobu”)2 and Hiyoshi et
al. (JP 02-083317 A, March 23, 1990) (“Hiyoshi”).
Claims 2, 13, 14, 16, and 17 also stand rejected as unpatentable under
35 U.S.C. § 103(a) as being obvious over the combination of Miyamoto et
al. (US 6,271,266 Bl, August 7, 2001) (“Miyamoto”), Sassover, Hedner,
Akinobu, and Hiyoshi.
Claims 2, 13, 14, 16, and 17 also stand rejected as unpatentable under
35 U.S.C. § 103(a) as being obvious over the combination of Y. Ikejiri et al.,
Idebenone Improves Cerebral Mitochondrial Oxidative Phosphorylation in a
Patient with MELAS, 47 Neurology 583 (1996) (“Ikejiri”), Sassover,
Hedner, Akinobu, and Hiyoshi.
2 The Examiner cites to this reference as “Kiyota et al.” and Appellants
employ the same usage. See Final Act. 3, App. Br. 7. However, Japanese
patent JP 2503571 B2, published June 5, 1996, lists Akinobu et al. as the
inventors of record, none of which is named “Kiyota.” Moreover, the
English translation of this patent entered into the record of this appeal
provides no translation of the names of any of the inventors. See Foreign
Reference, filed February 26, 2103, 9 pp. We consequently use “Akinobu”
to refer to this reference throughout this Decision.
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Claims 2, 13, 14, 16, and 17 stand further rejected as unpatentable
under 35 U.S.C. § 103(a) as being obvious over the combination of P.
Cortelli et al., Clinical and Brain Bioenergetics Improvement with
Idebenone in a Patient With Leber’s Hereditary Optic Neuropathy: A
Clinical and31P-MRS Study, 148 J. Neurol. Sci. 25 (1997) (“Cortelli”),
Sassover, Hedner, Akinobu, and Hiyoshi.
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants’ invention is directed to the use of a medicament
comprising idebenone for transmucosal administration. Abstract.
REPRESENTATIVE CLAIM
Claim 2 is representative of the claims on appeal and recites:
2. A method for the treatment of a mitochondrial,
neurological or neuromuscular disease comprising transmucosal
administration of a medicament comprising idebenone, wherein
said mitochondrial, neurological or neuromuscular disease is
Leber’s Hereditary Optic Neuropathy (LHON), mitochondrial
myopathy, encephalopathy, lactic acidosis with stroke-like
episodes (MELAS), Duchenne Muscular Dystrophy (DMD),
Becker Muscular Dystrophy (BMD), Alzheimer’s disease, or
Parkinson’s disease, wherein said idebenone is administered in a
dosage from 0.01 mg/kg/day to less than 5 mg/kg/day, and
wherein said idebenone is the sole therapeutic agent in said
medicament.
App. Br. 29.
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ISSUES AND ANALYSES
We agree with, and adopt, the Examiner’s findings and conclusions.
We address the arguments raised by Appellants below.
A. Rejection of claims 2, 13, 14, 16, and 17 over Takagi, Sassover,
Hedner, Akinobu. and Hiyoshi
Issue 1
Appellants argue the Examiner erred because Takagi neither teaches
nor suggests treatment of Duchenne’s muscular dystrophy with idebenone or
a dosage of idebenone. App. Br. 8.
Analysis
The Examiner finds Tagaki teaches treatment of Duchenne’s muscular
dystrophy with idebenone at a concentration of 10 mg/1 or more. Final Act.
3 (citing Takagi, Summary and Conclusions). The Examiner finds Tagaki
does not explicitly teach transmucosal administration of idebenone through
the nasal, oral or colonic mucosa at a concentration of 0.01 mg/kg/day to
less than 5 mg/kg/day, and in the form of a suppository, drop, chewing gum,
fast dissolving tablet or spray. Id. at 4. However, the Examiner finds
Sassover teaches that idebenone is a benzoquinone compound that has been
investigated in elderly patients with dementia. Id. The Examiner finds
Sassover teaches the precise mechanism(s) of action of idebenone remain
unknown, but in vitro and in vivo studies suggest that idebenone may
diminish nerve cell damage due to ischemia, correct neurotransmitter defects
and/or cerebral metabolism, and facilitate memory and learning. Id.
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The Examiner further finds that Sassover teaches that the
compositions may be in the form of a solid, liquid or aerosol and are
administered by a route selected from the group consisting of sublingual,
rectal, vaginal, intraocular, transdermal, respiratory mucosal, and pulmonary
routes. Final Act. 4 (citing Sassover || 101, 121, claim 32). The Examiner
finds Sassover further teaches that the composition may be delivered to a
patient by a number of means, including sublingual infusion, delivery
through nasal membranes, injection, oral administration, and transdermal
delivery. Id. The Examiner finds Sassover teaches that it is believed that
sublingual infusion is more targeted, convenient, and effective compared to
the alternative delivery methods. Id. (citing Sassover 199).
