Ex Parte Brossard et al

Patent Trial and Appeal Board

Mar 30, 2018

14732013 (P.T.A.B. Mar. 30, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
141732,013 06/05/2015
50446 7590 04/03/2018
HOXIE & ASSOCIATES LLC
75 MAIN STREET, SUITE 203
MILLBURN, NJ 07041
FIRST NAMED INVENTOR
PATRICK BROSSARD
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
AC-102-USC3 3717
EXAMINER
KIM, JENNIFER M
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
04/03/2018 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):
HoxiePatentMail@hoxpat.com
HoxiePatentMail@gmail.com
PTOL-90A (Rev. 04/07)
UNITED ST ATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PAT RICK BROSSARD, JASPER DINGEMANSE,
OLIVERNAYLER, MICHAEL SCHERZ, andBEAT STEINER1
Appeal 2017-005585
Application 14/732,013
Technology Center 1600
Before RICHARD M. LEBOVIT Z, FRANCISCO C. PRATS, and
T AWEN CHANG, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method for administering a selective S 1P1 receptor agonist or a
pharmaceutically acceptable salt thereof to a human subject in need thereof,
which have been rejected as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b).
We REVERSE.
1 Appellants identify the Real Party in Interest as Actelion Pharmaceuticals
Ltd. (Appeal Br. 2.)
Appeal 2017-005585
Application 14/732,013
STATEMENT OF THE CASE
Selective S 1P1 receptor agonists preferentially activate the human
S 1P1 receptor, which is a member of the family of sphingosine-1-phosphate-
sensitive human G-protein coupled receptors. (Spec. 1 :20-22.) "SIP
receptor agonists decrease the number of circulating lymphocytes in
peripheral blood in humans or animals after e.g. oral administration,
therefore they have therapeutic potential in a variety of diseases associated
with a dysregulatedimmune system." (Id. at 1:22-25.)
The Specification states that "[i]t has been surprisingly found ... that
[a] selective S 1P1 receptor agonist [("Compound 1 ")] transiently reduces
heart rate in humans" but that the effect "wane[ s] with repeated dosing."
(Id. at 2:16-18, 22-24.) The Specification also suggests thatthe acute
effects of the agonist may depend on the administered dosage. (Id. at 2:22-
24.) The Specification further explains that, while "[ t ]he acute effect[] on
heart rate ... [is] not seriously adverse," it is nevertheless undesirable, and
methods to minimize the effect would be valuable to maximize the
tolerability and safety of selective S 1P1 receptor agonists and minimize
monitoring requirements during the early phase of initiation or re-initiation
of drug therapy. (Id. at2:28-33.)
According to the Specification, therefore, the claimed invention is
directed to a dosing regimen for selective S 1P1 receptor agonists that
minimizes the incidence or severity of adverse effects of S 1P1 receptor
agonist administration, such as acute heart rate reduction. (Id. at 3: 1-3.)
2
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Claims 1-5, 15, and 16 are on appeal. Claim 1 is illustrative and
reproduced below:
1. A method for administering a selective S 1P1 receptor
agonist or a pharmaceutically acceptable salt thereof to a
human subject in need thereof wherein during an initial
treatment phase the selective S 1P1 receptor agonist or
pharmaceutically acceptable salt thereof is administered
at a dose which induces desensitization of the heart to
acute heart rate reduction said dose being below the
target dose, and at a dosing frequency that sustains
desensitization of the heart, until no further acute heart
rate reduction occurs, followed by dose up-titration to the
target dose of the selective S 1P1 receptor agonist or
pharmaceutically acceptable salt thereof.
(Appeal Br. 15 (Claims App.).)
The Examiner rejects claims 1-5, 15, and 16 under pre-AIA 3 5 U.S. C.
§ 103(a) as being unpatentable over Kovarik2 and Sanna. 3 (Ans. 2.)
