Ex Parte Ziegler et al

Board of Patent Appeals and Interferences

Sep 13, 2010

10837755 (B.P.A.I. Sep. 13, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/837,755 05/04/2004 Iris Ziegler 029310.50932D1 2048
23911 7590 09/13/2010
CROWELL & MORING LLP
INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON, DC 20044-4300
EXAMINER
SASAN, ARADHANA
ART UNIT PAPER NUMBER
1615
MAIL DATE DELIVERY MODE
09/13/2010 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte
IRIS ZIEGLER and JOHANNES BARTHOLOMAEUS
__________

Appeal 2009-013821
Application 10/837,755
Technology Center 1600
__________

Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and
STEPHEN WALSH, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1-22 on the grounds of lack of enablement, indefiniteness, and
obviousness. We have jurisdiction under 35 U.S.C. § 6(b).

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

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STATEMENT OF THE CASE
Claims 1, 8, and 21 are representative of the subject matter on appeal:
1. A sustained-release, oral pharmaceutical formulation of tramadol,
comprising a compound of (i) tramadol, or a pharmaceutically acceptable
salt thereof, and (ii) a pharmaceutically acceptable acidic substance, or a salt
thereof, wherein said compound is formed in situ, and wherein said
compound has a water solubility of ≤ 100 mg/ml.

8. The pharmaceutical formulation of claim 1, wherein the salt of
tramadol is tramadol hydrochloride and the salt of the acidic substance is
diclofenac sodium.

21. A method for preparing a sustained release oral pharmaceutical
formulation, said method comprising:
mixing tramadol, or a pharmaceutically acceptable salt thereof, and an
acidic substance, or a water-soluble salt thereof, to form a mixture;
moistening the mixture;
repeating the above mixing and moistening steps; and
formulating the mixture under an energy input.

The Examiner rejected claims 1-19 under the first and second
paragraphs of 35 U.S.C. § 112 as lacking enablement, and as indefinite.
The Examiner also rejected claims 1-22 under 35 U.S.C. § 103(a)
unpatentable over Raffa (U.S. Patent 5,516,803, issued May 14, 1996).
We reverse.
FINDINGS OF FACT (FF)
1. The Specification describes “the preparation of at least partially
sustained-release, oral pharmaceutical formulations of tramadol, in which
the sustained-release portion of the active substance is present as a
[sparingly water-soluble] compound, formed in situ, of tramadol and another
active substance and/or auxiliary substance with a water solubility of ≤ 100
mg/ml” (Spec. ¶¶ 9, 11).
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2. According to the Specification:
[I]n situ formation means that the tramadol or a water-soluble
salt thereof is mixed with another, acidic pharmaceutical active
substance or auxiliary substance or water-soluble salts thereof,
preferably during the preparation of the pharmaceutical
formulation according to the invention, moistened several times
and optionally extruded or formulated [with] energy input.
(Spec. ¶ 12.)
3. “The mixture is preferably moistened each time with aqueous
media and particularly preferably with water . . . The energy input preferably
takes the form of pressure and/or heat” (Spec. ¶ 34).
4. In Example 1 of the Specification:
125 g of tramadol hydrochloride, 125 g of diclofenac
sodium and 250 g of microcrystalline cellulose . . . were
homogeneously mixed . . . for 10 minutes, and then granulated
with water in an amount sufficient for moistening. The sticky
lumpy mass of granules was then extruded . . . with a 1.0 mm
extrusion die. While the rods of extrudate were initially still
extremely sticky, they changed in the course of the extrusion
process to a very dry extrudate with insufficient plasticity for
subsequent spheronization. The extrudate was moistened and
granulated again. The resulting granules were extruded again . .
. and the moist extrudate was then converted to round pellets of
uniform size . . . . The pellets were dried in a drying cabinet at a
temperature of approx. 50°C and fractionated into sieve
fractions, ≥90% of the pellets falling within the desired sieve
class of 800 - 1250 μm.
(Spec. ¶ 54.)
5. “For the pellets produced above, the water solubility of the
active substance tramadol from the compound formed in situ was found to
be 0.36 mg/ml” (Spec. ¶ 56 (emphasis added)), and the release profile was as
follows:
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(Spec. ¶ 57.)
6. Dr. Iris Ziegler2 describes a series of experiments
demonstrating the different properties of tablets “identical in size and shape
and . . . made from identical amounts of the same raw ingredients . . .
[which] differed only in their manner of processing” (Decl. 5).
Section I(a) of the Declaration describes the preparation of “Tablets
containing a mixture of Diclofenac-sodium and Tramadol-hydrochloride”
“by direct compression” (Decl. 2). “The resulting tablets . . . had a hardness
of approximately 100N, and the disintegration time of the tablets was 5
minutes” (id.).
Section I(b) of the Declaration describes the preparation of “Tablets
containing an in situ Compound of Diclofenac-sodium and Tramadol-
hydrochloride” by mixing, followed by repeated moistening, granulation,
and extrusion, conversion to pellets (section I(B)(i)), and finally, direct
compression into tablets (Decl. 3). “The resulting tablets containing the in
situ formed compound of Diclofenac-sodium and Tramadol-hydrochloride
had a hardness of 60-80N, and the disintegration time of the tablets was less
than 5 minutes” (id. at 4).

