Ex Parte Frome

Board of Patent Appeals and Interferences

Jun 4, 2010

10480162 (B.P.A.I. Jun. 4, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
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Ex parte BRUCE FROME
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Appeal 2009-015007
Application 10/480,162
Technology Center 1600
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Decided: June 4, 2010
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Before ERIC GRIMES, RICHARD M. LEBOVITZ, and STEPHEN
WALSH, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of directing a substance to cerebral circulation. The Examiner has rejected
the claims as indefinite and obvious. We have jurisdiction under 35 U.S.C.
§ 6(b). We reverse the indefiniteness rejection but affirm the obviousness
rejection.
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STATEMENT OF THE CASE
The Specification discloses “[m]ethods and compositions … to target
cerebral circulation and to treat headache.… [C]ontemplated methods and
compositions include … a transdermal formulation, which is topically
applied to an area of skin superficial to a carotid artery, a temporal artery, a
vertebral artery, or to a tender spot associated with a headache.” (Spec.
2: 19-24.)
Claims 1, 4-13, 17, 26-28, and 39 are on appeal. Claim 1 is
representative and reads as follows:
1. A method of directing a pharmacologically active substance to a
cerebral circulation, comprising:
providing a composition having a pharmacologically active substance
selected from the group consisting of a xanthine derivative, vitamin B6 and
digitalis, diuretics, or angiotensin-converting enzyme inhibitors;
including the composition in a transdermal formulation that comprises
a skin penetration enhancer selected from the group consisting of an azone
derivative, a synthetic terpene, oleic acid, N-methyl-2-pyrrolidone, an
epsilon-aminocaproic acid ester, a lecithin organogel, a pluronic-lecithin-
organogel, an aromatic S,S-dimethyl-iminosulfurane, a natural terpene,
padimate O, an oil-water emulsion with sub-micron droplets, and capsaicin;
and
topically applying the transdermal formulation to at least one area of
skin superficial to a temporal artery, and a vertebral artery, wherein the
pharmacologically active substance is applied in an amount of less than 5mg
per dose to the cerebral circulation.

The claims stand rejected as follows:
• Claims 1, 10-13, 17, and 26-28 under 35 U.S.C. § 112, second
paragraph, as being indefinite;
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• Claims 1, 4-9, 13, and 39 under 35 U.S.C. § 103(a) as being obvious
in view of Theoharides,1 Otto,2 Mendelson,3 and Liedtke;4 and
• Claims 10-12 under 35 U.S.C. § 103(a) as being obvious in view of
Theoharides, Otto, Mendelson, Liedtke, and Reed.5
I.
The Examiner has rejected claims 1, 10-13, 17, and 26-28 under 35
U.S.C. § 112, second paragraph, as being indefinite, on the basis that “[i]t is
not clear … what compounds are or are not considered to be derivatives of
xanthine.” (Ans. 3-4.)
Appellant contends that the Specification “clearly limits xanthine
derivatives to the group of molecules which contain structure 1” (Appeal Br.
15).
We agree with Appellant’s interpretation of the claim language. The
Specification states that
particularly preferred pharmacologically active substances
include xanthine derivatives according to structure 1, and
especially include caffeine, theophylline, and dimeric forms
such as aminophylline (ethylene diamine complex with
theophylline).

