Ex Parte Kink et al

Board of Patent Appeals and Interferences

Nov 15, 2007

09832233 (B.P.A.I. Nov. 15, 2007)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte
JOHN A. KINK and KATHERINE L. WORLEDGE
____________

Appeal 2007-3271
Application 09/832,233
Technology Center 1600
____________

Decided: November 15, 2007
____________

Before TONI R. SCHEINER, LORA M. GREEN, and NANCY J. LINCK,
Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s final rejection of claims 1-5 and 7-14. We have jurisdiction
under 35 U.S.C. § 6(b). Claims 1 and 9 are representative of the claims on
appeal, and read as follows:
Appeal 2007-3271
Application 09/832,233

1. A method of treatment for necrotizing enterocolitis, comprising:
a) providing:
i) a human neonate, wherein said human neonate has symptoms
of necrotizing enterocolitis;
ii) a therapeutic formulation comprising purified avian anti-
TNF polyclonal antibodies, and;
b) administering said formulation to said human neonate.

9. A method of treatment for necrotizing enterocolitis, comprising:
a) providing:
i) a neonate at risk for necrotizing enterocolitis,
ii) a therapeutic formulation comprising purified avian anti-
TNF polyclonal antibody, and;
b) administering said formulation to the lumen of the intestine of said
neonate.

The Examiner relies upon the following references:
Williams 5,601,823 Feb. 11, 1997
Le 5,656,272 Aug. 12, 1997
Eibl 5,833,984 Nov. 10, 1998

Eibl et al., “Prevention of Necrotizing Enterocolitis in Low-Birth-Weight
Infants by IgA-IgG Feeding,” New Eng. J. Med., Vol. 319, No. 1 pp. 1-7
(1988).

Wolf et al., “The anti-inflammatory effect of an oral immunoglobulin (Ig-A-
IgG) preparation and its possible relevance for the prevention of necrotizing
enterocolitis,” Acta Paediatr. Suppl., Vol. 396, pp. 37-40 (1994).

Muguruma et al., “Role of platelet activating factor in necrotizing
enterocolitis development in the rat,” Prenat Nonat Med., Vol. 3, pp. 571-
579 (1998).

We affirm.
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BACKGROUND
Necrotizing enterocolitis (NEC) has emerged as the most
common gastrointestinal emergency in neonatal intensive care
units (NICU). A.M. Kosloske, "Epidemiology of necrotizing
enterocolitis," Acta Paediatr. Suppl. 396:2 (1994). U.G.
Stauffer, "Necrotizing enterocolitis," Acta Paediatr 83:666
(1994). NEC can occur endemically as isolated cases, or at
times, epidemic clusters of cases are seen in neonatal nurseries.
In the United States the incidence ranges from 1 to 3 per 1000
live births and roughly 1 to 7.7% of NICU admissions. R. C.
Holman et al., "Necrotizing Enterocolitis Mortality in the
United States, 1979-85" AJPH 79:8 (1989). The average
annual mortality rate for NEC was 13.1 deaths per 100,000 live
births. In the United States, about 12,000 newborn infants per
year develop NEC, with a mortality rate of up to 40%.
Clinically, NEC is characterized by a triad of symptoms:
abdominal distention and tenderness, gastrointestinal bleeding,
and pneumatosis intestinalis, i.e., air within the intestinal wall.
R.M. Kliegman and A. A. Fanaroff, "Necrotizing Enterocolitis"
New Eng. J. Med. 310:1093 (1984). Death associated from
NEC occurs from intestinal perforation with sepsis with shock,
intravascular dissemination, pneumatosis, and short bowel
syndrome resulting in malabsorption after resection.

