Ex Parte Bilgic

Patent Trial and Appeal Board

Sep 19, 2018

13692138 (P.T.A.B. Sep. 19, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/692,138 12/03/2012
21559 7590
CLARK & ELBING LLP
101 FEDERAL STREET
BOSTON, MA 02110
09/21/2018
FIRST NAMED INVENTOR
Mahmut Bilgic
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
50840-034001 2563
EXAMINER
CABRAL, ROBERTS
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
09/21/2018 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):
patentadministrator@clarkelbing.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MAHMUT BILGIC 1
Appeal2017-009804
Application 13/692,138
Technology Center 1600
Before DEMETRA J. MILLS, RICHARD M. LEBOVITZ, and
RYAN H. FLAX, Administrative Patent Judges.
MILLS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b ).
We affirm.
1 According to the Appeal Brief the real party in interest is the applicant,
Mahmut Bilgic. App. Br. 2.
Appeal2017-009804
Application 13/692,138
NATURE OF THE INVENTION
The Specification states that present inventors have "surprisingly found
that when cephalosporin antibiotic and clavulanic acid are mixed with the
granules comprising effervescent couple and at least one excipient in the
presence of high-molecular weight PEG [polyethylene glycol], gelling or
agglomeration problem of cefdinir and also [a] stability problem of
clavulanic acid are eliminated." Spec. 5.
STATEMENT OF CASE
The following claim is representative.
27. An effervescent formulation comprising the combination
of a cephalosporin antibiotic and clavulanic acid or
pharmaceutically acceptable derivatives thereof characterized in
that said formulation comprises;
10-40% by weight of a cephalosporin antibiotic,
5-25% by weight clavulanic acid,
20-70% by weight effervescent couple,
0.2-5% by weight high molecular weight PEG and
1-20% by weight other pharmaceutically acceptable
excipients with respect to the total weight of unit dose,
wherein said cephalosporin antibiotic and said clavulanic
acid are present in a stable and homogenously soluble form.
Cited References
Crowley
Smith
Gao
Translation).
Grounds of Rejection
WO 9607408Al
EP 1034784 A2
CNl 850087 (A)
Mar. 14, 1996
Sept. 13, 2000
(Oct. 25, 2006) (English
1. Claims 27, 40, 41, 45 and 52-56 stand rejected under 35 U.S.C.
§ 112(b) or 35 U.S.C. § 112, second paragraph, as being indefinite
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for failing to particularly point out and distinctly claim the subject
matter.
2. Claims 27, 40, 41, 45 and 52-56 stand rejected under pre-AIA 35
U.S.C. § 103(a) as being unpatentable over Smith in view of Gao
and Crowley.
FINDINGS OF FACT
The Examiner's findings of fact are set forth in the Final Action at
pages 4--9 and are adopted in this Decision. The following findings of fact
highlight certain evidence.
1. Smith teaches a composition using effervescent couple (see ,r 27),
which reads on an effervescent formulation, comprising a
cephalosporin (see ,r 11) such as disclosed (see ,r 12) including
cefixime (see ,r 12); 10 - 60% by weight of the active materials such
as salts of clavulanic acid (see ,r 32), which reads on pharmaceutically
acceptable derivative of clavulanic acid, in unit dosage form (see
,r 34). Final Act. 4.
2. Smith discloses that clavulanic acid is used in formulations in
combination with B-lactam antibiotics. ,r,r 2, 11.
3. According to Smith, its antibiotic effervescent
[0035] [F]ormulations may contain 0.1 - 90% by weight,
preferably from 10 - 60% by weight of the active
materials, depending on the method of administration.
[0036] The clavulanate may suitably be administered to
the patient at a daily dosage of from 0.3 to 15 mg/kg,
preferably from 0.7 to 10 mg/kg, for example from 0.7 to
7 mg/kg, of body weight. For an adult human (of
approximately 70 kg body weight), from 25 to 1000 mg,
preferably from 50 to 500 mg, of clavulanate expressed
as its free acid equivalent may be administered daily,
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Smith, p. 4.
suitably in from 1 to 6, preferably from 2 to 4, separate
doses. Higher or lower dosages may, however, be used
in accordance with clinical practice.
