Ex Parte Kokai-Kun et al

Board of Patent Appeals and Interferences

Aug 29, 2008

10323907 (B.P.A.I. Aug. 29, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte JOHN FITZGERALD KOKAI-KUN,
SCOTT MICHAEL WALSH,
JAMES JACOB MOND,
and
TATYANA IVANOVA CHANTURIYA,
Appellants
____________________

Appeal 2008-4627
Application 10/323,9071
Technology Center 1600
____________________

Decided: August 29, 2008
____________________

Before CAROL A. SPIEGEL, RICHARD M. LEBOVITZ, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

SPIEGEL, Administrative Patent Judge.

DECISION ON APPEAL

1 Application 10/323,907 ("the 907 application"), "Methods and
Formulations for Eradicating or Alleviating Staphylococcal Nasal
Colonization using Lysostaphin," filed 20 December 2002, claims benefit
under 35 U.S.C. § 119 of provisional application 60/341,802, filed 21
December 2001. The real party in interest is said to be BIOSYNEXUS
INCORPORATED (Corrected Appellants' Brief, filed 19 December 2007
("App. Br."), at 3).
Appeal 2008-4627
Application 10/323,907

I. Statement of the Case
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 17-27, 30-53, and 56-60. Claims 28, 29, 54, and 55, the only other
pending claims, stand objected to (FR2 1). We have jurisdiction under 35
U.S.C. § 6(b). We AFFIRM.
The subject matter on appeal is directed to nasal administration of a
composition comprising at least 0.125% lysostaphin in either a cream-based
or polymer-containing liquid-based viscous formulation to reduce or
eliminate bacterial colonization in the nose to prevent subsequent infection.
Claim 17 and 51 are illustrative and read (App. Br. 16 and 20):
17. A method for treating a patient comprising,
administering to the nose of said patient via one or
more instillations, an effective amount of a
composition comprising a) a viscous formulation,
wherein said viscous formulation is selected from
the group consisting of a cream-based formulation
and a viscous liquid-based formulation comprising
a polymer, and b) at least 0.125% lysostaphin,
wherein said composition is effective at treating or
preventing bacterial colonization.
51. A method for treating a patient by
administering to the nose of said patient via one or
more installations an effective amount of a
lysostaphin intranasal consisting of a viscous
formulation, wherein said viscous formulation is
selected from the group consisting of a cream-
based formulation and a viscous liquid-based
formulation comprising a polymer, and at least
0.125% lysostaphin.

2 Final Office action mailed 26 October 2006.
2
Appeal 2008-4627
Application 10/323,907

The Examiner has rejected claims 17-27, 30-53, and 56-60 under 35
U.S.C. § 103(a) as unpatentable over Fischetti 954,3 Fischetti 324,4 Climo,5
and O'Callaghan6 (FR 2-3; Ans.7 3-5).
Appellants have not argued the patentability of claims 18-25, 28-33,
35-50, and 54-60 apart from the independent claims on which they depend.
Consequently, we decide this appeal on the basis of independent claims 17,
34, 51, and 52. 37 CFR § 41.37(c)(1)(v).
II. Findings of Fact ("FF")
The following findings of fact, and those set forth in the Discussion,
are supported by a preponderance of the evidence of record.
A. Appellants' invention
[1] Appellants' invention "relates to the administration of lysostaphin
intranasals to the nares to alleviate or block staphylococcal nasal
colonization" (Spec. ¶ 9).
[2] Lysostaphin is an endopeptidase which cleaves cross-linking
pentaglycine bridges in the cell walls of staphylococci (Spec. ¶ 8).
[3] Intranasal administration of a 0.5% lysostaphin saline spray to treat
staphylococcal colonization is known in the art (Spec. ¶¶ 35-37).