Appellants argue Takagi teaches only ex vivo experimentation on an
mdx mouse muscle preparation using idebenone. App. Br. 8. Appellants
contend, therefore, that the muscle was only tested after removal from the
subject mice with only a simple concentration in mg/L of the idebenone
provided, and not a dosage determined in the context of body weight or
frequency of administration for in vivo treatment of Duchenne’s muscular
dystrophy. Id. at 8—9. Appellants assert that the remaining references do not
remedy the alleged deficiencies of Takagi.
Appellants point to Sassover, which, they allege, relates to
compositions and their use in the regulation and modulation of neuro­
endocrinal and neuro-metabolic functions. App. Br. 9. Appellants contend
that the principal therapeutic agents in Sassover’s compositions do not
include idebenone, but rather to chemically-unrelated therapeutic agents, and
that idebenone is merely identified in a long list of optional (additional)
ingredients for inclusion in the compositions. Id. (citing Sassover || 26, 51—
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89; 27, 103, and 113). Appellants assert that there is no teaching or
suggestion of using idebenone as the sole therapeutic agent in any
composition of Sassover. Id.
Furthermore, Appellants argue, Sassover teaches away from such a
use, as it explicitly states that the efficacy of the optional ingredients “may
be greatly improved by combining them with the composition of the present
invention.” App. Br. 9 (citing Sassover 1119). Furthermore, Appellants
argue, Sassover does not mention idebenone when discussing the
components of the composition that act synergistically with one another. Id.
(citing Sassover 190). Rather, Appellants assert, Sassover is specifically
focused on its described compositions including, for example, its disclosed
routes of administration and dosage forms for those specific compositions.
Id. (citing Sassover 1119). Appellants argue that this focus does not
translate to the general suitability of particular routes of administration or
dosage forms for other therapeutic agents including those agents described
as optional, such as idebenone, used alone or in combination with further
therapeutic agents. Id.
Hedner, Appellants argue, is directed to the treatment of restless legs
syndrome (RLS) and/or periodic limb movements during sleep (PLMS)
using a cholinesterase inhibitor (“CEI”). App. Br. 12 (citing Hedner Abstr.,
e.g.). Appellants contend Hedner includes a long list of cholinesterase
inhibitors, including idebenone. Id. (citing Hedner 7). Appellants assert that
Hedner teaches peroral administration, and not absorption in the oral cavity,
as being the “most preferred route” of administration for the CEI or mixture
of CEIs. Id. (citing Hedner 8). Appellants further argue that Hedner does
not describe a dosage as recited in the present claims but rather relates to
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administration of a CEI at a dose from 0.1 to 2.500 mg, in the context of
“one major sleeping period,” in the treatment of RLS and/or PLMS. Id.
(citing Hedner claims 1, 11). Appellants contend that there is no obvious
way to translate that dosage into the dosage recited in the present claims. Id.
Appellants next point to Akinobu, which, Appellants assert, relates to
improvement of cerebral circulation metabolism using a combination of
idebenone and vinpocetine. App. Br. 10 (citing Akinobu transl. at 1).
Appellants argue Akinobu does not use the term “parenteral oral,” a term
that appears to originate from an independently—prepared abstract (by
“Derwent”) relied upon by the Examiner. Id. (citing Final Act. 5).
Appellants argue Akinobu explicitly distinguishes oral from parenteral,
making the term (parenteral oral) used by the Examiner awkward and
inconsistent with both Akinobu and the art generally. Id. (citing Akinobu
transl. at 2). Appellants explain that “parenteral” generally refers to routes
of administration other than through the digestive tract, and often refers to
administration of therapeutic agent by injection, for example, either
subcutaneously, intravenously, or intramuscularly. Id. at 10-11. Appellants
contend Akinobu does not teach or suggest dosages for idebenone as a sole
therapeutic agent, but rather discusses doses of idebenone specifically in the
context of a combination of idebenone and vinpocetine. Id. at 11 (citing
Akinobu transl. at 2). Appellants argue further that these doses (mg/kg), and
the frequency of dosage, for example, as an amount per day, is unclear and
provides no realistic foundation or means for determining the dosages
recited in the present claims. Id.
Finally, Appellants point to Hiyoshi which, Appellants argue, relates
to the use of idebenone in the context of treating schizophrenia. App. Br. 11
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(citing Hiyoshi Abstr.). Appellants argue Hiyoshi discusses amounts in
milligrams, and not as dosages, providing no realistic foundation or means
for determining the dosages recited in the present claims. Id.
