Juha Rouru et al.

Patent Trials and Appeals Board

Feb 24, 2020

14504925 - (D) (P.T.A.B. Feb. 24, 2020)

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.
14/504,925 10/02/2014 Juha ROURU 06267.0180-01000 3556
22852 7590 02/24/2020
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON, DC 20001-4413
EXAMINER
SOROUSH, LAYLA
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
02/24/2020 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):
regional-desk@finnegan.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte JUHA ROURU, MIKKO KUOPPAMÄKI,
JUHA ELLMEN, and PEKKA MÄNNISTÖ
____________

Appeal 2019-000350
Application 14/504,925
Technology Center 1600
____________

Before DONALD E. ADAMS, JOHN G. NEW, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims 26, 30–33, 37, 38, 40, 42, and 45.2 We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party in interest as “Orion
Corporation” (Appellant’s February 23, 2018 Appeal Brief (Appeal Br.) 1).
2 Pending claims 1, 5, 7–15, 17, 19, 22, 23, and 25 stand withdrawn from
consideration (Appeal Br. 3).
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STATEMENT OF THE CASE
Appellant’s disclosure “relates to a method for the treatment of
Parkinson’s disease as well as to pharmaceutical dosage forms used in said
method” (Spec.3 ¶ 1). Claims 26 and 42 are representative and reproduced
below:
26. An oral dosage form comprising
(i) levodopa in an amount ranging from 75 mg to 175 mg,
(ii) carbidopa in an amount ranging from 65 mg to 105, and
(iii) entacapone in an amount ranging from 100 mg to 200 mg,
wherein the proportion of entacapone to carbidopa ranges from
0.95:1.0 to 3.08:1.0 by weight.
(Appeal Br. 31.)
42. The dosage form according to claim 26, wherein the
proportion of levodopa to carbidopa in said dosage form ranges
from 1.4:1.0 to 2.3:1.0 by weight.
(Id. at 33.)

Grounds of rejection before this Panel for review:
Claims 26, 30–33, 37, 38, 40, 42, and 45 stand rejected under
35 U.S.C. § 103(a) as unpatentable over Virkki.4
Claims 26, 30–33, 37, 38, 40, 42, and 45 stand rejected under
35 U.S.C. § 103(a) as unpatentable over Han.5

3 Appellant’s October 2, 2014 Specification.
4 Virkki et al., US 6,500,867 B1, issued Dec. 31, 2002.
5 Han et al., US 2004/0166159 A1, published Aug. 26, 2004.
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ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Jenner declares:
Parkinson’s disease (PD) affects the ability to initiate voluntary
movement. The predominant treatment of PD is dopamine
replacement therapy. The most effective and most commonly
employed drug is L-dopa (also called levodopa) that is absorbed
by the gut after oral administration and then penetrates into
brain through the blood-brain barrier where it undergoes
conversion to dopamine. Levels of L-dopa in peripheral tissues
are largely determined by the extent of its metabolism by
aromatic amino acid decarboxylase (dopa decarboxylase) and
catechol O-methyl transferase (COMT). As a consequence,
inhibitors of dopa decarboxylase (carbidopa, benserazide) and
inhibitors of COMT (entacapone, tolcapone) are used as
adjuncts to L-dopa therapy to enhance the amounts of L-dopa
reaching the brain.
(Jenner Decl.,6 Exhibit B ¶ 3.1.)
FF 2. Jenner declares that carbidopa “allowed the more effective use of L-
dopa at lower doses to treat PD with a reduced side-effect profile,” but
cautions that “[a]t high doses, . . . [carbidopa can] penetrate into the brain
and . . . lead to the prevention of L-dopa conversion to dopamine and a
reduction in clinical effect” (Jenner Decl., Exhibit B ¶ 5.1).
FF 3. Jenner declares that entacapone “increases the delivery of L-dopa to
the brain and indirectly increases the duration of clinical efficacy of L-dopa
by approximately 1 hour per day compared to placebo treatment” (Jenner
Decl., Exhibit B ¶ 6.2, see also id. (Jenner declares that entacapone’s “main

