Ex Parte Hirsh et al

Patent Trial and Appeal Board

Sep 6, 2016

11014636 (P.T.A.B. Sep. 6, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111014,636 12/16/2004
25181 7590 09/08/2016
FOLEY HOAG, LLP
PA TENT GROUP, SEAPORT WEST
155 SEAPORT BL VD
BOSTON, MA 02210-2600
FIRST NAMED INVENTOR
Jane Hirsh
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.
LPX-007.01 2094
EXAMINER
CARTER, KENDRA D
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
09/08/2016 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):
Patent@foleyhoag.com
pair_foleyhoag@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JANE HIRSH and DONALD TIBBETTS
Appeal2014-007115
Application 11/014,636
Technology Center 1600
Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and
JOHN G. NEW, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to an
aqueous triamcinolone composition. The Examiner rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
Statement of the Case
Background
"Steroidal anti-inflammatory agents, known for the treatment of ...
forms of rhinitis, are commonly available as nasal sprays" (Spec. 2).
"Aqueous steroidal nasal solutions typically consist of the active ingredients
1 Appellants identify the Real Party in Interest as Lupin Atlantis
Holdings SA (see App. Br. 4).
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Application 11/014,636
dissolved in the aqueous medium without thixotropic agents; consequently,
the viscosity is much lower (approximately 40-50 cps) than a suspension.
Nasal steroidal solutions do not require shaking prior to actuation; and they
are simpler to manufacture" (Spec. 3). "Unfortunately, they have suffered
from significant stability issues involving precipitation when stored
inadvertently at temperatures below stated storage conditions as defined by
U.S. FDA (i.e., 20-25 C)" (Spec. 3).
"[T]he instant invention provides a way of stabilizing hydrophobic
drugs in water-containing formulae against precipitation on storage in the
cold." (Spec. 4).
The Claims
Claims 15-19 and 21-24 are on appeal. Claim 15 is representative
and reads as follows:
15. An aqueous formulation, comprising:
triamcinolone acetonide in an amount between about 0.01 % and
about 0.05% (w/v);
propylene glycol in an amount of 14% (w/v);
PEG 3350 in an amount between about 35% and 40% (w/v);
benzalkonium chloride in an amount of about 0.05% (w/v);
disodium EDTA in an amount of about 0.05%) (w/v);
citric acid in an amount of about 0.72% (w/v): and
sodium citrate dihydrate in an amount of about 0.74% (w/v);
wherein
at 20 °C the aqueous formulation is a solution, is not
supersaturated, has a viscosity between about 45 cps and about 50 cps,
and is suitable for nasal delivery; and at least 90.0% of the amount of
triamcinolone acetonide remains in solution after storage of the
aqueous formulation at 20 °C for 6 weeks.
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The issues
A. The Examiner rejected claims 15-18, 21, and 22 under 35 U.S.C.
§ 103(a) as obvious over Tri-Nasal,2 Admitted prior art, and Kamishita3
(Ans. 2-5).
B. The Examiner rejected claim 19 under 35 U.S.C. § 103(a) as obvious
over Tri-Nasal, Admitted prior art, Kamishita, and Fust4 (Ans. 5---6).
C. The Examiner rejected5 claims 23 and 24 under 35 U.S.C. § 103(a) as
obvious over Tri-Nasal, admitted prior art, Kamishita, Fust, Kalat, 6 and
Kuster7 (Ans. 7-8).
A. 35 U.S.C. § 103(a) over Tri-Nasal, Admitted prior art, and Kamishita
The Examiner finds that "Tri-Nasal comprises all of the claimed
components (i.e. ingredients) of claims 15 and 21" but "does not teach
wherein the propylene glycol is in an amount of 14%" (Ans. 3). The
Examiner finds that Kamishita teaches "a nasal aqueous spray ... that can
comprise multiple active ingredients ... such as triamicinolone [sic]
2 Tri-Nasal Spray, Muro Pharmaceutical, Inc., NDA#20-120 (Feb.
2000) ("Tri-Nasal").
3 Kamishita et al., US 5,215,739, issued June 1, 1993
("Kamishita").
4 Fust, C., US 2001/0007651 Al, published July 12, 2001 ("Fust").
5 The Examiner inadvertently erred in omitting Kalat and Kuster
from the statement of the obviousness rejection, but provided
specific analysis of their teachings in the body of the rejection (see
Ans. 7-8), so we hold this error harmless.
6 Kalat, E., US 4,511,069, issued Apr. 16, 1985 ("Kalat'').
7 Kuster, J., US 3,128,922, issued Apr. 14, 1964 ("Kuster").
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Application 11/014,636
acetonide ... wherein solvents such as propylene glycol are used" (Ans. 3-
4).