The Examiner responds that the mdx mouse is an established animal
model that is well known in the art as correlating to Duchenne’s muscular
dystrophy. Ans. 2. The Examiner finds Tagaki teaches that, in 1994, the
therapeutic effect of idebenone, a cerebral metabolic activator, was
measured in mdx mice, and showed improved membrane potential and
succeeded in completely preventing myotonic bursts at a concentration of 40
mg/1. Id. The Examiner finds Takagi also teaches that, in 1995, a similar
effect was achieved with a smaller dosage of 2—20 mg/1. Id. at 2—3. The
Examiner finds that Tagaki further teaches that idebenone was revealed to
improve membrane potential at a concentration of 10 mg/1 or more, and to
have a suppressing effect on myotonic bursts. Id. at 3. Therefore, the
Examiner finds that a person of ordinary skill would realize, from the
teachings of Tagaki, idebenone would be reasonably expected to be
successful in the treatment of Duchenne’s muscular dystrophy. Id.
With respect to Appellants’ arguments concerning Sassover, the
Examiner finds Sassover explicitly teaches: “[i]n another embodiment of the
invention, the composition may include idebenone. Idebenone is a
benzoquinone compound that has been investigated in elderly patients with
dementia.” Ans. 4 (quoting Sassover || 113). Therefore, the Examiner
finds, Sassover teaches incorporation of idebenone in the disclosed
compositions. Id.
The Examiner finds Sassover also teaches:
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The composition of the present invention may be delivered
to a patient by a number of means, including sublingual infusion,
delivery through nasal membranes, injection, oral
administration, and transdermal delivery. However, it is
believed that the sublingual infusion is more targeted,
convenient, and effective as compared to the alternative delivery
methods. For example, delivery through nasal membranes may
be irritating to the nasal mucosa and may be inefficient, because
it requires a dissolution of the composition prior to the
administration. Injection is inconvenient for self-administration.
Oral administration may limit the efficacy of the composition
due to a gastric acid breakdown of the composition and filtering
out of the composition by the liver before the composition
reaches the blood-brain barrier. Also, transdermal delivery may
be less efficient than sublingual infusion because it requires the
diffusion of the composition through the dermal layers.
Accordingly, in one embodiment of the present invention,
the composition is administered to the patients by sublingual
infusion. The delivery mechanism of sublingual infusion is
believed to enable the composition to cross the blood-brain
barrier and enter the central nervous system (CNS) without the
threat of breakdown in the gastric acid or on the initial passage
through the liver. It is also believed that the optimal dosing and
bioavailable delivery attributable to sublingual ingestion are
important factors in the stability and neurosystemic efficacy of
the composition of the present invention.
Ans. 4—5 (quoting Sassover H 99-100). The Examiner finds Sassover thus
expressly teaches the benefits of, and reason to, administer the compositions,
which include idebenone, via sublingual infusion. Id. at 5. The Examiner
finds Sassover further teaches that the compositions may be administered
through rectal, vaginal, respiratory and mucosal routes. Id. (citing Sassover
1101).
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With respect to Hedner, the Examiner finds the reference teaches that
idebenone is a suitable cholinesterase inhibitor for use in their invention, in
which the CEI is administered perorally for sublingual and/or buccal
absorption. Ans. 5 (citing Hedner claims 5, 7). The Examiner therefore
finds Hedner teaches that idebenone is suitable for sublingual absorption.
Id.
With respect to Appellants’ arguments concerning Akinobu, the
Examiner finds Akinobu teaches that the disclosed compositions may be
administered in the form of a suppository, and parenteral doses for an adult
are 1/10 those used for oral administration. Ans. 6. The Examiner therefore
finds Akinobu teaches that idebenone may be administered through
transmucosal administration (i.e., via a suppository). Id.
Finally, with respect to the teachings of Hiyoshi, the Examiner finds
the reference teaches that the daily dose of idebenone is 10—300 mg for an
adult in the case of oral administration and about 1/10 of the oral dosage
when administered parenterally. Ans. 6. The Examiner therefore finds that
a person having ordinary skill in the art would readily be able to determine
from these combined references the claimed dosage of idebenone in
mg/kg/day for parenteral administration. Id.
We are not persuaded by Appellants’ arguments. As an initial matter,
the Examiner finds, and Appellants do not dispute, that mdx mice are well
known in the art as an animal model of Duchenne’s muscular dystrophy.
