Ex Parte Marchetti et al

Patent Trial and Appeal Board

Aug 11, 2017

12667694 (P.T.A.B. Aug. 11, 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.
12/667,694 05/18/2010 Marcello Marchetti 353242US0PCT 1378
22850 7590 08/15/2017
OBLON, MCCLELLAND, MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA, VA 22314
EXAMINER
RAMACHANDRAN, UMAMAHESWARI
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
08/15/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
patentdocket @ oblon. com
oblonpat @ oblon. com
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MARCELLO MARCHETTI, FRANCESCA MARIOTTI,
LORELLA RAGNI, PAOLO SCARPETTI, and MAURO VALENTI
Appeal 2015-0071981
Application 12/667,6942
Technology Center 1600
Before DONALD E. ADAMS, RACHEL H. TOWNSEND, and
DAVID COTTA, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims 1, 2, 4—10, and
13—18 (App. Br. 2). Examiner entered rejections under 35 U.S.C. § 103(a).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
1 An Oral Hearing was held July 11, 2017.
2 Appellants identify the real party in interest as “Aziende Chimiche Riunite
Angelini Francesco A.C.R.A.F. S.p.A. of Rome, Italy” (App. Br. 1).
Appeal 2015-0071981
Application 12/667,694
STATEMENT OF THE CASE
Appellants’ disclosure “relates to a stable liquid pharmaceutical
composition based on trazodone” (Spec. 1: 4—5). Appellants define a
‘“stable composition’ [as] a solution of trazodone hydrochloride that does
not give rise to a precipitate after 30 days of storage at a temperature of 4°C
and in which the individual degradation products of trazodone hydrochloride
do not exceed 0.2% after 3 months at 40°C” (Spec. 4: 1—5). Claim 1 is
representative and reproduced below:
1. A stable liquid pharmaceutical composition,
comprising:
(a) water;
(b) 4 to 8 % w/v of trazodone hydrochloride;
(c) propylene glycol; and
(d) one or more cosolvents selected from the group
consisting of polyethylene glycol 200, polyethylene glycol 300,
polyethylene glycol 400, polyethylene glycol 600, polyethylene
glycol 1000, polyethylene glycol 1500, polyethylene glycol
3000; polyethylene glycol 3350, polyethylene glycol 4000, and
polyethylene glycol 6000,
wherein said pharmaceutical composition is a solution
and has a pH value between 5.0 and 6.0, and said propylene
glycol and said one or more cosolvents are present in a total
amount of 45 to 90 % w/v.
(App. Br. i.)
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The claims stand rejected as follows:
Claims 1, 2, 4—10, 13—16, and 18 stand rejected under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Balkrishna3 and Henning.4
Claim 17 stands rejected under 35 U.S.C. § 103(a) as unpatentable
over the combination of Balkrishna, Henning, and Dow.5
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Balkrishna
[Djiscloses a liquid pharmaceutical formulation for oral
administration to a subject in need thereof which comprises a
biologically equivalent and therapeutically effective amount of
Trazodone or a pharmaceutically acceptable salt thereof in
association with a pharmaceutically acceptable liquid carrier,
one or more taste-enhancing/masking agents, preservatives,
colouring agents and a buffering agent.
(Balkrishna, Abstract; see id. at 5: 7—9 (“In a preferred embodiment,
[Balkrishna’s] invention is directed to a liquid formulation of Trazodone or
its pharmaceutically acceptable salts, wherein the formulation comprises a
therapeutically effective amount of Trazodone in a liquid carrier” (emphasis
added)); id. at 6: 20 — 7: 22 (disclosing various embodiments within the
scope of Balkrishna’s disclosure wherein Balkrishna’s formulation
3 Mahajan Sunil Balkrishna, IN 1242/MUM/2005 A, published July 13,
2007.
4 Torsten Henning, Polyethylene glycols (PEGs) and the pharmaceutical
industry, FINE, SPECIALTY & PERFORMANCE CHEMICALS 57-59
(2002).
5 Product Safety Assessment, Salts of Ethylenediaminetetraacetic Acid
(EDTA), The Dow Chemical Company 1—5 (2006).
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comprises a therapeutically effective amount of Trazodone or its
pharmaceutically acceptable salt); Ans. 3.)
FF 2. Balkrishna’s disclosed compositions “comprising Trazodone HC1
and other carefully selected excipients, show: a) good physical stability;
[and] b) maintain[] solubility of the Trazodone and other excipients upon
storage under normal and stress conditions ...” (Balkrishna 6: 4—8; see also
id. at 8: 26—28 (Balkrishna’s composition “maintains more than . . . 95% of
its initial content when exposed to 40° C/75% Relative Humidity for three
months; and more than 98% of its initial content when stored at room
temperature for three years”); Ans. 3).