3 U.S. Patent 6,056,954, "Use of Bacterial Phage Associated Lysing
Enzymers for the Prophylactic and Therapeutic Treatment of Various
Illnesses," issued 2 May 2000, to Fischetti et al. ("Fischetti 954").
4 U.S. Patent 6,248,324 B1, "Bacterial Phage Associated Lysing Enzymes
for Treating Dermatological Infections," issued 19 June 2001, to Fischetti et
al. ("Fischetti 324").
5 U.S. Patent 6,028,051, "Method for the Treatment of Staphylococcal
Disease," issued 22 February 2000, to Climo et al. ("Climo").
6 U.S. Patent 6,315,996 B1, "Topical Lysostaphin Therapy for
Staphylococcus Ocular Infections," issued 13 November 2001, to Richard J.
O'Callaghan ("O'Callaghan").
7 Examiner's Answer mailed 18 March 2008 ("Ans.").
3
Appeal 2008-4627
Application 10/323,907

[4] According to the 907 specification, "the inventors have demonstrated
that administration of lysostaphin in a cream formulation improves
retention of lysostaphin in the nares and they believe that a viscous
liquid formulation would also improve the retention time in the
nares" (Spec. ¶ 40).
B. The prior art
1. Fischetti8
[5] Fischetti discloses administering a species-specific bacteriophage
lysin (lytic enzyme) in the form of a topical ointment or cream to
treat bacterial infections associated with topical or dermatological
infections (Fischetti 954 at 3:47-51; Fischetti 324 at 3:62-66).
[6] For example, the bacteriophage lysin formulation may be directly
applied by nasal sprays, nasal drops, nasal ointments, nasal washes,
nasal injections, and nasal packings or by ointments applied to the
nasal nares (Fischetti 954 at 5:1-8; Fischetti 324 at 5:21-28;
emphasis added).
[7] According to Fischetti, lysostaphin, an enzyme which lyses
Staphylococcus aureus, and/or conventional antibiotics, such as
bacitrin, may also be included in the bacteriophage lysin topical
ointment or cream (Fischetti 954 at 3:51-58, 11:1-17; Fischetti 324 at
4:1-7, 11:18-34).
[8] Fischetti expressly states the bacteriophage lysin formulation

8 Fischetti 954 issued based on application 09/395,636 (Fischetti 954
cover page, § 21). Fischetti 324 issued based on application 09/671,879,
which is a continuation of application 09/395,636 (Fischetti 324 cover
page, §§ 21 and 63). Fischetti 954 and 324 share common disclosures
which are referred to in this Decision as "Fischetti."

4
Appeal 2008-4627
Application 10/323,907

may further comprise the enzyme lysostaphin for
the treatment of any Staphylococcus aureus
bacteria. Mucolytic peptides, such as lysostaphin,
have been suggested to be efficacious in the
treatment of S. aureus infections of humans . . .
Lysostaphin . . . exerts a bacteriostatic and
bactericidal effect upon S. aureus by enzymatically
degrading the polyglycine crosslinks of the cell
wall. . . . [R]ecombinant mucolytic bactericidal
protein, such as r-lysostaphin, can potentially
circumvent problems associated with current
antibiotic therapy because of its targeted
specificity, low toxicity and possible reduction of
biologically active residues. Furthermore,
lysostaphin is also active against non-dividing
cells, while most antibiotics require actively
dividing cells to mediate their effects . . . . There
is a degree of added importance in using both
lysostaphin and the lysin enzyme in the same
therapeutic agent. Frequently, when a body has a
bacterial infection, the infection by one genus of
bacteria weakens the body or changes the bacterial
flora of the body, allowing other potentially
pathogenic bacteria to infect the body. One of the
bacteria that sometimes co-infects a body is
Staphylococcus aureus. Many strains of
Staphylococcus aureus produce penicillinase, such
that Staphylococcus, Streptococcus, and other
gram positive bacterial strains will not be killed by
standard antibiotics. Consequently, the use of the
lysin and lysostaphin, possibly in combination
with antibiotics, can serve as the most rapid and
effective treatment of bacterial infections.
(Fischetti 954 at 11:18-60; Fischetti 324 at 11:35-
12:9) (citations omitted.)

