Ex Parte Teng et al

Patent Trial and Appeal Board

Jul 30, 2018

13852779 (P.T.A.B. Jul. 30, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/852,779 03/28/2013
27148 7590 08/01/2018
POLSINELLI PC
900 WEST 48TH PLACE
SUITE 900
KANSAS CITY, MO 64112-1895
FIRST NAMED INVENTOR
Joyce M.C. Teng
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.
064072-454672 9009
EXAMINER
WANG, SHENGTIJN
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
08/01/2018 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):
uspt@polsinelli.com
PTOL-90A (Rev. 04/07)
UNITED ST ATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JOYCE M.C. TENG, ANNA K. HAEMEL,
andMARLAJ. AHLGRIMM 1
Appeal 2017-007882
Application 13/852, 779
Technology Center 1600
Before JOHN G. NEW, RICHARD J. SMITH, and
RY ANH. FLAX, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellants state that the real party-in-interest is INNOVA
DERMACEUTICALS, LLC. App. Br. 1.
Appeal 2017-007882
Application 13/852, 779
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 1-3, 7, and 8, which stand rejected as
unpatentableunder 35 U.S.C. § 103(a) as being obvious over A. Rauktys et
al., Topical Rapamycinlnhibits Tuberous Sclerosis Tumor Growth in a Nude
Mouse Model, 8(1) BMC Dermatology 1-9 (2008) ("Rauktys").
Claims 1-3, 7, and 8 also standrejectedunder35 U.S.C. § 103(a)as
being obvious over the combination of Rauktys and Ormerod et al (US
6,958,153 B 1, October 25, 2005) ("Ormerod"). 2
We have jurisdiction under35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to a method and a topical
composition to treat cutaneous vascular lesions in a Tuberculous Sclerosis
("TSC") patient by applying from about 0.25% to about 2% rapamycin to a
2 Claims 1-3 and 7-8 were also rejected by the Examiner as unpatentable
under 35 U.S.C. § 112, frrst paragraph, as failing to comply with the
written description requirement and under 35 U.S. C. § 112, second
paragraph as being indefmite. Final Act. 4, 5. The Examiner has
withdrawn these objections. Final Act. 10. The Examiner also
provisionally rejected claims 1-3 and 7-8 as unpatentable over claims 1-3
and 7-12 of Appellants' copendingApplication Ser. No. 13/852,773 under
the judicially-created doctrine of obviousness-type double patenting. Final
Act. 2. Appellants have indicated that they will file a terminal disclaimer
upon receiving indication of allowable subject matter in the instant
application. Appellants' Argument 13-14, July 20, 2016. Because
Appellants do not argue the merits of this rejection on appeal, and because
we affrrm the Examiner's rejections under 35 U.S.C. §103(a), we
summarily affrrm the rejection upon this ground.
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small body surface area. Abstract. According to the Specification,
"cutaneous vascular lesions ... include facial angiofibromas in patients with
TS[C]." Spec. ,r 13.
REPRESENT AT IVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A method of reducing a cutaneous vascular lesion
in a human subject in need thereof, the method
compnsmg:
topically administering to a local skin area affected with the
cutaneous vascular lesion a composition comprising no
more than about 2% by weight rapamycin and a
dermatologically acceptable carrier,
wherein after about three months of twice daily topical
administration of the composition to the local skin area of
the subject, the serum rapamycin level of the human
subject is less than 2 ng/ml.
App. Br. 20.
ISSUES AND ANALYSES
We are persuaded by, and expressly adopt, the Examiner's fmdings,
reasoning, and conclusions establishing that Appellants' claims are prima
faci e obvious over the combined cited prior art. We address the arguments
raised by Appellants below.
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A. Rejection of claims 1-3, 7, and 8 overRauktys
Issue 1
Appellants argue the Examiner erred because Rauktys neither teaches
nor suggests reducing a cutaneous vascular lesion in a human by topically
administering a composition comprising no more than about 2% by weight
rapamycin and a dermatologically acceptable carrier, where serum
rapamycin levels are less than 2 ng/ml after about three months of twice
daily topical administration. App. Br. 5.