2 Declaration of Dr. Iris Ziegler, dated December 14, 2006, and initially
submitted in the present application on March 14, 2008 under the provisions
of 37 C.F.R. § 1.132 (“Decl.”).
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7. The procedure described in section I(b) of the Declaration is
comparable to that of Example 1 in the Specification.
8. Section I(c) of Dr. Ziegler’s Declaration demonstrates that:
The tablets of I(a) which contained a mixture of Diclofenac-
sodium and Tramadol-hydrochloride exhibited a fast release of
100% of both active ingredients within approximately 15
minutes. In contrast thereto, 600 minutes were required to
release 100% of the Tramadol and approximately 85% of the
Diclofenac from the tablets of I(b) containing the inventive, in
situ formed compound . . .
(Decl. 5).
9. According to Dr. Ziegler:
The fact that the tablets of I(a) and I(b) exhibited similar
hardness and disintegration times shows that the slower release
from I(b) is not attributable to different physical characteristics
of the tablets. Rather, the slower release profiles from the
tablets of I(b) demonstrate that the Diclofenac and Tramadol in
the tablets of I(b) are present in a physical/chemical form (i.e., a
lower solubility compound) which is clearly different from the
mixture contained in the tablets of I(a).
(Decl. 5-6.)
10. Exhibits A-E, which accompanied Dr. Ziegler’s Declaration
show the results of Differential Scanning Calorimetry (DSC) thermal
analyses of several formulations of tramadol-hydrochloride and diclofenac-
sodium, including the tablets of I(a), the pellets of I(b)(i), and a tramadol-
diclofenac salt.
11. Dr. Ziegler concluded:
The different release profiles of the Tramadol and
Diclofenac from the tablets of I(b) . . . compared to the tablets
of I(a) . . . containing a mixture of Diclofenac-sodium and
Tramadol-hydrochloride, are indicative of a significant
difference in solubility and demonstrate that the Diclofenac and
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Tramadol must be present in a physical/chemical form which is
different from a mixture . . . . The different differential scanning
calorimetry results of the pellets of I(b)(i) produced according
to the present invention compared to the tablets of I(a)
containing a mixture of Diclofenac-sodium and Tramadol-
hydrochloride . . . and particularly the endothermic peak at
approximately 292°C which has no counterpart in the DSC of
the crushed tablets of I(a), corroborate the presence of a
different physical/chemical species in the product of the present
invention which is not present in the tablets containing a
mixture of Diclofenac-sodium and Tramadol-hydrochloride . . .
These results evidence that the product of the present invention
contains an in situ formed compound of Diclofenac-sodium and
Tramadol-hydrochloride which is not present in the tablets
containing a mixture of Diclofenac-sodium and Tramadol-
hydrochloride . . .
(Decl. 9).
12. Raffa describes compositions comprising a tramadol material,
e.g., the hydrochloride salt of tramadol, and one of dozens of non-steroidal
anti-inflammatory drugs (NSAIDs), e.g., ibuprofen and diclofenac (Raffa,
col. 3, ll. 16-17, 25, 29; col. 3, l. 60 to col. 4, l. 30).
13. Raffa’s working examples are limited to solutions containing
various ratios of tramadol and ibuprofen (Raffa, Examples 1-4), but the
reference also teaches that “solid preparations (such as, for example,
powders, capsules and tablets)” (id. at col. 5, ll. 36-37), “can be prepared
according to conventional pharmaceutical compounding techniques” (id. at
col. 5, ll. 25-26). In addition, Raffa suggests that the tablets can be sugar-
coated or enteric-coated (id. at col. 5, ll. 42-43).
14. There is no evidence on this record that ibuprofen meets the
claims’ requirement for a pharmaceutically acceptable acidic substance.