[0037] When the formulations according to the invention
are presented in unit dosage form, each unit dose may
suitably comprise from 12.5 to 1000 mg, preferably from
12.5 to 250 mg, of clavulanate. Each unit dose may, for
example, be 12.5, 25, 50, 75, 100, 125,150,200, or 250
mg of clavulanate.
4. Smith discloses an effervescent couple such as solid carboxylic acid
and an alkali metal carbonate (see ,r 27).
5. Smith discloses a lubricant such as polyethylene glycol (see ,r 27),
which is PEG.
6. Smith discloses other conventional excipients (see ,r 27) such as
binding agents (see ,r 27) and disintegrants (see ,r 27), which read on
other pharmaceutically acceptable excipients.
7. Smith discloses tablets formulations (see ,r 24), which read on tablet
form.
8. Smith discloses the ratio of the amount of the clavulanate to the
amount of any antibacterial agent (see ,r 38) such as cefixime (see
,r 12) is from 1:1 to 1:12 (see ,r 38) (Note: Providing salts of
clavulanate comprise 10 - 60% by weight in unit dosage form, the
cephalosporin must comprise at least 10 - 60% by weight in unit
dosage form according to a proportionality of the salts of clavulanate
to the cephalosporin of 1: 1.)
9. According to Smith, suitable unit dosages and maximum daily
dosages of any antibacterial agent used in combination with
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clavulanate may be determined according to the unit dosages and
maximum daily dosages of the agent used conventionally (see ,r 39);
and pharmaceutical formulation (see Abstract) using an effervescent
couple (see ,r 27) containing clavulanic acid and an antibacterial agent
(see Abstract) such as cefixime (see ,r 12).
10. Gao discloses an effervescent tablet containing cefixime (Abstract).
Final Act. 5.
11. The tablet of Gao wherein contains pharmaceutically-acceptable acid
base pair (see Abstract) causing releasing carbon dioxide after
chemical reaction (see page 3, second and third paragraphs), which
reads on effervescent couple, such as citric acid (see page 3, sixth
paragraph), which reads on carboxylic acid, and sodium carbonate
(see page 3, ninth paragraph), which is alkali metal carbonate. Final
Act. 5.
12. The acidic compound of Gao comprises 15-40% per weight of the
tablet (see page 3, eighth paragraph), which reads on unit dose, and
basic compound comprises 20-40% per tablet weight (see page 3,
eleventh paragraph). (Note: Thus, acid-base pair comprises a total of
35-80% per weight of the tablet.) Final Act. 5.
13. Gao discloses effervescent tablets add lubricant (0.1 to 5 per weight
%) (see page 4, sixth to ninth paragraphs) such as PEG 6000 (see page
4, eighth paragraph), which is a high molecular weight PEG (see page
7, second paragraph of instant specification) to ensure the preparation
process of cefixime effervescent smooth resistance
(see page 4, sixth paragraph); pharmaceutically-acceptable (see
Abstract) binder (0.1 to 5% per weight) (see page 4, third to fourth
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paragraphs), which is binding agent, and disintegrating agent (0-2%
weight) (see page 4, fifth to seventh paragraphs), which is disintegrant
(Note: Binder and disintegrating agent are other pharmaceutically
acceptable excipients which comprise a total of 0.1-7% per weight of
the tablet.); use of cefixime effervescent tablets for easy storage,
transport, carry, suitable for patients who cannot swallow solid dosage
(see page 2, last paragraph); contain disintegrants to further accelerate
the rate of disintegration of effervescent tablets (see page 4, fifth
paragraph); and add a binder to facilitate the combination of each
component in the effervescent tablet (see page 4, third paragraph).
Final Act. 5.
