Ex Parte Testa et al

Board of Patent Appeals and Interferences

Jan 18, 2011

10933455 (B.P.A.I. Jan. 18, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte RAYMOND THOMAS TESTA, JASON CALHOUN,
JON TERRY MADER, and DONNA MADER
__________

Appeal 2010-009744
Application 10/933,455
Technology Center 1600
__________

Before TONI R. SCHEINER, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating bone infections with tigecycline. The Examiner rejected the
claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm-
in-part.

1 The two-month time period for filing an appeal or commencing a
civil action, as recited in 37 C.F.R. § 1.304, or for filing a request
for rehearing, as recited in 37 C.F.R. § 41.52, begins to run from
the “MAIL DATE” (paper delivery mode) or the
“NOTIFICATION DATE” (electronic delivery mode) shown on
the PTOL-90A cover letter attached to this decision.
Appeal 2010-009744
Application 10/933,455

2
Statement of the Case
The Claims
Claims 1-42 are on appeal. Claims 1, 2, 3, 24, 25, and 26 are
representative, and the remaining claims have not been argued separately
and therefore stand or fall together with claims 1 and 24. 37 C.F.R.
§ 41.37(c)(1)(vii). Claims 1, 3, 24, and 26 read as follows:
1. A method of treating an infection in bone or
bone marrow in a mammal comprising
administering to the mammal a pharmacologically
effective amount of tigecycline.

3. The [method of claim 1 further comprising
administering an antimicrobial agent] where the
antimicrobial is rifampin.

24. A method of treating a joint infection or an
infection of surrounding tissues of the joint in a
mammal comprising administering to the mammal
a pharmacologically effective amount of
tigecycline.

26. The [method of claim 24 further comprising
administering an antimicrobial agent] where the
antimicrobial is rifampin.

The issue
The Examiner rejected claims 1-42 under 35 U.S.C. § 103(a) as
obvious over Sayada,2 Rothstein,3 and Merck4 (Ans. 3-7).

2 Sayada, Chalom, US 2003/0236265 A1, published Dec. 25, 2003.
3 Rothstein et al., Development potential of rifalazil, 12 EXPERT
OPINION INVESTIG. DRUGS 255-271 (2003).
4 Merck Manual, 7th Edition 455-460 (1999).
Appeal 2010-009744
Application 10/933,455

3
The Examiner finds that
Sayada teaches treatment of multi drug resistant
strains of bacteria, particularly Gram-positive bacterial
infections ([0030] including vancomycin resistant,
quinolone resistant (moxifloxacin is a quinolone type
antibiotic) (paragraph [0029-0031] comprising
administration of tigecycline (paragraph [0038] and [0063],
combined with rifamycin type antibiotics such as for
treatment of diseases associated with bacterial infections of
the bone and joint (paragraphs [0027] and [0072]).
Treatment of mammals is recited . . .

(Ans. 4). The Examiner finds that “Sayada does not teach the combination
of tigecycline with rifampin specifically, however, Sayada teaches the
combination of tigecycline with a rifamycin type antibiotic of formula I such
as rifalazil” (id. at 5). The Examiner finds that “Rothstein et al. teach that
rifalazil was developed to replace rifampin and as a result of its superior
antimicrobial activity and high intracellular levels, rifalazil has potential to
treat indications caused by intracellular pathogens” (id.).
The Examiner finds it obvious “to interchange or select rifampin or
the rifalazil taught in Sayada for the predictable result of treating bone and
joint infections motivated by the knowledge of one skilled in the art that
either agent would work for treatment of the recited pathogens” (id.).
Appellants contend that in
order to obtain the invention of claim 1 based on the
teachings of Sayada, one skilled in the art would have to
take “pick” tigecycline out of the more than 110 antibiotics
of [0063] or [0038] of Sayada and bone or joint infections
out of the more than twenty indications or conditions listed
in [0027] of Sayada.