(Specification 1.)
The present invention is drawn to the prevention and treatment of
NEC, and in particular, the use of antibody therapy (id. at 6). According to
the Specification, it “is not intended that the present invention be limited to
any particular type of antibody.” (Id.) Thus, the Specification states
“[p]olyclonal and monoclonal antibodies are contemplated in the context of
the present invention. Such antibodies may be made in a variety of animals
[e.g., rabbits, horses, cows (e.g., in the milk), and birds]. The present
invention also contemplates human and "humanized" antibodies. (Id.) The
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Specification notes that non-complement fixing antibodies, such as avian
antibodies (chicken antibodies from eggs), are preferred (id.).
Moreover, the Specification notes that the method is not limited to
antibodies to a specific inflammatory mediator, but that a variety of
mediators may be used, with the preferred mediators being PAF and/or TNF
(id. at 8). In addition, the Specification contemplates a variety of delivery
preparations, such as a spray, an oral formulation, a topical formulation or an
injectable formulation (id. at 10-11).

DISCUSSION
Claims 1-5 and 7-14 stand rejected under 35 U.S.C. § 103(a) as being
obvious over the combination of Le, Eibl ’984, Wolf, Maguruma, Eibl 1998
and Williams. Appellants argue that all the claims stand alone (Br.1 6).
Appellants do not separately argue the claims, however, and merely pointing
out differences in what the claims cover is not an argument as to why the
claims are separately patentable. Thus the claims stand or fall together. 37
C.F.R. § 41.37(c)(1)(vii) (2006). We thus focus our analysis on independent
claim 1.
Le is cited by the Examiner for teaching the use of anti-TNF
antibodies in a number of TNF-mediated conditions, such as Crohn’s disease
(Answer2 4). The Examiner acknowledges that Le fails to teach the use of
anti-TNF antibodies to treat neonatal necrolizing enterocolitis (NEC) (id.).