Analysis
The Examiner finds that Rauktys teaches the utility of topically
applied rapamycin as a therapeutic strategy for tuberous sclerosis ("T SC")
skin disease by evaluating its efficacy on TSC-related tumors in a preclinical
model. Final Act. 6 ( citing Rauktys 2). The Examiner fmds Rauktys
teaches a topical ointment comprised of rapamycin and petroleum jelly
administered, inter ali a, topically to nude mice. Id. ( citing Rauktys 2-3 ).
The Examiner fmds Rauktys teaches that a concentration of rapamycin used
was 0. 8% and 0.4% rapamycin, and that 24 hours after the topical
application of a composition comprising 0.4% or 0. 8%, the systemic
concentration of rapamycin detected was greater than 3 ng/ml. Id. ( citing
Rauktys 5). However, the Examiner fmds that Rauktys teaches that 48 hours
after the application the concentration may drop below systemic effective
concentration ( 1. 7 ± 0. 9 ng/ml) for the O. 4 % of rapamycin treatment group.
Id. The Examiner fmds Rauktys concludes that topical administration of
rapamycin is an effective treatment for TSC-related tumors, and suggests
that it is likely that the effect topical rapamycin in the experiments was due
to systemic rapamycin exposure. Id. ( citing Rauktys 7).
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The Examiner concludes that it would have beenprimafacie obvious
for a person of ordinary skill in the art to apply rapamycin, as taught by
Rauktys, to humans for treatment of cutaneous vascular lesions. Final Act.
7. The Examiner further concludes that a person of ordinary skill in the art
would have been motivated to apply the ointment rapamycin composition to
humans for treatment of cutaneous vascular lesions, because it is known that
topical administration of rapamycin is an effective treatment for cutaneous
vascular lesions. Id. The Examiner also concludes that it would have been
obvious to try topical rapamycin compositions with and without systemic
absorption to apply the therapy of the preclinical model to a human patient
the preclinical model on human with a reasonable expectation of success.
Id. at 6.
Finally, the Examiner concludes that it would have been obvious to a
person of ordinary skill in the art to vary and/ or optimize the amount of
rapamycin provided in the composition, and any other pharmaceutical
excipients that might affect the systemic absorption according to the
guidance provided by Rauktys. Id. at 8.
Appellants argue that Rauktys teaches only that rapamycin was
applied to nude mice, and that doing so resulted in systemic levels of
rapamycin that produced a therapeutic effect. App. Br. 5. Appellants assert
that Rauktys teaches that topical rapamycin applied to mouse skin achieves a
systemic blood concentration in an amount effective to impede TSC-tumor
growth. Id. Appellants argue that Rauktys also expressly teaches that a
rapamycin systemic blood concentration is necessary for treatment of the
TSC-tumor. Id. Appellants contend that a person of ordinary skill in the art
would have learned from Rauktys that a TSC-tumor is treatable via topical
administration of rapamycin by achieving a systemic concentration of the
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drug within its known therapeutic range of 3-15 ng/ml. Id. at 6 ( citing
Rauktys4).
Appellants argue, therefore, that Rauktys teaches methods of
administration intended to achieve 24 hour blood levels of at least 3 ng/ml.
App. Br. 6. Appellants assert that Rauktys expressly teaches that the
rapamycin effect was due to systemic exposure in the known therapeutic
range for rapamycin, whereas, in contrast, the claimed method comprising
topically administering a rapamycin composition such that the serum
rapamycin level is less than 2 ng/ml. Id.
Appellants argue further that Rauktys fails to teach or suggest any
method involving topical administration of a rapamycin composition to
human skin. App. Br. 6. Nor, argue Appellants, does Rauktys teach or
suggest that rapamycin can, following topical administration to human skin,
reach levels in the human dermis that are therapeutically effective against
cutaneous vascular lesions, in the absence of systemic exposure to a blood
level in the known therapeutic range. Id. Appellants point out that Rauktys
teaches using a nude mouse model for testing topical administration of
rapamycin. Id. However, Appellants assert, topical administration of
rapamycin in nude mice is not comparable to topical administration in
humans. Id. ( citing Declaration of Dr. Joyce Teng3 , December 16, 2014 (the
"Teng Declaration")). Consequently, Appellants argue, Rauktys cannot be
said to teach that the topical dosage would be the same for humans or that
the topical absorption through the skin would be the same. Id. at 7. Rather,
Appellants contend, Rauktys teaches only that the systemic, whole blood
3 We note that Dr. Teng is one of the named inventors of the application on
appeal.
