Ex Parte Schwarz

Patent Trial and Appeal Board

Dec 29, 2017

11813380 (P.T.A.B. Dec. 29, 2017)

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.
11/813,380 07/05/2007 Franz Xaver Schwarz 34106-US-PCT 64608.US 1732
84983 7590 12/29/2017
SandozAG (Austria)- LUEDEKA NEELY GROUP, P.C.
P.O.BOX 1871
Knoxville, TN 37901
EXAMINER
GREENE, IVAN A
ART UNIT PAPER NUMBER
1619
MAIL DATE DELIVERY MODE
12/29/2017 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 PATENT TRIAL AND APPEAL BOARD
Ex parte FRANZ XAVER SCHWARZ1
Appeal 2016-001544
Application 11/813,380
Technology Center 1600
Before ULRIKE W. JENKS, JOHN G. NEW, and TAWEN CHANG,
Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
process for preparing a stable granulate of a mixture comprising amoxicillin
trihydrate and amoxicillin sodium, which have been rejected as obvious. We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
The Specification states that
[ajmoxicillin is an antibacterial agent extensively used for the
treatment of a wide range of bacterial infections, e.g.[,] for the
1 Appellant identifies the Real Party in Interest as Sandoz AG. (Appeal Br.
2.)
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Application 11/813,380
treatment of respiratory infections and urinary tract infections. . . .
Amoxicillin trihydrate is the stable form of amoxicillin and is
available on the market in a number of different formulations for oral
administration, for example, as granulate or powders, oral suspension,
hard gelatine capsules, tablets, chewable tablets, pediatric drops.
Amoxicillin sodium is used in the therapy for parenteral
administration.
(Spec. 2.)
According to the Specification,
[tjhere is a constant need for preparing stable dosage forms of a
combination of amoxicillin trihydrate and amoxicillin sodium or
alternatively, pure amoxicillin sodium, e.g.[,] granulate or tablets, for
use in humans and animals, which may be used for reconstitution of
said granulate with water into aqueous suspension, for parenteral
injection administration, for preparing solid dosage forms, e.g.[,]
tablets, dispersible tablets, capsules, powders, chewable tablets.
(Id. at 1.) Further according to the Specification, prior art processes for
preparing amoxicillin sodium salt “require a high level of technical effort or
cost expenditure.” (Id. at 3.)
The Specification states that
[t]he object of the present invention is to find a novel process for
preparing a stable granulate comprising a mixture of amoxicillin
trihydrate and amoxicillin sodium . . . wherein the exacting spray­
drying or freeze-drying methods and the use of organic solvents and
amine . . . used in the prior art processes for preparing amoxicillin
sodium, would be omitted.
(Id. at 4.) The Specification suggests that this object is achieved by a
process
wherein amoxicillin trihydrate is extruded with an aqueous solution of
sodium hydroxide, sodium bicarbonate, sodium carbonate and mixture
thereof or with an aqueous solution of a sodium salt of (Ci g) organic
acid as a sodium source, by means of commercially available extruder
to obtain granulate of the mixture of amoxicillin trihydrate and
amoxicillin sodium.
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(Id. at 4—5.)
Claims 1—4 and 7—12 are on appeal. Claim 1 is illustrative and
reproduced below:
1. A process for preparing a stable granulate of a mixture
comprising amoxicillin trihydrate and amoxicillin sodium, the process
comprising the following steps:
a. extruding, at an extrusion temperature of from about 10°C to
about 40°C, amoxicillin trihydrate in an aqueous mixture containing at
least a source of sodium ions which is either (a) selected from the
group consisting of sodium hydroxide, sodium bicarbonate, sodium
carbonate, and mixtures of one or more thereof or (b) a sodium salt of
a Ci_8 organic acid to form a moist, extruded mass comprising a
mixture of amoxicillin trihydrate and amoxicillin sodium,
b. granulating the moist extruded mass through a sieve so as to
yield a granulate comprising a mixture of amoxicillin trihydrate and
amoxicillin sodium, without spray-drying, freeze drying, or
lyophilization,
c. drying the granulate, and
d. optionally re-drying the granulate.
(Appeal Br. 12 (Claims App.).)
The Examiner rejects claims 1—4 and 7—12 under 35 U.S.C. § 103(a)
as being unpatentable over Lintz,2 Schwarz,3 de Jonge,4 Butterly,5 and
Storm.6 (Ans. 2.)