Issue
DISCUSSION
The Examiner fmds that Kovarik teaches
use of a S 1 P receptor modulator or agonist in the manufacture of
a medication, whereby said medication is administered in such a
way to a subject that a steady-state of the SIP receptor modulator
or agonist blood levels is attained in less than a week whereby
the dosage of said S 1 P receptor modulator or agonist during the
initial 4 to 5 days or 3 to 6 days of treatment is increased stepwise
2 Kovarik et al., WO 2006/058316 Al, published June 1, 2006 ("Kovarik").
3 M. Germana Sanna et al., Sphingosine I-Phosphate (SJ P) Receptor
Subtypes SIP1 and SJP3, Respectively, Regulate Lymphocyte Recirculation
and Heart Rate, 279 J. BIOLOGICAL CHEMISTRY 13839 (2004) ("Sanna").
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Application 14/732,013
up to the 3 to 21 fold standard daily dosage of said SIP receptor
agonist.
(Final Act. 5.) The Examiner also fmds that Kovarik teaches that "the S 1 P
receptor agonist or modulator can be a selective S 1P1 receptor." (Id.)
The Examiner fmds that Kovarik does not expressly teach that "the
administered dosage induces desensitization of the heart to acute heart rate
reduction." (Id.) However, the Examiner fmds that Sanna teaches that
"S 1P1 selective agonist does not produce bradycardia." (Id.) The Examiner
concludes that the claimed invention would have been obvious to a skilled
artisan, because
[Kovarik] teaches the administration of the same active agent
comprising the same method step of dose up-titration to the same
subject in need thereof with the same overlapping duration of
therapy of initial 4 days .... Further, the dose administered on
. . . day 4 of the initial therapy would be below the remainder
target daily dose of 5th or 6th days of the therapy since the dose
increased daily stepwise up to the 3 to 21 fold up to 6 days. With
regard to limitation of the dose which induces desensitization of
heart to acute heart rate reduction such is obvious because SIP1
agonists do not produce bradycardia in view of [Sanna]. One of
ordinary skill in the art would administer selective S 1P1 agonist
in a step up titration dosages for 6 days as an initial dosage
regimen therapy without concerned about the acute heart rate
reduction since [Sanna] teach[ es] that S 1P1 selective agonist does
not produce bradycardia.
(Id. at 5---6.)
Appellants contend that the cited prior art does not teach all of the
limitations of the claims. (Appeal Br. 8-11.) Appellants contend that the
claimed invention solved a problem not previously recognized in the art.
(Id. at 3-5.) Appellants contend that modifying Kovarik in the manner
proposed by the Examiner would render Kovarik unfit for its intended
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Application 14/732,013
purpose. (Id. at 11-12.) Finally, Appellants contend thatthe subject matter
of the invention exhibits unexpected results. (Id. at 5, 12-13.)
The issue with respect to this rejection is whether a preponderance of
evidence supports the Examiner's conclusion that the claims are obvious
over Kovarik and Sanna.
Findings of Fact ("FF'')
1. The Specification teaches that the compound (R)-5-[3-chloro-4-
(2,3-dihydroxy-propoxy)-benz[Z]ylidene ]-2-([Z]propylimino )-3-o-tolyl-
thiazolidin-4-one ("Compound 1 ") is a selective S 1P1 receptor agonist and
that selective daily oral dosing of 5 mg or more to humans results in
"consistent, sustained, and dose dependent reduction in the number of
peripheral blood lymphocytes." (Spec. 2:11-16.)
2. The Specification teaches that
S 1 P receptor agonists have been described to reduce heart rate in
rodent animal models, an effect that has been attributed to the
activation of the S 1P3 receptor in the sinoatrial nodal tissue of the
heart, which increases the IK1Ach inward rectifier current, and
slows the sinoatrial pacemaker .... Moreover, the non-selective
S 1 P receptor agonist FTY720 reduces heart rate in humans ... ,
and the literature suggests that S 1P1 selective compounds would
have diminished effects on heart rate in humans, compared to
non-selective SIP receptor agonists ....
. . . It has been surprisingly found, however, that the
selective S 1P1 receptor agonist Compound 1 transiently reduces
heart rate in humans, with maximal effects 1-3 hours after
administration. . .. The[] acute effect[] of Compound 1 on heart
rate ... are milder at 10 mg than at 20 mg. All of these effects
wane with repeated dosing. Thus, after 2 to 4 days of daily oral
doses of 5 to 20 mg, an acute heart rate reduction, compared to
the pre-dose value, is no longer observed upon administration of
Compound 1.
