Ex Parte Drechsel et al

Board of Patent Appeals and Interferences

Jan 25, 2012

10392558 (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 2011-002775
1

Application 10/392,558
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 1-4 and 8-21, directed to a tiotropium-containing composition. The
claims have been rejected as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b).

1
This appeal is related to Appeal No. 2011-003867 in Application Serial
No. 10/735,959, and we have considered the appeals together.
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STATEMENT OF THE CASE
Claims 1-4 and 8-21 are pending and on appeal. Claims 6 and 7 have
been canceled (App. Br. 1). Appellants do not present separate arguments
for the claims, with the exception of claim 21. Therefore, we select claims 1
and 21 as representative of the subject matter on appeal, as provided by 37
C.F.R. § 41.37(c)(1)(vii). Claims 1 and 21 read as follows:
1. A pharmaceutical composition consisting essentially of:
(a) a dissolved active substance consisting of one or more
tiotropium salts, in a concentration based on tiotropium of between 0.01 g
per 100 mL of the composition and 0.06 g per 100 mL of the composition;
(b) water;
(c) acid for adjusting the pH to between 2.7 and 3.1;
(d) a pharmcologically acceptable preservative; and
(e) sodium edetate in an amount of from 5 to 20 mg per 100 mL of
the composition and
(f) optionally, one or more other pharmacologically acceptable
excipients and additives.
21. A pharmaceutical composition consisting of:
(a) tiotropium bromide, in a concentration based on tiotropium of
between 0.02 g per 100 mL of the composition and 0.05 g per 100 mL of the
composition;
(b) water, as the only solvent;
(c) acid for adjusting the pH to between 2.7 and 3.1;
(d) benzalkonium chloride in an amount of from 8 to 12 mg per
100 ml of the composition; and
(e) sodium edetate in an amount of from 8 to 12 mg per 100 mL of
the composition, and
(f) optionally, sodium chloride.
The Examiner relies on the following evidence:
Freund et al. US 2001/0008632 A1 Jul. 19, 2001
Hochrainer et al. US 6,481,435 B2 Nov. 19, 2002
Freund et al. US 6,491,897 B1 Dec. 10, 2002
Freund et al. WO 97/01329 A1 Jan. 16, 1997
Remington’s Pharmaceutical Sciences, 18th ed., 245-246 (1990).
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Claims 1-4 and 8-21 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over Freund '632, Freund '329 (and its English language
version Freund '897), Hochrainer and Remington’s.
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?
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 effect” (id. at ¶ 6). In addition, Freund '632 teaches
that “[a] concentration range from 10 mg to 20,000 mg/100 ml is
conceivable for the active ingredients, depending on the dose per operation
and their solubility” (id. at ¶ 52).

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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
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
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 1 N 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:

2
Ethylenediamine tetraacetic acid or edetic acid.
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(Freund '632 ¶¶ 48, 49).
7. Remington’s provides evidence that it is well known in the art
that the stability of a pharmaceutical preparation is affected by pH
(Remington’s 246).
8. Hochrainer discloses a container in which an active ingredient
and a solvent are stored separately until the container is used in a nebulizer
(Hochrainer, Abstract). According to Hochrainer, “a liquid formulation
containing tiotropium bromide as active substance may be stored in the
container . . . at a pH of less than or equal to 3.0” until use, at which time it
may be mixed with buffer substances to raise the pH to “ensure[ ] that a pH
of from 3.0 to 7.0, preferably from 3.0 to 4.0, is obtained when these buffers
are mixed with the tiotropium formulation” (id. at col. 11, ll. 12-28).
9. According to the present Specification, “[s]urprisingly, it has
now been found that aqueous formulations of solutions of tiotropium salts
are particularly stable when the pH is below 3.2, preferably below 3.1”
(Spec. 3: 16-17), and “[i]t has also been found that formulations of this kind
show a reduction in the scattering of the composition delivered . . . if the
quantity of sodium edetate is between 5 mg and 20 mg per 100 g of
formulation” (id. at 3: 19-22).
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10. 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).
11. 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
We agree with the Examiner’s conclusion that the compositions of
claim 1 and 21 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 5-20 mg/100 ml solution), and a higher
pH (3.2-3.4 versus 2.7-3.1).
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
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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.
Moreover, the Examiner cites Remington’s as evidence that it is well
known in the art that pH affects the stability of a pharmaceutical preparation
(FF7), and Hochrainer as evidence that tiotropium bromide is stable at a pH
of less than or equal to 3.0 (FF8).
Appellants contend that nothing in Freund '632, or the remaining
references, provides a reason to lower either the pH or the sodium edetate
(i.e., Na-EDTA) concentration of Freund '632’s compositions (id. at 5).
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. at 4), 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.). Appellants further contend that Hochrainer merely
teaches that “tiotropium can initially be provided in one of the chambers at a
pH less than or equal to 3.0. But, when used with the inhaler device, the
tiotropium is mixed with buffers to attain a pH of from 3 to 7” (id. at 6). As
for Remington’s, Appellants contend that “[i]t may suggest - as would
always be the case- that pH should be optimized for a drug solution. But the
fact that it is desirable to optimize pH provides no suggestion at all as to how
to optimize the pH for a particular solution” (id.).
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 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, generally directs one of ordinary
skill in the art to the lower end of the range.
Second, we disagree with Appellants that Freund '632 “requires the
very specific range of 3.2 to 3.4 pH” (App. Br. 5). 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
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
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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 (FF10), Appellants have not established that the effect of pH on the
stability of this, or any other solution, would have been 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 sodium edetate 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
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
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up to 20 mg sodium edetate, set to pH 3.1. 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 (FF11). 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 sodium edetate
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 2-4 and 8-20 have not been argued separately and
therefore stand or fall with claim 1. 37 C.F.R. § 41.37(c)(1)(vii).
Claim 21
Appellants contend that claim 21 “differs from claims 1 and 13 in that
it recites that transition term „consisting of‟” and therefore “specifically
excludes components other than those recite[d], such as [the] steroid actives
and ethanol solvent” (App. Br. 8) disclosed by the secondary reference,
Freund '897.
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This argument is not persuasive. As the Examiner points out, the
proposed modification is to “the primary reference, Freund '632” (Ans. 12),
which is not directed to ethanolic solutions of steroid actives.
SUMMARY
The rejection of claims 1-4 and 8-21 under 35 U.S.C. § 103(a) as
unpatentable over Freund '632, Freund '329, Freund '897, Hochrainer and
Remington’s is affirmed.
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

DM