The Examiner finds it obvious "to increase the amount of propylene
glycol to 14 [%] (claims 15 and 21 ), to solubilize the triamcinolone
acetonide, since propylene glycol is known as a solvent as taught by
Kamishita" (Ans. 4).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner's conclusion
that Tri-Nasal, Admitted prior art, and Kamishita render claim 15 obvious?
(ii) If so, have Appellants presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness?
Findings of Fact
1. The Specification teaches "an aqueous formulation, comprising
... propylene glycol in an amount between about 13% and about 20%
(w/v)" (Spec. 4).
2. The Specification teaches that in the "case of Muro TriNasal®
spray, the solution is saturated at 25°C, seed crystals form below 20°C and
once seed crystals form, crystallization takes place at any temperature below
25°C" (Spec. 23).
3. Tri-Nasal teaches "a metered-dose manual spray pump in an
amber polyethylene terephthalate (PET) bottle with 0.05% w/v
triamcinolone acetonide in a solution containing citric acid, edetate
disodium, polyethylene glycol 3350, propylene glycol, purified water,
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Application 11/014,636
sodium citrate, and 0.01 % benzalkonium chloride as a preservative" (Tri-
Nasal 1-2).
4. Tri-Nasal teaches: "Store at controlled room temperature: 20°-
250C (68°-77°F). Protect from freezing" (Tri-Nasal 20).
5. Admitted prior art in the form of Appendix A of Appellant's
response filed Nov. 12, 2008 is reproduced below:
Appendix A shows that in addition to the 0.05% active amount of
triamcinolone, Tri-Nasal further comprises 40% PEG 3350, 12% propylene
glycol, 0.02% benzalkonium chloride, 0.05% EDTA, 0.72% citric acid, and
0.74% sodium citrate, and has a viscosity of 45.55 mPa•s.
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6. Kamishita teaches that, in spray compositions, "it is preferable
to prepare the spray gel preparation by using a solubilizer ... suitable water-
soluble organic solvent includes ... propylene glycol" (Kamashita 5:31-37).
7. Kamishita teaches that a "suitable active medicament of the
present invention includes ... triamcinolone acetonide" (Kamishita 4:51 to
5:3).
Principles of Law
"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
"[E]vidence rising out of the so-called 'secondary considerations'
must always when present be considered en route to a determination of
obviousness." Stratojlex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1538 (Fed.
Cir. 1983).
Analysis
We adopt the Examiner's findings regarding the scope and content of
the prior art (Ans. 2-5; FF 1-7) and agree that the claimed method would
have been obvious over the teachings of Tri-Nasal, Admitted prior art, and
Kamishita. In particular, the Examiner has established a prima facie case
that modifying the Tri-Nasal composition from 12% propylene glycol to
14% propylene glycol would have been obvious "to solubilize the
triamcinolone acetonide, since propylene glycol is known as a solvent as
taught by Kamishita" (Ans. 4).
We address Appellants' arguments below.
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Claim 15
Appellants contend that
An example of a formulation that is supersaturated at a given
storage temperature is the 12% propylene glycol formulation
stored at 20 °C, which decreases from 97 .2% solute in solution
(t = "O") to 87.2% (t = 8 weeks) .... The 12% propylene glycol
solution listed Table 4 is TRI-NASAL; in other words, TRI-
NASAL is supersaturated.
(App. Br. 15).
We do not find this argument persuasive of unexpected results.
Specifically, Appellants have not shown that increasing the content of
propylene glycol-a known solvent-in the Tri-Nasal composition would
not have been expected to lower the temperature at which the solution
becomes supersaturated. Indeed, Appellants' own Specification does not
identify this result using 14% propylene glycol as unexpected. The Hirsh
Declaration also does not identify the change in supersaturation as
unexpected, instead simply noting that "[t]he supersaturation temperature of
each formulation can be obtained by determining the point at which each
trendline drops below 100% triamcinolone acetonide. At about 25°C and
below, the formulation containing 12% propylene glycol (the TRI-NASAL
formulation) is supersaturated" (Hirsch Dec. i-f 23).
"It is not enough to show that results are obtained which differ from
those obtained in the prior art: that difference must be shown to be an
unexpected difference." In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972).