Appellants’ argument with respect to Takagi is that Takagi teaches
data obtained from ex vivo experiments which, Appellants argue, cannot be
compared to experiments performed in vivo for treatment of Duchenne’s
muscular dystrophy. See App. Br. 8—9; see also Oral Heating Transcript 6,
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11. 21—26. However, we can find no evidence of record, either in Takagi or
elsewhere, to support this assertion.
Specifically, Takagi teaches that it was well-known in the
contemporary art that:
The cerebral metabolic activator, idebenone, is known to have
the following medicinal actions:
(1) activates the respiratory activity of mitochondria and
enhances the glucose utilization rate and ATP production of
brain neurons. (Suppresses the decrease in ATP production of
brain mitochondria during ischemia.) Further, suppresses the
increase of lactic acid and
(2) in anoxia state [sic], it suppresses the mitochondrial damage
by its activity to scavenge free radicals that were produced during
the course of cell death due to the influx or release of Ca ions
into the cell, and suppresses cytoclasis.
Takagi 2 (internal references omitted).
With respect to the latter, Takagi teaches:
In this research of 1994, we examined the therapeutic effect of
idebenone, a cerebral metabolic activator on mdx mice. The use
of idebenone at a concentration of 40 mg/1 improved membrane
potential and succeeded in completely preventing myotonic
burst. In 1995, we examined whether the effect can be achieved
with a smaller dosage of 2—20 mg/1.
Improvement in electrophysiological abnormality of sarcolemma
of mdx mice had [sic] been confirmed by our experiment this
time. ... Regarding the drug dosage, at the beginning,
improvement of membrane potential and suppressing effect on
myotonic burst could be observed by acting the drug at a high
concentration of 40 mg/1 in Tyrode solution on the mdx mouse
muscle preparation. Since this dosage seemed massive, hoping
a therapeutic effect with lesser amount, we conducted the
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experiment with four levels of concentrations between 2-20 mg/1
and concluded that idebenone is effective at 10 mg/1 or more.
Exercise load: In B10 mice, no decrease in membrane
potential was observed even with the application of exercise
load. However, in mdx mice, nerve stimulation at 30 Hz, 5V of 5
minutes decreased the membrane potential from -76.2 mV to
-69.9 mV.
Takagi 2—3. To be sure, even if we view the phrase “the mdx mouse muscle
preparation” as indicating an ex vivo preparation, Appellants have provided
no evidence that the mdx mouse is not a model for Duchenne’s muscular
dystrophy. Ans. 2.
Furthermore, we note that Takagi teaches: “the improving effect of
idebenone could also be confirmed using a muscle preparation of mdx mouse
which shows decreased membrane potential by anoxia.” Takagi 2—3. This
sentence’s language reciting “using a muscle preparation of mdx mouse”
could seem to suggest an ex vivo preparation, as argued by Appellants, but
also suggests a study that is additional in comparison to the main findings.
In the larger context, the Examiner finds that Takagi teaches that
idebenone improves the muscular properties of the Duchenne’s muscular
dystrophy model of mdx mice. We agree with the Examiner that Takagi
would at least suggest to a person of ordinary skill in the art that idebenone
would be beneficial in the treatment of Duchenne’s muscular dystrophy,
because it was well known in the art that the mdx mouse is a useful model of
Duchenne’s muscular dystrophy.
The Examiner next turns to Sassover, which teaches the use of a
combination of therapeutic agents, including idebenone: “to provide a neuro-
degenerative inhibitor, a neuroendocrine modulator, and a neuro-cerebral
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metabolism enhancer that enable the mitigation of preexisting medical
and/or age-related degenerative disorders with minimal toxicity and side
effects.” Sassover 17. With respect to idebenone, Sassover teaches:
In another embodiment of the invention, the composition may
include idebenone. Idebenone is a benzoquinone compound that
has been investigated in elderly patients with dementia. Its
precise mechanism(s) of action remains unknown, but in vitro
and in vivo studies suggest that idebenone may diminish nerve
cell damage due to ischaemia, correct neurotransmitter defects
and/or cerebral metabolism, and facilitate memory and learning.
An amount of idebenone added to the composition of the present
invention may be in the range from 1 mg to 2 g.
Sassover 113 (internal reference omitted). We agree with the Examiner that
Sassover teaches that it was well known in the prior art that idebenone had
been had been investigated as a therapeutic agent in the treatment of elderly
individuals with dementia, e.g., Alzheimer’s or Parkinson's disease, as
recited in claim 2.
Moreover, with respect to the administration of the therapeutic agents,
Sassover teaches:
The composition of the present invention may be delivered to a
patient by a number of means, including sublingual infusion,
delivery through nasal membranes, injection, oral
administration, and transdermal delivery. However, it is
believed that the sublingual infusion is more targeted,
convenient, and effective as compared to the alternative delivery
methods.