Appeal 2010-009744
Application 10/933,455

4
(App. Br. 4.) Appellants contend that “out of over 2,200 possible
combinations of an antibiotic with a condition, one skilled in the art would
have to choose the only one that corresponds to instant claim 1 (directed to
the treatment of infection in bone or bone marrow) or instant claim 24” (id.).
Appellants contend that, in an example in the Specification, “a patient
suffering from osteomyelitis did not benefit from treatment with a number of
drugs (lines 20-25). In contrast, tigecycline effectively treated osteomyelitis
(lines 27-30), a surprising result given that all the aforementioned active
agents had failed” (id. at 5).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that the prior art renders obvious the instant claims?
(ii) If so, have Appellants provided evidence of unexpected results
that outweighs the evidence supporting the prima facie case of obviousness?
Findings of Fact
1. Sayada teaches “[g]ram-positive bacterial infections that can be
treated according to the method of the invention include infections by
Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis,
Enterococcus faecium, Clostridium perfringens, Streptococcus pyogenes,
Streptococcus pneumoniae, other Streptococcus spp., and other Clostridium
sp” (Sayada 3 ¶ 0030).
2. Sayada teaches that “[m]ulti-drug resistant strains of bacteria
can be treated according to the methods of the invention. Resistant strains of
bacteria include . . . quinolone-resistant, macrolide-resistant, and/or
vancomycin-resistant bacterial strains” (Sayada 3 ¶ 0031).
Appeal 2010-009744
Application 10/933,455

5
3. Sayada teaches “a pharmaceutical composition that includes (i)
a rifamycin antibiotic of formula (I) and a second antibiotic selected from . .
. tigecycline” (Sayada 3-4 ¶ 0038).
4. Sayada teaches that the “compositions of the present invention
can be used to treat . . . bone and joint infections” (Sayada 6 ¶ 0072).
5. Sayada teaches that the “patient can be any warm-blooded
animal including but not limited to a human, cow, horse, pig, sheep, bird,
mouse, rat, dog, cat, monkey, baboon, or the like. It is most preferred that
the patient be a human” (Sayada 2 ¶ 0023).
6. The Examiner finds that “Sayada does not teach the
combination of tigecycline with rifampin specifically, however, Sayada
teaches the combination of tigecycline with a rifamycin type antibiotic of
formula I such as rifalazil (paragraph [0009])” (Ans. 5).
7. Rothstein teaches that “[r]ifalazil represents a new generation of
ansamycins that contain a unique four-ring structure. Originally rifalazil
was developed as a therapeutic agent to replace rifampin as part of a
multiple drug regimen in the treatment of tuberculosis” (Rothstein 255
abstract).
8. Rothstein teaches that as “a result of its superior antimicrobial
activity and high intracellular levels, rifalazil has potential to treat
indications caused by the intracellular pathogen, Chlamydia trachomatis”
(Rothstein 255, abstract).

Appeal 2010-009744
Application 10/933,455

6
9. Figure 3 of the Specification is reproduced below:

“Figure 3 shows the colony-forming units per gram of marrow and bone in
each of the treatments” (Spec. 5, ll. 3-4).
Principles of Law
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445
(Fed. Cir. 1992). “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).
Prima facie obviousness can be rebutted by presenting evidence of
secondary considerations and when such evidence is submitted, all of the
evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472-
1473 (Fed. Cir. 1984). Secondary considerations include: long-felt but
Appeal 2010-009744
Application 10/933,455