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Application 14/732,013
(Id. at 2:16-26.)
3. The Specification teaches that
Compound 1, when given as a 20-mg once-daily dose by the oral
route, results in an acute heart rate reduction on Day 1, and when
the second 20-mg dose is administered 24 hours later, no acute
heart rate reduction is observed. Desensitization has been
sustained over this 24-hour dosing interval. Yet, when a second
20-mg dose is administered 7 days after the first dose, it results
in an acute heart rate reduction of similar magnitude as on Day
1. Desensitization has not been sustained over this 7 -day dosing
interval of the 20-mg dose. This example illustrates that a
suitable dosing interval is necessary to sustain desensitization of
the heart.
(Id. at 3:33--4:5.)
4. The Specification teaches embodiments wherein the initial dose
is between2- to 5-fold or 5- to 16-fold lower than the target dose. (Id. at
4:13-18.)
5. The Specification teaches embodiments wherein a dose below
the target dose is administered to the subject during the initial 2 to 4 days of
the treatment. (Id. at 19-22.)
6. The Specification teaches embodiments wherein the dose below
the target dose is administered once or twice daily. (Id. at 4:23-25.)
7. The Specification teaches that
[ d]ose up-titration to the target dose can be achieved in one or
several dose increments. For example, a suitable dosing regimen
for Compound 1 can be 5 mg p.a. (once daily for 3 days; the
initial treatment phase), followed by up-titration to 10 mg p.a
(once daily for 3 days), followed by up-titration to 20 mg p.a
(the target dose) given once daily indefmitely. Another example
of a suitable dosing regimen for Compound 1 can be 5 mg p.a
(once daily for 3 days; the initial treatment phase), followed by
up-titration to 20 mg p.o. (the target dose) given once daily
indefmitely.
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Application 14/732,013
(Id. at 6:20-26.)
8. "Desensitization of the heart" for purposes of this application
refers to "the absence of an acute heart rate reduction after drug
administration." (Id. at6:10-11.)
9. "Acute heart rate reduction" for purposes of this application
refers to "a heart rate decrease from pre-dose values of, for example, 10 or
more beats per minute (bpm ), that is maximal within a few hours, for
example 1-3 hours, after drug administration, and thereafter the heart rate
returns towards the pre-dose value." (Id. at 6:12-15.)
10. "Target dose" for purposes of this application refers to "the
dose of a selective S 1P1 receptor agonist that achieves target peripheral
blood lymphocyte counts, e.g., 400-800 lymphocytes per micro liter. The
target dose for a given S 1P1 receptor agonist may vary depending on the
nature and severity of the disease to be treated." (Id. at 6:16-19.)
11. The Specification discloses that "Compound 1 has been
administered to humans in three Phase 1 studies." (Id. at 8:21.) These
studies include a single-ascending dose study ( AC-058-101) wherein
Compound 1 doses of 1, 3, 8, 20, 50 and 75 mg were orally administered to
sequential groups of 8 subjects. (Id. at 8:24--27.) These studies also include
a multiple-ascending dose study (AC-058-102) wherein "Compound 1 was
administered orally with doses of 5, 10, and 20 mg once-daily for 7 days"
(Part A) and also in an "up-titration scheme" in which "[t]reatment with
Compound 1 started for 4 days with 10 mg once daily, followed by 4 days
with 20 mg once daily, and 7 days with 40 mg once daily" (Part B). (Id. at
9:1-18.) Table 1 of the Specification is reproduced below:
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Application 14/732,013
Table 1 Comparison of the mean HR reduction at 2.5 h post-dose with and
without up-titration
Without up-titration With up-titration
Part A Mean HR reduction
Part B
Mean HR reduction
(10 and 20-mg) (2.5 h post-dose vs
(40-rng dose group)
(2,5 h post-dose vs
and 50-mg SAD baseline) pre-dose)
10 mg 14 bpm 10 mg 14 bpm
20 mg 22 bpm 20 mg 9bpm
50mg 18 bpm 40 mg 4 bpm
Table 1 compares
the mean heart rate (HR) reduction at 2.5 h post-dose vs. pre-
dose in the 40-mg dose group (AC-058-102, Part B) after each
titration step (Day 1 for 10 mg, Day 5 for 20 mg, and Day 9 for
40 mg) vs. HR reduction without up-titration on Day 1 (10 and
20 mg Part A of AC-058-102 and 50 mg of AC-058-101.