Accordingly, in one embodiment of the present invention, the
composition is administered to the patients by sublingual
infusion. The delivery mechanism of sublingual infusion is
believed to enable the composition to cross the blood-brain
barrier and enter the central nervous system (CNS) without the
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threat of breakdown in the gastric acid or on the initial passage
through the liver. It is also believed that the optimal dosing and
bioavailable delivery attributable to sublingual ingestion are
important factors in the stability and neuro-systemic efficacy of
the composition of the present invention.
Sassover || 99-100 (emphasis added). We agree with the Examiner that
Sassover thus teaches that its compositions, including idebenone can be
delivered via sublingual infusion.
Appellants define “mucosae” as used in the claim term “transmucosal
administration” as: “includ[ing] the nasal mucosa, the colon mucosa and the
oral mucosae. The oral mucosae comprise the sublingual and buccal
mucosa. Idebenone is preferably applied through the oral or nasal mucosa,
more preferably via the sublingual or buccal mucosa.'1'’ Spec. 4.
Furthermore, the Specification discloses: “The medicament for transmucosal
administration of idebenone can be prepared, for example, as fast-dissolving
tablets, emulsions, solutions, sprays, gels, mucoadhesive tablets or pastes,
pastilles, sublingual tablets, drops, chewing tablets, suppositories or gums.”
Id. at 5. We therefore agree with the Examiner Sassover’s teaching that
compositions, including idebenone, may be optimally administered via
sublingual infusions, directly teaches or suggests claim 2’s recitation of:
“transmucosal administration of a medicament comprising idebenone.”
Similarly, we agree with the Examiner that Hedner teaches the use of
idebenone, among other cholinesterase inhibitors, which can be effectively
administered via: “absorption within the oral cavity such as sublingual
absorption,” which we find also teaches “transmucosal administration” as
recited in claim 2. We similarly agree with, and adopt, the Examiner’s
findings with respect to Akinobu and Hiyoshi. We therefore agree with the
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Examiner that the cited references teach or suggest the disputed limitations
of claim 2.
Issue 2
Appellants argue the Examiner erred in disregarding Appellants’
proffered evidence of “surprising and unexpected results.” App. Br. 12.
Analysis
Appellants contend that their claimed method for treating the various
conditions recited in claim 2 by transmucosal administration of idebenone at
relatively low dosages is both surprising and unexpected. App. Br. 12—13.
Specifically, Appellants’ Specification discloses:
It has surprisingly been found that high plasma levels of free
idebenone, meaning idebenone which is neither conjugated nor
otherwise metabolized, can be reached by transmucosal
administration of idebenone whereby idebenone can be absorbed
into the body through mucosal absorption. Thus, although
transmucosal administration of Coenzyme Q10 has been
described in an earlier publication^] we unexpectedly were able
to demonstrate that the much more polar compound idebenone is
rapidly absorbed through mucous membranes. By use of
transmucosal formulations the high first pass metabolism
observed after conventional oral administration of idebenone can
be circumvented.
Id. at 13 (quoting Spec. 4). Appellants assert that such secondary
considerations of nonobviousness, as exemplified by Example 6 of their
Specification and the Declaration of Dr. Thomas Meier (the “Meier
Declaration”), are sufficient to overcome the Examiner’sprima facie case of
obviousness. Id.
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Specifically, Appellants contend that the allegedly surprising and
unexpected results of the method of claim 2 include at least 10-fold higher
plasma levels for transmucosal administration than after oral administration
of idebenone. App. Br. 14 (citing Meier Decl. 119). Appellants argue that,
even more surprising and unexpected is the rapid achievement of peak
plasma concentrations following transmucosal administration of idebenone.
Id. (citing Meier Decl. 120). Appellants assert further that it is also
surprising that such results were achieved with a very short residence time of
the liquid formulation in the oral cavity and that, with a longer residence
time, plasma levels were shown to be even higher. Id. (citing Meier Decl. |
21-23).
Appellants point to explained in Example 6 of their Specification, in
which plasma levels of idebenone were determined after sublingual
administration and compared with those measured following oral
administration of a micro-emulsion in dogs. App. Br. 14. Appellants assert
the pharmacokinetic analysis in Example 6 includes determination of the
maximum plasma concentration (Cmax), the time at which maximum plasma
concentration was observed (Tmax), and the area beneath the plasma
concentration versus time curves from time 0-480 min (AUCo-480min). Id.