1 Theoharides, US 5,250,529, Oct. 5, 1993
2 Otto et al., DE10025644 A1, Dec. 6, 2001 (English translation)
3 Mendelson et al., US 5,552,406, Sept. 3, 1996
4 Liedtke, US 5,840,755, Nov. 24, 1998
5 Reed et al., US 6,299,900 B1, Oct. 9, 2001
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wherein [the substituents of Structure 1 are defined].
(Spec. 4: 14-18.) The Specification’s discussion of Structure 1 also states
that the nitrogens or carbonyl oxygen can be replaced with specified
substituents (id. at 4: 21-24). The Specification also states that “[i]n
alternative aspects, suitable pharmacologically active compounds also
include various vaso-active substances other than xanthine derivatives, and
particularly include vitamin B6, digitalis, diuretics, or angiotensin-
converting enzyme inhibitors” (id. at 4: 25-27).
We agree with Appellant that, when claim 1 is read in light of the
Specification, a person of ordinary skill in the art would interpret the claim’s
recitation of “xanthine derivative” to mean those including a structure
meeting the requirements of structure 1 as defined in the Specification,
including those modified at the nitrogen or carbonyl oxygen atom(s).
II.
Issue
The Examiner has rejected claims 1, 4-9, 13, and 39 under 35 U.S.C.
§ 103(a) as being obvious in view of Theoharides, Otto, Mendelson and
Liedtke. The Examiner has also rejected claims 10-12 under 35 U.S.C.
§ 103(a) as being obvious in view of Theoharides, Otto, Mendelson, Liedtke
and Reed. Since the same issues are dispositive with respect to both
rejections, we will consider them together.
The Examiner finds that Theoharides discloses “alleviating migraine
headaches by delivering certain active agents” including xanthine
compounds (Ans. 4) and that “[t]ransdermal administration is preferred”
(Ans. 4-5). The Examiner finds that Otto discloses administering a
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“transdermal formulation to the carotid, subclavian, or iliac artery” (id. at 5)
and Mendelson discloses that “compounds can be administered by the
transdermal route by adding a penetration enhancer that can be a terpene”
(id.). The Examiner finds that Liedtke “discloses a composition for topical
therapy of headaches.… The use of local transdermal delivery of the
therapeutic agents allows lower than normal doses of active agent to be
used” (id.).
The Examiner concludes that it “would have been obvious to one of
ordinary skill in the art … to administer the transdermal compositions of
Theoharides to the temporal or vertebral artery … because Otto et al.
discloses that administration to the carotid or subclavian artery causes the
transdermal composition to reach the target tissue faster, and one of ordinary
skill in the art would reasonably expect that other arteries branching from
the carotid or subclavian artery, such as the vertebral or temporal arteries,
could similarly be used as points [of] drug delivery” (id. at 5-6). The
Examiner reasons that “with respect to … the dose of less than 5 mg of
active agent, one of ordinary skill in the art would have recognized that
various concentrations of active agent can be used in a particular application,
and adjusted the amount of the composition accordingly to administer the
desired dose, particularly in view of … Leidtke [sic] et al. disclosing that
local topical therapy can reduce the necessary dose of active agent” (id. at
6).
With respect to both rejections under § 103(a), Appellant contends
that the cited art does not disclose or suggest the transdermal application of
less than 5 mg of a xanthine derivative (Appeal Br. 15, Reply Br. 3).
Appellant also contends that none of the references suggest that
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“transdermal application of less than 5 mg of a xanthine derivative would
reach the CNS almost immediately (see Pg18/L6-13) of the instant
application). Rather, such topical application unexpectedly proved a marked
improvement over prior applications of xanthine derivatives.” (Reply Br. 3.)
The issues with respect to both rejections are:
Does the evidence of record support the Examiner’s finding that the
cited references suggest the method of claim 1, including a dosage of 5 mg
or less? and, if so,
Has Appellant provided evidence of unexpected results that outweighs
the evidence showing prima facie obviousness?
Findings of Fact
1. Theoharides discloses “that administration of mast cell blocking
agents … will prevent or alleviate the onset of the two later stages in the
migraine process” (Theoharides, col. 5, l. 23-l. 32).
2. Theoharides discloses that drugs that are useful in its method
include methyl xanthines such as aminophylline, caffeine, and theophylline
(id. at col. 6, ll. 33-38).
3. Theoharides discloses that the compositions can be administered
transdermally and that “[a] transdermal route is preferred for convenience,
comfort, safety and avoidance of first pass metabolism” (id. at col. 9, l. 67 to
col. 10, l. 5).
4. Mendelson discloses a method for treating pain by administering
an opioid derivative (Mendelson, col. 3, l. 65-col. 4, l. 1).
5. Mendelson discloses that the opioid derivative can be administered
transdermally (id. at col. 7, ll. 58-60) using a terpene as a carrier (id. at col.
8, ll. 26-29).
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6. Otto discloses applying a “transdermal therapeutic system (TTS) in
the region of the subcutaneously running branches of the vascular system
which supply the target tissue with blood” (Otto 4, ¶ 0006).
7. Otto discloses that
TTS application is advantageous in the course of the carotid
arteries (external carotid artery) which runs subcutaneously in
sections in the neck area in order to deliver the active
ingredients in direct arterial supply to the central nervous
system (CNS) therapy region (brain or spinal cord).…. The
TTS application as claimed in the invention is furthermore
advantageous for branches of the iliac artery and subclavian
artery, right and/or left, which branches are near the surface.
(Id. at 4, ¶ 0007, ¶ 0009.)
8. Liedtke discloses “a composition for topical therapy of headaches,
which contains a topical carrier system for application to … a mammalian
forehead or temples or both and a local anesthetic for delivery to a region of
skin underneath the topical carrier system” (Liedtke, col. 2, ll. 25-30).
9. Liedtke discloses that
topical therapy with local anesthetics in the present topical
carrier system makes possible a locally targeted and prolonged
therapeutically effective treatment of the terminal and
functionally interlinked nerve paths in the area of the head.
Since this area also has good cutaneous absorption
capacity, topical doses which are very low can also be used.