(Id. at 9:19-22.) The Specification further states that
[ t ]he mean HR reduction at 2. 5 h post-dose vs pre-dose in the 40-
mg dose group ( AC-05 8-102, Part B) on days 2, 3, and 4 ( 10 mg)
was 2 bpm, 1 bpm, and 1 bpm, respectively, and 4 bpm, 3 bpm,
and 3 bpm on days 6, 7, and 8 (20 mg), respectively.
(Id. at 10:1-3.)
12. Kovarik teaches a specific dosage regimen for an SIP receptor
modulator or agonist "particularly in the course of the treatment of transplant
patients or patients suffering from autoimmune diseases or disorders."
(Kovarik 1.)
13. In particular, Kovarik teaches including a "loading dose"
whereby "during the initial 3 to 6 days of treatment the daily dosage [of the
S 1 P receptor modulator or agonist] is raised so that in total the R-fold (R
being the accumulation factor) standard daily dosage is administered and
thereafter continued at the standard daily dosage or at daily dosage lower
than the standard daily dosage." (Kovarik Abstract, 1 ("loading dose").)
8
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Application I4/732,0I3
I4. Kovarik teaches that, "[i]n view of the normally prolonged
taking of the medication, the standard daily dosage (also called maintenance
dose) refers to the dosage of an SIP receptor modulator or agonist necessary
for a steady-state trough blood level[, i.e., a pre-dose blood level,] of the
medication or its active metabolite( s) providing effective treatment." (Id. at
I4.)
I 5. Kovarik teaches that the daily dosage lower than the standard
daily dosage referred to in FFI3 may be "about 1/50 to 1/2, preferably 1/50
to I/10, of the standard daily dosage."(Id. at I4.)
I6. Kovarik teaches thatthe initial treatment period (i.e., where
dosage is raised) is 3 to 6 days, preferably 4 to 5 days, and most preferably 4
days. (Id. at I3-I4.)
I 7. Kovarik teaches that dosage of SIP receptor modulator or
agonist preferably increased step-wise (e.g., increased incrementally from 3-
to 2 I-fold, more preferred from 4[-] to I2-fold, particularly about IO-fold,
the standard daily dosage) during the initial treatment period. (Id. at I 4.)
I 8. Kovarik teaches that,
[a]ccording to a preferred embodiment of the invention, the
highest loading regimen dose instalment on the last day of the
loading regimen, e.g. on day4, is 4x the maintenance dose of the
SIP receptor modulator or agonist. The instalment doses on days
I, 2 and 3 of the loading regimen may be e.g. about 1/4; 1/2; and
3 I 4 of the highest instalment dose of the SIP receptor modulator
or agonist.
A particularly preferred dosage of the SIP receptor
modulator or agonist, e.g. the preferred SIP receptor modulator
FTY720, is e.g. 2-5, 5-IO, IO-I5 and I5-20mg, e.g. a regimen
of 2.5mg/5mg/7.5mg/IOmg or 5mg/IOmg/I5mg/20mg
respectively, during the initial period of 4 days. Thereafter the
treatment is continued with the maintenance therapy, e.g. a daily
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Appeal 20I 7-005585
Application I4/732,0I3
dosage of2.5 mg or 5 mg, or at a lower daily dosage, e.g. O. I to
0.5mg.
In a further embodiment of the invention, a preferred
loading regimen of a SIP receptor agonist or modulator, e.g. the
preferred SIP receptor modulator FTY720, may also be e.g
0.5mg!I mgll.5mgl2mg during the initial period of 4 days.
Thereafter the treatment is continued with the maintenance
therapy, e.g. a daily dosage of0.5 mg.