2 Lintz et al., WO 2004/041253 Al, published May 21, 2004.
3 Schwarz, WO 03/063820 A2, published Aug. 7, 2003.
4 de Jonge et al., U.S. 4,607,029, issued Aug. 19, 1986.
5 Butterly et al., WO 99/62910, published Dec. 9, 1999.
6 Storm et al., US 2004/0241227 Al, published Dec. 2, 2004.
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DISCUSSION
Issue
The Examiner finds that Lintz teaches
a process for preparing pharmaceutical granules containing an active
ingredient as a salt, the process including (a) providing a powder
containing the active ingredient as a free base or free acid; and (b)
agglomerating the powder by adding a granulation liquid to form
granules; and wherein step (b) is conducted in the presence of a
neutralization agent which [is] capable of neutralizing the active
agent, and for sufficient amount of time to allow the active ingredient
to be at least partially converted to the salt.
(Ans. 2 (citation omitted).)
The Examiner finds that Lintz teaches amoxicillin as a particularly
preferred active ingredient for its process. {Id. at 2—3.) The Examiner also
finds Lintz teaches that the bases, basic salts or cations that can form a salt
with the active ingredient include, among others, sodium hydroxide and
sodium bicarbonate, that the granulation liquid is most preferably water, and
that the neutralization process may be conducted at room temperature. {Id.
at 3.)
The Examiner finds that Lintz does not expressly teach “extruding . . .
amoxicillin trihydrate with an aqueous solution of sodium hydroxide or with
an aqueous solution of a sodium salt such as sodium 2-ethylheaxanoate.”
{Id. at 4.) However, the Examiner finds that Lintz teaches an example using
another beta-lactam antibiotic, aztreonam, wherein “aztreonam is neutralized
with sodium hydroxide to form the sodium salt of aztreonam, formed into a
moist mass and extruded through a sieve to form granules which are
then dried for 3 hours at 40°C.” (Id. at 3 (citation omitted).)
The Examiner finds that, moreover, “[Schwarz] teaches extruding
amoxicillin trihydrate, [de Jonge] teaches preparing the sodium salt of
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amoxicillin using sodium hydroxide, [Butterly] teaches preparing the sodium
salt of amoxicillin using an organic acid such as sodium 2-ethylhexanoate,”
and Storm teaches mixtures of amoxicillin trihydrate and sodium
amoxicillin. (Id. at 4, 6.) In particular, the Examiner finds that Schwarz
teaches
the process of preparing a granulate of amoxicillin trihydrate
comprising the steps of (i) moistening a B-lactam antibiotic with a
granulating liquid to obtain a granulation mass; (ii) extruding the
granulation mass to form an extruded mass; (iii) passing the extruded
mass through a sieve; and (iv) drying the granulation mass or extruded
mass. [Schwarz] teaches extrusion temperatures are, for example,
temperatures from room temperature and below (which would include
temperatures in the range of 10°C to 40°C).
(Id. at 4 (citations omitted).)
The Examiner finds that de Jonge teaches stable sodium amoxicillin
compositions in dry or solution form, wherein the compositions are prepared
by gradually adding sodium hydroxide to a suspension of amoxicillin
trihydrate in water. (Id. at 5.) The Examiner finds that de Jonge teaches that
its process avoids undesirable organic solvents. (Id.) The Examiner finds
that Butterly teaches
a process for the preparation of crystalline salts of amoxicillin, a
process that converts amoxicillin trihydrate to sodium amoxicillin by
reacting amoxicillin trihydrate with an amine oxide to form an amine
salt of amoxicillin and subsequently admixing an organic acid
solution (containing a salifying compound such as sodium 2-
ethylhexanoate) to form the sodium salt of amoxicillin.
(Id. at 5 (citation omitted).) The Examiner further finds that Butterly teaches
that its process produces a product suitable for oral formulation or injection
and that the salifying agent may be the salt of a Ci-n organic acid. (Id. )
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The Examiner concludes that it would have been obvious for a skilled
artisan to arrive at the claimed process in view of the cited prior art, because
“incorporating the step of reacting the amoxicillin trihydrate with a sodium
source to form the sodium amoxicillin would have provided a more efficient
process, one which does not require a separate step of forming the sodium
amoxicillin” and which is less costly. {Id. at 6—7.)