(Id. at col. 3, ll. 23-30.)
10. The Specification states:
The inventors have observed an unexpected result, in that
topical application of a pharmacologically active agent to the
skin superficial to the arteries of the extracranial circulation will
direct (i.e., deliver) the agent to the cerebral circulation of the
hypothalamus and midbrain, and that such a delivery requires
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significantly less agent to achieve a therapeutically effective
concentration.
(Spec. 12: 21-25.)
11. The Specification states that “the inventors contemplate that …
when applied to the temples, the agent will enter the superficial temporal
artery and lacrimal arteries” (id. at 12: 25-30).
12. The Specification describes an “exemplary formulation (4% w/w
with respect to the active substance [aminophylline]) compris[ing] 1,000
gram lecithin, 510 gram octyl palmitate, 100 gram water, and 64.4 gram of
aminophylline” (id. at 14: 16-18).
13. The Specification provides a working example in which patients
with intermittent acute headaches applied the above formulation
transdermally (id. at 18: 5-7). The Specification states that one group of
patients “was instructed to apply about 500mg of the formulation to the
pulse points of their temples. … Application to the pulse points lead to rapid
relief of the headache within 2-5 minutes in about 75% of the patients” (id.
at 18: 9-12).
Principles of Law
“It is not inventive to discover the optimum or workable ranges by
routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955).
“Although it is well settled that comparative test data showing an
unexpected result will rebut a prima facie case of obviousness, the
comparative testing must be between the claimed invention and the closest
prior art.” In re Fenn, 639 F.2d 762, 765 (CCPA 1981) (emphasis added).
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Analysis
Claim 1 is directed to a method administering a pharmacologically
active substance (e.g., a xanthine derivative) by topically applying a
formulation that also includes a penetration enhancer (e.g., a synthetic
terpene) to skin superficial to a temporal artery or a vertebral artery, where
the “pharmacologically active substance is applied in an amount of less than
5mg per dose to the cerebral circulation.”
Theoharides discloses a method of treating a migraine headache by
administering a mast cell blocking agent such as a xanthine derivative,
preferably transdermally. Mendelson discloses using a terpene as a carrier
for transdermal delivery of a pharmacologically active substance.
Otto discloses administering an active agent via transdermal delivery
in the region of the subcutaneously running branches of the vascular system
which supply blood to the target tissue, particularly the carotid, iliac, or
subclavian arteries. Liedtke discloses that the topical application of a local
anesthetic to the forehead or temples, or both, to treat headache allows for
the use of low doses.
In view of these disclosures, it would have been obvious to one of
ordinary skill in the art to treat headaches by transdermal administration of
Theoharides’ methyl xanthine compounds in combination with a terpene
carrier as taught by Mendelson. It would have been obvious to apply the
transdermal composition to the temples (an area of skin superficial to a
temporal artery) because Liedtke discloses that application of an active agent
to the temple allows the use of low doses and because Otto discloses
transdermal administration to the region supplying the target tissue with
blood.
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Appellant contends that the cited references do not teach or suggest
the transdermal application of less than 5 mg of a xanthine derivative
(Appeal Br. 15, Reply Br. 3). In particular, Appellant contends that “both
Theoharides and Leidtke [sic] are silent regarding transdermal application of
xanthine derivatives, and their combination therefore fails to suggest any
ranges for such application.… [D]etermination of suitable ranges requires
more than mere optimization of a dosage level” (id.).
This argument is not persuasive. We agree with the Examiner’s
reasoning (Ans. 6) that optimizing the dosage of xanthine compound used in
the method suggested by the cited references would have been routine for
those skilled in the art, and that Liedtke would have led a skilled worker to
expect that administering a drug by applying it to the temple would have
required less active agent than would normally be required. Appellant has
pointed to no evidence showing that those skilled in the art would have
expected a 5 mg dose to be ineffective when administered as suggested by
the cited references.
Appellant also contends that the topical application xanthine
derivatives unexpectedly showed “improvement over prior applications of
xanthine derivatives” in requiring lower doses (Reply Br. 3). Appellant
points to the Specification’s working example on page 18, lines 6-13 as
evidence supporting his position (id.).
Appellant’s argument is not persuasive. While “[o]ne way for a
patent applicant to rebut a prima facie case of obviousness is to make a
showing of ‘unexpected results,’” In re Soni, 54 F.3d 746, 750 (Fed. Cir.
1995), the unexpected results must be shown for the claimed method. In re
Fenn, 639 F.2d at 765. The claims here require administration of no more
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than 5mg of active agent. The example on page 18 of the Specification that
Appellant relies on to support the assertion of unexpected results describes
administering 500 mg of a composition comprising 4% w/w aminophylline.
Four percent of 500 mg (0.04 x 500) is 20 mg. Thus, the evidence cited by
Appellant shows the effect of administering 20 mg of active agent, not the 5
mg or less required by the claims; it therefore does not show unexpected
results for the claimed method.
Conclusion of Law
The evidence of record supports the Examiner’s finding that the cited
references suggest the method of claim 1, including a dosage of 5 mg or less,
and the conclusion of obviousness. Appellant has not provided evidence of
unexpected results that outweighs the evidence showing prima facie
obviousness.
SUMMARY
We affirm the rejection of claims l and 10 under 35 U.S.C. § 103(a).
We also affirm the rejections of claims 4-9, 11-13, and 39 under 35 U.S.C.
§ 103(a) because those claims were not argued separately. 37 C.F.R.
§ 41.37(c)(1)(vii). However, we reverse the rejection of claims 1, 10-13, 17,
and 26-28 under 35 U.S.C. § 112, second paragraph.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED-IN-PART

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