5
Appeal 2008-4627
Application 10/323,907

2. Climo
[9] According to Climo, administration of single or short course,
relatively high dosages of lysostaphin (at least 50-100 mg/kg body
weight in a 24-hour period) is a dramatically effective therapy for the
treatment of staphylococcal infections, particularly infections that are
resistant to treatment, and/or typically associated with significant
morbidity and mortality (Climo 3:29-35 and 49-54).
[10] Climo also discloses that lysostaphin may be coadministered with
other antimicrobial agents to treat an infectious disease more
effectively (Climo 6:11-14).
3. O'Callaghan
[11] According to O'Callaghan, "[l]ysostaphin is more effective than any
currently available drug for treating Staphylococcus keratitis. When
applied as a single drop (0.3%) every 30 min from 4 to 9 hr post-
infection, or from 10 to 15 hr post-infection, lysostaphin caused
significant reductions in the number of Staphylococcus CFU per
cornea" (O'Callaghan 5:5-10).
[12] Further according to O'Callaghan, "lysostaphin may also be mixed
with pharmaceutically acceptable carriers to form an ointment"
(O'Callaghan 8:7-9).
III. Discussion
A. Obviousness
A claimed invention is not patentable if its subject matter would have
been obvious to a person of ordinary skill in the art. 35 U.S.C. § 103(a);
KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1734 (2007). Facts relevant to
a determination of obviousness include (1) the scope and content of the prior
6
Appeal 2008-4627
Application 10/323,907

art, (2) any differences between the claimed invention and the prior art, (3)
the level of ordinary skill in the art and (4) relevant objective evidence of
nonobviousness. KSR, 127 S.Ct. at 1734.
The test for obviousness is what the combined teachings of the
references would have suggested to one of ordinary skill in the art. In re
Young, 927 F.2d 588, 591 (Fed. Cir. 1991); In re Keller, 642 F.2d 413, 425
(CCPA 1981). In evaluating such references it is proper to take into account
not only the specific teachings of the references but also the inferences
which one skilled in the art would reasonably have been expected to draw
therefrom. In re Preda, 401 F.2d 825, 826 (CCPA 1968).
B. The Examiner's findings and conclusions
The Examiner found Fischetti discloses compositions for therapeutic
and prophylactic treatment of bacterial infections of the upper respiratory
tract and mucous membranes comprising lysostaphin (Ans. 3). The
Examiner further found Fischetti discloses the composition may (a) include
antibiotics, such as bacitracin, (b) be applied as a nasal ointments and (c)
comprise carriers, such as polymer thickeners, surfactants and emulsifiers
(Ans. 4). The Examiner also found the compositions can be directed to the
mucosal lining where the enzymes in the compositions will be able to kill
colonizing bacteria (Ans. 4). The Examiner found Fischetti failed to
disclose the concentration of lysostaphin in the composition (Ans. 4).
The Examiner found Climo discloses large doses of lysostaphin, i.e.,
at least 50 mg/kg body weight, are effective in eradicating staphylococcal
infections (Ans. 4).
The Examiner concluded it would have been obvious to formulate a
viscous nasal formulation of lysostaphin for administration to a patient in
7
Appeal 2008-4627
Application 10/323,907

need thereof and to include antibiotics, such as bacitrin, in the formulation
because Fischetti teaches beneficial administration of lysostaphin-containing
compositions to mucosal surfaces of the upper respiratory tract as well
conventional inclusion of antibiotics in the compositions (Ans. 4). The
Examiner further concluded it would have been within routine skill in the art
to optimize the percent of lysostaphin in the formulation "since Climo . . .
teaches that larger amounts are desirable and will result in discernable
reductions in staphylococci . . . within 24 hours" (Ans. 4-5). According to
the Examiner, the disclosure in O'Callaghan of topical administration of a
0.3% lysostaphin formulation for treatment of ocular staphylococcus
infection provides further motivation to formulate an ointment for topical
administration to sensitive surfaces for the treatment of staphylococci and a
reasonable expectation of success (Ans. 5).
C. Arguments and Analysis
1A. Argument: "The cited references fail to enable the
presently claimed invention and fail to provide a
reasonable expectation of success for carrying out the
claimed invention" (App. Br. 7).