Appellant contends that the cited art does not suggest “extruding
amoxicillin trihydrate in an aqueous mixture containing the specified source
of sodium ions to form a moist, extruded mass comprising a mixture of
amoxicillin trihydrate and amoxicillin sodium,” and also does not suggest a
separate sieve granulation step. (Appeal Br. 9.)
The issue with respect to this rejection is whether a preponderance of
the evidence of record supports the Examiner’s conclusion that the
combination of cited prior art suggests the claimed process for preparing a
stable granulate of a mixture comprising amoxicillin trihydrate and
amoxicillin sodium.
Findings of Fact
1. Lintz teaches
a process for preparing pharmaceutical granules which contain an
active ingredient in the form of a salt, said process comprising the
steps of (a) providing a powder containing the active ingredient as a
free base or acid, and (b) agglomerating the powder by adding a
granulation liquid to form granules; wherein step (b) is conducted in
the presence of a neutralization agent capable of neutralizing the
active ingredient, and for a sufficient amount of time to allow the
active ingredient to become at least partially converted into a salt.
(Lintz Abstract.) Lintz teaches that, “[a]s an option, the granules formed in
step (b) can be dried immediately after their formation.” {Id. at 13:23—24.)
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2. Lintz teaches that the granules resulting from its process
“comprise the active ingredient as a salt, typically with improved solubility.
The granules are prepared with high efficiency as the process combines the
neutralization of the drug substance to form a salt and the agglomeration of
the powder to form a granular material in a single step.” {Id. at 5:11—14.)
3. Lintz teaches that “powders can be agglomerated to granules by
various methods” and that the invention uses wet granulation methods, i.e.,
granulation methods wherein “a suitable granulation liquid is added to the
powder to agglomerate it.” {Id. at 7:23—27.) Lintz teaches that water is one
of the most preferred granulation liquid for use in its process. {Id. at 11:8—
12.)
4. Lintz teaches that examples of active ingredients include beta-
lactam antibiotics such as aztrenonam and amoxicillin, which are among the
particularly preferred drug substances for use in the invention. (Id. at 10:1—
8, 11:1—4.)
5. Lintz teaches that
[t]he neutralization of the active compound and its conversion into a
salt is achieved during the agglomeration step in which the powder is
wetted by the granulation liquid: this step is conducted in the presence
of the neutralization agent. Accordingly, the neutralization agent
must be provided as a component of the powder, or as a component of
the granulation liquid, or separately but simultaneously. As defined
above, the neutralization agent is any base, acid, ion, or salt which is
capable of forming a salt with the active ingredient.
{Id. at 11:19—25.) Lintz further teaches that, “[w]hen provided with the
granulation liquid, the neutralizing agent is preferably in the dissolved state
to ensure a rapid and controlled neutralization process.” {Id. at 12:15—17.)
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6. Lintz teaches that
[pjharmaceutically acceptable bases, basic salts or cations which can
form a salt with a drug substance which is provided as a free acid
include the following, non-limiting examples: ammonium, alkali
metal hydroxides, alkaline earth metal hydroxides, including sodium
hydroxide, magnesium hydroxide, calcium hydroxide and amines,
carbonates such as sodium carbonate, sodium bicarbonate, potassium
carbonate, potassium bicarbonate, magnesium carbonate, and the
mixtures thereof.
(Id. at 12:6-12.)
7. Lintz teaches that “[l]ike other wet-granulation methods, the
process of the invention can be carried out in any type of equipment adapted
for the agitation of powders, and the wetting of powders with liquids.” (Id.
at 13:1—3.) Lintz teaches that “[n]o specific type of granulator is required
for carrying out the process of the invention” and that “[t]he process
temperature may be room temperature (20 °C), or it may be lower for
sensitive ingredients, or it may be elevated to 40°C or even up to about
110°C to speed up the process of removing volatile materials.” (Id. at
13:11-12, 18-22.)
8. Lintz provides an example of preparing granules containing
Aztreonam, a beta-lactam antibiotic, wherein “ethanolic sodium hydroxide
solution [was] added to [Aztreonam] under stirring,” “[t]he resulting
suspension was allowed to dry at room temperature (20 °C)[] until a slightly
wet mass with good plasticity was obtained,” “[the] mass was passed
through a sieve ... in order to obtain granules,” and “[t]he granules were
dried on trays for three hours at 40°C” and equalized by being passed
through another sieve. (Id. at 22:3—15 (Example 2).)
