Ex Parte Drechsel et al

Board of Patent Appeals and Interferences

Jan 25, 2012

10735959 (B.P.A.I. Jan. 25, 2012)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte KARIN DRECHSEL, BARBARA NIKLAUS-HUMKE,
CHRISTEL SCHMELZER, and PETRA BARTH
_________

Appeal 2011-003867
1

Application 10/735,959
Technology Center 1600
__________

Before TONI R. SCHEINER, DONALD E. ADAMS, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1-14, 16, 18-20, 22-31, 38-66, 68, and 70-95, directed to a propellant-
free tiotropium composition. The claims have been rejected on the grounds
of obviousness and non-statutory obviousness-type double patenting. We
have jurisdiction under 35 U.S.C. § 6(b).

1
This appeal is related to Appeal No. 2011-002775 in Application Serial
No. 10/392,558, and we have considered the appeals together.
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STATEMENT OF THE CASE
“The present invention relates to a propellant-free inhalable [aerosol]
formulation of a pharmaceutically acceptable salt of tiotropium dissolved in
water or a mixture of water and ethanol” (Spec. 1: 11-13).
Claims 1-14, 16, 18, 19, 22-31, 38-66, 68, and 70-95 are pending and
on appeal; claims 15, 17, 20, 21, 32-37, 67, and 69 have been canceled
(Supp. App. Br.). Appellants do not present separate arguments for the
claims. Therefore, we select claim 1 as representative of the subject matter
on appeal, as provided by 37 C.F.R. § 41.37(c)(1)(vii):
1. A propellant-free pharmaceutical composition comprising:
(a) an active substance comprising tiotropium or a
pharmaceutically acceptable salt thereof, in a concentration based on
tiotropium of between 0.0005 and 5% by weight;
(b) a solvent selected from water or a water/ethanol mixture;
(c) acid for achieving a pH of from 2.5 to 3.0;
(d) a pharmacologically acceptable preservative; and
(e) a complexing agent comprising edetic acid or an edetic acid salt
in an amount from greater than 0 to 25 mg/100 mL,
optionally including a stabilizer, a pharmacologically acceptable
cosolvent, or other pharmacologically acceptable adjuvants and additives but
containing no propellant; and wherein the amount of edetic acid or an edetic
acid salt results in a reduction in the incidence of spray anomalies.
The Examiner relies on the following prior art:
Weston et al. WO 91/14468 Oct. 3, 1991
Freund et al. US 2001/0008632 A1 Jul. 19, 2001
Freund et al. US 6,491,897 B1 Dec. 10, 2002
Freund et al. DE 19653969 Dec. 20, 1996

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The claims stand rejected as follows:
Claims 1-14, 16, 18, 19, 22-31, 50, 53-66, 68, 70, 72-80, and 93 under
35 U.S.C. § 103(a) as unpatentable over Freund '969 (“as evidenced by” the
English language Freund '632 publication), Freund '329 (“as evidenced by”
the English language Freund '897 patent) (Ans. 4-6);
Claims 38-49, 51, 52, 81-92, 94, and 95 under 35 U.S.C. § 103(a) as
unpatentable over Freund '969 (“as evidenced by” Freund '632), Freund '329
(“as evidenced by” Freund '897), and Weston (Ans. 7);
Claims 1-14, 16, 18, 19, 22-31, 38-66, 68, 70, and 72-95,
provisionally, on the ground of nonstatutory obviousness-type double
patenting as unpatentable over the claims of copending Application No.
10/392,558 (Ans. 8);
Claims 1-6, 38, 53-58, and 81, provisionally, on the ground of
nonstatutory obviousness-type double patenting as unpatentable over claims
1-13 of copending Application No. 12/201,149 (Ans. 9); and
Claims 1-14, 16, 18, 19, 22-31, 38-66, 68, 70, and 72-95 on the
ground of nonstatutory obviousness-type double patenting as unpatentable
over the claims of US Patent 7,776,315 (Application No. 11/006,940) (Ans.
10).
OBVIOUSNESS
Issue
Does the preponderance of the evidence of record support the
Examiner’s conclusion that it would have been obvious to modify the
tiotropium bromide formulations disclosed in the working examples of
Freund '632 to lower both the concentration of sodium edetate and the pH?
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If so, have Appellants provided evidence of unexpected results sufficient to
rebut the Examiner’s conclusion?
Findings of Fact
1. Freund '632 discloses propellant-free aerosol formulations of
pharmaceutical compounds, including tiotropium bromide, suitable for
inhalation through a nebulizer (Freund '632 ¶¶ 1-3, 14, 15).
2. Freund '632 teaches that “pharmaceuticals intended for
inhalation are [usually] dissolved in an aqueous or ethanolic solution”
(Freund '632 ¶ 4), and “[t]he proportion of dissolved pharmaceutical in the
finished pharmaceutical preparation is between 0.001 and 30% - preferably
between 0.05 and 3%, especially 0.01 to 2% (weight/volume)” and is
“dependent on the solubility in solvent and on the dosage required to achieve
the desired therapeutical [sic] effect” (id. at ¶ 6). In addition, Freund '632
teaches that “[a] concentration range from 10 mg to 20,000 mg/100ml is
conceivable for the active ingredients, depending on the dose per operation
and their solubility” (id. at ¶ 52).
3. According to Freund '632, “spraying anomalies [can occur]
when using aqueous pharmaceutical solutions” in a nebulizer (Freund '632
¶ 8), but “[s]urprisingly, it was discovered that these spraying anomalies no
longer occur when the aqueous pharmaceutical preparations . . . contain a
defined effective quantity of a complexing agent, especially of EDTA
[2]
. . .
or salts thereof” (id. at ¶ 9).
4. Freund '632 teaches that “[t]he quantity of complexing agent is
selected so that an effective quantity of complexing agent is added to