14. Crowley teaches pharmaceutically acceptable salts of clavulanic acid,
which is a B-lactamase inhibitor, referred as clavulanate (see page 1,
second paragraph) coformulated with an antibiotic compound such as
cephalosporins (see page 7, last paragraph), which is a lactamase
antibiotic (see page 7, last paragraph), e.g., cefixime (see page 8, first
paragraph), in a tablet (see page 9, fifth paragraph) to increase their
(antibiotics) resistance to the B-lactamase enzymes produced by
microorganisms (see page 1, second paragraph), thus preventing
bacterial resistance. Final Act. 6.
PRINCIPLES OF LAW
In making our determination, we apply the preponderance of the
evidence standard. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427
(Fed. Cir. 1988) (explaining the general evidentiary standard for proceedings
before the Office).
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"The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Claim indefiniteness
The Examiner argues that the claim term "stable" is indefinite. Ans.
3. The Examiner argues that,
[t]he term "stable" in claim 27 is a relative term which renders
the claim indefinite. The term "stable" is not defined by the
claim, the specification does not provide a standard for
ascertaining the requisite degree, and one of ordinary skill in
the art would not be reasonably apprised of the scope of the
invention.
Final Act. 3.
Appellant contends that one of skill in the art would appreciate that
the term "stable" as recited in the instant claims refers to formulations in
which the clavulanic acid moiety has undergone negligible hydrolysis of the
B-lactam functionality. App. Br. 3-4, italicized emphasis added.
We are not persuaded by Appellant's argument. The fact that claim
language includes words of degree, or relative terms that may not be precise,
does not automatically render the claim indefinite under Section 112, second
paragraph. Seattle Box Co. v. Industrial Crating & Packing, Inc., 731 F.2d
818, 826 (Fed. Cir. 1984). However, acceptability of the claim language
depends on whether one of ordinary skill in the art would understand what is
claimed, in light of the Specification. When a term of degree or relative
term is recited in a claim, the first determination is whether the Specification
provides some standard for measuring that degree. In re Oetiker, 951 F .2d
1267 (Fed. Cir. 1991). If the Specification provides no guidance, a
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determination is made as to whether one of ordinary skill in the art, in view
of the prior art, would nevertheless be reasonably apprised of the scope of
the invention. Seattle Box 731 F.2d at 825, 829. Even if the Specification
uses the same term as the claim, a rejection may be proper if the scope of the
term would not be understood when read in light of the Specification.
Here, we find that the Examiner has the better position. While
Appellant does present attorney argument as to how they believe one of
ordinary skill in the art would understand the meaning of the term "stable"
when read in light of the Specification (App. Br. 3-4), that meaning is not
supported by the Specification itself. Unsupported attorney argument,
presented for the first time on appeal, is an inadequate substitute for record
evidence. See Gemtron Corp. v. Saint-Gobain Corp., 572 F.3d 1371, 1380
(Fed. Cir. 2009) (emphasizing that "unsworn attorney argument ... is not
evidence"). See also Becton, Dickinson and Co. v. Tyco Healthcare Group
LP, 616 F.3d 1249, 1259 (Fed. Cir. 2010).
In particular, Appellant argues that the term "stable" means that the
"clavulanic acid moiety has undergone negligible hydrolysis of the B-lactam
functionality." App. Br. 5, italicized emphasis added. The term or concept
of "negligible hydrolysis" does not appear in the Specification as filed, and
such interpretation is not supported with evidence directing our attention to
any cited prior art or other supporting evidentiary disclosure. For example,
the term "stable" could mean 1 % hydrolysis, 25% hydrolysis, or up to 50%
hydrolysis (99% stability, 75% stability, 50% stability) of the clavulanic acid
moiety, depending upon how those of ordinary skill in the art routinely
interpret the term. There is no evidence presented by Appellant regarding
the degree of hydrolysis of the clavulanic acid tolerated in the art, or
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associated with degree of stability of the compound. Without such evidence
the claim terms cannot be properly interpreted.
The claim indefiniteness rejection is affirmed.
Obviousness Rejection - Smith, Gao, Crowley
Appellant does not argue individual claims separately, therefore we
select claim 27 as representative claim.