6 Declaration of Peter Jenner, signed March 20, 2017.
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use is in the treatment of later stage patients experiencing the signs and
symptoms of ‘wearing off’ to the actions of L-dopa”)).
FF 4. Jenner declares that “[a]s the [Parkinson’s] disease process
progresses . . . the effect of L-dopa shortens, and starts to reflect its
peripheral pharmacokinetics. This phenomenon results in fluctuations in the
ability to move and it is known as ‘wearing off’” (Jenner Decl., Exhibit B
¶ 4.1).
FF 5. Jenner declares that “[a]s the changes in the clinical effect of L-dopa
occur, a significant proportion of patients . . . start to exhibit abnormal
involuntary movements (dyskinesia). Dyskinesia invariably occurs at peak
L-dopa levels in plasma,” as do “[h]allucinations and psychosis,” therefore,
PD treatment “aims to keep levels of L-dopa above the threshold for ‘on’ for
a significantly longer period of the day so achieving more continuous
dopaminergic stimulation in brain, whilst minimising the time when the
patient is ‘on’ but dyskinetic or psychotic” (Jenner Decl., Exhibit B ¶¶ 4.2–
4.3).
FF 6. Virkki discloses:
An oral solid fixed dose composition comprising
pharmacologically effective amounts of entacapone, levodopa,
and carbidopa, or pharmaceutically acceptable salts or hydrates
thereof, and comprising at least one pharmaceutically
acceptable excipient. The composition can be used, e.g., for the
treatment of Parkinson’s disease.
(Virkki, Abstract; see Ans.7 3–4.)

7 Examiner’s August 16, 2018 Answer.
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FF 7. Virkki discloses:
The amount of entacapone in the formulation according to the
invention is preferably 25 to 400 mg, e.g. 25 to 300 mg,
especially 50 to 200 mg, the amount of levodopa is preferably
25 to 300 mg, especially 50 to 250 mg, and the amount of
carbidopa is preferably 5 to 75 mg, especially 10 to 50 mg.
(Virkki 6: 20–25; see Ans. 3–4.)
FF 8. Virkki discloses that “[t]he amount of entacapone, levodopa, and
carbidopa, or their pharmaceutically acceptable salts or hydrates, in the oral
composition is dependent on numerous factors known to one skilled in the
art, such as, the severity of the condition of the patient, the desired duration
of use, etc.” (Virkki 6: 15–19; see Ans. 4.)
FF 9. Virkki discloses “a method for treating Parkinson’s disease, e.g. at
end of dose ‘wearing-off’, by administering to a patient in need thereof an
oral solid composition according to the invention, e.g. up to 8–10 times a
day” (Virkki 2: 63–67; see Ans. 4 (Examiner finds that Virkki “teaches an
oral solid composition according to the invention, administered up to 8-10
times a day”)).
FF 10. Han discloses:
Patients undergoing levodopa therapy for Parkinson’s disease
frequently can develop motor fluctuations characterized by end-
of-dose failure, peak dose dyskinesia and akinesia. An
advanced form of motor fluctuations is known as the “on-off
effect” in which the patient suffers from unpredictable swings
from mobility to immobility. This on-off effect might be
minimized in some patients with a treatment regimen that
produces narrow ranges of plasma levels of levodopa.
(Han ¶ 5.)
FF 11. Han discloses a pharmaceutical dosage form comprising “an