2
Ethylenediamine tetraacetic acid or edetic acid.
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prevent further occurrence of spraying anomalies” (Freund '632 ¶ 12). “The
effective quantity of the complexing agent Na-EDTA is between 10 and
1000 mg/100 ml solution, especially between 10 and 100 mg/100 ml
solution,” and “[t]he preferred range . . . is between 25 and 75 mg/100 ml
solution, especially between 25 and 50 mg/100 ml solution” (id. at ¶ 13).
Similarly, Freund '632 teaches that “[t]he concentration range for the
complexing agents (for example DiNa-EDTA) is between 10 and 1000
mg/100 ml (dependent on the pH value of the solution)” and “[t]he preferred
range is between 25 mg and 100 mg/100 ml” (id. at ¶ 53).
5. Freund '632 discloses solutions containing water and 17-833
mg tiotropium bromide per 100 ml solution, 10 mg benzalkonium chloride,
and 50 mg Na-EDTA (Freund '632 ¶ 51), which were “set to a pH of 3.2 to
3.4 with 0.1 or 1N HCl” (id. at ¶ 55).
6. Table 1 of Freund '632 shows the results “with regard to spray
anomalies” for solutions of ipratropium bromide, set to pH 3.4, with various
concentrations of EDTA:

(Freund '632 ¶¶ 48, 49).
7. According to the present Specification, “[s]urprisingly, it has
now been found that formulations of solutions of tiotropium salts in water or
a water-ethanol mixture wherein the proportion of the additive sodium
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edetate is significantly less than 50 mg/100 ml show a reduction in the
scattering of the composition delivered” (Spec. 3: 28-31).
8. The present Specification also teaches that “[a]nother advantage
of the formulation is that, thanks to the absence of or reduction in the
additive sodium edetate in the active substance formulation, the pH of the
. . . formulation can be lowered. Low pH levels are necessary for the long-
term stability of the formulation” (Spec. 4: 4-7).
9. Appellants submitted the following data on the decomposition
of aqueous formulations of tiotropium bromide, with 10 mg/100 ml sodium
edetate, at pH 3.0, 3.2, 3.3, and 3.4 (Evidence Appendix 1):