FF 3. Balkrishna discloses “[a] stable liquid pharmaceutical formulation
suitable for oral administration comprising Trazodone HC1 in ... a
pharmaceutically suitable liquid carrier . . ., wherein the pH of the
formulation ranges from 2.5 to 5.5” (Balkrishna 11: 2—7; Ans. 3).
FF 4. Balkrishna discloses a “liquid pharmaceutical composition [of
Trazodone HC1 that is] optionally in association with a water-miscible co[-
] solvent selected from the group comprising ethanol, benzyl alcohol or
polyhydric alcohols such as glycerin, propylene glycol, sorbitol, and
polyethylene glycols [(“PEGs”)] in the amount varying from 5% to 70%”
(Balkrishna 11: 8—12; see also id. at 5: 12—14 (Balkrishna’s “liquid carrier is
water and contains other miscible [cosolvents] selected from the group
consisting of ethanol, benzyl alcohol, polyhydric alcohols such as . . .
propylene glycol. . . and [PEGs]”); Ans. 3; see Ans. 7).
FF 5. Balkrishna discloses that the preservative in Balkrishna’s “liquid
pharmaceutical formulation [] comprises anti-microbial preservatives, anti-
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oxidants and chelating agents in the range of 0.05% to 0.25%” (Balkrishna
11:29-31; Ans. 3).
FF 6. Balkrishna discloses a
liquid formulation [that] contains at least one or more of the
following components: about 0.5 to about 5% by weight of
Trazodone HCl, about 5% to about 40% by weight of
polyhydric alcohol, about 30% to about 70% by weight of
polyhydroxy sugar, about 5% to about 20%) by weight of
[PEG], about 5% to about 20%o by weight of propylene glycol,
about 5% to about 60% by weight of glycerin, about 0.05% to
about 0.25% by weight of preservative, about 0.05% to about
0.2% by weight of artificial sweetener, about 0.05% to about
0.1 % by weight of artificial flavoring agent, and about 0.05%
to about 2% by weight of buffering agent and the rest being
made up with purified water. The pH of such embodiment is
carefully adjusted to 2.5 to 5.5 pH units using either alkali or
acid.
(Balkrishna 6: 9—19; see generally Ans. 3 and 6—7.)
FF 7. Examiner finds that Balkrishna fails to disclose “PEG-200, PEG-
300[,] etc.” (Ans. 4).
FF 8. Examiner finds that Henning discloses that PEG has a “mean
molecular weight range[] from 200-35,000[,] has different physical
properties based on the weighty is commercially available and used as an
excipient [] in pharmaceuticals []” (Ans. 4, citing Henning 1—2; see also
Curatolo Decl.6124 (“Henning merely provides for the fact that
polyethylene glycols that fall within the scope of component (d) of
[Appellants’] claim 1 were known” in the art at the time of Appellants’
claimed invention)).
6 Declaration of William Curatolo, Ph.D. signed Apr. 22, 2013.
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FF 9. Examiner finds that although the combination of Balkrishna and
Henning suggests a liquid formulation comprising trazodone and chelating
agents, the combination fails to suggest “EDTA [(ethylenediaminetetraacetic
acid)] or salts of EDTA” and relies on Dow to make up for this deficiency in
the combination of Balkrishna and Henning (Ans. 5).
FF 10. Curatolo declares that “[although Balkrishna contains some general
disclosure in regard to pH, there is no disclosure in this reference of any
composition which has both: a pH of 5.0 to 6.0; and a trazodone
hydrochloride concentration of 4 to 8 % w/v” (Curatolo Deck 1 15).
FF 11. Curatolo declares that when trazone hydrochloride is formulated
alone, without other reagents, including cosolvents, “the solubility of
trazodone hydrochloride precipitously drops at about a pH of 5, which was
well-known at the time of [Appellants’] invention” (Curatolo Deck 118; see
also id. ]]17, citing Spec. 5: 11—14 (the “solubility of trazodone
hydrochloride[, when formulated alone, without other reagents, including
cosolvents,] decreases with decrease in acidity of the aqueous medium”)).
FF 12. Curatolo declares that “it is the surprising discovery of the present
inventors that the concentration of trazodone hydrochloride can be increased
by selection of the certain solvents without increasing the acidity (lowering
the pH” (Curatolo Deck 121, citing Spec. 5: 14-17; cf. FF 2).
FF 13. Curatolo declares that “even permitting that propylene glycol and
polyethylene glycol can be added to a formulation with trazodone
hydrochloride, the artisan would not have found the specific selection of
these components to be readily apparent from the disclosures of Balkrishna,
Henning, and Dow, much less in the claimed amount together with the
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claimed amount of trazodone hydrochloride at the claimed pH” (Curatolo
Decl. 125).
ANALYSIS
The rejection over the combination of Balkrishna and Henning'.