aromatic amino acid decarboxylase (AAAD) inhibitor (such as carbidopa),
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levodopa, and optionally a cathecol-O-methyltransferase (COMT) inhibitor,
for the treatment of medical conditions associated with reduced dopamine
levels in a patient’s brain” (Han, Abstract; id. ¶ 18 (Han discloses that a
medical condition within the scope of its disclosure includes Parkinson’s
disease); see also id. at 14: claims 1 and 2; Ans. 5).
FF 12. Han discloses that its “pharmaceutical dosage form . . . comprises an
AAAD inhibitor and levodopa in a ratio of from about 1:1 to about 1:50”
(Han 14: claim 1; Ans. 5).
FF 13. Han discloses that its COMT inhibitor may be “selected from the
group consisting of CGP-28014, entacapone, and tolcapone” (see Han ¶ 21;
see also Han 14: claim 23; Ans. 5).
FF 14. Han discloses a dosage form that
comprises from about 2.5 mg to about 75 mg of carbidopa and
from about 25 mg to about 300 mg levodopa. In yet another
embodiment of the present invention, the pharmaceutical
dosage form may include a controlled release component that
comprises from about 2.5 mg to about 200 mg of (preferably
from about 5 mg to about 150 mg, and more preferably from
about 12.5 mg to about 50 mg) carbidopa and from 25 mg to
about 600 mg (preferably from about 50 mg to about 500 mg,
and more preferably from about 50 mg to about 200 mg)
levodopa.
(Han ¶ 23; see Ans. 5.)
FF 15. Han discloses a dosage form that comprises “up to about 1000 mg
(preferably from about 20 mg to about 500 mg, more preferably from about
50 mg to about 500 mg, and even more preferably from about 100 mg to
about 200 mg) COMT inhibitor” (Han ¶ 21; see Ans. 5).
FF 16. Han discloses oral dosage forms (see Han ¶ 50; see also id. at ¶ 65;
Ans. 5).
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FF 17. Han discloses:
It should be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors
including body weight, general health, gender, diet, time and
route of administration, rates of absorption and excretion,
combination with other drugs, and the severity of the particular
disease being treated. Actual dosage levels of active ingredient
in the compositions of the present invention may be varied so as
to obtain an amount of active ingredient that is effective to
obtain a desired therapeutic response for a particular
composition and method of administration. The selected
dosage level, therefore, depends upon the desired therapeutic
effect, on the route of administration, on the desired duration of
treatment, and other factors.
(Han ¶ 47; see also id. ¶ 5 (Han recognizes “the ‘on-off effect’ in which the
patient suffers from unpredictable swings from mobility to immobility” and
discloses that “[t]his on-off effect might be minimized in some patients with
a treatment regimen that produces narrow ranges of plasma levels of
levodopa”); see Ans. 5.)
FF 18. Müller discloses a clinical study comparing the results of PD
treatment with Stelevo, a conventional levodopa/carbidopa/entacapone
(LEC) therapeutic, to ODM-101/65mg and ODP-101/105mg, which
comprise levodopa, entacapone, and higher amounts (65 or 105 mg) of
carbidopa regardless of the levodopa dosage (see Müller8 2).