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ENABLEMENT
According to the Examiner, the Specification “does not reasonably
provide enablement for a formulation comprising a “compound” of (i)
tramadol and (ii) a pharmaceutically acceptable acidic substance” (Ans. 3)
because “[t]here is no direction provided regarding a ‘compound’” (id. at 4);
“[t]here is nothing in the specification that would indicate that a ‘compound’
is formed from adding tramadol and a pharmaceutically acceptable acidic
substance” (id.); and “[t]here is no quantifiable measurement or mention of a
‘compound’ . . . in the working examples” (id.).
Nevertheless,
[A] disclosure which contains a teaching of the manner and
process of making and using the invention in terms which
correspond in scope to those used in describing and defining the
subject matter sought to be patented must be taken as in
compliance with the enabling requirement of the first paragraph
of § 112 unless there is reason to doubt the objective truth of
the statements contained therein which must be relied on for
enabling support.
In re Marzocchi, 439 F.2d 220, 223 (CCPA 1971). “[I]t is incumbent upon
the Patent Office . . . to explain why it doubts the truth or accuracy of any
statement in a supporting disclosure and to back up assertions of its own
with acceptable evidence or reasoning which is inconsistent with the
contested statement.” Id. at 224. In other words,
the PTO bears an initial burden of setting forth a reasonable
explanation as to why it believes that the scope of protection
provided by that claim is not adequately enabled by the
description of the invention provided in the specification . . .
this includes . . . providing sufficient reasons for doubting any
assertions in the specification as to the scope of enablement.
In re Wright, 999 F.2d 1557, 1561-1562 (Fed. Cir. 1993).
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Thus, the threshold issue raised by this rejection is not whether
Appellants have established that their Specification is enabling for a
sustained-release formulation containing a “compound” of tramadol and a
pharmaceutically acceptable acidic substance. Rather, the issue is whether
the Examiner has met the initial burden of establishing that it isn’t.
The Examiner’s explanation as to why a “compound” of tramadol and
a pharmaceutically acceptable acidic substance is not adequately enabled by
the Specification is insufficient to satisfy that initial burden.
First, it is not true that the Specification doesn’t provide direction for
forming a compound of tramadol and an acidic pharmaceutical substance.
In fact, the Specification plainly states that a sustained-release formulation
comprising a sparingly water soluble compound of tramadol and an acidic
pharmaceutical substance, like diclofenac, can be formed in situ by simply
mixing tramadol (or its water soluble salts) with the acidic pharmaceutical
substance (or its water soluble salts), and repeatedly moistening the mixture.
In addition, Example 1 of the Specification demonstrates that combining
tramadol hydrochloride and diclofenac sodium and repeatedly moistening
and extruding the mixture resulted in a sustained-release formulation in
which “the water solubility of . . . tramadol from the compound formed in
situ was found to be 0.36 mg/ml” and both tramadol and diclofenac were
continuously released for at least 10 hours (Spec. ¶¶ 54-57; FF 1-5).
Second, if the Examiner doubts the objective truth or accuracy of the
Specification’s statements and working examples, it is up to the Examiner to
come forward with “acceptable evidence or reasoning which is inconsistent
with the contested statement.” Marzocchi, 439 F.2d at 224. The Examiner
has not done so.
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Conclusion
The Examiner has failed to provide a reasonable explanation as to
why a “compound” of tramadol and a pharmaceutically acceptable acidic
substance is not adequately enabled by the Specification. The rejection of
claims 1-19 under 35 U.S.C. § 112, first paragraph, is reversed.

INDEFINITENESS
According to the Examiner:
The term “compound” in claim 1 is used by the claim to mean
“mixture”, while the accepted meaning is “a substance whose
molecules consist of unlike atoms, and whose constituents
cannot be separated by physical means … A compound differs
from a physical mixture by reason of the definite proportions of
its constituent elements which depend on their atomic weights,
by the disappearance of the properties of the constituent
elements, and, by entirely new properties characteristic of the
compound formed.
(Ans. 5.)
The Examiner’s “interpretation of the term ‘compound’ is based on
the definition of the term in Hackh’s Chemical Dictionary” (Ans. 13).3