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levels of rapamycin in the mice were in the therapeutic range of systemic
levels that have been used for humans. Id. Appellants maintain that
Rauktys teaches that to be therapeutically effective in humans, the whole
blood level of rapamycin must be in the known human therapeutic range of
3-15 nglml, which is above the 2 nglml maximum recited in the claims. Id.
Appellants argue further that Rauktys fails to teach or suggest that
there is less than 2 nglml rapamycin in the subject's serum after three
months of twice daily administration, as required by the claims. App. Br. 7.
According to Appellants, Rauktys teaches that 24 hours after application the
rapamycin systemic concentration was greater than 3 nglml and 48 hours
after application the rapamycin systemic concentration was below 1. 7 nglml.
Id. ( citing Rauktys 2). However, Appellants point out, Rauktys applied
rapamycin once per day, three days per week, and tested serum levels 24
hours or 48 hours after the last treatment; treatment was stopped after the
tumorreacheda volume of3000mm3 • Id. (citing Rauktys4).
Appellants dispute the Examiner's finding that the level of rapamycin
"would have been reasonably expected to drop to less than 2 nglml after
three months of treatment." App. Br. 7 (quoting Final Act. 13). Appellants
argue that this statement is no more than conjecture by the Examiner, based
on the drop in systemic rapamycin levels observed in mice after 48 hours
with no further administration of rapamycin. Id.
Finally, Appellants argue that Rauktys does not teach or suggest a
dose of no more than 2% rapamycin being sufficient for reducing cutaneous
vascular lesions in a human subject. App. Br. 8. Appellants assert that the
0.4% and 0. 8% rapamycin ointments applied to nude mice, as taught by
Rauktys, would not have informed one of skill in the art what topical
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concentration of rapamycin would be effective in treating cutaneous vascular
lesions on human skin. Id.
We are not persuaded by Appellants' arguments. The obviousness
analysis requires that the cited prior art teaches or suggests the limitations of
the claims on appeal. See CFMT, Inc. v. Yieldupint'l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003).
Rauktys teaches that: "there is evidence that systemic treatment with
rapamycin or other mTOR inhibitors may be a useful approach to targeted
therapy for the kidney and brain manifestations. Here we investigate topical
rapamycin in a mouse model for TSC-related tumors." 4 Rauktys Abstr.
Rauktys teaches that: "0.4% and 0. 8% rapamycin ointments were applied to
nude mice bearing subcutaneous, T SC-related tumors" and that "Topical
rapamycin treatment resulted in systemic drug levels within the known
therapeutic range." Id.
Specifically, Rauktys teaches that:
The rapamycin level in whole blood 24 hours after a single 0.8%
dose of topical rapamycin was 13.0 ± 2.5 nglml. After a single
0.4% dose the rapamycin level was 5.9 ± 0.5 nglml. These 24
hour levels are within the typical therapeutic range for rapamycin
when used for immunosuppression after organ transplantation
(3-15 nglml). 48 hour levels were also measured and show that
in animals treated with a single 0.4% dose, rapamycin levels
dropped below therapeutic range (1. 7 ± 0.9 nglml) while those
treated with a single 0.8% dose did not (4.1 ± 2.3 nglml).
4 We note here that cutaneous vascular lesions include facial angiofibromas
in patients with TSC. See Spec. ,r 13.
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Rauktys 4--5. Rauktys expressly concludes that: "transdermal delivery of
rapamycin is feasible and topical rapamycin should be further investigated
as a novel treatment approach for T SC skin disease such as facial
angiofibromas." 5 Id. at 7.
Claim 1 requires: "a composition comprising no more than about 2%
by weight rapamycin." Rauktys teaches application of 0.4 and 0. 8 wt%
rapamycin in a "topical vehicle" (see Rauktys 2); both concentrations fall
within the recited "no more than about 2% by weight rapamycin." We agree
with Appellants that Rauktys teaches that, in the nude mouse model, serum
levels that exceed the "less than 2 nglml" at 24 hours for both 0.4 and
0. 8 wt% and similarly at 48 hours for 0. 8 wt%, though not for 0.4 wt%.
Nevertheless, as we explain in the following sections, the knowledge of a
person of ordinary skill in this art, as explained at least in part by the Teng
Declaration, would have made it obvious to such a skilled artisan that, by
altering the dosages of topically applied rapamycin when applied to a human
patient, the serum level of rapamycin could be optimized, and thereby satisfy
the requirement of the claims.