According to Appellants, the relative bioavailability of idebenone after
sublingual administration compared to the oral administration was calculated
for each dog from normalized (1 mg/kg) AUC values and the AUC ratios of
the metabolites were also calculated. Id. The results are shown in Tables 6
and 7 of the Specification’s Example 6, which are reproduced below:
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Pammeter T. AUCswsft
jkte&ttMfte 10S.6 C7B/CM3M) {8,3 $3^) 1126S ««7S^2S1)
I orc-
mucosal 1 conjugates 1871 (272-
40 fftg/Hg |titfabaiioaa
0fi3:! }esnjMpi@s
jSftftS-120) 98083
30 {1SJ1-42.M) EJi5STp®7i^ fB85-^____ _
®S’ci^4^63) 1 IS (1S-30) ”) 448013 (272390-737465)
Table 6 presents mean pharmacokinetic parameters of
idebenone and total conjugated (i.e. inactive) metabolites after
oral (40 mg/kg) vs. sublingual (4 mg/kgl administration in
dogs. Numbers in round brackets indicate the minimum and
maximum values observed
Table 7 presents AUC and Cmm ratios for idebenone and total
conjugated metabolites of oromucosal (4 mg/kg) and oral (40
mg/kg) administration in dogs. The ratios were normalized to a
1 mg/kg dose
Appellants argue that Table 6 demonstrates that the oromucosal
formulation of idebenone gives unexpectedly superior plasma levels of
idebenone compared to conventional oral application, and even if idebenone
is orally administered at a 10-fold higher dose. App. Br. 15. Furthermore,
Appellants argue, the maximum plasma concentration after oromucosal
(sublingual) administration of 4 mg/kg sublingual (105.6 ng/ml) exceeds the
maximum plasma concentration (Cmax) after oral application of 40 mg/kg
oral (31.9 ng/ml) in an unexpected way and level. Id. Similarly, Appellants
argue, the data of Table 7 demonstrate that the normalized AUCo-48o
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obtained with the oromucosal formulation is 11.1 times higher than the
normalized AUCo-480 obtained after oral administration of idebenone. Id. at
17.
Appellants next point to Figure 1 of their Specification which, they
contend, further supports their argument. Figure 1 is reproduced below:
Appellants’ Figure 1 depicts the plasma levels of idebenone
after oromucosal administration (4 mg/kg sublingual) vs. oral
(40 mg/kg oral) in the same dogs (n=3)
According to Appellants, Figure 1 illustrates the mean plasma levels
of idebenone over the first two hours after oromucosal administration of 4
mg/kg (triangles) compared to oral administration of 40 mg/kg of idebenone
(squares) in dogs. Appellants point out that the oromucosal formulation
results in a much greater Cmax and an earlier Tmax compared to the oral
dosage. App. Br. 15.
Appellants then turn to paragraph 19 of the Meier Declaration which,
they argue, presents further evidence in support of the pharmacokinetic data
provided by Example 6. Appellants assert that Dr. Meier further explains
that the results of Example 6 are unexpected and surprising, given the known
physicochemical properties of idebenone and that this study used conditions
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for optimal absorption of idebenone (i.e., in a TPGS-containing formulation)
following gavage administration. App. Br. 17. Appellants contend Dr.
Meier attests that, in Example 6, the mean Cmax achieved following oral
administration of idebenone 40 mg/kg under optimized conditions was 31.9
ng/ml, whereas following a single dose of idebenone of 500 mg/kg (at least
10 times higher) administered in capsules, the mean Cmax was only 5.7 ng/ml
(highest concentration 10.0 ng/ml). Id. (citing Meier Deck 119, Attachment
A). Appellants therefore assert that, under optimized conditions for oral
absorption, it was surprising that a 10-fold higher plasma level of idebenone
was still observed. Id. Appellants contend that these data demonstrate that
the ratio of Cmax following oromucosal versus oral gavage is underestimated
by the optimized conditions reported in application Example 6, which means
the ratio would be much higher if a usual dosage form for the oral route is
used. Id.
Appellants next point to paragraph 20 of the Meier Declaration, in
which Dr. Meier attests that the rapid time in which peak plasma
concentrations following oromucosal administration, i.e., within the first few
minutes of administration, is achieved in Example 6 is also unexpected and
surprising. App. Br. 18. Dr. Meier attests that Cmax was reached
approximately 4 times quicker in the oromucosally-treated animals when
compared to the optimized oral conditions. Id. According to Appellants,
achieving high Cmax (high plasma gradient) is very important for the entry of
idebenone into the brain and the eye, for example, in the case of the
treatment of Leber’s hereditary optic neuropathy (LHON) and, thus,
essential for all indications in which the effect occurs in the brain or the eye.
Id.