1 All references to the Brief (Br.) are to the substitute Appeal Brief dated July
10, 2006.
2 All references to the Answer are to the Examiner’s Answer dated
December 8, 2006.
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Eibl ’984 is cited for teaching that anti-TNF antibodies have been
used to reduce the inflammatory response caused by gram-negative bacteria
(id.). Eibl ’984 is also cited for teaching that there is correlation between
levels of TNF and necrolizing enterocolitis (id. at 4-5).
Wolf, Eibl 1998, and Magnamure are all cited as evidence that the
“role of TNF in the development of neonate NEC has been well established
in the art.” (Id. at 5.)
Williams is cited by the Examiner for teaching the state of the art in
formulating polyclonal avian antibodies, specifically, for treating
inflammatory eterocolitis caused by Clostridium difficile (id.). The avian
antibodies of Williams may be given to neonates or infants, and Williams
also teaches that oral administration is a preferred route of administration
(id. at 6).
According to the Examiner, as the role of TNF in neonatal necrolizing
enterocolitis is well established in the art, it would have been obvious to use
anti-TNF antibodies to treat neonatal necrolizing enterocolitis, as Le teaches
the use of anti-TNF antibodies in the treatment of TNF mediated pathologies
and conditions (id.). Because Eibl ’984, Muguruma, Eibl 1998, and Wolf all
teach that TNF plays a role in neonatal necrolizing enterocolitis, and Le
teaches the use of anti-TNF antibodies in the treatment of TNF mediated
pathologies and conditions, one of ordinary skill in the art would have had a
reasonable expectation of success of treating neonatal necrolizing
enterocolitis using anti-TNF antibodies (id.).
Furthermore, according to the Examiner, “one of ordinary skill in the
art would have been motivated to formulate an avian polyclonal anti-TNF,
because as suggested by Williams such type of antibodies can be
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administered orally are non-immunogenic and are well tolerated by infants.”
(Id.)
Also, as TNF “potentiates the progress of NEC . . . reducing the
effects of TNF activity among human infants would improve or alleviate the
pathological changes that lead to NEC.” (Id.) The Examiner notes further
that any alleviation of the neonatal necrolizing enterocolitis “would read on
the scope of the instant claims, and the [person of] ordinary skill in the art
would have had a reasonable expectation of success in at least observing
some symptomatic relief when administering the anti-TNFs taught by . . .
Le.” (Id.)
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
Cir. 1993) (citations omitted). In order to determine whether a prima facie
case of obviousness has been established, we consider the factors set forth in
Graham v. John Deere Co., 383 U.S. 1, 17 (1996): (1) the scope and content
of the prior art; (2) the differences between the prior art and the claims at
issue; (3) the level of ordinary skill in the relevant art; and (4) objective
evidence of nonobviousness, if present. We conclude that the Examiner has
set forth a prima facie case of obviousness that has not been rebutted by
Appellants, and affirm the rejection.
Appellants argue that Le fails to properly disclose NEC, and that even
if the reference did, it would only amount to an invitation to try (Br. 9). Eibl
’984, Appellants assert, discloses inhibiting TNF-α release through the use
of an IgA multimer complex that sequesters TNF-α, but does not suggest
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using anti-TNF antibodies to treat NEC (id.). Thus, Appellants assert, Eibl
’984 “teaches that necrotizing enterocolitis immunotherapy does not involve
direct neutralization by specific antibodies (i.e., for example, anti-TNF
antibody).” (Id.) Wolf, Appellants argue, also does not teach anti-TNF
antibody, and also “provides support for the hypothesis that immunotherapy
inhibits the release of TNF-α,” and “does not involve direct neutralization by
specific antibodies.” (Id. at 9-10.)
As to Le, Appellants assert that Le teaches the use of humanized
antibodies and does not teach anti-TNF antibodies of a generic nature (Reply
Br. 8). Le, according to Appellants, also teaches away from enteral antibody
administration, such as oral administration (id.). Thus, Le cannot be
combined with Williams (id. at 11).
Eibl 1998, Appellants assert, is silent on both TNF-α and anti-TNF
antibodies (Br. 10). Muguruma, Appellants assert, not only does not
disclose anti-TNF antibodies, but also provides evidence “that TNF-α may
not directly cause necrotizing enterocolitis.” (Id.) Williams, Appellants
contend, is silent on TNF-α and on anti-TNF antibody (id.). Thus,