Based on the combination of Balkrishna and Henning, Examiner
concludes that, at the time Appellants’ invention was made, it would have
been prima facie obvious to use one or more of Henning’s commercially
available PEG cosolvents having a molecular weight in the range “from 200-
35,000” in Balkrishana’s composition comprising propylene glycol,
polyethylene glycol(s), and about 0.5 to about 5% trazodone having a pH of
2.5 to 5.5 (Ans. 4—5; see FF 1—8).
Claim 1:
Appellants’ claim 1 is reproduced above and requires a stable liquid
pharmaceutical composition that comprises: (a) water; (b) 4—8% w/v
trazodone HC1; (c) propylene glycol; and (d) PEG having a molecular
weight of 200, 300, 400, 600, 1000, 1500, 3000, 3350, 4000 or 6000;
wherein the total amount of propylene glycol and PEG in the composition is
45—90% and the pH of the composition is between 5.0 and 6.0 (App. Br. i).
Henning discloses that PEG having a molecular weight required by
Appellants’ claimed invention was known in the art at the time of
Appellants’ claimed invention (FF 8).
Balkrishna discloses a trazodone HC1 composition that exhibits “good
physical stability” and “maintains solubility of the Trazodone and other
excipients upon storage under normal and stress conditions” (FF 2). In this
regard, Balkrishna discloses a pharmaceutical composition having a pH of
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between 2.5 and 5.5 that comprises: (a) water; (b) about 0.5—5% w/v
Trazodone HC1; (c) about 5—20% propylene glycol; (d) about 5—20% PEG;
and (e) about 5 40% polyhydric alcohol, which may be either propylene
glycol or PEGs; thus Balkrishna discloses a composition that has a total
amount of propylene glycol and PEGs of about 15—80% (see FF 4 and 6; cf.
App. Br. i). Overlapping ranges support a prima facie case of obviousness.
See In re Geisler, 116 F.3d 1465, 1468 (Fed. Cir. 1997).
Balkrishna discloses the use of a therapeutically effective amount of
trazodone HC1 in combination with concentration ranges for polypropylene
glycol, PEG, and polyhydric alcohols, such as propylene glycol and PEG
(see FF 4 and 6). Therefore, we find no error in Examiner’s conclusion that,
at the time of Appellants’ claimed invention, a person of ordinary skill in
this art would have found it prima facie obvious to identify the optimum or
workable ranges by routine experimentation (see, e.g., Ans. 4). See In re
Alter, 220 F.2d 454, 456 (CCPA 1955) (“where the general conditions of a
claim are disclosed in the prior art, it is not inventive to discover the
optimum or workable ranges by routine experimentation”).
For the foregoing reasons, we are not persuaded by Appellants’
contention that: “Examiner []failed to establish what parameters would be
modified and/or that the art recognizes the same as a variable which
achieves a recognized result” (App. Br. 15; see Reply Br. 15—16);
Balkrishna fails to “disclose . . . any composition which has both: a pH of
5.0 to 6.0; and a trazodone hydrochloride concentration of 4 to 8 % w/v”
(App. Br. 6 and 7; Reply Br. 7 and 18); or “not a single embodiment within
Balkrishna combines the high concentration of trazodone with the high pH
as claimed” (App. Br. 9).
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We are not persuaded by Appellants’ unsupported contention that,
notwithstanding Balkrishna’s disclosure to the contrary, “polyethylene
glycol is generally not considered in the art to be a polyhydric alcohol”
(App. Br. 11; see Reply Br. 13; cf. FF 4; Ans. 12 (Balkrishna “clearly . . .
include[d] polyethylene glycol in the category of ‘polyhydric alcohol’.
From such a definition in the [Balkrishna] reference, a person of ordinary
skill in the art would have found it obvious to add PEG in the composition
as a polyhydric alcohol”)). Therefore, we are not persuaded by Appellants’
contention that “[t]he range of 5 to 70%[, for polyhydric alcohol,] appearing
in Claim 3 of Balkrishna was apparently written to embrace the amounts
disclosed on [Balkrishna’s] pages 6-7 of glycerin (5 to 60%) and
polyhydroxy sugars (30 to 70%)” (App. Br. 12; see id. at 13).
We are not persuaded by Appellants’ contention that because
Balkrishna separately lists propylene glycol and PEG as components of
Balkrishna’s composition, the polyhydric alcohol component of Balkrishna’s
composition cannot also be propylene glycol or PEG, which is contrary to
Balkrishna’s disclosure (see App. Br. 13 (“when it comes to the amount of
propylene glycol and polyethylene glycol, the specification of Balkrishna
only provides support for 5 to 20% of each for a total of 10 to 40% . . .”); see
also App. Br. 12 and 14; see generally Reply Br. 13—14; cf. FF 4 and 6).