8 Müller, Novel levodopa product ODM-101 vs
levodopa/carbidopa/entacapone in Parkinson’s disease with response
fluctuations, The MDS 17th International Congress of Parkinson’s Disease
and Movement Disorders, Abst. No. 550375, available at
http://www.call4abstracts.com/mds/finalpreview.php?absnum=550375, last
accessed March 1, 2013.
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FF 19. Müller discloses that “[b]oth ODM-101 dosages significantly
decreased daily OFF-time vs LCE without increasing ON-time with
troublesome dyskinesia” (Müller 2).
FF 20. Jenner declares that Müller “show[s] that when the
entacapone:carbidopa ratio is reduced from 4:1 to a ratio of 3:1 or 0.95:1
there was a significant decrease in daily ‘off’ time without increasing the
amount of ‘on’ time with troublesome dyskinesia” (Jenner Decl. Exhibit B
¶ 8.4; cf. Appeal Br. 31 (Appellant’s claim 26 requires an entacapone to
carbidopa range from 0.95:1.0 to 3.08:1.0)).
ANALYSIS
Given the similarity between the evidence and arguments relating to
both the Virkki and Han rejections, we address them together.
With regard to the Virkki rejection, Examiner finds:
Although, Virkki . . . fails to specify the proportion of
entacapone to carbidopa, the reference teaches a general range
of entacapone from 25 to 400 mg; carbidopa in a[ ]preferabl[e]
amount of 5 to 75 mg; and levodopa in a preferabl[e] amount of
25 to 300 mg. Therefore, the general ratio of entacapone:
carbidopa based on the broader ranges of Virkki . . . is 0.3:1 to
80:1 and the general ratio of levodopa: carbidopa based on the
broader ranges of Virkki . . . is 0.3:1.0 to 60:1, rendering
obvious the specific ranges of the claims (i.e., entacapone:
carbidopa 0.95:1.0 to 3.08:1.0 and levodopa: carbidopa 1.4:1.0
to 2.3:1.0).
(Ans. 4.) Therefore, based on Virkki, Examiner concludes that, at the time
Appellant’s invention was made, “the claimed ratio and proportions” of
entacapone, carbidopa, and levodopa
would have been obvious because the skilled artisan would
have appreciated that certain factors would influence the dosage
required to effectively treat the subject for the purpose taught
by the reference[], including, but not limited to the severity of
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the disease or disorder, previous treatments, the weight, general
health and/or age of the subject and the presence of other
diseases. The dosage would thus have been expected to be
variable and, in the absence of evidence to the contrary, the
determination of the optimum ratio and proportions to employ
would have been a matter well within the purview of the skilled
artisan.
(Ans. 4.)
With regard to the Han rejection, Examiner finds:
Although, Han . . . fails to specify the proportion of
entacapone to carbidopa, the reference teaches a general range
of entacapone from 20 mg to about 500 mg; carbidopa in a
preferabl[e] amount of 2.5 mg to about 75 mg; and levodopa in
a preferabl[e] amount of 25 to 300 mg. Therefore, the general
ratio of entacapone: carbidopa based on the broader ranges of
Han . . . is 0.26:1 to 200:1 and the general[ ]ratio of levodopa:
carbidopa based on the broader ranges of Han . . . is 0.3:1.0 to
120:1, rendering obvious the specific ranges of the claims (i.e.,
entacapone: carbidopa 0.95:1.0 to 3.08:1.0 and levodopa:
carbidopa 1.4:1.0 to 2.3:1.0).
(Ans. 6.) Therefore, based on Han, Examiner concludes that, at the time
Appellant’s invention was made, “the claimed ratio and proportions” of
entacapone, carbidopa, and levodopa
would have been obvious because the skilled artisan would
have appreciated that certain factors would influence the dosage
required to effectively treat the subject for the purpose taught
by the reference[], including, but not limited to the severity of
the disease or disorder, previous treatments, the weight, general
health and/or age of the subject and the presence of other
diseases. The dosage would thus have been expected to be
variable and, in the absence of evidence to the contrary, the
determination of the optimum ratio and proportions to employ
would have been a matter well within the purview of the skilled
artisan.
(Ans. 6.)
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With respect to both rejections, Examiner reasons that “the claimed
amounts clearly overlap in range with the prior art” and that “[a] prima facie
case of obviousness exists where the claimed ranges ‘overlap or lie inside
ranges disclosed by the prior art’” (id. at 6–7 (emphasis omitted)). See In re
Geisler, 116 F.3d 1465, 1468 (Fed. Cir. 1997) (Overlapping ranges support a
prima facie case of obviousness). We are not persuaded.
As Appellant explains, Virkki and Han both “disclose[] very broad
ranges of levodopa, carbidopa, and entacapone, encompassing thousands if
not tens of thousands of possible dosage forms” (Appeal Br. 10 and 18).
More specifically, Appellant explains that
to arrive at a proportion of entacapone to carbidopa falling
within the specifically claimed range of 0.95:1.0 to 3.08:1.0 in
claim 26, . . . Examiner created a hypothetical range by
combining the minimum amount of entacapone disclosed
with the maximum amount of carbidopa disclosed (to create
the lower end of the range) and by combining the maximum
amount of entacapone disclosed with the minimum amount
of carbidopa disclosed (to create the upper end of the range).
(Appeal Br. 10 and 18 (citing Final Act.9 5–8).) In this regard, Appellant
contends that although both Virkki and Han may broadly disclose a range
that encompasses its claimed invention, Appellant demonstrated that “[t]he
presently claimed dosage forms have unexpectedly been able to extend a PD
patient’s on time over and above the current gold standard treatment”
(Appeal Br. 8; see id. at 24–26 (Appellant intimates that Stalevo®,
encompassed by both Virkki and Han’s disclosure, is the current gold
standard treatment)).