(Id. at I4--I5.)
I 9. Kovarik teaches embodiments where during the initial 4 days of
treatment dosage is I, I. 5-2, 2-3, and 3--4 fold the standard daily dosage or
Ix, 2x, 3x, and4x the standard daily dosage. (Id. at I5-I6.)
20. Kovarik teaches administering FTY720, a SIP receptor
modulatory or agonist, at a daily dosage of about O. I to 0. 5 mg after the
initial loading regiment. (Id. at I6, I 7.)
2 I. Kovarik teaches a prophetic example of a 2-phase loading
regimen wherein subjects receive 5, IO, I5, and 20 mg ofFTY720 oral dose
on day I through day 4 respectively, "in order to achieve the FTY720
steady-state concentration typically measured in patients on chronic dosing
ofFTY720 5mgqd," and continued to receive 5 mg FTY720 oral dose once
daily on day 5 through day 7. (Id. at I 8.) Kovarik teaches that patients may
instead receive daily maintenance dose of 0. 5 mg/kg starting on day 5,
which would be expected to result in lower steady-state blood levels. (Id. at
I9.)
22. Kovarik teaches that alternative loading treatments include (I)
2.5, 5, 7.5, and IO mg FTY720 oral dose on day I through day 4
respectively, in order to achieve FTY720 steady-state concentration typically
measured in patients on chronic dosing ofFTY720 2.5 mg qd, followed by
IO
Appeal 20I 7-005585
Application I4/732,0I3
2.5 mg FTY720 oral dose daily from day 5 through day 7, or (2) 1.25, 2.5,
3.75, and 5 mg FTY720 oral dose on day I through day 4 respectively, in
order to achieve FTY720 steady-state concentration typically measured in
patients on chronic dosing ofFTY720 I.25 mgqd, followed by I.25 mg
FTY720 oral dose from day 5 through day 7. (Id. at I9.)
23. Kovarik teaches that the dosage regimen of its invention allows
attaining, in less than a week, "a steady-state of the SIP receptor modulator
or agonist blood levels" such that the subject is sufficiently
immunosuppressed. (Id. at I5.)
24. Kovarik teaches an embodiment of the invention wherein the
SIP receptor agonist or modulator is a selective SIP 1 receptor. (Id. at I I.)
25. Sanna teaches that "[i]nhibition of lymphocyte recirculation by
non-selective SIP receptor agonists produces clinical immunosuppression
preventing transplant rejection but is associated with transient bradycardia."
(Sanna Abstract; see also id. at I3839-I3840 (relatively non-selective SIP
receptor agonists such as FY720 mediates both lymphopenia and a transient
dose-dependent bradycardia on initial dosing in humans).)
26. Sanna teaches that "SIP 3 and not SIP 1 [] is directly implicated
in sinus bradycardia" based on the finding that"[ t ]he sustained bradycardia
induced by SIP receptor non-selective immunosuppressive agonists in wild-
type mice is abolished in SIP 3 -/-mice, whereas SIP 1-selective agonist
does not produce bradycardia." (Id. at Abstract; see also id. at I3845 (IO
mg/kg selective SIP I receptor SEW287 I induced full lymphopenia but not
bradycardiain either wild-type or SIP3-/-mice), I3847 (stating that "[b]oth
SIP 1 and SIP 3 are expressed on cardiac endothelium and perhaps
myocardium ... , yet deletion of S IP3 alone abolishes the bradycardia
II
Appeal 20I 7-005585
Application I4/732,0I3
induced by non-selective SIP receptor agonists, and an SIP 1-selective
agonist does not induce bradycardia").)
2 7. Jones teaches pharmaceutical compositions containing SIP I
receptor agonist compounds, and methods of using such compounds and
compositions to treat SIP I-associated disorders such as autoimmune
diseases. (Jones Abstract.)