Where a skilled artisan merely pursues "known options" from a "fmite
number of identified, predictable solutions," obviousness under§ 103 arises.
KSRint'l Co. v. Teleflex Inc., 550U.S. 398,421 (2007). Furthermore:
"where the general conditions of a claim are disclosed in the prior art, it is
not inventive to discover the optimum or workable ranges by routine
experimentation." In re Aller, 220 F.2d454, 456 (C.C.P .A. 1955). This rule
is limited to cases in which the optimized variable is a "result-effective
5 See id.
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variable." In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed. Cir.
2012) (citing In re Antonie, 559 F.2d 618,620 (C.C.P.A. 1977); see also In
re Boesch, 617 F.2d272, 276 (C.C.P.A. 1980) ("[D]iscoveryofanoptimum
value of a result effective variable ... is ordinarily within the skill of the art").
Rauktys teaches that the serum concentrations of rapamycin reflect
the rapamycin concentration of the topically applied composition, thus, the
concentration of topically applied rapamycin is a "result effective variable."
Consequently, and as we explain further below, we agree with the Examiner
that it would be well within the abilities of, and obvious to, a person of
ordinary skill in the art to optimize the concentration of the topically-applied
rapamycin composition to achieve the claimed results.
Issue 2
Appellants next argue that a person of ordinary skill in the art would
have had no reasonable expectation of success in reducing cutaneous
vascular lesions in humans based on the teachings of Rauktys. App. Br. 8.
Analysis
Appellants argue that a skilled artisan with knowledge of the
teachings of Rauktys would have had no expectation of success that
Rapamycin, when topically applied to provide a serum level of less than
2 ng/ml will reduce cutaneous vascular lesions in a human. App. Br. 8.
According to Appellants, Rauktys teaches that a topical formulation which
provides a systemic blood concentration of rapamycin is necessary for a
therapeutic effect. Id. Therefore, assert Appellants, there is no basis in
Rauktys to form an expectation that administering rapamycin topically to
provide a less than systemic therapeutic blood level would reduce cutaneous
vascular lesions. Id. Furthermore, Appellants contend, Rauktys neither
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teaches nor suggests that such therapeutic results could be achieved after
three months of twice daily, i.e., topical application. Id. at 9.
We are not persuaded by Appellants' arguments. The limitations of
claim 1 require that, upon administration of less than about 2% rapamycin in
a suitable carrier, a serum level of rapamycin is obtained that is less than
2 ng/ml. Rauktys teaches that 0.4% and 0. 8% concentrations of rapamycin,
applied topically, result in serum concentrations that exceed the required
serum concentrations of rapamycin in a nude mouse model. We fmd that it
would be within the skill of an ordinary artisan to further alter the
concentration of the topically-applied rapamycin concentration to reduce the
serum rapamycin levels in nude mice. We address Appellants' arguments
concerning the differences between transdermal absorption of rapamycin in
the nude mouse model and humans, as presented in the Teng Declaration,
below.
Finally, Rauktys expressly encourages the use of topically-applied
rapamycin in humans with cutaneous vascular lesions, including facial
angiofibromas: "Our data demonstrates [sic] that transdermal delivery of
rapamycin is feasible and topical rapamycin should be further investigated
as a novel treatment approach for T SC skin disease such as facial
angiofibromas." Rauktys 7. We fmd that this teaching ofRauktys, together
with the data presented in the reference, would give a person of ordinary
skill a reasonable expectation of success in topically applying rapamycin to
achieve the serum levels recited in claim 1.
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Issue 3
Appellants argue that, at the time of filing, it would not have been
predictable or foreseeable topically administering a composition with no
more than about 2% rapamycin to a human would reduce cutaneous vascular
lesions while having a serum level of rapamycin less than 2 nglml. App. Br.
9.
Analysis
Appellants point to the Teng Declaration as evidence demonstrating
the unexpected therapeutic effects on cutaneous vascular lesions in human
skin by low-dose, topical administration of rapamycin over a period of
months. App. Br. 9. Appellants contend the Examiner has not adduced
evidence sufficient to rebut the evidence presented in the Teng Declaration.
Id. at 10.