We are not persuaded by Appellants’ contention that “nothing in
Balkrishna relates the concentration of propylene glycol and/or the
specifically recited [PEGs] to improving the solubility of trazodone” (Reply
Br. 16; cf. FF 4 (Balkrishna’s “liquid carrier is water and contains other
miscible [cosolvents] selected from the group consisting of ethanol, benzyl
alcohol, polyhydric alcohols such as . . . propylene glycol. . . and [PEGs]”
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(emphasis added)); see also FF 6 (disclosing a composition that comprises
propylene glycol; PEG; and polyhydric alcohols, such as propylene glycol
and PEG)).
We recognize the statements in the Curatolo Declaration regarding the
stability of a composition that consists of trazodone HC1 and water over a pH
range (FF 10-11). Curatolo, however, fails to establish that the solubility of
Appellants’ composition, which comprises, inter alia, trazodone HC1,
propylene glycol and PEG, differs from the solubility of the composition
comprising, inter alia, trazodone HC1, propylene glycol and PEG
composition disclosed by the closest prior art, Balkrishna (see FF 10-11; cf.
FF 1—6). “[W]hen unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
the closest prior art.” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
Cir. 1991).
We recognize Appellants’ illustrative examples, which compare
formulations comprising 40% of either propylene glycol or PEG (Spec. 7—8
(Examples 1 and 2)) to formulations comprising 40% (Spec. 11—12
(Examples 8—9)), 45% (Spec. 9—10 (Example 6), 50% (Spec. 8 (Example
3)), or 65% (Spec. 8—9, 10, and 12 (Examples 4—5, 7, and 10)), of a
combination of propylene glycol and PEG. According to Appellants,
“[fjormulations 1 and 2 produced a precipitate when stored in the
refrigerator at 4°C. [Whereas,] [fjormulations 3 to 10 [] remained stable on
storage in the refrigerator, remaining clear and free from precipitate” (Spec.
13; see generally Reply Br. 19). We recognize Appellants’ contentions
relating to the comparative examples in their Specification and their
assertion that “Applicants may compare the claimed invention with prior art
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that is more closely related to the invention that the prior art relied upon by
the examiner” (Reply Br. 19—20).
In this regard, we note that even if Appellants correctly interpreted
Balkrishna’s disclosure of polyhydric alcohol as excluding both propylene
glycol and PEG, Appellants failed to establish unexpected results when
compared with the closest prior art, Balkrishna, or what Appellants may
consider to represent even closer prior art (see id.). Specifically, Appellants
recognize that when propylene glycol and PEG are excluded from
Balkrishna’s genus of polyhydric alcohols “Balkrishna [] provides support
for [a composition comprising] 5 to 20% of each [of propylene glycol and
PEG] for a total of 10 to 40% (see pages 7-8 of Balkrishna)” (App. Br. 12;
see also Curatolo Deck 114 (when propylene glycol and PEG are excluded
from Balkrishna’s genus of polyhydric alcohols, “the total amount of
polyethylene glycol and propylene glycol in the formulation of Balkrishna
ranges from 10% to 40% by weight of the formulation . . .”)).
As Appellants’ examples make clear, trazodone HC1 compositions
comprising both propylene glycol and PEG in a total amount of 40% are
stable upon storage for 30 days in the refrigerator at 4°C remaining clear and
free from precipitate (see Spec. 11—12 (Examples 8—9) and 13; see also id. at
4). Therefore, we are not persuaded by Appellants’ contentions that their
claimed invention yields unexpected results (see App. Br. 11; see id. at 7—9
and 15—16; Reply Br. 5, 9, and 19) and that “the fact that Appellants have
been able to provide a stable liquid pharmaceutical composition as claimed
is an unexpected discovery” (App. Br. 10; see also id. at 15).
Notwithstanding Appellants’ contentions to the contrary, the evidence
on this record supports a conclusion that Balkrishna discloses compositions
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falling with the scope of Appellants’ claimed invention and that Balkrishna’s
disclosed compositions exhibit the same stability as Appellants’ claimed
composition. Appellants provide no comparative evidence to support a
conclusion that compositions within the scope of Balkrishna’s disclosure
that may have a total propylene glycol and PEG concentration in a range of
10% to below 40% do not also exhibit the same stability as required by
Appellants’ claimed invention. In addition, Appellants fail to provide
persuasive argument or evidence to support a conclusion that a person of
ordinary skill in this art following Balkrishna’s disclosure regarding the
formulation of trazodone HC1 compositions that exhibit good physical
stability and maintain solubility of the trazodone and other excipients upon
storage under normal and stress conditions, would not have found it prima
facie obvious to identify the optimum or workable ranges of pH,
polypropylene glycol, PEGs, and polyhydric alcohols, such as polypropylene
glycol and PEGs, by routine experimentation (see FF 1—3; Ans. 4). See In re
Alter, 220 F.2d at 456.
As discussed above, when Balkrishna’s genus of polyhydric alcohols
is properly interpreted as including propylene glycol or PEGs, compositions
falling within the scope of Balkrishna’s disclosure comprise a total amount
of propylene glycol and PEG of about 15—80%, which overlaps Appellants’
claimed range for the total amount of propylene glycol and PEG (cf. App.