28. Jones cites Sanna and states:
In one embodiment, the present invention encompasses
compounds which are agonists of the SIP I receptor having
selectivity over the S IP3 receptor. The S IP3 receptor, and not
the SIP I receptor, has been directly implicated in bradycardia
(Sanna et al., J Biol. Chem., 279:I3839-I3848, 2004). An S IPI
receptor agonist selective over at least the S IP3 receptor has
advantages over current therapies by virtue of an enhanced
therapeutic window, allowing better tolerability with higher
dosing and thus improving efficacy as therapy. The present
invention encompasses compounds which are agonists of the
SIP I receptor and which exhibit no or substantially no activity
for bradycardia.
(Id. at 6:I9-30.)
29. Jones teaches a prophetic example involving an exemplary
bradycardia assay and states:
It is expressly contemplated that the rats can be used to
show that a compound of the invention has no or substantially no
activity for bradycardia. By way of illustration and not
limitation, the rats are administered vehicle or a test com pound
and heart rate is then measured over a I20 min period. No or
substantially no reduction of heart rate in response to the test
compound in comparison with vehicle is indicative of the test
I2
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Application I4/732,0I3
compound exhibiting no or substantially no activity for
bradycardia.
(Id. at I09:24--33.)
30. Brinkmann4 teaches that "[t]here is accumulating evidence that
SIP and its receptors regulate heart rate, coronary artery blood flow, blood
pressure, and endothelial integrity. [Endothelial cells (ECs)] and [smooth
muscle cells [SM Cs] express predominantly SIP I, SIP I 2 and SIP 3 receptor
subtypes at various levels, depending on vessel type and tissue origin."
(Brinkmann 9 I, left column (citations omitted).)
3 I. Brinkmann states:
Studies in SIP3-deficientmice suggested a dominant role of this
receptor in the regulation of heart rate. Later experiments with
isolated guinea pig atrial myocytes revealed that FTY720-P and
the SIP I-selective agonist AUY954 effectively activate GIRK
channels, suggesting that SIP I contributes to heart rate
regulation. Accordingly, the phosphorylated SIPI,4,5 agonist
KRP-203 (that is inactive at rat SIP3) also reduces heart rate in
vivo in rats. Precisely, intravenous administration ofFTY720-P
at a dose of O.OI mg/kg to rats produced an acute and transiet
reduction of heart rate, whereas a dose of 0. I mg/kg of KRP-203-
p was required to affect heart rate in the same model. Taken
together the data suggest that both SIP I and S IP3 contribute to
heart rate regulation.
Detailed analysis of human cardiovascular tissue by in situ
hybridization and immunohistochemistry has revealed that in
man, SIP I mRNA and protein are strongly expressed in
ventricular, septal, and atrial cardiomyocytes, and EC layers of
cardiac vessels. ln contrast, S IP3 receptors are found in the SMC
layer of aorta and cardiac vessels, but the receptor is only weakly
expressed in cardiomyocytes from both atria and ventricles. The
4 Volker Brinkmann, Sphingosine I-Phosphate Receptors in Health and
Disease: Mechanistic Insights from Gene Deletion Studies and Reverse
Pharmacology, I I5 PHARMACOLOGY & THERAPEUTICS 84 (2007)
("Brinkmann").
I3
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Application I4/732,0I3
data suggest that in humans, SIP I receptors (rather than S IP3)
may play a dominant role in the regulation of ... heart rate and
that the relative involvement of the two receptors may vazy
depending on the experimental model and the species. SIP
receptor agonists readily down-modulate SIP I but not S IP3,
suggesting that the higher serum SIP levels in rodents may lower
steady-state levels of cell membrane SIP I and shift the
responsive[e]ness ofmyocytes to SIP3.
(Id. at 94, left column (citations omitted).)
32. Gergely5 teaches that, "[ w ]hile in vivo animal models indicated
a predominant role of S IP3 in mediating transient heart rate reductions,
human Phase I data with the SIP 1/5 selective agonist BAF3 I2 suggest a
predominant role of SIP I for heart rate reduction in humans." (Gergely I.)