According to Appellants, “[s]urprisingly, it has been found that
stability of tiotropium bromide in the range of 3.0 to 3.4 is strongly pH
dependent, whereas, at pH of 3.0, the tiotropium solutions are relatively
stable” (Evidence Appendix 1).
10. In addition, Appellants submitted the following “Experimental
findings on spray quality of formulations” (Evidence Annex A):
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According to Appellants, “[a]n improvement of spray quality at lower
pH values (ph 2.7-3.0) in combination with lower NaEDTA concentrations
(10 and 25 mg) is observed” (Evidence Annex A).
Principles of Law
“[D]iscovery of an optimum value of a result effective variable in a
known process is ordinarily within the skill of the art. … [However] a prima
facie case of obviousness may be rebutted „where the results of optimizing a
variable, which was known to be result effective, (are) unexpectedly good.‟”
In re Boesch, 617 F.2d 272, 276 (CCPA 1980) (quoting In re Antonie, 559
F.2d 618, 620 (CCPA 1977)).
“The law is replete with cases in which the difference between the
claimed invention and the prior art is some range or other variable within the
claims.” In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990) (citations
omitted). “In cases involving overlapping ranges … even a slight overlap in
range establishes a prima facie case of obviousness.” In re Peterson, 315
F.3d 1325, 1329 (Fed. Cir. 2003). “These cases have consistently held that
in such a situation, the applicant must show that the particular range is
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critical, generally by showing that the claimed range achieves unexpected
results relative to the prior art range.” Woodruff, 919 F.2d at 1578.
The burden of demonstrating unexpected results rests on the party
asserting them.
In order for a showing of “unexpected results” to be
probative evidence of non-obviousness, it falls upon the
applicant to at least establish: (1) that there actually is a
difference between the results obtained through the claimed
invention and those of the prior art; and (2) that the difference
actually obtained would not have been expected by one skilled
in the art at the time of [the] invention.
In re Freeman, 474 F.2d 1318, 1324 (CCPA 1973) (internal citations
omitted).)
Discussion
The Examiner rejected claims 1-14, 16, 18, 19, 22-31, 50, 53-66, 68,
70, 72-80, and 93 as unpatentable over Freund '969 (“as evidenced by” the
English language Freund '632 publication), Freund '329 (“as evidenced by”
the English language Freund '897 patent) (Ans. 4-6).
We agree with the Examiner’s conclusion that the composition of
claim 1 would have been obvious over the prior art.
Freund '632 discloses a solution in its working examples which
consists of water, 17-833 mg tiotropium bromide per 100 ml solution, 10 mg
benzalkonium chloride, and 50 mg DiNa-EDTA (a complexing agent), “set
to a pH of 3.2 to 3.4 with . . . HCl” (Freund '632 ¶¶ 51, 55; FF5). This
example differs from the claimed composition in having a higher amount of
the complexing agent (50 mg versus 0-25 mg/100 ml solution), and a higher
pH (3.2-3.4 versus 2.5-3.0).
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However, Freund '632 teaches that the concentration of the
complexing agent (e.g., EDTA or DiNa-EDTA) should be selected to
prevent the occurrence of spraying anomalies (FF4), and is generally
between 10 and 1000 mg/100 ml (which overlaps with the amounts required
by claims 1 and 21), and also teaches that the effective concentration
depends on the pH of the solution (id.).
In other words, Freund '632 identifies the concentration of the
complexing agent as a result effective variable with respect to preventing
spraying anomalies (see Boesch, 617 F.2d at 276), and also ties the effective
concentration to the pH of the solution, since one is dependent on the other.
Therefore, we agree with the Examiner that it would have been obvious to
optimize the concentration of the complexing agent within the disclosed
range, and to adjust the pH accordingly.
Appellants contend that nothing in Freund '632, or in Freund '897,
provides a reason to lower either the pH or the sodium edetate (i.e., Na-
EDTA) concentration of Freund '632’s compositions (App. Br. 5-6).
Appellants contend that “Freund '632 specifically teaches that the pH
of its compositions be 3.2 to 3.4,” which does not overlap with the claimed
compositions (App. Br. 5). Moreover, Appellants contend that Freund '632
“clearly directs one of ordinary skill in the art to compositions which contain
a higher amount of sodium edetate, i.e., an amount of 25 mg per 100 ml or
higher” (id.), since the reference expresses a preference for 25 mg or higher
(id.), and Table 1 of Freund '632 (which Appellants concede relates to
ipratropium solutions, not tiotropium solutions) “shows that anomalies occur
when the lower amounts of sodium edetate . . . were used” (id. at 7).
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In addition, Appellants contend that “Freund '897 discloses ethanolic
solutions of budesonide (a steroid)” (id. at 5), and “[t]he differences between
the Freund '897 compositions and the Freund '632 compositions are such
that one . . . would not have had a reason to adjust the pH taught . . . [by]
Freund '632” (id. at 6).
Appellants’ arguments are not persuasive. First, we disagree that
Freund '632 clearly directs one of skill in the art to higher amounts of
complexing agent than required by the present claims. It is true that Freund
'632 generally prefers a concentration of 25 to 50 mg/100 ml, but that
preference is within the context of a much broader generic range of 10 to
1000 mg/100 ml - in our view, that preference, if anything, directs one of
ordinary skill in the art to the lower end of the range, which overlaps with