9. Schwarz teaches a process for producing “granulate particles
comprising at least one B-lactam antibiotic and one B-lactamase inhibitor,
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. . in which both the 13-lactam antibiotic and the 13-lactamase inhibitor are
distributed evenly over the different particle size of the granulate.”
(Schwarz 1:27—31.) In particular, Schwarz teaches that granulated particles
of a 13-lactam antibiotic or a 13-lactamase inhibitor may be prepared
according to the following steps:
a. moistening a 13-lactam antibiotic or a 13-lactamase inhibitor with a
granulating liquid to obtain a granulation mass,
b. optionally extruding the granulation mass obtained to form an
extruded mass,
c. optionally passing, e.g.[,] pressing, the extruded mass through a
sieve,
d. drying the granulation mass or (sieved) extruded mass, and
e. diminuishing [sic] the size [of] grain [] of the granulate obtained.
{Id. at 6:27—34; see also id. at 9:21—10:5 (describing process for producing
excipient-free agglomerates of 13-lactam antibiotic or 13-lactamase inhibitor
by extruding mass suitable for extrusion consisting of a liquid and particles
from said antibiotic or inhibitor, followed by drying.)
10. Schwarz teaches that “[s]uitable 13-lactam antibiotics . . . include
. . . solvates such as hydrates, preferably . . . amoxicillin e.g.[,] in the form of
a hydrate, such as a trihydrate.” {Id. at 3:6—10.)
11. Schwarz teaches that “[a] granulation liquid includes water or
an organic solvent, or an organic solvent mixed with water, preferably water
or an organic solvent mixed with water.” (Id. at 5:14—16; see also id. at
10:1—3 (describing water as a suitable liquid for preparing a mass suitable
for extrusion consisting of a liquid and particles from a 13-lactam antibiotic
or 13-lactamase inhibitor).)
12. Schwarz teaches that “[preferably, the granulation mass is
extruded, e.g.[,] according, e.g.[,] analogously, to conventional extruding
methods, e.g.[,] at appropriate extrusion temperatures, e.g.[,] including
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temperatures from room temperature and below, e.g.[,] 0°C to 10°C.” (Id. at
5:27-31.)
13. Schwarz teaches an example producing a granulate containing
amoxicillin and potassium clavulanate, wherein amoxicillin agglomerate
was produced by processing particles of amoxicillin trihydrate moistened
with acetone into an extrudable mass, which is extruded using a twin-screw
extruder, dried, and broken up through a sieve. (Id. at 17:17—18:20
(Example III a.)).)
14. De Jonge teaches a method of preparing sodium amoxicillin
compositions that have an “excellent degree of stability, as well in the form
of a dry preparation as in solution,” and that are “easily converted into
stable, suitably injectable solutions which are free of allergic reactions-
causing chemicals,” comprising gradual addition of sodium hydroxide to a
suspension of amoxicillin trihydrate in water until the amoxicillin has
completely dissolved, optionally neutralizing part of excess sodium
hydroxide with hydrochloric acid while keeping the temperature between
0°—30-C, sterilely filtrating the obtained solution, freezing the solution, and
freeze drying the obtained solid, (de Jonge Abstract, 2:65—68.)
15. De Jong teaches that its process avoids stabilizers or organic
solvents that may cause undesired side phenomena. (Id. at 5:5—12.)
16. Storm teaches treating bacterial infections with a regimen of
amoxicillin and potassium clavulanate. (Storm Abstract.)
17. Storm teaches that, for purposes of its disclosure, “the term
‘amoxicillin’ is used generically to refer to amoxicillin or an alkaline salt
thereof, in particular amoxicillin trihydrate and (crystallised) sodium
amoxicillin, without distinction unless otherwise indicated.” (Id. 142.)
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18. Storm teaches a modified release formulation of its invention
where
the portion of amoxicillin which is released immediately may be
provided as amoxicillin trihydrate or an alkaline salt thereof, for
instance potassium or sodium amoxicillin, preferably, (crystallized)
sodium amoxicillin or a mixture thereof, preferably amoxicillin
trihydrate; whilest the portion of amoxicillin which is released slowly
is provided as amoxicillin trihydrate or an alkaline salt thereof, for
instance potassium or (crystallized) sodium amoxicillin or a mixture
thereof, preferably (crystallized) sodium amoxicillin.