Appellants conclude, “[i]t is easily seen that the Examiner has not offered a
single reference that discloses an anti-TNF antibody used for treating
necrotizing enterocolitis. Consequently, on this fact alone, the obviousness
rejection fails.” (Id.)
Appellants’ arguments are not convincing. Obviousness is
determined in view of the sum of all of the relevant teachings in the art, not
isolated teachings in the art. See In re Kuderna, 426 F.2d 385, 389 (CCPA
1970); see also In re Shuman, 361 F.2d 1008, 1012 (CCPA 1966).
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Appellants’ arguments focus on the teachings of the individual references,
and not what the prior art as a whole would suggest to the ordinary artisan.
Le teaches the use of anti-TNF antibodies in the treatment of TNF-α
mediated pathologies, such as Crohn’s disease (Le abstract). Le teaches the
disadvantages of the use of murine mononoclonal antibodies, and thus
suggests using chimeric or human antibodies to overcome those
disadvantages (col. 20, ll. 17-23). The preferred method of administration is
parental (col. 36, ll. 17-40). Le demonstrates that the antibodies are capable
of inhibiting and/or neutralizing the biological activity of TNF in vitro as
well as in vivo (col. 56, Example XVI). Le exemplifies the treatment of
sepsis (col. 58, Example XIX), rheumatoid arthritis (col. 58, Example XX;
col. 68, Example XXII), Crohn’s disease (col. 66, Example XXI), and severe
ulcerative colitis (col. 78, Example XXIII).
Eibl ’984 teaches treatment of inflammation with a human IgA
fraction (Eibl ’984 abstract). Eibl ’984 teaches that deleterious inflammation
occurs in diseases such as Crohn’s diseases and rheumatoid arthritis (col. 1,
ll. 36-46) and septic shock (col. 1, ll. 58-61). With respect to NEC, Eibl
’984 teaches that “[h]igh levels of TNF-α have also been found in neonates
with necrotizing enterocolitis, suggesting that TNF-α may be involved in the
pathogenesis of this disease. Indeed, endotoxin challenge and administration
of TNF-α has induced bowel necrosis in an experimental model of neonatal
necrotizing enterocolitis.” (Col. 1, ll. 62-67.)
With respect to antibody therapy, ’Eibl ’984 teaches that it “is well
known . . . that immunoglobulins can be useful because a specific antibody
recognizes and binds to a specific antigen to neutralize that antigen.” (Col.
2, ll. 40-42.) Eibl ’984 also teaches that the “lethality of gram-negative
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bacteremia or endotoxemia has been prevented by the administration of
specific, anti-TNF antibodies.” (Col. 2, ll. 8-10.)
Wolf teaches “[i]nflammatory cytokines such as TNF-α and IL-6 play
a central role in multiple effector functions and cellular interactions
necessary to mount an effective host defense during inflammation and
immune response,” but that “uncontrolled production leading to high levels
of inflammatory cytokines may be noxious to the host.” (Wolf, p. 38, first
column.) With regard to NEC, Wolf teaches that “[e]ndotoxin challenge and
administration of TNF-alpha induced bowel necrosis in a rat model of
neonatal NEC, which is predominantly mediated by PAF [platelet activating
factor].” (Id.) Wolf uses a non-specific oral IgA-IgG preparation for the
prophylaxis of NEC (id. at second column). Eibl 1998 is cumulative of
Wolf, and thus we do not separately discuss it.
Muguruma teaches that a “number of factors known to facilitate
necrotizing enterocolitis formation, such as tumor necrosis factor- α (TNF-α)
and endotoxin, have been reported to increase the PAF concentration.”
(Muguruma, p. 572, first column.) While recognizing a previous report in
which the administration of TNF-α and lipopolysaccharide (LPS) caused
necrotizing enterocolitis in an animal model, Muguruma found that in their
experiments necrosis could not be demonstrated in animals receiving LPS
and TNF-α, or TNF-α alone (p. 575, second column-page 576, first column).
Muguruma teaches:
Others have reported that the administration of either LPS or
TNF-α of the combination of both cytokines caused necrotizing
enterocolitis in the rat, as judges by both gross and microscopic
examination. Although we were successful in producing a full
thickness hemorrhage by the treatment with these agents, a
clearly identifiable necrosis was not evident . . . . The severe
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hemorrhage, similar to that found in necrotizing enterocolitis,
was completely prevented by treatment with r-PAF-AH. It is
not clear at present why the necrosis did not develop as
previously reported. If the hemorrhage is associated with the
subsequent development of necrosis in all these cases, r-PAF-
AH pretreatment clearly prevents its development.