that claimed. Moreover, the fact that the best results for ipratropium
bromide were observed with 50 or 75 mg of EDTA per 100 ml of solution
(FF6) does not necessarily mean that the same would be true of tiotropium
bromide solutions. Freund '632 teaches that the concentration of
complexing agent can vary between 10 and 1000 mg per 100 ml of solution,
and should be chosen to prevent spraying anomalies (FF4). One of ordinary
skill in the art would have recognized that an appropriate concentration of
complexing agent for a given active ingredient should be determined on an
empirical basis.
Second, we disagree with Appellants that Freund '632 “requires the
very specific range of 3.2 to 3.4 pH” (App. Br. 6). Freund '632 teaches that
the concentration of the complexing agent, which can vary between 10 and
1000 mg/100 ml, and the pH of the solution, are tied (FF4). While the
tiotropium bromide solutions disclosed in the working examples were “set to
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a pH of 3.2 to 3.4” (Freund '632 ¶¶ 51, 55), those solutions contained 50 mg
disodium EDTA (FF5). However, Freund '632 identifies the concentration
of the complexing agent as a result effective variable with respect to
preventing spraying anomalies (FF4), thus (with or without Freund '897), it
would have been obvious for one of ordinary skill in the art to empirically
adjust and/or optimize the concentration of the complexing agent within the
range taught by Freund '632. It follows that it would have been obvious to
empirically adjust the pH of the solution as well, since Freund '632 teaches
that the concentration of complexing agent and the pH of the solution are
tied (id.).
Finally, we are not persuaded that Appellants “have provided . . .
evidence of the unexpected advantage and nonobviousness of the claimed
invention” (App. Br. 6) sufficient to rebut the Examiner’s conclusion that the
proposed modifications to the solutions disclosed by Freund '632 would
have been obvious. While the data on decomposition of tiotropium bromide
show that a pH 3.0 solution is “relatively stable” compared to higher pH
solutions (FF9), Appellants have not established that the effect of pH on the
stability of this, or any other solution, would have been critical or
unexpected to one of ordinary skill in the art. Moreover, even if the prior art
does not point to a specific pH that is optimal for tiotropium bromide, that
does not mean that the optimal pH, once determined by routine
experimentation, would have been in any way surprising.
Nor are we persuaded by the data provided in Annex A that the
concentration of edetic acid salt and the pH required by the claims provide
any unexpected advantage over the solutions disclosed by Freund '632. For
example, Freund '632 discloses aqueous tiotropium bromide solutions
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containing 50 mg Na-EDTA/100 ml (Freund '632 ¶ 51), which were “set to a
pH of 3.2 to 3.4” (FF5). The present claims encompass solutions containing
up to 25 mg edetic acid salt, set to pH 3.0. According to Annex A, for
solutions containing 10, 25, or 50 mg NaEDTA/100 ml, and set to pH 3.2,
the relative percent of actuations exhibiting spray anomalies was 0, 0.01, and
0.02, respectively; for solutions set to pH 3.1, the relative percent of spray
anomalies was 0.01, 0.01, and 0.01, respectively; and for solutions set to pH
3.0, the relative percent of spray anomalies was 0.01, 0, and 0.08,
respectively (FF10). While the data reflect some differences in spray
anomalies among the various solutions, and a general trend toward fewer
spray anomalies at lower pH when lower concentrations of NaEDTA are
used (although we note a lower relative percent of spray anomalies were
observed at pH 3.1 versus pH 3.2 with 50 mg NaEDTA), there is no
indication that these differences are critical, or even statistically significant,
nor is there evidence that one of ordinary skill in the art would have found
these differences to be unexpected.
Having considered all the evidence of record, particularly in light of
the evidence provided in the Appendices accompanying Appellants’ Appeal
Brief, we conclude that the weight of the evidence favors the Examiner’s
conclusion that the invention of claim 1 would have been obvious over the
prior art. Claims 2-14, 16, 18, 19, 22-31, 50, 53-66, 68, 70, 72-80, and 93
have not been argued separately and therefore stand or fall with claim 1. 37
C.F.R. § 41.37(c)(1)(vii).
The Examiner also rejected claims 38-49, 51, 52, 81-92, 94, and 95 as
unpatentable over Freund '969 (“as evidenced by” Freund '632), Freund '329
(“as evidenced by” Freund '897), and Weston (Ans. 7).
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Appellants contend that “Weston teaches a particular type of inhaler”
and “provides no teachings which make up for the above-discussed
deficiencies of the primary references to teach or suggest the claimed
compositions” (App. Br. 8).
Nevertheless, as discussed above, we do not agree with Appellants
that the primary references fail to suggest the claimed compositions.
DOUBLE PATENTING
There are three rejections of the claims on the grounds of nonstautory
obviousness-type double patenting, two provisional, and one which is no
longer provisional.
We will summarily affirm these rejections, as Appellants do not
provide any arguments on the merits of the rejections (moreover, in the case
of the provisional rejections, the obviousness-type double patenting
rejections are not the only rejections remaining in the case).
SUMMARY
Both of the obviousness rejections of the claims are affirmed, as are
the three rejections on the grounds of nonstatutory obviousness-type double
patenting.
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

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