Br. i). “[D]isclos[ure of] a multitude of effective combinations does not
render any particular formulation less obvious.” Merck & Co. Inc. v.
Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989).
For the foregoing reasons, we are not persuaded by Appellants’
contention that “Examiner clings to the generic disclosure of Balkrishna, but
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offers little in response to the Curatolo Declaration,” which “as discussed
[in] paragraphs 18 and 19 of the Curatolo Declaration shows that at the time
of the present invention ... it was well-known that the solubility of [a
composition consisting of only] trazodone hydrochloride precipitously drops
at about a pH of 5” (App. Br. 10; see Reply Br. 5—6, 8—12, and 17; cf. Ans.
9—10). As discussed above, Curatolo’s statements relating to the solubility
of a composition consisting of trazodone HC1, in the absence of cosolvents,
is not commensurate in scope with either of Appellants’ claimed invention
or the closest prior art, Balkrishna (see Ans. 9—10; cf. FF 10—13). Therefore,
Appellants’ reliance on the Curatolo Declaration is not persuasive (see also
Ans. 9-10).
Because, as Appellants recognize, Balkrishna discloses compositions
comprising both propylene glycol and PEG, we are not persuaded by
Appellants’ contentions regarding synergy (see Reply Br. 18; cf. App. Br.
12; see also Curatolo Deck 14).
A reference disclosure is not limited only to its preferred
embodiments, but is available for all that it discloses and suggests to one of
ordinary skill in the art. In re Lamberti, 545 F.2d 747, 750 (CCPA 1976).
Therefore, we are not persuaded by Appellants’ contentions regarding
Balkrishna’s preferred embodiments or examples (see App. Br. 9; cf. id. at
13 (“it is well-established that consideration of a reference is not limited to
the preferred embodiments or working examples, but extends to the entire
disclosure for what it fairly teaches, when viewed in light of the admitted
knowledge in the art, to [a] person of ordinary skill in the art”); Reply Br.
13; see also Ans. 8—9.)
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We find no requirement in Balkrishna that limits the PEG to one
specific molecular weight. In this regard, we note that Balkrishna makes
reference to the use of more than one PEG (see FF 4 (Balkrishna discloses a
composition comprising “polyethylene glycols” (emphasis added)).
Henning discloses that PEGs within the scope of the PEGs listed in
Appellants’ claim 1 were known in the art at the time of Appellants’ claimed
invention (FF 8). Therefore, we find no error in Examiner’s conclusion that
the combination of Balkrishna and Henning makes obvious a composition
comprising more than one PEG, in the concentration disclosed by Balkrishna
(i.e., about 5—20% PEG and about 5 40% polyhydric alcohol, which may be
PEG), which overlaps Appellants’ claimed concentration. Accordingly, we
are not persuaded by Appellants’ contention that the combination of
Balkrishna and Henning fails to “suggest the claimed amount (45 to 90 %
w/v) of propylene glycol and specifically recited cosolvents (Markush group
of specific polyethylene glycol species)” (Reply Br. 15).
We are not persuaded by Appellants’ contention that Balkrishna’s
Examples, which do not include PEG, would have led an “artisan ... to
believe that the cosolvent is irrelevant due to its omission (far from a results-
effective variable), but also that the optimum concentration of propylene
glycol would be from 5 to 10 % w/v” (Reply Br. 17). Disclosed examples
and preferred embodiments do not constitute a teaching away from a broader
disclosure or non-preferred embodiments. In re Susi, 440 F.2d 442, 446 n.3
(CCPA 1971). In this regard, notwithstanding Appellants’ contention to the
contrary, Balkrishna’s exemplification of the use of polyhydric alcohols
such as glycerin and sorbitol does not teach away from or otherwise lead to a
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conclusion that PEG or other polyhydric alcohols, such as PEG, are
irrelevant (see Balkrishna 6—8; FF 6).
Claim 2\
Appellants’ claim 2 depends from and further limits the composition
of Appellants’ claim 1 to have a pH value between 5.0 and 5.5 (App. Br. i).
As discussed above, the combination of Balkrishna and Henning
discloses a stable composition falling within the scope of Appellants’ claim
1, wherein the composition has a pH of 2.5—5.5 (FF 2; see also FF 1 and 3—
8). For the foregoing reasons, we are not persuaded by Appellants’
contention, with reference to the Curatolo Declaration, that “the narrow pH
range of Claim 2 would not be expected to be accessible to form a stable
liquid composition as claimed” (App. Br. 18). Iron Grip Barbell Co. v. USA
Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (“[W]here there is a range
disclosed in the prior art, and the claimed invention falls within that range,
there is a presumption of obviousness”).