Appellants assert that
[ i]t was well known in the art that that mouse skin is not an
optimal equivalent for human skin[,] because the very thin skin
of nude mice provides a relatively poor absorption barrier such
that a topically applied therapeutic agent essentially amounts to
systemic administration of the agent in the nude mouse.
App. Br. 10.
Appellants point to Dr. Teng's statement that:
The thickness and the structure of an animal's skin is a
significant factor in the rate and extent of topical medication
absorption and thus systemic exposure in humans and other
animals. There is a near 10 fold difference in the thickness of the
skin in nude mice compared to humans .... [T]he very thin skin
of nude mice provides a relatively poor absorption barrier such
that a topically applied therapeutic agent essentially amounts to
systemic administration of the agent in the nude mouse. I further
submit that this is confrrmed by the results described in Rauktys.
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Id. (quoting TengDecl. ,r,r 6-7).
Appellants further quote Dr. Teng' s Declaration as opining that:
[M]y co-inventors and I were also faced with ample literature
teaching that rapamycin is too large a molecule to sufficiently
penetrate intact human skin to achieve a subcutaneous,
therapeutic level. The molecular weight of rapamycin is
approximately 914 g/mol, which was generally considered too
large to be absorbed through intact human skin. . . . We therefore
believed that rapamycin topically applied to intact human skin
was highly unlikely to penetrate through the stratum comeum
layer and thus unlikely to have much, if any, effect on cutaneous
neoplasms. As such, we were very surprised to observe the
results we did in the patient described in Example 1 of the '779
application, especially when we further observed that there was
no measurable systemic absorption of the rapamycin even after
three months of topical application of 1 % rapamycin to
approximately 1 % of the body surface area.
Id. at 10-11 (quoting TengDecl. ,r 10). (Emphasis omitted).
Appellants, relying on these statements in the Teng Declaration,
therefore contend that Appellant developed a method for reducing cutaneous
vascular lesions by daily, topical administration of rapamycin, while
maintaining less than2 ng/ml ofrapamycin in the serum. App. Br. 11. In
addition to reducing cutaneous vascular lesions, Appellants argue, the
chronic topical administration does not result in measurable systemic blood
levels of rapamycin, thus avoiding the negative effects associated with
higher systemic levels of rapamycin. Id.
We find the statements of the Teng Declaration insufficient to
overcome the Examiner's primafacie conclusion of obviousness. As an
initial matter, reviewing Dr. Teng's qualifications, as set forth in the Teng
Declaration, we fmd Dr. Teng sufficiently qualified to provide an expert
opinion in this matter, and we accord her statements due probative weight.
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Claim 1 requires: (1) topically applying a composition of less than
2 wt% rapamycin in a suitable carrier, such that; (2) the resulting blood
serum level is less than 2 ng/ml after the recited administration regimen.
Appellants argue, relying upon the Teng Declaration, that it was well
known in the art that there is a near 10-fold difference in permeability
between human and nude mouse skin and that a large molecular weight
compound such as rapamycin, would have a difficult time permeating such a
barrier. We fmd that a person of ordinary skill, familiar with these facts, and
knowing that Rauktys teaches that 0.4 and 0. 8 wt% rapamycin compositions,
when topically applied to nude mouse skin, produce serum rapamycin
concentrations in the range of 1. 7 to 13. 0 ng/ml, might reasonably expect
that applying a concentration of high molecular weight rapamycin of
approximately an order of magnitude greater onto human skin, which is at
least an order of magnitude more resistant to transdermal penetration, would
reasonably produce serum concentrations less than 2. 0 ng/ml: indeed even
0 ng/ml falls within the claimed range. We agree with the Examiner that
altering the result effective concentration of topically applied rapamycin to
achieve that outcome would be within the skill of a person of ordinary skill
to achieve and optimize. See Aller, 220 F.2d at 456. We consequently
affrrm the Examiner's rejection of the claims.
B. Rejection of claims 1-3, 7, and 8 over Rauktys and Ormerod
Issue 1
Appellants argue that the Examiner erred because Ormerod neither
teaches nor suggests topical administration of rapamycin for the treatment of
cutaneous vascular lesions, or achieving less than 2 ng/ml rapamycin in the
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subject's serum after three months of twice daily administration. App. Br.
12.