(P. 578, first column.)
Thus, Le teaches that TNF-α related pathologies, such as
inflammatory conditions, may be treated with a specific, anti-TNF antibody,
and Eible ’984, Wolf, and Muguruma establish that NEC is an inflammatory
condition that is a TNF-α related pathology. Eibl ’984 further provides
evidence of the state of the art in antibody therapy at the time of filing.
Thus, it would have been obvious to one of ordinary skill in the art at the
time of filing to use an anti-TNF antibody to treat NEC.
With regard to the use of avian polyclonal antibodies, Williams
teaches an avian antitoxin directed to Clostridial toxin (Williams abstract).
Williams teaches that avian antitoxin (i.e., avian polyclonal antibodies) does
not fix mammalian complement, and thus will not cause a complement-
dependent reaction, and will not exhibit complement-related side-effects
(col. 9, l. 64-col. 10, l. 8). Hens laying eggs transport immunoglobulin to the
egg yolk (IgY) in concentrations equal to or greater than that in serum, and
the volume of egg yolk greatly exceeds that in serum (col. 10, ll. 10-18).
Williams teaches further that antibody from egg is purer and more
homogenous, there is less non-immunoglobulin protein, and only one class
of immunoglobulin is transported to the yolk (col. 10, ll. 19-22). Williams
also teaches that infant formula may be used to deliver the antitoxin (col. 12,
ll. 4-5).
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Thus, one of ordinary skill at the time of filing would have been aware
of the advantages of using avian polyclonal antibodies and that such
antibodies could be delivered in infant formula, thus it would have been
obvious to use avian polyclonal antibodies as the source of anti- TNF-α
antibodies.
Appellants argue further that there is no motivation to combine the
references (Br. 11). According to Appellants, the teachings of Eibl ’984
regarding IgA “are contrary to the teachings” of Wolf and Eibl 1998 (id.).
Specifically, Eibl ’984 teaches that it is preferable to use IgA free of IgG as
IgG appears to enhance inflammatory activity (Br. 11 (citing Eibl ’984, col.
6, ll. 31-34)).
Appellants argue further that Eibl ’984 teaches away from the claimed
invention by teaching “that a non-specific antigen/antibody interaction is the
preferred approach to immunoprotection against necrotizing enterocolitis.”
(Br. 11.) Specifically, Appellants quote Eibl ’984 as teaching that “[t]his
effect [when using IgA/IgG] is believed to be a result of the formation of
antigen-antibody complexes caused by high titers of antibodies against a
multitude of potential pathogens and their toxins.” (Br. 11 (quoting Eible
’984, col. 2, ll. 24-27)). Appellants assert that “the Examiner's assumption
that an unstimulated crude fractionated IgA-IgG plasma preparation is
equivalent to anti-TNF antibody (as described in the Applicants'
specification) demonstrates a basic misunderstanding of Applicants' claimed
embodiment and is contrary to level of skill in the art.” (Br. 11.)
Appellants assert that the Examiner has failed to point to any
statement in the combination that would suggest or motivate the ordinary
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artisan to use anti-TNF antibodies to treat NEC, and thus the rejection must
fall (id. at 11-12).
As to the specific question of “teaching away,” a reference may be
said to teach away when a person of ordinary skill, upon examining the
reference, would be discouraged from following the path set out in the
reference, or would be led in a direction divergent from the path that was
taken by the applicant. In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). In
the instant case, Eibl ’984 is limited to the use of non-specific IgA, which
Eibl’ 984 teaches is different “from the well-known model of antibody
neutralization of specific foreign antigens.” (Eibl ’984, col. 5, ll. 25-29.)
Moreover, in view of the teaching of Le that anti-TNF-α may be used to
treat TNF-α mediated pathologies, the ordinary artisan would not have been
led in a divergent direction from that taken by Appellants in view of the
teachings of Eibl ’984. Finally, avian polyclonal antibodies are IgY, not
IgG, thus the argument is not relevant to the method of the combination.
As to motivation to combine, the Supreme Court in KSR Int’l Co. v.
Teleflex Inc., 127 S. Ct. 1727, 1739 (2007), rejected a rigid application of the
teaching-suggestion-motivation test. The Court recognized that it is often
necessary to look at the interrelated teaches of multiple references; the
effects of demands of the marketplace; and the background knowledge
possessed by a person of ordinary skill, “all in order to determine whether
there was an apparent reason to combine the known elements in the fashion
claimed.” Id. at 1740-41. Moreover, the “obviousness analysis cannot be
confined by a formalistic conception of the words teaching, suggestion, or
motivation, or by overemphasis on then importance of published articles and
explicit content of issued patents.” Id. at 1741. Finally, one “of the ways in
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which a patent’s subject matter can be proved obvious is by noting that there
existed at the time of the invention a known problem for which there was an
obvious solution encompassed by the patent’s claims.” Id. at 1742.
In the case before us, NEC was a known pathology, and was known to
be “a major life-threatening illness in neonates of low birth weight and/or
low gestational age.” (Wolf, p. 37, first column.) Eibl ’984, Wolf, and
Muguruma all establish that NEC is an inflammatory condition that is a
TNF-α related pathology. Le teaches that TNF-α related pathologies, such
as inflammatory conditions, may be treated with a specific, anti-TNF
antibody, and Williams teaches the advantages of using avian polyclonal
antibodies, which antibodies were specific to a toxin, and also teaches that
the antibodies may be administered in infant formula. Thus, the method of
instant claim 1 would have been obvious to the ordinary artisan at the time
of filing in view of the teachings of the references cited by the Examiner.
Appellants also argue that the combination does not provide a
reasonable expectation of success of achieving the claimed invention (Br.
12). According to Appellants, citing In re O'Farrell, 853 F.2d 894 (Fed. Cir.
1988), “the Federal Circuit requires any reference asserted for an
‘expectation of success’ to explicitly predict that the recited claims will
work.” (Br. 13 (emphasis in original).)
According to Appellants, the Examiner is speculating without facts
(id.). Appellants assert that Eibl ’984, Wolf, and Eibl 1998 all teach
preparations of IgA and IgG that are merely fractionated plasma extractions,
whereas production on anti-TNF antibodies requires immunization
procedures (Br. 13). As those references do not teach immunization,
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Appellants argue that they cannot explicitly predict the success of using anti-
TNF antibodies (id.).
It is submitted that Appellants are advocating an improper standard of
the expectation of success required by an obviousness rejection.
Obviousness does not require absolute predictability of
success. Indeed, for many inventions that seem quite obvious,
there is no absolute predictability of success until the invention
is reduced to practice. There is always at least a possibility of
unexpected results, that would then provide an objective basis
for showing that the invention, although apparently obvious,
was in law nonobvious. In re Merck & Co., 800 F.2d at 1098,
231 USPQ at 380; Lindemann Maschinenfabrik GMBH v.
American Hoist & Derrick Co., 730 F.2d 1452, 1461, 221
USPQ 481, 488 (Fed.Cir.1984); In re Papesch, 315 F.2d 381,
386-87, 137 USPQ 43, 47-48 (CCPA 1963). For obviousness
under § 103, all that is required is a reasonable expectation of
success. In re Longi, 759 F.2d 887, 897, 225 USPQ 645, 651-
52 (Fed. Cir. 1985); In re Clinton, 527 F.2d 1226, 1228, 188
USPQ 365, 367 (CCPA 1976).