7
unsolved needs, failure of others, unexpected results, commercial success,
copying, licensing, and praise. In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir.
1998); U.S. Surgical Corp. v. Ethicon, Inc., 103 F.3d 1554, 1565 (Fed. Cir.
1997).
Analysis
Claims 1 and 24
Sayada teaches compositions for treatment of multi-drug resistant
bacterial strains which comprise rifamycin and a second antibiotic selected
from a group which comprises tigecycline (FF 1-3). Sayada teaches that the
composition can be applied to a variety of diseases including bone and joint
infections, and that the compositions are used in mammals (FF 4-5).
Rothstein teaches that rifampin is a known equivalent of rifamycin (FF 7-8).
Applying the KSR standard of obviousness to the findings of fact, we
agree with the Examiner that it would have been obvious to treat bone
infections in mammals with tigecycline since Sayada expressly teaches
treatment with compositions which may include tigecycline, may be applied
to bone infections and may be administered to mammals. Such a
combination is merely a “predictable use of prior art elements according to
their established functions.” KSR, 550 U.S. at 417.
Appellants contend that in
order to obtain the invention of claim 1 based on the
teachings of Sayada, one skilled in the art would have to
take “pick” tigecycline out of the more than 110 antibiotics
of [0063] or [0038] of Sayada and bone or joint infections
out of the more than twenty indications or conditions listed
in [0027] of Sayada

Appeal 2010-009744
Application 10/933,455

8
(App. Br. 4-5). Appellants contend that “out of over 2,200 possible
combinations of an antibiotic with a condition, one skilled in the art would
have to choose the only one that corresponds to instant claim 1 (directed to
the treatment of infection in bone or bone marrow) or instant claim 24”
(App. Br. 4).
We are not persuaded. Sayada specifically lists tigecycline as a useful
antibiotic. See Perricone v. Medicis Pharm. Corp. 432 F.3d 1368, 1376
(Fed. Cir. 2005) (“This court rejects the notion that one of [14 listed]
ingredients cannot anticipate because it appears without special emphasis in
a longer list.”); see also Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804,
807 (Fed. Cir. 1989) (holding that the prior art’s disclosure of a multitude of
combinations failed to render any particular formulation less obvious).
In the instant case, the rejection is obviousness, not anticipation, so it
is only necessary that the teaching of Sayada render obvious the use of
tigecycline for treatment of bone infections (FF 1-5). In Gleave, the Federal
Circuit expressly addressed the issue of lists of large numbers of
compounds, where the “list includes more than 1400 sequences.” In re
Gleave, 560 F.3d 1331, 1333 (Fed. Cir. 2009). The Court, found that
“Wraight expressly lists every possible fifteen-base-long
oligodeoxynucleotide sequence in IGFBP-2, and under our precedent, this
list anticipates Gleave’s claims.” Id. at 1338. Consequently, we find that
Sayada reasonably renders claims 1 and 24 obvious.
Appellants contend that, in an example in the Specification, “a patient
suffering from osteomyelitis did not benefit from treatment with a number of
drugs (lines 20-25). In contrast, tigecycline effectively treated osteomyelitis
Appeal 2010-009744
Application 10/933,455

9
(lines 27-30), a surprising result given that all the aforementioned active
agents had failed” (App. Br. 5).
We are not persuaded. Claims 1 and 24 are drawn to treatment of
bone infections with tigecycline. The asserted unexpected results are found
at page 15 of the Specification, which teaches that a particular patient who
had been treated with certain drugs “was reported doing well ten weeks post
treatment with tigecycline” (Spec. 15, ll. 20-30). The evidence of record
does not demonstrate that successful treatment of a patient with tigecycline
sensitive infection is unexpected. Appellants have the burden of showing
that the claimed invention imparts not just any improvement, but an
unexpected improvement. In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972);
see also In re Skoner, 517 F.2d 947, 948 (CCPA 1975) (Expected results are
evidence of obviousness just as unexpected results are evidence of
unobviousness). Appellants have provided no evidence that the result here
was unexpected.
Appellants also argue that “the treatment of a group of rabbits with
tigecycline resulted in a lower count of colony forming units (CFU’s) in
bone and marrow than both an untreated control group and a group treated
with vancomycin” (App. Br. 5).
The data in Figure 3 of the Specification shows that tigecycline had
statistically significant improvement relative to an untreated control, but
does not show such a difference relative to treatment with vancomycin
alone, even if vancomycin was the closest prior art. We are not persuaded
that the data for treatment with tigecycline alone demonstrates unexpected
results. Also, the data was not compared with the disclosure of Sayada,
Appeal 2010-009744
Application 10/933,455