(Id. 172.)
19. Storm further teaches that
[i]t will be appreciated that the use of a mixture of amoxicillin
trihydrate and sodium amoxicillin is more generally applicable to
other pharmaceutical formulations comprising amoxicillin and
potassium clavulanate.
Accordingly, in a further aspect, the present invention provides
for a pharmaceutical formulation comprising amoxicillin and
potassium clavulanate . . . , in which amoxicillin is provided as a
mixture of amoxicillin trihydrate and sodium amoxicillin ....
Preferably, sodium amoxicillin is crystallised sodium amoxicillin.
Representative formulation types include tablets, including immediate
release and modified release tablets as herein described, as well as
other solid dosage forms such as capsules, single dosage sachets and
granules.
{Id. 1176—77.)
Analysis
Lintz teaches a method of preparing pharmaceutical granules of active
ingredient such as amoxicillin in the form of a salt, comprising
agglomerating amoxicillin powder by adding a granulation liquid and a
neutralizing agent such as sodium hydroxide or sodium bicarbonate. (FF1,
FF4, FF6.) Lintz also teaches that water is one of the most preferred
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granulation liquid and that the neutralization agent may be provided in a
dissolved state with the granulation liquid. (FF5.) Thus, Lintz suggests
agglomerating amoxicillin powder by using an aqueous solution containing a
source of sodium ions selected from, e.g., sodium hydroxide or sodium
bicarbonate. Lintz further teaches an example of preparing granules
containing Aztreonam (a beta-lactam antibiotic like amoxicillin), where the
wet mass of Aztreonam and a granulation liquid comprising sodium
hydroxide was passed through a sieve and then dried. (FF8.)
Lintz does not specifically teach the use of amoxicillin trihydrate or
the use of an extruding step in preparing its pharmaceutical granules.
However, Lintz suggests that any wet-granulation methods, which involve
“equipment adapted for the agitation of powders [] and the wetting of
powders with liquids” may be used to carry out the process of its invention.
(FF7.) Schwartz teaches a process for producing granulate particles
comprising B-lactam antibiotic such as amoxicillin trihydrate by moistening
the antibiotic with granulating liquid to obtain a granulation mass, extruding
the granulation mass, passing the mass through a sieve, and drying the
sieved extruded mass. (FF9, FF10.) In addition, de Jonge specifically
teaches that sodium amoxicillin may be prepared from addition of sodium
hydroxide to amoxicillin trihydrate in water (FF14), while Storm shows that
the mixture of amoxicillin trihydrate and sodium amoxicillin is known to be
useful in pharmaceutical compositions. (FF19.)
Finally, as to the limitation in claim 1 that the extrusion occurs at a
temperature of from about 10°C to about 40°C, Lintz teaches a temperature
for its process may be room temperature (20 °C), lower for sensitive
ingredients, or “elevated to 40°C or even up to about 110°C to speed up the
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process of removing volatile materials.” (FF7.) Likewise, Schwarz teaches
that appropriate extrusion temperatures include “temperatures from room
temperature and below, e.g., 0°C to 10°C.” (FF12,) Thus, the prior art
suggests a temperature or temperature range that falls within and/or overlaps
the claimed temperature range. In re Peterson, 315 F.3d 1325, 1329 (Fed.
Cir. 2003) (“In cases involving overlapping ranges, we and our predecessor
court have consistently held that even a slight overlap in range establishes a
prima facie case of obviousness.”).
In light of the above, we find claim 1 recites “a combination of
familiar elements according to known methods [that] does no more than
yield predictable results”; accordingly, we agree with the Examiner that the
combination of the cited prior art renders claim 1 prima facie obvious. KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The combination of
familiar elements according to known methods is likely to be obvious when
it does no more than yield predictable results.”). We address Appellant’s
arguments below.