Smith teaches an effervescent formulation comprising a
cephalosporin, which can be cefixime. The Smith formulation may include
10-60% active materials including salts of clavulanic acid. Smith's
effervescent formulation includes an effervescent couple, such as solid
carboxylic acid and an alkali metal carbonate. Smith's tablet may include a
lubricant, such as polyethylene glycol (PEG). In Smith,
the ratio of the amount of the clavulanate to the amount of any
antibacterial agent (see [0038]) such as cefixime (see [0012])
is from 1: 1 to 1: 12 (see [0038]) (Note: Providing salts of
clavulanate comprise 10 - 60% by weight in unit dosage form,
the cephalosporin must comprise at least 10 - 60% by weight
in unit dosage form according to a proportionality of the salts
of clavulanate to the cephalosporin of 1: 1.)
Final Act 4. Smith does not specify that the PEG is a high molecular weight
PEG. Final Act. 4. The Examiner relies on the disclosure of Gao for the
conventional inclusion of PEG 6000 in an effervescent antibiotic tablet.
Appellant contends that
Smith fails to teach or suggest effervescent cephalosporin
formulations containing clavulanic acid and high molecular
weight PEG that are stable and water-soluble. Importantly, the
relevant examples set forth in Smith are limited to experiments
in which the antibiotic and clavulanic acid are dissolved
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separately in individual aqueous solutions prior to
administration to animal subjects. Indeed, nowhere in Smith is
there any empirical showing whatsoever that cephalosporin and
clavulanic acid can be co-formulated in a water-soluble
composition of any kind, much less one in which the clavulanic
acid component is protected from hydrolysis.
App. Br. 5.
Appellant additionally argues that
Gao and Crowley fail to remedy this deficiency, as neither of
these documents provide any examples of a cephalosporin
antibiotic and clavulanic acid or a pharmaceutically acceptable
derivative thereof coformulated in a water-soluble dosage form.
Instead, Gao describes effervescent cefixime formulations
devoid of clavulanic acid altogether. Crowley merely describes
the utility of clavulanic acid as a B-lactamase inhibitor in
antibiotic formulations, and provides no teaching or suggestion
as to the development of water soluble cephalosporin
formulations containing clavulanic acid.
App. Br. 5.
ANALYSIS
We agree with the Examiner's fact finding, statement of the rejection,
and responses to Appellant's arguments as set forth in the Answer. We find
that the Examiner has provided evidence to support a prima facie case of
obviousness, which Appellant has not persuasively shown to be in error. We
provide the following additional comment to the Examiner's argument set
forth in the Final Rejection and Answer. The claimed ranges of formulation
components are:
10-40% by weight of a cephalosporin antibiotic,
5-25% by weight clavulanic acid,
20-70% by weight effervescent couple,
0.2-5% by weight high molecular weight PEG and
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1-20% by weight other pharmaceutically acceptable excipients with
respect to the total weight of unit dose.
Smith is a very good prior art reference that essentially teaches similar
ranges of antibiotic effervescent formulation ingredients, which overlap the
claimed formulation component ranges. For example, the claimed ranges of
active ingredients (including combinations of active ingredients) are
disclosed to be 10-60% of the formulation. FF 1-3. Smith's formulation
may be an effervescent tablet formulated with an effervescent couple, and
polyethylene glycol. FF 4--5. Gao discloses that it is conventional in the
effervescent antibiotic art to include 0.1-5% of a lubricant in each tablet.
Gao 4. The lubricant may be PEG 4000-6000. Id. Gao discloses a
minimum amount of acidic component to be 15% and a minimum amount of
basic compound to be 20%. 2 Id. at 3. Thus, the combined percent of the
effervescent couple is 35% falling within the claimed range of20-70% of
effervescent couple. Gao also includes 0-8% of a disintegrant, falling within
the claimed range of acceptable excipients. Id. at 4. There is motivation to
combine the cited references as they are both from the antibiotic effervescent
tablet art. The effervescent formulation of the primary reference, Smith,
includes polyethylene glycol, and Gao is cited to show typical or
conventional types and amounts of polyethylene glycol used in effervescent
tablets. "The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007).
2 The acidic and basic components of Gao form an effervescent couple. Gao
3--4.