10
which would represent the closest prior art. See In re Baxter Travenol Labs.,
952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art.”).
Claim 2, 3, 25, and 26
Appellants separately argue claim 2, and specifically argue that there
“is no guidance in Sayada to select either tigecycline or rifampin, let alone
both in combination” (App. Br. 6).
We are not persuaded. Sayada expressly teaches treatment with
rifamycin and a second antibiotic, which second antibiotic may be
tigecycline (FF 1-5). Rothstein teaches rifamycin type antibiotics including
rifampin (FF 7-8). We agree with the Examiner that selection of these two
types of antibiotics for treatment of bone infection was reasonably obvious.
See Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989)
(holding that the prior art’s disclosure of a multitude of combinations failed
to render any particular formulation less obvious).
Appellants, relying upon figure 3, argue that the “superior efficacy of
the tigecycline + rifampin combination is therefore unexpected” (App. Br.
8). With regard to claims 2 and 25, which are not limited to tigecycline +
rifampin, but may include second antibiotics other than rifampin, we are not
persuaded since the unexpected results are not commensurate in scope with
the degree of protection sought. See In re Harris, 409 F.3d 1339, 1344 (Fed.
Cir. 2005) (Unexpected results must also be “commensurate in scope with
the degree of protection sought by the claimed subject matter.”)
Appeal 2010-009744
Application 10/933,455

11
However, with regard to claims 3 and 26, which are limited to
treatment with tigecycline and rifampin, we find the results of the
combination relative to the combination of vancomycin and rifampin
persuasive of unexpected results. Unlike tigecycline alone, which does not
fully eliminate the positive cultures in both samples, the combination of
tigecycline and rifampin “demonstrated no infection in bone in 10 rabbits
while controls showed infection in 11 of 15 rabbits. Treatment in bone
marrow also demonstrated no infection in 10 rabbits” (Spec. 17, ll. 1-3).
The Specification further notes that the “association of tigecycline and
rifampin allowed the complete eradication of bacteria from the bone and
marrow, whereas in the vancomycin plus rifampin group a sample was still
positive” (Spec. 17, l. 33 to 18, l. 2).
The Examiner finds that “the prior art teach the same superiority over
vancomycin combinations (vancomycin resistant bacterial strains (paragraph
31)” (Ans. 11).
We disagree, since paragraph 31 of Sayada does not show the same
result as that demonstrated in the Specification. That is, the Specification
shows that in methicillin-resistant S. aureus, the combination of tigecycline
and rifampin works better than vancomycin and rifampin (see Spec. 17, ll.
28-33). At best, Sayada might suggest that the combination of tigecycline
and rifampin would be superior to vancomycin and rifampin in vancomycin-
resistant organisms, but paragraph 31 does not render obvious the superior
results in methicillin-resistant S. aureus.

Appeal 2010-009744
Application 10/933,455

12
Conclusion of Law
(i) The evidence of record supports the Examiner’s conclusion that the
prior art renders obvious the instant claims.
(ii) Appellants have provided evidence of unexpected results that
outweighs the evidence supporting the prima facie case of obviousness for
claims 3 and 26.
SUMMARY
In summary, we affirm the rejection of claims 1, 2, 24, and 25 under
35 U.S.C. § 103(a) as obvious over Sayada, Rothstein, and Merck. Pursuant
to 37 C.F.R. § 41.37(c)(1)(vii)(2006), we also affirm the rejection of claims
4-23 and 27-42, as these claims were not argued separately.
We reverse the rejection of claims 3 and 26 under 35 U.S.C. § 103(a)
as obvious over Sayada, Rothstein, and Merck.

AFFIRMED-IN-PART

cdc

WYETH LLC
PATENT LAW GROUP
5 GIRALDA FARMS
MADISON, NJ 07940