We are not persuaded by Appellants’ contentions regarding In re
Baird, 16 F.3d 380, 382 (Fed. Cir. 1994) (see App. Br. 17—18). Baird relates
to the selection of an undisclosed species from a prior art genus, of what the
Baird court found to represent more than 100 million dipheols, that
encompassed the species if specific variables where chosen. See Baird, 16
F.3d at 382. On this record, Balkrishna discloses compositions comprising
trazodone HC1, propylene glycol and PEG in concentration ranges that
overlap Appellant’s claimed invention (see, e.g., FF 4 and 6). Thus, in
contrast to Baird, there is no selection of an undisclosed compound or a
selection of one compound from a genus of over 100 million different
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compounds. As Appellants’ recognize, Balkrishna discloses compositions
comprising polypropylene glycol and PEG (App. Br. 12; see also Curatolo
Decl. 114); thus a person of ordinary skill in this art would have been
directed to the selection of PEG from Balkrishna’s listed genus of
polyhydric alcohols, and optimized the pH and concentration of
polypropylene glycol, PEG, and trazodone HC1 within the ranges for each
disclose by Balkrishna. Therefore, notwithstanding Appellants’ contention
to the contrary, “[rjeading a list and selecting a known compound to meet
known requirements is no more ingenious than selecting the last piece to put
into the last opening in a jig-saw puzzle. It is not invention.” Sinclair &
Carroll Co. v. Interchemical Corp., 325 U.S. 327, 335 (1945); see also
Merck & Co. Inc. v. Biocraft Laboratories, Inc., 874 F.2d at 807.
Appellants’ reliance on Cuaratolo’s statements regarding a composition
consisting of trazodone HC1, without cosolvents does not persuade us
otherwise (see App. Br. 18).
Claims 4 and 5:
Appellants’ claims 4 and 5 depend from and further limit the one or
more cosolvents of Appellants’ claim 1 to a total amount of from: 45% to
85% (claim 4) or 45% to 80% (w/v) (claim 5) (see App. Br. i).
As discussed above, the combination of Balkrishna and Henning
discloses a stable composition falling within the scope of Appellants’ claims
4 and 5, wherein the composition comprises: (i) about 5—20% propylene
glycol; (ii) about 5—20% PEG; and (iii) about 5 40% polyhydric alcohol,
which may be either propylene glycol or PEGs; thus Balkrishna discloses a
composition that has a total amount of propylene glycol and PEGs of about
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15—80%, wherein, for example, PEG may be present in the composition in
an amount of 10—60% of the composition (see FF 4 and 6). Overlapping
ranges support a prima facie case of obviousness. See In re Geisler, 116
F.3d at 1468 (Fed. Cir. 1997).
For the reasons set forth above with respect to Appellants’ claim 1, we
are not persuaded by Appellants’ contentions relating to polyhydric alcohol
or that the total amount of propylene glycol and PEG in Balkrishna’s
composition is limited to a total of 10-40% (see App. Br. 19; cf. FF 4 and 6).
Claims 6 and 7:
Appellants’ claims 6 and 7 depend from and further limit Appellants’
claim 1 to comprise: two cosolvents, each independently in an amount of
from 5% to 50% (w/v), and in total amount not greater than 90% (w/v)
(Claim 6) or three cosolvent, each independently in an amount of from 5%
to 40% (w/v), and in total amount not greater than 90% (claim 7) (see App.
Br. ii).
Cosolvents within the scope of Appellants’ disclosure comprise
“glycols and polyglycols,” wherein “[a] typical example of a glycol used
advantageously in [Appellants’ disclosure] is propylene glycol” and
“[t]ypical examples of polyglycols . . . are[] polyethylene glycol[s] . . .”
(Spec. 4: 20-21 and 6: 7—10). Therefore, Appellants’ claim 6 may be read to
require both propylene glycol and PEG each independently in an amount of
from 5% to 50% (w/v), and in total amount not greater than 90% (w/v) (see
App. Br. ii). For the reasons set forth above with respect to Appellants’
claims 1, 4, and 5; we find no error in Examiner’s conclusion that the
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combination of Balkrishna and Henning makes obvious the subject matter of
Appellants’ claim 6.
In addition, as discussed above with respect to Appellants’ claims 1,
4, and 5, the combination of Balkrishna and Henning discloses a stable
composition falling within the scope of Appellants’ claims 6 and 7, wherein
the composition comprises: (i) about 5—20% propylene glycol; (ii) about 5—
20% PEG; and (iii) about 5^40% polyhydric alcohol, which may be PEG
(see FF 4 and 6). Overlapping ranges support a prima facie case of
obviousness. See In re Geisler, 116 F.3d at 1468.
As discussed above, we find no requirement in Balkrishna that limits
the PEG to one specific molecular weight. In this regard, we note that
Balkrishna makes reference to the use of more than one PEG (see FF 4
(Balkrishna discloses a composition comprising “polyethylene glycols”
(emphasis added)). Henning discloses that PEGs within the scope of the
PEGs listed in Appellants’ claim 1 were known in the art at the time of
Appellants’ claimed invention (FF 8). Therefore, we find no error in
Examiner’s conclusion that the combination of Balkrishna and Henning
makes obvious a composition comprising more than one PEG, in the
concentration disclosed by Balkrishna (i.e., about 5—20% PEG and about 5—
40% polyhydric alcohol, which may be PEG), which overlaps Appellants’
claimed concentration.