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Thus, the claimed formulation is obvious over the cited prior art
combination. Appellant argues that the relevant examples set forth in
Smith are limited to experiments in which the antibiotic and clavulanic acid
are dissolved separately in individual aqueous solutions prior to
administration to animal subjects. App. Br. 5. We are not persuaded. Smith
discloses many types of formulations including, "tablets, capsules, powders,
granules, lozenges, creams or liquid preparations, such as oral or sterile
parenteral solutions or suspensions." Smith i-f24. Smith also discloses that,
"clavulanate and an antibacterial agent such as the penicillin or
cephalosporin antibiotics, e.g amoxycillin, cefaclor or cefprozil, may be
administered together, simultaneously, successively or in any order, but
typically may be administered together as a co-formulation." Smith i-f23.
Gao and Crowley also disclose solid effervescent antibiotic formulations.
See, Gao, p. 3-4; Crowley, p. 1.
We conclude that a prima facie case of obviousness has been made in
this case. In particular,
Selecting a narrow range from within a somewhat broader
range disclosed in a prior art reference is no less obvious than
identifying a range that simply overlaps a disclosed range. In fact,
when, as here, the claimed ranges are completely encompassed by
the prior art, the conclusion is even more compelling than in cases of
mere overlap. The normal desire of scientists or artisans to improve
upon what is already generally known provides the motivation to
determine where in a disclosed set of percentage ranges is the
optimum combination of percentages. See In re Boesch, 617 F .2d
272, 276, (CCPA 1980) ("[D]iscovery of an optimum value of a
result effective variable in a known process is ordinarily within the
skill of the art." (Citations omitted)).
In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003).
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We are not persuaded by Appellant's arguments to the contrary, that
no prima facie case has been made by the Examiner. Essentially all of the
claimed formulation components are known in similar amounts, as shown in
the cited prior art. While Appellant argues surprising improvements in
solubility, stability and dissolution over prior art formulations (Spec. 5, App.
Br. 6), they do not provide evidence of unexpected results. Attorney
argument cannot take the place of evidence, and Appellants have not
compared formulation results with those of the closet prior art. Nor are
these features, characteristics, or attributes clearly recited in the claims. The
burden of demonstrating unexpected results rests on the party asserting
them, and "it is not enough to show that results are obtained which differ
from those obtained in the prior art; that difference must be shown to be an
unexpected difference." In re Klosak, 455 F.2d 1077, 1080, 173 USPQ 14,
16 (CCP A 1972). In addition, "[ m Jere improvement in properties does not
always suffice to show unexpected results." In re Soni, 54 F.3d 746, 751
(Fed. Cir. 1995). Moreover, it has been long held that "even though
applicant's modification results in great improvement and utility over the
prior art, it may still not be patentable if the modification was within the
capabilities of one skilled in the art, unless the claimed ranges 'produce a
new and unexpected result which is different in kind and not merely in
degree from the results of the prior art." In re Huang, 100 F.3d 135, 139, 40
USPQ2d 1685, 1688 (Fed. Cir. 1996) (quoting In re Aller, 220 F.2d 454,
456, 105 USPQ 233,235 (1955), and citing In re Woodruff, 919 F.2d 1575,
1578, 16 USPQ2d 1934, 1936-37 (Fed. Cir. 1990)). Appellant has not
provided legally sufficient evidence of unexpected results in this case.
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"From the standpoint of patent law, a compound and all of its
properties are inseparable; they are one and the same thing." In re Papesch,
315 F.2d 381,391 (CCPA 1963). Thus, the prior art antibiotic effervescent
formulations including similar ranges of similar components are assumed to
possess the same properties.
The Examiner has additionally argued that the claimed invention is a
result of optimization of known result effective variables in the art. Ans. 6.
Appellant provides no evidence to support the position that one of ordinary
skill in the art is not selecting from result effective variables.
The obviousness rejection is affirmed for the reasons of record.
CONCLUSION OF LAW
The cited references support the Examiner's obviousness rejection,
which is affirmed for the reasons of record.
The claim indefiniteness rejection is also affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l )(iv).
AFFIRMED
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