Analysis
On balance, we agree with Appellants that the Examiner has not
established a prima facie case that the claims are obvious over Kovarik and
Sanna. The Examiner concedes that Kovarik does not explicitly teach the
limitation of administering "a dose which induces desensitization of the
heart to acute heart rate reduction." (Final Act. 5.) However, the Examiner
fmds that Sanna teaches that "SIP I selective agonist does not produce
bradycardia" (i.e., a heartrate reduction). (Id.) Accordingly, the Examiner
concludes that a skilled artisan would have found the invention of claim I
obvious because Kovarik otherwise teaches "administration of the same
active agent comprising the same method step of dose up-titration to the
5 Gergely et al., Abstract, Phase I Study with the Selective SIP 1/SJP5
Receptor Modulator BAF312 Indicates that SIP 1 rather than SJP3 Mediates
Transient Heart Rate Reduction in Humans, 25th Congress of the European
Committee for the Treatment and Research in Multiple Sclerosis
(ECTRIMS) (Sept. 9-I2, 2009) ("Gergely").
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same subject in need thereof with the same overlapping duration of therapy
of initial 4 days." (Id. at 5---6.)
We are not persuaded. The Specification defmes "desensitization of
the heart" as "the absence of an acute heart rate reduction after drug
administration" and "acute heart rate reduction" as "a heart rate decrease
from pre-dose values of, for example, 10 or more beats per minute (bpm ),
that is maximal within a few hours, for example 1-3 hours, after drug
administration, and thereafter the heart rate returns towards the pre-dose
value." (FF8, FF9.) The Examiner appears to conclude that this limitation
is inherently met because Sanna teaches that S 1P1 selective agonist would
not produce bradycardia and, therefore, any dosage amounts, including that
disclosed in Kovarik, would "induce [the absence of an acute heart rate
reduction after drug administration]."
As an initial matter, we are not persuaded that a dosage amount has
"induced" an absence of an acute heart rate reduction after drug
administration if the drug never produces an acute heart rate reduction in the
frrst place. The plain and ordinary meaning of "induce" is to effect or cause,
and the Examiner has not shown how a dose has "effected" or "caused" the
absence of an acute heart rate reduction after drug administration if such
heart rate reduction would not have taken place after drug administration in
the frrst place. 6
6 "induce." Merri am-Webster Online Dictionary, https ://www .merriam-
webster. com/ dictionary/induce (last visited March 24, 2018) ("effect,
cause"); see also "induce." Oxford English Dictionary Online,
http://www. oed. com/view /Entry/94 7 58?redirectedFrom =induce#eid (last
visited March24, 2018) ("[t]o bring about, bring on, produce, cause, give
rise to"). We note that this construction is also supported by the remaining
claim language and the Specification. For instance, claim 1 further recites
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Furthermore, in order to fmd that inducing desensitization is an
inherent result of the dose regimen taught by Kovarik, desensitization "must
inevitably result from the disclosed steps; '[i]nherency ... may not be
established by probabilities or possibilities.'" In re Montgomery, 677 F.3d
1375, 1379-80(Fed. Cir. 2012) (citations omitted). In light of the combined
disclosures in the Specification, Sanna, Brinkman, and Jones, the Examiner
did not establish that the administration of selective S 1P1 agonists will
necessarily result in no heart rate reduction. 7 (FF2, FF3, FFl 1, FF25-
FF31.) In particular, the combination of their teachings suggest that, while
S 1 P receptor agonist-induced bradycardia is primarily mediated by S 1P3
receptors in mice, S lP1 may also be involved in such agonist-induced
bradycardia in humans. 8 (Id.)
To the extent the Examiner concludes that a prima facie case of
obviousness has been established because Kovarik teaches a dosage regimen
administering the desensitizing dose "at a dosing frequency that sustains
desensitization of the heart, unless no further heart rate reduction occurs."
(Appeal Br. 15 (Claims App.).) Thus, the rest of the claim 1 itself suggests a
requirement that heart rate reduction occurs upon initial administration of a
selective S 1P1 receptor agonist.
7 Because Gergely is cited for the frrst time in the Reply Brief, we do not
rely on this reference. See Ex parte Nakashima, 93 USPQ2d 1834 (BP AI
2010) (informative) (arguments and evidence not timely presented in the
principal Brief will not be considered when filed in a Reply Brief, absent a
showing of good cause). We note, however, that Gergely supports our
analysis. (FF32.)