Appellant contends that the cited art does not suggest “extruding
amoxicillin trihydrate in an aqueous mixture containing the specified source
of sodium ions to form a moist, extruded mass comprising a mixture of
amoxicillin trihydrate and amoxicillin sodium.”7 (Appeal Br. 9.) Appellant
first argues that Lintz refers only to amoxicillin in general terms and that
“Lintz says nothing about extrusion at all, much less extruding amoxicillin
7 Appellant also appears to argue that the cited prior art combination does
not suggest a sieve granulation step distinct from the extrusion step. (Appeal
Br. 9.) To the extent Appellant relies on this argument, we are not
persuaded. Schwarz teaches a method wherein a granulation mass is
extruded before being passed through a sieve. (FF9.)
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trihydrate together with a source of sodium ions to provide a mixture of
amoxicillin trihydrate and amoxicillin sodium.” (Id.; see also Reply Br.8 2.)
We are not persuaded. “Non-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references. . . . [The reference] must be read,
not in isolation, but for what it fairly teaches in combination with the prior
art as a whole.” In re Merck & Co. Inc., 800 F.2d 1091, 1097 (Fed. Cir.
1986). In this case, both Schwarz and de Jonge teaches the trihydrate form
of amoxicillin (FF10, FF14), and de Jonge specifically teaches that
amoxicillin trihydrate reacts with sodium hydroxide in water to form sodium
amoxicillin (FF14), i.e., the same kind of reaction generally disclosed in
Lintz (FF1). Similarly, as discussed above, although Lintz does not
specifically teach extrusion, Lintz teaches that its process may be performed
using wet granulation methods (FF7), while Schwarz teaches wet
granulation through extrusion, passage through a sieve, and subsequent
drying (FF9.)
Neither are we persuaded by Appellant’s argument that the alleged
deficiencies of Lintz are not cured by other cited references. Although
Appellant acknowledges that Schwarz teaches “extruding and drying
antibiotics such as amoxicillin trihydrate together with other medicants such
as clavulanic acid,” they argue that Schwarz’s disclosure “appears to be
limited to the simple mixing of these two materials via exclusion” and does
not suggests any “reactive extrusion . . . , i.e., reaction being carried out via
8 The Reply Brief is not paginated. Accordingly, we refer to page numbers
therein as if the brief was paginated consecutively beginning with the first
page as page 1.
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extrusion in order to produce a different final product in the extruded
composition.” (Appeal Br. 9; see also Reply Br. 2—3.) Appellant further
argues that
Schwarz does not disclose or suggest the addition of a sodium ion
source, such as from an aqueous mixture of sodium hydroxide,
sodium carbonate, sodium bicarbonate or a sodium salt of an organic
acid, in order to provide a mixture of amoxicillin trihydrate and
amoxicillin sodium, as called for in the present claims.
(Appeal Br. 10; see also Reply Br. 2—3.)
To the extent that Appellant’s argument is that Schwarz does not
suggest the addition of a sodium ion source to amoxicillin trihydrate to form
a mixture of amoxicillin trihydrate and amoxicillin sodium, Appellant is
once again attacking Schwarz individually rather than considering what it
teaches in combination with the prior art as a whole. In re Merck & Co., 800
F.2d at 1097. As discussed, the reaction between amoxicillin and a sodium
source to form amoxicillin sodium is taught by Lintz and de Jonge.9
To the extent Appellant’s argument is that Schwarz does not teach
“reactive extrusion,” we are similarly unpersuaded. As the Examiner points
out, the claim does not require that amoxicillin sodium be formed through
extrusion. (Ans. 7—9.)
Appellant focuses on the use of the phase “to form” in claim 1,
arguing that,
9 Although Lintz and de Jonge do not appear explicitly to teach a resulting
mixture of amoxicillin trihydrate and amoxicillin sodium, Storm teaches the
desirability of such a mixture in pharmaceutical formulations (FF19), and a
skilled artisan would understand that the ratio of amoxicillin trihydrate and
amoxicillin sodium in the final product of a reaction between amoxicillin
trihydrate and sodium hydroxide depends on the relative amounts of the
initial reactants.
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[njotably, the limitations of Claim 1 require, “extruding . . .
amoxicillin trihydrate in an aqueous mixture containing at least a
source of sodium ions . . . to form a moist, extruded mass comprising
a mixture of amoxicillin trihydrate and amoxicillin sodium.”
(emphasis added). By using this language of “to form” Claim 1 clearly
indicates that something new is created in the extrusion process,
namely, that amoxicillin sodium is formed from the reaction of
amoxicillin trihydrate and the sodium ions during the extrusion step.