3 HACKH’S CHEMICAL DICTIONARY 171 (Julius Grant ed., 4th ed.,
1969) - wherein the word “compound” is defined as:
(1) A substance whose molecules consist of unlike atoms, and
whose constituents cannot be separated by physical means. A
c. differs from a physical mixture by reason of the definite
proportions of its constituent elements which depend on their
atomic weights, by the disappearance of the properties of the
constituent elements, and, by entirely new properties
characteristic of the c. formed. (2) To mix drugs, or make up a
prescription.
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“Since the term ‘compound’ as used in instant claim 1 does not fit the
definition in Hackh’s Chemical Dictionary . . . [the Examiner] interpreted
[the claimed compound] as a mixture of the constituent components
(tramadol and an acidic substance)” (id.).
Appellants contend that the “claim language makes it clear that a
compound is required and not a simple mixture of ingredients” (App. Br. 9),
that they “have consistently used the word compound in its traditional sense
as designating a chemical entity different from its constituents and having
different properties than its constituents” (Reply Br. 1), and “[n]owhere in
the specification . . . is there any indication that Applicants intended to us[e]
the word compound in any sense other than its conventional meaning” (id.).
“The test for definiteness is whether one skilled in the art would
understand the bounds of the claim when read in light of the specification.”
Miles Laboratories, Inc. v. Shandon Inc., 997 F.2d 870, 875 (Fed. Cir.
1993). “The purpose of claims is not to explain the technology or how it
works, but to state the legal boundaries of the patent grant. A claim is not
‘indefinite’ simply because it is hard to understand when viewed without
benefit of the specification.” S3 Incorporated v. NVIDIA Corp., 259 F.3d
1364, 1369 (Fed. Cir. 2001).
Thus, the issue is not whether the claimed compound has been
described by its precise chemical structure, or even whether “compound” is
the best of all possible words to describe what is claimed. The issue is
whether one of skill in the art would understand what the word means when
read in the context of the Specification.
We find that one of skill in the art would understand from the
Specification that the claimed sustained-release formulation contains a
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compound (a physical/chemical entity) with a solubility of ≤ 100 mg/ml, that
is the product of the compounding process described in the Specification.
Conclusion
One of skill in the art would understand what the word “compound”
means when read in the context of the Specification.
The rejection of claims 1-19 as indefinite under 35 U.S.C. § 112,
second paragraph, is reversed.

OBVIOUSNESS
The Examiner rejected claims 1-22 (of which claims 21 and 22 are
directed to a method of preparing a sustained-release formulation) as
unpatentable over Raffa.
As discussed above, Raffa describes compositions comprising a
tramadol material, e.g., the hydrochloride salt of tramadol, and one of
dozens of non-steroidal anti-inflammatory drugs (NSAIDs), e.g., ibuprofen
and diclofenac (Raffa, col. 3, ll. 16-17, 25, 29; FF12).
The Examiner concluded that combining tramadol, or its
hydrochloride salt, with a pharmaceutically acceptable acidic substance,
such as diclofenac, would have been obvious in view of Raffa’s disclosure,
and moreover, that a “sustained release, oral formulation . . . would have
been obvious over the tablet and enteric-coated tablet disclosed by Raffa”
(Ans. 7). In addition, the Examiner reasoned that “[t]he limitation of a
‘compound’ . . . would have been obvious over the mixture of tramadol and
the NSAID diclofenac . . . [and] the limitation of the water solubility of less
than 100mg/ml would be an intrinsic feature” of Raffa’s formulation (id.).
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As for claims 21 and 22 - directed to a method of preparing a
sustained-release formulation - the Examiner concluded that “[t]he
limitations of moistening the mixture, [and] repeating the mixing and
moistening steps, would have been obvious variants of pharmaceutical
product development” (Ans. 9).
We disagree with the Examiner’s rationale and conclusions, as they
are based upon the unsupported assertion that the Specification and claims
are directed to a simple mixture of tramadol and diclofenac. There is no
apparent dispute about Raffa’s disclosure - Appellants and the Examiner
agree that Raffa discloses a simple mixture of tramadol and an NSAID,
which can be in solution or in solid form. However, the Examiner has failed
to come to grips with the evidence of record which is consistent with Dr.
Ziegler’s conclusion (and Appellants’ assertion) that there is “a
physical/chemical species in the product of the present invention which is
not present in . . . tablets containing a mixture of Diclofenac-sodium and
Tramadol-hydrochloride” (FF 6-11), and which has a substantially different
solubility and release profile than a simple mixture of tramadol and
diclofenac (id.).
Finally, the Examiner has provided no evidence that the steps of
repeatedly mixing and moistening a mixture of tramadol and an acidic
substance (as required by claims 21 and 22) would have been “obvious
variants of pharmaceutical product development” (Ans. 9).

The Examiner has not established that a sustained-release formulation
comprising an in situ-formed compound of tramadol and an acidic
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pharmaceuticaly acceptable substance, wherein the compound has a water
solubility of ≤ 100 mg/ml, would have been obvious over Raffa’s disclosure.
Nor has the Examiner established that the method of claims 21 and 22 would
have been an “obvious variant[] of pharmaceutical product development.”
The rejection of claims 1-22 as unpatentable over Raffa is reversed.

SUMMARY
The rejections of claims 1-19 under the first and second paragraphs of
35 U.S.C. § 112 as lacking enablement, and as indefinite, are reversed.
The rejection of claims 1-22 under 35 U.S.C. § 103(a) unpatentable
over Raffa is reversed.

REVERSED

cdc

CROWELL & MORING LLP
INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
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