For the foregoing reasons, we are not persuaded by Appellants’
contention that “[n]either Balkrishna nor Henning provide for the specific
selection of two (Claim 6) or three (Claim 7) [PEGs] from the list [of PEGs]
provided in [Appellants’] Claim 1” (App. Br. 19). We are also not
persuaded by Appellants’ contention that Balkrishna alone fails to disclose
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specific PEG species, which fails to account for Henning’s contribution to
the combination of Balkrishna and Henning (see id.). Similarly, we are not
persuaded by Appellants’ contention that Henning does not disclose or
suggest the specific selection of two (Claim 6) or three (Claim 7) [PEGs]
from the list provided in [Appellants’] Claim 1, or the claimed amounts of
the [PEGs] or their use with trazodone, which fails to account for
Balkrishna’s contribution to the combination of Balkrishna and Henning”
(see id. at 19—20).
Claim 8:
Appellants’ claim 8 depends from and further limits Appellants’ claim
1 to require that trazodone hydrochloride is present in the composition in an
amount of between 4% and 6% (w/v) (App. Br. ii).
As discussed above, the combination of Balkrishna and Henning
suggests a stable liquid pharmaceutical formulation comprising about 0.5—
5% trazodone hydrochloride and having a pH in the range of 2.5—5.5 (see
FF 6; see generally FF 1—5, and 8). Overlapping ranges support a prima
facie case of obviousness. See In re Geisler, 116 F.3d at 1468.
Therefore, for the reasons set forth above, we are not persuaded by
Appellants’ contentions regarding pH or Appellants’ contention that an
“artisan reading the disclosures of Balkrishna and Henning would not be led
to an expectation of success for Claim 8” (App. Br. 20-21).
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Claims 9 and 10:
Appellants’ claims 9 and 10 depend from and further limit Appellants’
claim 1 to comprise trazodone hydrochloride in an amount of: between 6%
and 8% (w/v) (claim 9) and about 6% (w/v) (claim 10) (App. Br. ii).
Dismissing Balkrishna’s disclosure of a stable liquid pharmaceutical
formulation comprising a “therapeutically effective amount” of trazodone or
its pharmaceutically acceptable salts, Appellants rely on select preferred
embodiments of Balkrishna’s disclosure and Balkrishna’s examples to
support their contention that “contrary to [] Examiner’s allegations, the
artisan would not have found a trazodone hydrochloride amount of between
6% to 8% (w/v) (Claim 9) or of about 6% (w/v) (Claim 10) to be even prima
facie obvious” (App. Br. 22). We are not persuaded.
Notwithstanding Appellants’ contention to the contrary, Balkrishna is
not limited to its preferred or exemplified disclosure. Balkrishna is, instead,
available for all that it discloses, which includes a formulation comprising a
therapeutically effective amount of trazodone HC1 (see FF 3). In re
Lamberti, 545 F.2d at 750; see also App. Br. 13 (Appellants “agree[] that it
is well-established that consideration of a reference is not limited to the
preferred embodiments or working examples”; Reply Br. 13). On this
record, Appellants fail to establish that a therapeutically effective amount of
trazodone HC1 is limited to a composition comprising 0.5 to 5% trazodone
HC1 or that a person of ordinary skill in this art, at the time of Appellants’
claimed invention, would not have found it prima facie obvious to optimize
the amount of trazodone HC1 in the composition suggested by the
combination of Balkrishna and Henning to include therapeutically effective
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amounts of about 6% (w/v) or between 6% and 8%. See In re Aller, 220
F.2d at 456.
On this record, Appellants’ reliance on In re Sebek, 465 F.2d 904, 907
(CCPA 1972), does not compel a different result (see App. Br. 22; see also
Reply Br. 16). To the contrary, the Sebek court held that
while it may ordinarily be the case that the determination of
optimum values for the parameters of a prior art process would
be at least prima facie obvious, that conclusion depends upon
what the prior art discloses with respect to those parameters.
Where, as here, the prior art disclosure suggests the outer limits
of the range of suitable values, and that the optimum resides
within that range, and where there are indications elsewhere
that in fact the optimum should be sought within that range, the
determination of optimum values outside that range may not be
obvious.
In re Sebek, 465 F.2d at 907. Notwithstanding Appellants’ contentions to
the contrary, Appellants failed to establish an evidentiary basis on this
record to support a conclusion that Balkrishna limits the “optimum” or
therapeutically effective amount of trazodone HC1 to the range of 0.5 to 5%
(see App. Br. 22).