Appellants argue Fischetti treats bacterial infections by administering
bacteriophage lysin (phage lytic enzyme) formulations, which may
optionally contain one or more other materials selected from a vast array of
materials which happen to include lysostaphin (App. Br. 7-9; Reply Br.9 4-
7). Appellants contend there is no motivation in any of the cited references
to select lysostaphin from this broad selection of materials useful in
combination with phage lytic enzymes or in the absence of phage lytic
enzymes (App. Br. 9-12; Reply Br. 7-9).

9 Appellant's Reply Brief filed 19 May 2008 ("Reply Br.").
8
Appeal 2008-4627
Application 10/323,907

Appellants point out that all the specific examples and experimental
data of Fischetti use phage lytic enzyme formulations, i.e., none use the
claimed cream-based or polymer-containing liquid-based viscous
formulation containing at least 0.125% lysostaphin as recited claims 17, 34,
51, and 52 (App. Br. 9-10; Reply Br. 6-7). According to Appellants, this
lack of data and detail in the cited references, individually or in combination,
"fail[s] to enable one of ordinary skill in the art to practice the claimed
invention, fail[s] to foretell the functionality of the claimed methods and
compositions of the claimed invention, and fail[s] to provide a reasonable
expectation of success for carrying out the claimed invention" (Reply Br. 5).
1A. Analysis
A reference must be considered for everything it discloses. In re
Burckel, 592 F.2d 1175, 1179 (CCPA 1979).
Here, Fischetti teaches that lysostaphin is a known bacteriostatic and
bacterioside for Staphylococcus aureus (FF 8) which may be directly applied
as part of a therapeutic nasal ointment or cream (FF 5-7). Climo also
teaches that lysostaphin, at high doses, is a "dramatically effective therapy"
for treating staphylococcal infections (FF 9). Similarly, O'Callaghan teaches
use of lysostaphin to treat staphylococcal infection (FF 11). In sum, as
pointed out by the Examiner (Ans. 5-6), all the cited references disclose
treating staphylococcal infections with lysostaphin.
As also pointed out by the Examiner, the open "comprising" language
of claims 17 and 34 (Ans. 6), permits the inclusion of both bacteriophage
lysin and lysostaphin in the same therapeutic formulation as taught by
Fischetti. Indeed, in the paragraph referenced by the Examiner (Ans. 6),
Fischetti states that infection by one genus of bacteria may potentiate
9
Appeal 2008-4627
Application 10/323,907

infection by a second pathogenic bacteria, that Staphylococcus aureus is one
of these co-infecting bacteria, and that using bacteriophage lysin and
lysostaphin, “possibly in combination with antibiotics, can serve as the most
rapid and effective treatment of bacterial infections” (FF 8). Fischetti also
suggests administering lysin, which is explicitly described in combination
with lysostaphin (see above), as a therapeutic nasal ointment or cream (FF5,
6).
In short, this argument is not persuasive of reversible Examiner error.
2B. Argument: "The Cited References Do Not Teach Each Element
of the Present Invention and Actually Teach Away From the
Claimed Invention" (App. Br. 12).

Appellants argue that, since claims 51 and 52 expressly exclude phage
lytic enzymes in the recited formulations, Fischetti teaches away from the
claimed invention (App. Br. 12-13; Reply Br. 9-10), citing the following
Fischetti disclosure:
There is a degree of added importance in using both lysostaphin
and the lysin enzyme in the same therapeutic agent. Frequently,
when a body has a bacterial infection, the infection by one
genus of bacteria weakens the body or changes the bacterial
flora of the body, allowing other potentially pathogenic bacteria
to infect the body. One of the bacteria that sometimes co-
infects a body is Staphylococcus aureus. Many strains of
Staphylococcus aureus produce penicillinase, such that
Staphylococcus, Streptococcus, and other gram positive
bacterial strains will not be killed by standard antibiotics.
Consequently, the use of the lysin and lysostaphin, possibly in
combination with antibiotics, can serve as the most rapid and
effective treatment of bacterial infections.
(Fischetti 954 at 11:46-59; Fischetti 324 at 11:63-12:9.)