8 The Examiner fmds that the data provided in the Specification is not
persuasive because "the administration of ... 'Compound 1 ' ... shown in
the data has been previously issued as a parent patent." (Ans. 3--4; see also
Ans. 6.) The Examiner does not explain, however, how the issuance of the
parent patent renders the data unpersuasive for purposes of an obviousness
analysis.
16
Appeal 2017-005585
Application 14/732,013
having overlapping active ingredient and dosing amount, frequency, and
duration with the claimed invention (see, e.g., Ans. 5---6), we remain
unpersuaded despite our agreement with the Examiner's fmding that
Kovarik teaches a dosage regimen that shares many characteristics of the
claimed regimen. 9 As discussed above, neither Kovarik nor Sanna suggests
administering "a dose which induces desensitization of the heart to acute
heart rate reduction ... at a dosing frequency that sustains desensitization of
the heart, until no further acute heart rate reduction occurs." To the
contrary, Kovarik's dosing regimen uses an initial, relatively high, loading
dosage, which is subsequently reduced several-fold to the daily dosage
ultimately administered. FF 13-FF23. Thus, even if, during certain portions
of its dosage regimen, Kovarik describes overlapping active ingredients and
dosing amount, frequency, and duration, the Examiner has not provided
sufficient evidence that the difference between what is claimed and what is
9 For instance, the Specification teaches that 2 to 4 days of daily oral doses
of 5 to 20 mg desensitized the heart to the acute heart rate reduction
resulting from administration of Compound 1, a selective S 1 P 1 receptor.
(FF2; see also FF3 (desensitization resulting from 1 day administration of20
mg of Compound 1), FF5-FF7, FFl 1.) The Specificationfurtherteaches a
suitable dosing regimen for Compound 1 wherein a desensitization-inducing
dose of 5 mg daily for 3 days is followed by either ( 1) up-titration of 10 mg
p.a. once daily for 3 days followed by up-titration to 20 mg p.a. (target dose)
once daily indefmitely, or (2) up-titration to 20 mg p.a. (target dose) once
daily indefmitely. (FF7.) Similarly, Kovarik teaches a dosing regimen for
S 1 P receptor agonists, which include selective S 1P1 agonists, wherein
dosage is increased (i.e., up-titrated) in step-wise fashion from 2-5 mg to
15-20 mg over 4 days, including exemplary regimens of, e.g.,
0.5mgllmgll.5mg/2mg, 1.25mg/2.5mg/3.75mg/5 mg,
2.5mg/5mg/7.5mg/10mg, and 5mg/10mg/15mg/20mgfrom day 1 to day 4.
(FF18, FF21, FF22.)
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Appeal 2017-005585
Application 14/732,013
in the prior art is so close that a skilled artisan would have arrived at the
claimed dosage regimen through routine optimization. In particular, the
Examiner has not shown that the cited prior art established the dosing
amount, frequency, and duration as result effective variables in inducing
desensitization of the heart to acute heartrate reduction. In re Boesch, 617
F.2d272, 276(CCPA1980) (holding that "discovery of an optimum value
of a result effective variable in a known process is ordinarily within the skill
of the art") (emphasis added).
Finally, we are cognizant that "[ w ]here ... the claimed and prior art
products are identical or substantially identical ... the PTO can require an
applicant to prove that the prior art products do not necessarily or inherently
possess the characteristics of his claimed product." In re Best, 562 F.2d
1252, 1255(CCPA1977) (citation omitted). However, we fmd that, while
the active ingredients and the dosage amount, frequency, and duration in the
prior art and claimed dosage regimen overlap, the Examiner has not
established that they are "identical" or "substantially identical" such that the
burden should be shifted to Appellants to prove otherwise.
Accordingly, we reverse the Examiner's rejection of claim 1. The
rejection of claims 2-5, 15, and 16, which depend from claim 1, are reversed
for the same reasons.
SUMMARY
For the reasons above, we reverse the Examiner's decision rejecting
claim 1-5, 15, and 16 as obvious over Kovarik and Sanna.
REVERSED
18