Analysis
Appellants repeat their arguments, presented supra, that the claims on
appeal are not obvious over Rauktys and assert that Ormerod fails to cure the
alleged deficiencies of Rauktys. App. Br. 12.
Appellants argue further that Ormerod teaches a topical formulation
of an immunosuppressive macrolide and a permeation modulator to produce
a minimal systemic effect. App. Br. 12(citing Ormerod col. 2, 11. 38--47).
According to Appellants, Ormerod is directed to the use of topical
rapamycin in inflammatory skin diseases, such as psoriasis. Id. ( citing
Ormerod col. 1, 11. 9-32). Appellants also note that Ormerod teaches the
treatment of psoriasis with topical sirolimus (i.e., rapamycin) in doses of
2.2% and 8% and a permeation modulator ( capric acid) and further teaches
that a low barrier to penetration or higher concentration of sirolimus is
needed for a "more marked efficacy." Id. Appellants assertthat Ormerod
also teaches that: "assuming penetration to be the problem, topical sirolimus
would be expected to be more effective ... where the barrier to penetration is
less." Id. at 13. However, Appellants argue, Ormerod does not teach that a
2% dose of topical rapamycin would be effective against cutaneous vascular
lesions, which has a more intact barrier than psoriasis. Id.
Appellants argue further that the Examiner's fmding that: "one would
expect that lower doses would also not be systemically absorbed" goes
against the actual teachings of the references: Rauktys teaches that topical
application of ointments comprising 0.4% and 0. 8% of rapamycin are
systemically absorbed. App. Br. 13. The doses disclosed by Rauktys (0.4%
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and 0.8%) are lower than the doses of Ormerod (2.2% and greater), and are
systemically absorbed, resulting in at least 5. 9 ng/ml rapamycin in the blood.
Id. Appellants argue the two references are in conflict because Rauktys
teaches that systemic absorption is achieved with doses of 0.4% and 0. 8%
for the treatment of T SC tumors, whereas Ormerod teaches that systemic
levels of rapamycin are not achieved with doses of2.2% and 8% for the
treatment of psoriasis. Id. Therefore, Appellants argue the teachings of
Rauktys and Ormerod cannot be reconciled and one of ordinary skill in the
art would not expect that lower doses would not be systemically absorbed in
humans with cutaneous vascular lesions. Id.
Appellants dispute the Examiner's fmding that Ormerod suggests
modifying Rauktys by teaching a desire to minimize the systemic absorption
of topical rapamycin. App. Br. 13 (citing Final Act. 10). Appellants assert
that this fmding ignores the divergent approaches to therapy taught by
Rauktys and Ormerod. Id. First, Appellants argue, there is no basis to assert
that the compositions of Ormerod, designed for treating inflammatory skin
diseases, would be effective to treat the cutaneous vascular lesions in the
mice of Rauktys. Id. According to Appellants, Ormerod is directed to the
use of topical rapamycin in inflammatory skin diseases such as psoriasis,
which are completely unrelated to non-inflammatory conditions such as
cutaneous vascular lesions. Id. Appellants assert that Ormerod teaches only
the treatment of psoriasis and fails to teach or suggest treatment for any non-
inflammatory conditions, such as cutaneous vascular lesions. Id.
Appellants point out that inflammatory skin disease and cutaneous
vascular lesions have different disease morphologies and pathogenesis, and,
thus, call for different treatment strategies. App. Br. 13. Appellants argue
that it was well known in the art that inflammatory skin conditions such as
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psoriasis disrupt the skin's barrier function and are considered immune
dysregulation disorders, whereas cutaneous vascular lesions on the other
hand result from uncontrolled cell proliferation and vascular neogenesis and
do not have a disrupted skin barrier. Id. ( citing Teng Deel. ,r 12-13 ).
Appellants argue further that Ormerod neither teaches nor suggests
the limitation of claim 1 requiring serum concentrations less than 2 nglml
rapamycin in the subject's serum after three months of twice daily, i.e.,
chronic, topical administration of less than 2% rapamycin. App. Br. 13.
We are not persuaded by Appellants' arguments. As we have
explained in Section A, we conclude that the claims are obvious over
Rauktys. Rauktys further teaches that:
[T]ransdermal delivery of rapamycin is feasible and topical
rapamycin should be further investigated as a novel treatment
approach for T SC skin disease such as facial angiofibromas.