10
Appeal 2008-4627
Application 10/323,907

2B. Analysis
"[T]he suggestion to modify the art to produce the claimed invention
need not be expressly stated in one or all of the references used to show
obviousness. 'Rather, the test is what the combined teachings of the
references would have suggested to those of ordinary skill in the art.'" Cable
Elec. Prods., Inc. v. Genmark, Inc., 770 F.2d 1015, 1025 (Fed. Cir. 1985)
(quoting In re Keller, 642 F.2d 413, 425 (CCPA 1981).
This argument is unpersuasive because it fails to address the
combined teachings of the references. Fischetti, Climo, and O'Callaghan all
teach treating bacterial (staphylococcal) infections with lysostaphin.
Fischetti teaches that a combination of lysin and lysostaphin, possibly in
combination with antibiotics, can serve as the most rapid and effective
treatment of bacterial infections (FF 8). In particular, Fischetti teaches that
the phage lytic enzymes are used to treat organisms other than
Staphlococcus aureus (see Fischetti 954 4:3-7), so an ordinary artisan would
have recognized that the lytic enzymes need not be included in the treatment
composition with the lysostaphin when Staphlococcus aureus alone was the
infective agent, as in the situations disclosed by Climo and O’Callaghan.
Climo teaches that high dose lysostaphin is an effective treatment for even
resistant staphylococcal infections (FF 9). Moreover, as pointed out by the
Examiner (Ans. 6-7), Fischetti and O'Callaghan both teach cream or
ointment formulations containing lysostaphin for topical application (FF 5-7
and 12).
Thus, this argument is not persuasive of reversible Examiner error.
3C. Argument: "The 37 C.F.R. 1.137 Declaration by John
Kokai Kun, Ph.D. Evidences The Absence Of An
11
Appeal 2008-4627
Application 10/323,907

Expectation of Success for Carrying Out the Claimed
Methods" (App. Br. 14).

Finally, Appellants assert that the declaration of inventor John Kokai-
Kun, Ph.D. is objective evidence of unexpected results sufficient to rebut the
Examiner's prima facie conclusion of obviousness (App. Br. 14-15; Reply
Br. 10). According to Appellants, "[c]ontrol experiments indicated that
small molecule anti-infectives were effective at diffusing out of creams and
forming clear zones, but that the larger lysostaphin protein molecule would
not diffuse out of the cream" (App. Br. 14-15). Surprisingly, however, the
lysostaphin cream cleared Staphylococcus aureus nasal colonization in the
cotton rat nose with a single dose (App. Br. 15). Appellants conclude the
declaration rebuts the prima facie case of obviousness (App. Br. 15).
3C. Analysis
1. The Declaration
[13] John Kokai-Kun testified he is co-inventor of the subject matter and
employee of the assignee of the 907 application (Declaration10 ¶1).
[14] According to Dr. Kokai-Kun, "[w]hile small molecules like
conventional antibiotics have long been formulated in cream or
ointment bases, there is little to no experience with formulation of
proteins for use as topical treatments rather than systemic
treatments" (Declaration ¶ 2).
[15] Dr. Kokai-Kun testified,
As an initial screen for the efficacy of this
formulation, an assay similar to a disk diffusion

10 Declaration of Applicant Under 37 C.F.R. 1.132, executed 22 June 2006,
by John Kokai-Kun, Ph.D., and filed 29 June 2006 ("Declaration").
12
Appeal 2008-4627
Application 10/323,907