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Appellants also invoke paragraph 21 of the Meier Declaration, which
states that it is also surprising that the above-mentioned effect was achieved
within a very short residence time of the liquid formulation in the oral cavity
of the dogs. App. Br. 18. Dr. Meier states that the liquid form could be kept
in the dogs (i.e., prevented from swallowing) for only 1 minute in the
experiment of Example 6, meaning that the absorption had to have taken
place within a very short time. Id. In contrast, Dr. Meier attests, the
absorption in the gastrointestinal tract may take hours and is highly
dependent on the presence of food. Id.
Continuing, Appellants next cite paragraph 22 of the Meier
Declaration, which Appellants argue further demonstrates that the
transmucosal absorption is unexpected and superior in several properties.
App. Br. 18. Dr. Meier attests that additional experiments were conducted
under the supervision of Dr. Meier, and the details of these experiments are
set forth as Attachment C to his declaration. Id. According to Appellants, it
was a surprising result of these additional experiments that oromucosal
administration of idebenone strongly improves the relative bioavailability of
idebenone by approximately 100-fold over oral (gavage) administration. Id.
Appellants assert that, according to paragraph 23 of the Meier
Declaration, the results of these additional experiments show that with a
longer residence time (at least 15 min), plasma levels are even higher than
those reflected in the data provided in Example 6 of Appellants’
Specification. App. Br. 22. Appellants argue that the results demonstrate
that, if oral wafer formulations with longer residence time in the oral mucosa
(compared to the liquid form referred to in Examples 1 and 6 the
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Specification) are used, the plasma levels of idebenone are 25-fold to 100-
fold higher compared to oral gavage. Id. (citing Meier Decl. Attachment C).
Appellants argue that the evidence presented in their Specification and
in the Meier Declaration demonstrate that the method of claims 2 and 16
have unexpected and superior results compared to other methods which use
previous oral routes of administration of idebenone and these results are not
taught or suggested in the cited references. App. Br. 22.
We do not find Appellants’ argument that their data constitute
unexpected and/or surprising secondary considerations to be either
persuasive or sufficient to overcome the Examiner’s prima facie case of
obviousness. Briefly stated, it is Appellants’ contention that the findings
presented in Example 6 of the Specification and in the Meier Declaration
demonstrate that transmucosal administration of idebenone, as recited in
claim 2, results in a surprising and unexpectedly effective and rapid loading
of the serum with the drug (i.e., a greater Cmax and shorter Tmax) than does
oral administration of the drug, even when the latter is administered in
significantly higher doses.
However, even if we accept Appellants’ results at face value, we do
not find them probative of unexpected or surprising results because
Appellants provide no evidence of record to demonstrate that, as a general
principle, transmucosal administration of a drug is not generally a more
rapid and effective means of administering similar cholinesterase inhibitors
or, indeed, any drug at all.
“[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 Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991)
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(emphasis added). Appellants’ evidence, as presented both in the
Specification and in the Meier Declaration, concerns primarily their own or
very similar studies providing evidence with respect to the administration of
idebenone via transmucosal versus oral routes.3 The prior art cited by the
Examiner suggests the very conclusion argued by Appellants. Dr. Meier
particularly argues that achieving:
high Cmax (high plasma gradient) is very important for the entry
of idebenone into the brain and the eye, for example, in the case
of the treatment of Leber’s hereditary optic neuropathy (LHON)
and, thus, essential for all indications in which the effect occurs
in the brain or the eye.
Meier Decl. 20. However, Sassover expressly suggests this very point in
teaching:
The method of sublingual ingestion of the composition ensures
enhanced bioavailability and transit through the blood brain
barrier in the most direct and usable manner. For example,
sublingual ingestion avoids dissipation and breakdown of
ingredients, which is likely to occur when composition is orally-
ingested due to the intervention of gastric mucous and other
interruptive actions of the digestive process.
Sassover 128 (emphasis added). Sassover further teaches:
However, it is believed that the sublingual infusion is more
targeted, convenient, and effective as compared to the alternative
delivery methods. For example .... [o]ral administration may
3 The Meier Declaration also points to C.D. Earl et al., Effects on
Cardiovascular and Respiratory Function in the Telemetered Dog, RCC
Study Number 859414, SNT-MC-17, which Dr. Meier asserts demonstrates
that emphasizes that the ratio of Cmax following oromucosal vs. gavage
administration is underestimated by the optimized conditions reported in
Example 6. See Meier Decl. 119 (citing Attachment A).
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limit the efficacy of the composition due to a gastric acid
breakdown of the composition and filtering out of the
composition by the liver before the composition reaches the
blood-brain barrier. Also, transdermal delivery may be less
efficient than sublingual infusion because it requires the
diffusion of the composition through the dermal layers.