9 Examiner’s June 1, 2017 Final Office Action.
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Appellant discloses that Stalevo®, a commercially available
formulation of levodopa:carbidopa:entacapone, comprises the following
amounts of levodopa, carbidopa, and entacapone, with corresponding
entacoapone:carbidopa ratios:

(see Appeal Br. 14 and 21; Spec. ¶ 3 (disclosing the concentrations of
levodopa, carbidopa, and entacapone present in Stalevo®).) As Appellant
explains, although the amounts of levodopa, carbidopa, and entacapone in
Stalevo® fall within the range disclosed by both Virkki and Han, Appellant’s
“claimed range of carbidopa is 65-105 mg, and this range falls entirely
outside (i.e., above) the amounts of carbidopa present in Stalevo®” (Appeal
Br. 14 and 22; see id. at 14 and 22 (Appellant further explains that its
“claimed range of entacapone is 100-200 mg, and this range falls below and
only just abuts the amounts of entacapone present in Stalevo®”)).
The evidence of record supports a conclusion that these differences
are significant. Specifically, although Virkki recognized the “wearing-off”
problem associated with the treatment of Parkinson’s disease with
compositions comprising levodopa, carbidopa, and entacapone, Virkki
suggested that the resolution of this problem involved the administration of a
composition within the scope of Virkki’s disclosure “up to 8–10 times a
day” (FF 9). Similarly, although Han recognized an “‘on-off effect’ in
which the patient suffers from unpredictable swings from mobility to
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immobility,” Han suggested that the resolution of this problem involved “a
treatment regimen that produces narrow ranges of plasma levels of
levodopa” (FF 17).
Appellant, however, took a different tack. In this regard, it cannot be
gainsaid that those of ordinary skill in this art, at the time of Appellant’s
invention, recognized the potential negative effect of administering high
concentrations of carbidopa (see FF 2; see also Appeal Br. 13–14 (Appellant
contends that “because carbidopa permits more levodopa to be transported
into the brain, certain adverse effects, e.g., dyskinesia (involuntary
movements), may occur more quickly and at lower doses of levodopa when
the carbidopa dose is increased”); Appeal Br. 21–22). Neveretheless,
Appellant’s claimed invention requires the use of a composition comprising
an amount of carbidopa that is more than that conventionally administered in
the art. Specifically, Appellant’s claimed composition comprising levodopa,
entacapone, and 65–105 mg carbidopa, results in a “significant decrease in
daily ‘off’ time without increasing the amount of ‘on’ time with troublesome
dyskinesia” (see FF 18–20).
Thus, although Examiner is correct in asserting “that the discovery of
an optimum value of a variable in a known process is normally obvious,” the
predecessor to our reviewing court “found exceptions to this rule in cases
where the results of optimizing a variable, which was known to be result
effective, were[, as on this record,] unexpectedly good.” See In re Antonie,
559 F.2d 618, 620 (CCPA 1977). Further,
even if it was obvious to experiment with these options
[pertaining to the concentration ranges of levodopa, carbidopa,
and entacapone, as opined by Examiner, and claimed by
Appellant], “there is nothing to indicate that a skilled artisan
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would have had a reasonable expectation that such an
experiment would succeed in being therapeutically
effective.” . . . There is no indication in the prior art which of
these possible formulations would be the most promising to
try. . . . Without a reasonable expectation of success or clues
pointing to the most promising combinations, an artisan could
have spent years experimenting without success.
Leo Pharmaceutical Products, Ltd. V. Rea, 726 F.3d 1346, 1357 (Fed. Cir.
2013). Therefore, we find that when considered as a whole, the evidence of
record fails to support a conclusion of obviousness, or corresponding
reasonable expectation of success, when, as here, Appellant demonstrated
that the claimed oral dosage form unexpectedly achieves an extended
therapeutic window without the negative effects, i.e., dyskensia, associated
with the use of higher than conventionally recognized amounts of carbidopa
(see generally Appeal Br. 15).
CONCLUSION
The preponderance of evidence relied upon by Examiner fails to
support a conclusion of obviousness.
The rejection of claims 26, 30–33, 37, 38, 40, 42, and 45 under
35 U.S.C. § 103(a) as unpatentable over the combination of Virkki is
reversed.
The rejection of claims 26, 30–33, 37, 38, 40, 42, and 45 under
35 U.S.C. § 103(a) as unpatentable over the combination of Virkki is
reversed.

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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
26, 30–33, 37,
38, 40, 42, 45
103 Virkki 26, 30–33,
37, 38, 40,
42, 45
26, 30–33, 37,
38, 40, 42, 45
103 Han 26, 30–33,
37, 38, 40,
42, 45
Overall
Outcome
26, 30–33,
37, 38, 40,
42, 45

REVERSED