assays was performed using the lysostaphin
formulated in cream. A culture of S. aureus was
inoculated onto a solid agar media and then a strip
of lysostaphin cream was over-laid on the agar . . .
Instead of observing inhibition of bacterial growth
by lysostaphin, we were surprised to find S. aureus
growing on the cream. In control experiments we
overlaid the agar with cream containing a small
molecule anti-infective and this formed a zone of
inhibition suggesting that the anti-infective
diffused out the cream into the agar. . . .
At this point we considered abandoning the
project, however we decided instead to try the
cream in our cotton rat model of S. aureus nasal
colonization, and much to our surprise the
lysostaphin cream was actually capable of clearing
S. aureus nasal colonization in the cotton rat nose
with a single dose (an unanticipated finding based
on the observed in vitro data) (Declaration ¶ 2.)
2. Analysis
As noted by the Examiner (Ans. 7), Dr. Kokai-Kun did not explain
what specific components were in the various cream formulations. Dr.
Kokai-Kun did not explain the experimental protocol used for the diffusion
assay or explain the cotton rat model assay at all. For example, Dr. Kokai-
Kun did not testify as to whether a disk was used in the "assay similar to a
disk diffusion assay” and, if so, what was the pore size of the strip/disk (the
size of the pores would determine what size molecules would be able to
diffuse out of the pores) what concentrations of active agents were used,
whether these concentrations normalized to the same LD50, e.g., for
comparison, whether all active agents stabile under the test conditions, what
size innocula were used, were the same ratios of active agent concentration
13
Appeal 2008-4627
Application 10/323,907

to bacterial count used in both the assays, etc. Moreover, instead of
comparing one protein cream formulation to another protein cream
formulation, e.g., a bacteriophage lysin cream formulation to a lysostaphin
cream formulation, the diffusion assay was tested versus a "small molecule"
cream formulation. Appellants contend that the Declaration
indicates that one of ordinary skill in the art, conducting
experiments in an effort to develop embodiments of the present
invention, would not have expected a claimed composition (i.e.,
a composition comprising a. a viscous formulation selected
from the group consisting of a cream-based formulation and a
viscous liquid-based formulation comprising a polymer, and b.
at least 0.125% lysostaphin) to be successful at inhibiting
bacterial growth, let alone at treating a patient (e.g., for
inhibiting or clearing nasal bacterial colonization).
(App. Br. 14).
This argument is not persuasive. First, Dr. Kokai-Kun did not
expressly state that “one of ordinary in the art” would not have expected at
the time of the invention that a viscous formulation would have been
successful at inhibiting bacterial growth. This statement is made in the
Appeal Brief, but not by the declarant. Secondly, even had Dr. Kokai-Kun
made such statement – and assuming that he did – Fischetti expressly states
that its antibacterial formulations can be a nasal ointment (FF 6), evidence
contrary to this position. When we weigh the evidence, we conclude that the
preponderance of the evidence in this record supports the Examiner’s
position that nasal ointments comprising lysostaphin would have been
obvious to persons of ordinary skill in the art.
For similar reasons, we do not find Appellants’ argument convincing
that “the declaration of Dr. Kokai-Kun exemplifies the fact that at the time
of the invention, one of ordinary skill in the art would have had little to no
14
Appeal 2008-4627
Application 10/323,907

experience with a cream formulation comprising lysostaphin” (Reply Br.
10). To the contrary, Fischetti provides explicit evidence to the contrary.
Furthermore, the Declaration is not commensurate in scope with the
claims, which are not limited to cream-based formulations. Therefore, we
find the Kokai-Kun Declaration is entitled to little, if any, weight.
Consequently, balancing the weight of the evidence of record for both
obviousness and non-obviousness, we conclude that the evidence weighs in
favor of a prima facie conclusion of obviousness.
D. Conclusion
Based on the foregoing, we sustain the rejection of claims 17-27, 30-
53, and 56-60 under § 103 over Fischetti 954, Fischetti 324, Climo, and
O'Callaghan.
IV. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the decision of the Examiner rejecting claims 17-27,
30-53, and 56-60 under 35 U.S.C. § 103(a) as unpatentable over Fischetti
954, Fischetti 324, Climo, and O'Callaghan is AFFIRMED; and
FURTHER ORDERED that 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

rvb

Casimir Jones, S.C.
440 Science Drive
Suite 203
Madison, WI 53711
15