Accordingly, in one embodiment of the present invention,
the composition is administered to the patients by sublingual
infusion. The delivery mechanism of sublingual infusion is
believed to enable the composition to cross the blood-brain
barrier and enter the central nervous system (CNS) without the
threat of breakdown in the gastric acid or on the initial passage
through the liver. It is also believed that the optimal dosing and
bioavailable delivery attributable to sublingual ingestion are
important factors in the stability and neuro-systemic efficacy of
the composition of the present invention.
Sassover || 99-100 (emphasis added). Sassover thus expressly suggests
that sublingual infusion (which Appellants do not contest is transmucosal
administration) is a more rapid and effective method of delivering drugs,
including idebenone, than regular oral administration.
In summary, we are not persuaded by Appellants’ argument that the
data presented in their Specification, or in the Meier Declaration, would
necessarily have been surprising to, or unexpected by, a person of ordinary
skill in the art, particularly in view of the teachings of Sassover. We
conclude that Appellants have not met their burden of showing that their
results would have been surprising when compared to the closest prior art,
i.e., similar studies of transmucosal administration of cholinesterase
inhibitors, and in view of the express teaching and suggestions of Sassover.
We consequently affirm the Examiner’s rejection of claims 2, 13, 14, 16,
and 17 on this ground.
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B. Rejection of claims 2, 13, 14, 16, and 17 over Miyamoto, Sassover,
Hedner, Akinobu, and Hiyoshi
Issue
Appellants argue the Examiner erred because Miyamoto fails to teach
or suggest transmucosal administration at a relatively low dosage as required
by claim 2. App. Br. 23.
Analysis
Appellants argue that Miyamoto teaches that: “The pharmaceutical
dosage form for the cytoprotective composition of the present invention may
be any form that can be orally administered for the treatment of the above-
mentioned diseases.” App. Br. 23 (quoting Miyamoto col. 6,11. 44-47).
Appellants also argue that the remaining references fail to remedy the
deficiencies of Miyamoto for the same reasons presented supra. Id.
Appellants also argue that the Examiner has failed to establish the
predictability of the proposed combination of references and, instead, has
made the conclusory statement that one of ordinary skill in the art would
have had a reasonable expectation of success based on the alleged teachings
of the relied upon references. App. Br. 24.
The Examiner acknowledges that Miyamoto teaches oral
administration of idebenone as opposed to transmucosal administration.
Ans. 8. However, the Examiner finds that a person having ordinary skill in
the art would have known from the cited prior art that transmucosal
administration is more effective than conventional oral administration
because the drug, idebenone, and will enter the blood without the possibility
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of breakdown from the gastric acid and passage through the liver. Id.
Therefore, the Examiner concludes, a person having ordinary skill in the art
would have known that the dosage for transmucosal administration could
predictably be lower than the dosage for conventional oral administration.
Id. at 8—9.
By way of examples, the Examiner points to Akinobu and Hiyoshi,
which teach that the daily dose of idebenone is 10-300 mg for an adult in the
case of oral administration and about 1/10 of that dosage transmucosally.
Ans. 9. The Examiner therefore concludes that a person having ordinary
skill in the art would have been readily able to determine the dosage of
idebenone in mg/kg/day for transmucosal administration. Id.
C. Rejection of claims 2, 13, 14, 16, and 17 over Ikejiri, Sassover,
Hedner, Akinobu, and Hiyoshi
Appellants argue that Ikejiri relates to results for a single individual
with lactic acidosis with stroke-like episodes (“MELAS”) treated with a high
oral dose of idebenone for five months and that there is no teaching or
suggestion that the results were repeatable in others or could be achieved by
a non-oral route at a low dosage as recited in the present claims. App. Br. 25
(citing Ikejiri Abstr.). Appellants repeat their arguments presented supra
and, for the reasons we have explained, we similarly affirm the Examiner’s
rejection of the claims.
D. Rejection of claims 2, 13, 14, 16, and 17 over Cortelli, Sassover,
Hedner, Akinobu, and Hiyoshi
Appellants argue that Cortelli relates to the treatment of a single
individual with Leber’s hereditary optic neuropathy using idebenone at high
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doses for several months and concludes by stressing the use of high doses of
idebenone. App. Br. 27 (citing Cortelli 26). Appellants assert that there is
no teaching or suggestion in Cortelli that the results were repeatable in
others or could be achieved by a non-oral route at a low dosage as recited in
the present claims. Id. Appellants repeat their arguments presented supra
and, for the reasons we have explained, we similarly affirm the Examiner’s
rejection of the claims.
DECISION
The Examiner’s rejection of claims 2, 13, 14, 16, and 17 as
unpatentable under 35 U.S.C. §103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1). See 37 C.F.R.
§ 1.136(a)(l)(iv).
AFFIRMED
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