Thus, reactive extrusion is clearly required, even though the wording
“reactive extrusion” is not explicitly used in the claim.
(Reply Br. 2.)
Although the claim language recited by Appellant does require that
the outcome of the extrusion process be “a moist, extruded mass comprising
a mixture of amoxicillin trihydrate and amoxicillin sodium,” and that
“amoxicillin trihydrate in an aqueous mixture containing at least a source of
sodium ions” be extruded, we find that the broadest reasonable interpretation
of the claim language in light of the Specification does not require the
reaction between amoxicillin trihydrate and the source of sodium ions to
occur through extrusion as opposed to, e.g., the mixture of the amoxicillin
trihydrate and the sodium ion source.
Furthermore, as discussed above, the cited prior art combination
suggests extruding amoxicillin trihydrate in an aqueous mixture containing
at least a source of sodium ions at the claimed temperatures. Our reviewing
court has held that
[wjhere ... the claimed and prior art products are identical or
substantially identical... the PTO can require an applicant to prove
that the prior art products do not necessarily or inherently possess the
characteristics of his claimed product. . . . Whether the rejection is
based on ‘inherency’ under 35 U.S.C. § 102, on ‘prima facie
obviousness’ under 35 U.S.C. § 103, jointly or alternatively, the
burden of proof is the same, and its fairness is evidenced by the PTO’s
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inability to manufacture products or to obtain and compare prior art
products.”
In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (citations and footnote
omitted). Appellant has not persuasively rebutted why the method suggested
by the cited prior art, which is substantially identical to the claimed method,
would not inherently result in “reactive” extrusion. Thus, even assuming
that claim 1 requires “reactive” extrusion, we find that the Examiner has
established a prima facie case of obviousness with respect to the claim,
while Appellant has not cited evidence that, when considered together with
the evidence of obviousness, shows claim 1 to be non-obvious.
With respect to de Jonge, Appellant argues that the reference cannot
be combined with Lintz and Schwarz because de Jonge discloses a process
that includes a freeze drying step whereas the claim “specifically exclude the
use of a spray drying or freeze drying step in the granulating process.”
(Appeal Br. 10.) De Jonge is cited by the Examiner to show that the reaction
between sodium hydroxide and amoxicillin trihydrate is known to produce
amoxicillin sodium. (Ans. 4—5; FF14.) Appellant has pointed to no
teaching in de Jonge, and we have found none, that suggests the above-
discussed chemical reaction would not occur absent freeze-drying, or that
the method suggested by the combination of Lintz, Schwarz, and Storm
would be unlikely to produce the claimed mixture of amoxicillin trihydrate
and amoxicillin sodium.10 Indeed, the reaction taught in de Jonge is merely
10 Appellant contends that “[t]he focus of de Jonge is directed to a freeze
drying process” and that a skilled artisan would also incorporate this spray
or freeze drying process if he or she were to incorporate the teaching of
de Jonge.” (Reply Br. 3.) However, “[t]he test for obviousness is not
whether the features of a secondary reference may be bodily incorporated
into the structure of the primary reference,” but rather “what the combined
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a more specific example of the general class of reactions taught in Lintz,
which does not teach a freeze-drying step. Accordingly, we are not
persuaded by Appellant’s argument that de Jonge cannot be combined with
Lintz and Schwarz, or Appellant’s apparent argument that de Jonge teaches
away from the claimed invention. In re Gurley, 27 F.3d 551, 553 (Fed. Cir.
1994) (“[I]n general, a reference will teach away if it suggests that the line of
development flowing from the reference’s disclosure is unlikely to be
productive of the result sought by the applicant.”) (citations omitted).
Finally, with respect to Butterly, Appellant contends that Butterly’s
process requires two separate organic solvents while preparing sodium
amoxicillin whereas the claim requires using an aqueous mixture of
amoxicillin trihydrate with a sodium source. (Appeal Br. 9; Reply Br. 3.)
Appellant further argues that Butterly does not suggest directly mixing
amoxicillin trihydrate with a sodium ion source in order to provide a mixture
of amoxicillin trihydrate and amoxicillin sodium. (Appeal Br. 10—11; Reply
Br. 3.) Accordingly, Appellant contends that Butterly teaches away from the
claims on appeal. (Appeal Br. 11; Reply Br. 3.)