Here, Appellants have provided no evidence that the change in
supersaturation behavior based on increasing the amount of a known organic
solvent, propylene glycol, for drug dissolution, constitutes an unexpected
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result. Indeed, given Kamishita's teaching that propylene glycol is a
solubilizer of water-insoluble medicaments and its specific identification of
triamcinolone as a medicament (FF 6-7), increasing the amount of
solubilizer would reasonably have been expected to increase the solubility of
the medicament rendering the change in supersaturation as an expected, not
unexpected, result. See In re Skoner, 517 F .2d 94 7, 950 (CCP A 197 5)
("Expected beneficial results are evidence of obviousness of a claimed
invention. Just as unexpected beneficial results are evidence of
unobviousness. ")
Appellants contend that:
One of ordinary skill in the art would have appreciated the
complicated relationship between the formulation viscosity,
active agent solubility, and eventual therapeutic efficacy.
Indeed, the Exhibits and the Hirsh Declaration establish that the
viscosity of a formulation necessarily dictates the quantity of
formulation deposited onto a target area, which dictates the
level of therapeutic benefit ... One of ordinary skill would
have expected a change in the amount of a single component to
be associated with a change in the viscosity of the formulation
as a whole; therefore, changing the quantities of several
components and maintaining an appropriate formulation
viscosity and efficacy was unexpected because both changes
would have been expected to decrease the viscosity of the
formulation.
(App. Br. 17-18).
We do not find this argument persuasive for several reasons. First,
claim 15 is drawn to a viscosity range of "about 45 cps and about 50 cps", a
range reasonably encompassing both the prior art Tri-Nasal composition as
well as all of the compositions shown in Table III of Appendix A other than
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Formula 10-32A and 10-32D. Each of the remaining compositions has
viscosities from 44.98 to 51.16, values that are reasonably interpreted as
falling with the "about" language used in claim 15. The "[a]pplication's use
of the term 'about' shows that the applicants did not intend to limit the
claimed ranges to their exact end-points." In re Harris, 409 F.3d 1339, 1343
(Fed. Cir. 2005).
Second, Table III of Appendix A essentially establishes that as the
amount of water is reduced, and the amount of PEG 3350 increased,
viscosity increases. That is, as more of a more viscous component, PEG
3350, is used to replace a less viscous component, water, viscosity increases.
(See, e.g., Spec. 39, "The viscosity enhancing agent [in the prior art Tri-
Nasal composition] is polyethylene glycol 3350"). That is an expected
result, not an unexpected result.
We recognize that the Hirsh Declaration teaches that
The relationship between viscosity and PEG 3350 concentration
is exponential in both the system based on the literature values .
. . and the system based on the formulations containing 14%
propylene glycol (represented by diamonds in Exhibit F, Figure
A and Figure B). However, in the presence of the claimed
higher concentration of propylene glycol the viscosity versus
PEG curve is displaced upward ... Also the increase in
propylene glycol concentration does not simply displace the
viscosity versus PEG curve upward in the seven test
formulations; rather it fundamentally changes the shape of the
curve.
(Hirsh Dec. i-fi-f 15-16). However, neither the Specification nor the Hirsh
Declaration states that altering the ratio of PEG 3350 and water yields an
unexpected result, or that obtaining a desired viscosity using a 14%
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Application 11/014,636
propylene glycol concentration in the Tri-Nasal composition would have
required more than routine experimentation. The only statement that this
result is unexpected is found in Appellants' attorney argument. However,
"attorney argument [is] not the kind of factual evidence that is required to
rebut a prima facie case of obviousness." In re Geisler, 116 F.3d 1465, 1470
(Fed. Cir. 1997).
Appellants contend that:
Muro Pharmaceuticals recognized a need for spray formulations
of triamcinolone acetonide suitable for nasal delivery more than
11 years before the priority date of the present application. See
Hirsh Declaration, paragraphs 4-5; and Exhibit M. The
recognized problem, therefore, has persisted for more than two
decades without the development of an acceptable solution,
either prior to the priority date of the present application or
subsequently.
(App. Br. 19).
We are not persuaded. To establish a long-felt need, three elements
must be proven: First, the need must have been a persistent one that was
recognized by ordinarily skilled artisans. In re Gershon, 372 F.2d 535, 538
(CCPA 1967). Second, the long-felt need must not have been satisfied by
another before Appellants' invention. See Newell Companies, Inc. v. Kenney
Mfg. Co., 864 F.2d 757, 768 (Fed. Cir. 1988) ("[O]nce another supplied the
key element, there was no long-felt need or, indeed, a problem to be solved .
. . . "). Third, the invention must, in fact, satisfy the long-felt need. In re
Cavanagh, 436 F.2d 491, 496 (CCPA 1971).