Furthermore, the utility of topical rapamycin should be further
investigated for other skin disorders such as psoriasis, Kaposi's
Sarcoma, basal cell carcinoma, and squamous cell carcinoma.
Rauktys 7 ( emphasis added). Rauktys thus expressly suggests that topical
treatment with rapamycin may be useful in the treatment of both T SC-
related facial angiofibroma and psoriasis. This contradicts Appellants'
contention that the two conditions and their treatments are wholly unrelated
Ormerod is directed, in relevant part, to:
[ A] topical formulation for the treatment of a dermatological
condition . . . [that] further comprises a permeation modulator
and the permeation modulator and the macrocyclic lactone or
macrolide or the biologically active analogue, derivative or pro-
drug thereof are present in relative amounts such that when a
therapeutic amount is applied to the skin a minimal systemic
effect is produced.
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Ormerod Abstr. The Examiner relies upon Ormerod as providing: "guidance
as how to manipulate the absorption rate of topical rapamycin. With the
knowledge, it would have been within the purview of ordinary skill in the art
to optimize the rate of absorption for an optimal therapeutic efficacy." Final
Act. 12.
Appellants' claims on appeal are directed to the use of: "a
composition comprising no more than about 2% by weight rapamycin and a
dermatologically acceptable carrier." The use of the term "comprising" does
not prohibit the inclusion of additional elements in the composition. See
Crystal Semiconductor Corp. v. Tri Tech Microelectronics Int'l, Inc., 246
F.3d 1336, 1348 (Fed. Cir. 2001) ("Use of the transition 'comprising' in the
language of a claim creates a presumption ... that the claim does not exclude
additional, unrecited elements"). Consequently, addition of a permeation
modulator is within the scope of the claims.
Ormerod teaches that its compositions comprising:
[T]he permeation modulator and the macrocyclic lactone
antibiotic, immunosuppressive macrolide or a pharmacologically
active analogue, derivative or pro-drug [ and, expressly,
rapamycin] are present in relative amounts such that when a
therapeutic amount is applied to the skin, a minimal systemic
effect is produced.
By the term "minimal systemic effect", is meant that the
amount of active principal detectable in the blood stream is
preferably less than 0.3 nglnl over 4 to 24 hours after
administration, more preferably below 0.1 nglml over the same
period.
Ormerod col. 2, 11. 42-52. We agree with the Examiner that a person of
ordinary skill in the art would be motivated to combine the teachings and
suggestions ofRauktys with those of Ormerod to regulate the systemic
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Application 13/852, 779
levels of rapamycin to achieve the minimal systemic effects both taught by
Ormerod and required by the claims.
Finally, Appellants' argument that Ormerod is not directed to the
treatment of T SC-related cutaneous vascular lesions is irrelevant. We have
explained why Rauktys teaches that rapamycin could be an effective
treatment for both TSC-related cutaneous vascular lesions and psoriasis.
Ormerod is cited as teaching a permeation modulator to limit the systemic
penetration of topically applied rapamycin. "[ 0 ]ne cannot show non-
obviousness by attacking references individually where ... the rejections are
based on combinations of references." In re Keller, 642 F.2d413, 426
(C.C.P.A. 1981).
With respect to Appellants' argument that the teachings of Rauktys
and Ormerod are irreconcilable, we note that Appellants' own declarant, Dr.
Teng, has stated that it was well-known in the art that human epidermis is
approximately ten times less permeable than the epidermis of nude mice.
See Teng Deel. ,r 8. We therefore fmd that a person of ordinary skill would
understand that rapamycin is much more likely to penetrate the epidermis in
nude mice and be present in measurable amounts systemically, whereas the
epidermis of humans would be much more resistant to penetration and
systemic circulation, even if presented at higher dosages.
Issue 2
Appellants argue the Examiner erred because the combination of
references fails to teach the claimed method. App. Br. 15.
Analysis
Appellants essentially repeat their arguments presented in Section A
supra, and argue that Ormerod fails to cure the alleged deficiencies of
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Application 13/852, 779
Rauktys. See App. Br. 15-17. For the reasons we have explained supra, we
do not fmd Appellants' arguments persuasive. We consequently affirm the
Examiner's rejection upon this ground.
DECISION
The Examiner's rejection of claims 1-3, 7, and 8 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)(l )(iv).
AFFIRMED
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