We are not persuaded that Butterly teaches away from the claimed
invention for the same reasons discussed above: that is, Appellant has
pointed to no disclosures in Butterly that shows the method suggested by the
combination of Lintz, Schwarz, de Jonge, and Storm would be unlikely to
teachings of the references would have suggested to those of ordinary skill
in the art.” In re Keller, 642 F.2d 413, 425 (CCPA 1981). As discussed
above, Appellant has not persuasively shown either de Jonge itself, or more
importantly de Jonge in combination with the other cited prior art, would
suggest to a skilled artisan that freeze drying is a necessary step for
granulation.
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produce the claimed mixture of amoxicillin trihydrate and amoxicillin
sodium. In re Gurley, 27 F.3d at 553. We also do not find Appellant’s other
arguments regarding Butterly to be persuasive with respect to the alleged
non-obviousness of claim 1, because, as discussed above, we find claim 1 to
be obvious over the combination of Lintz, Schwarz,
de Jonge, and Storm. See generally In re Bush, 296 F.2d 491, 496 (CCPA
1961) (the Board may rely on less than all of the references relied upon by
Examiner).11
Finally, Appellant argues only in the Reply Brief that Storm does not
aid in rendering claim 1 obvious because, although Storm discloses
pharmaceutical formulations including amoxicillin trihydrate and sodium
amoxicillin, it does not disclose “how the sodium amoxicillin is prepared[]
except to note . . . that in the past sodium amoxicillin has been prepared by
spray-drying — a technique which is excluded from the subject matter of the
present claims.” (Reply Br. 3—4.) As an initial matter, Appellant fails to
explain why this argument was not presented in the Appeal Brief. Thus, the
argument is considered waived. See Ex parte Nakashima, 93 USPQ2d 1834
(BPAI 2010) (informative) (explaining that arguments and evidence not
timely presented in the principal Brief will not be considered when filed in a
Reply Brief, absent a showing of good cause explaining why the argument
could not have been presented in the principal Brief); Ex parte Borden, 93
USPQ2d 1473, 1477 (BPAI 2010) (informative) (“Properly interpreted, the
11 Appellant also points out that de Jonge and Butterly are silent with respect
to an extrusion process. (Appeal Br. 10.) To the extent Appellant intends
this to be a separate argument, we are not persuaded because Schwarz
teaches an extrusion process, and the test for obviousness is what is
suggested by the combination of prior art. In re Keller, 642 F.2d at 425.
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Rules do not require the Board to take up a belated argument that has not
been addressed by the Examiner, absent a showing of good cause.”).
In any event, we are not persuaded by Appellant’s argument with
respect to Storm, which again attempts to attack the reference individually.
In re Merck & Co., 800 F.2d at 1097. The Examiner cites Storm merely to
show that a skilled artisan would have known that a mixture of amoxicillin
trihydrate and amoxicillin sodium is useful in pharmaceutical formulations,
while Lintz, Schwarz, and de Jonge are cited for the chemical reaction that
results in production of amoxicillin sodium from amoxicillin trihydrate and
the extrusion process that may be used for such production.12
Accordingly, we affirm the Examiner’s rejection of claim 1. Claims
2-4 and 7—12, which were not separately argued, fall with claim 1.
37C.F.R. §41.37(c)(l)(iv).
12 Appellant concludes in the Reply Brief that
the cited combination of references . . . fail[s] to appreciate and obtain
the benefits of the claimed invention — to provide a simple and
inexpensive process for the preparation of stable compositions of
amoxicillin trihydrate and amoxicillin sodium which may be prepared
without the need for spray-drying or freeze-drying method and
without the use of undesirable organic solvents or amines.
(Reply Br. 4.) We note that several of the alleged benefits described above
are not claimed and thus do not show that the claims are non-obvious even if
the prior art does not disclose such alleged benefits. In re Hiniker Co., 150
F.3d 1362, 1369 (Fed. Cir. 1998) (explaining that in determining
patentability, “the name of the game is the claim”). Fikewise, “[i]t is a
general rule that merely discovering and claiming a new benefit of an old
process cannot render the process again patentable.” In re Woodruff, 919
F.2d 1575, 1578 (Fed. Cir. 1990) (citations omitted).
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SUMMARY
For the reasons above, we affirm the Examiner’s decision rejecting
claims 1—4 and 7—12
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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