While the Hirsh Declaration states that "TRI-NASAL was withdrawn
from the market due to solubility and stability issues" (Hirsh Dec. i-f 6), the
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Hirsh Declaration does not specifically state that the long-felt need was not
satisfied by other compositions, whether they comprised triamcinolone or
other active components, only that the Tri-Nasal composition was no longer
marketed (id.).
In addition, Exhibit D states that removal was because "in some
batches the active ingredient, T AA, decreases in content over time when the
product is exposed to temperatures below 20°C" (Exhibit D 1 ). Thus, the
product was removed because of improper storage, not because the product
itself was defective when produced. Moreover, Exhibit D notes that "Muro
has decided to discontinue marketing Tri-Nasal Spray. Muro is in the
process of being sold. If the new owners decide to recommence work on
resolving the issues, FDA will be notified" (Exhibit D 5). Thus, the reason
for discontinuation was due, at least in part, to business issues, and not
because the key element and problem was unsolved.
Finally, Appellants have not established that the inventive product
satisfied the long felt need with sales or other objective evidence. Given the
clear evidence that improper storage conditions below 20°C were the cause
of the recall (see Exhibit D 1), and the clear evidence that even the 14%
formulations are subject to supersaturation at temperatures below 20°C (see
Spec. 43, table 5), there is no clear evidence that any long-felt need for a
product that would withstand improper temperatures would be satisfied by
the 14% propylene glycol formulation because temperatures below 20°C
reduce triamcinolone content below 90% in four weeks or less (see Spec. 42,
table 4, where storage at 10°C and l 5°C reduce triamcinolone content to
89.9 and 77.1 % after four weeks).
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Appellants contend that "for a number of years others have failed to
develop a stable nasal formulation comprising a concentration of solubilized
triamcinolone acetonide sufficient to confer a therapeutic benefit" (App. Br.
19).
We find this argument unpersuasive because Tri-Nasal itself is a
formulation that is stable at temperatures between 20°C and 25°C and
comprises a solution of triamcinolone acetonide that is sufficient to confer a
therapeutic benefit (FF 3--4 ). Appellants provide no evidence, merely
attorney argument, of the asserted failure to develop a stable nasal
formulation. Indeed, even Appellants' own data demonstrates that the 12%
propylene glycol formulation of Tri-Nasal "is stable down to 25°C" (see
Spec. 42).
Claims 16--18
Appellants provide a separate headings for claims 16-18, but simply
repeat the arguments made regarding claim 15. Appellants do not identify
any specific elements of these claims that is separately patentable.
Conclusion of Law
(i) The evidence of record supports the Examiner's conclusion that
Tri-Nasal, Admitted prior art, and Kamishita render claim 15 obvious.
(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
B. and C. 35U.S.C.§103(a)
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Appellants contend that "claims 19, 23, and 24 contain additional
limitations that are entitled to patentable weight, relating to a separate
irrigating solution (claim 19), a bottle having a specific shape and cap (claim
23), or an aerosol spray bottle having a specific shape and cap with a
propellant (claim 24)" (App. Br. 40). Most of Appellants' arguments with
regard to these claims has already been addressed above with regard to claim
15.
Appellants specifically contend that "Fust teaches away from
administering nasal spray formulations containing active ingredients. Fust
notes the exorbitant costs of drugs, in addition to the possible
contraindications the active agents have in patients simultaneously suffering
from heart disease, hypertension, diabetes, and other disorders. See Fust,
paragraph [0012]" (App. Br. 47).
We are not persuaded. A teaching away requires a reference to
actually criticize, discredit, or otherwise discourage the claimed solution.
See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004) ("The prior art's
mere disclosure of more than one alternative does not constitute a teaching
away from any of these alternatives because such disclosure does not
criticize, discredit, or otherwise discourage the solution claimed").
Fust, at paragraph 12, does not teach away from incorporation of
additional ingredients, but simply points out that some ingredients may have
some risks in some individuals (see Fust i-f 12). This does not discourage the
inclusion of these ingredients, but rather directs their use to particular patient
populations, including those who are not at risk for the medical conditions
indicated.
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SUMMARY
In summary, we affirm the rejection of claims 15-18, 21, and 22
under 35 U.S.C. § 103(a) as obvious over Tri-Nasal, Admitted prior art, and
Kamishi ta.
We affirm the rejection of claim 19 under 35 U.S.C. § 103(a) as
obvious over Tri-Nasal, Admitted prior art, Kamishita, and Fust.
We affirm the rejection of claims 23 and 24 under 35 U.S.C. § 103(a)
as obvious over Tri-Nasal, admitted prior art, Kamishita, Fust, Kalat, and
Kuster.
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
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