Claims 13 and 18:
Appellants’ claim 13 depends from and further limits the propylene
glycol and PEG components of Appellants’ claim 1 to the group consisting
of: propylene glycol + PEG 200, propylene glycol + PEG 400, propylene
glycol + PEG 6000, propylene glycol + PEG 200 + PEG 6000, and
propylene glycol + PEG 400 + PEG 6000 (App. Br. ii-iii).
Appellants’ claim 18 depends from and further limits the PEG
component of Appellants’ claim 1 to “one or two cosolvents wherein said
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cosolvents are selected from the group consisting of polyethylene glycol
200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol
600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene
glycol 3000; polyethylene glycol 3350, polyethylene glycol 4000, and
polyethylene glycol 6000” (App. Br. iii).
As discussed above, Balkrishna’s disclosure encompasses a
composition comprising both propylene glycol and PEGs (FF 4 and 6). In
addition, as Appellants’ recognize, Henning discloses that PEGs within the
scope of Appellants’ claimed invention were known in the art, prior to
Appellants’ filing date, for use as excipients in pharmaceuticals (FF 8; see
generally App. Br. 19). Thus, the combination of Balkrishna and Henning
suggests a composition comprising both propylene glycol and one or more
PEG falling within the scope of Appellants’ claimed invention (see FF 4, 6,
and 8). Merck & Co. Inc. v. Biocraft Laboratories, Inc., 874 F.2d at 807
(“[D]isclos[ure of] a multitude of effective combinations does not render any
particular formulation less obvious”).
Therefore, we are not persuaded by Appellants’ contention that
“neither Balkrishna nor Henning disclose or suggest the[] specific
combinations” required by Appellants’ claims 13 and 18 (App. Br. 20).
Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. at 335 (“Reading a
list and selecting a known compound to meet known requirements is no
more ingenious than selecting the last piece to put into the last opening in a
jig-saw puzzle. It is not invention”).
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The rejection over the combination of Balkrishna, Henning, and Dow.
Appellants’ claim 17 depends ultimately from and further limits the
composition of Appellants’ claim 1 to comprise a chelating agent selected
from a group which includes EDTA (App. Br. iii).
Based on the combination of Balkrishna, Henning, and Dow,
Examiner concludes that, at the time Appellants’ invention was made, it
would have been prima facie obvious “to use a chelating agent such as
EDTA or its salts[, as suggested by DOW,] in the formulation of [an]
aqueous stable liquid trazodone pharmaceutical composition” suggested by
the combination of Balkrishna and Henning, which comprises chelating
agents (Ans. 5—6; see also id. at 21—22; FF 9).
We are not persuaded by Appellants’ contention that “[a]t not point
does Dow disclose or suggest a stable liquid pharmaceutical composition
containing trazodone hydrochloride at a pH ranging from 5.0 to 6.0 as
claimed,” which fails to account for the disclosures of Balkrishna and
Henning in the combination of Balkrishna, Henning, and Dow (see App. Br.
23; see Reply Br. 20-21; cf. FF 1-9).
Appellants do not dispute that EDTA was a well-known chelating
agent at the time of Appellants’ claimed invention (see App. Br. 23—24;
Reply Br. 20—21). Instead, Appellants contend that “[t]here is nothing in
Dow much less Balkrishna or Henning to suggest how EDTA would
function in a trazodone-containing composition as claimed much less
whether the resulting composition would be stable” and “Balkrishna’s
generic disclosure of a chelating agent does not provide any reasonable
expectation of success for any and all chelating agents, especially when one
considers that based on the disclosure of Balkrishna and as supported by the
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Curatolo Declaration, the skilled artisan would not have thought it possible
to obtain a stable trazodone hydrochloride solution with such a high pH and
high concentration” (App. Br. 23; see Reply Br. 21). We are not persuaded.
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Inti Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). On this record,
Appellants failed to establish an evidentiary basis to support a conclusion
that a person of ordinary skill in this art would not have found it prima facie
obvious to utilize EDTA as the chelating agent in the composition suggested
by the combination of Balkrishna and Henning. It is well settled that
argument by counsel cannot take the place of evidence. In re Geisler, 116
F.3d at 1471 (Fed. Cir. 1997).
For the reasons set forth above, we are not persuaded by Appellants’
contention, with reference to the Curatolo Declaration, that a person of
ordinary skill in this art would not have found it prima facie obvious to
formulate a stable composition within the scope of Appellants’ claimed
invention with a reasonable expectation of success in view of the
combination of Balkrishna, Henning, and Dow (see App. Br. 23—24).
CONCFUSION OF FAW
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness.
The rejection of claims 1, 2, 4—10, 13, and 18 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Balkrishna and Henning is
affirmed. Claims 14—16 are not separately argued and fall with claim 1.
The rejection of claim 17 under 35 U.S.C. § 103(a) as unpatentable
over the combination of Balkrishna, Henning, and Dow is affirmed.
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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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