O’Farrell, 853 F.2d at 903-04.
Thus, all that is required is a reasonable expectation of success, which
is provided by the combination. Le teaches the treatment of a wide variety
of TNF-α related pathologies, and Williams teaches the use of polyclonal
antibodies to successfully target toxins produced by Clostridium. In
addition, Eibl ’984 provides evidence of the state of the art by teaching that
it is well known that immunoglobulins can be useful because a specific
antibody recognizes and binds to a specific antigen to neutralize that antigen,
and that the lethality of gram-negative bacteremia or endotoxemia has been
prevented by the administration of specific, anti-TNF antibodies. The fact
that Eibl ’984, Wolf, and Eibl 1998 do not teach immunization is irrelevant
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as they teach the use of IgA/IgG fractions in treating, as both Le and
Williams teach immunization.
Appellants also argue that the link between TNF-α and NEC is not
well established (Reply Br.3 6). Eibl ’984, Appellants assert, only states that
TNF-α may be involved with NEC, thus the reference is clearly speculating
(id. at 5). Wolf provides further evidence that the link between NEC and
TNF-α is uncertain, by stating that the release of mediators of inflammation,
such as TNF-α, has been implicated in NEC (id.). Finally, Appellants assert
that Muguruma administers a combination of TNF-α and lipopolysaccharide,
but NEC was not observed, and Muguruma never administers TNF-α alone
(id.).
First, it is not clear that this argument is properly before us, as it was
first presented in the Reply Brief, and does not appear to be in response to a
new argument of the Examiner. Notwithstanding that, we also find this
argument is not convincing. The use of the terms “may” and “implicated”
are often used in scientific communications, and one of ordinary skill would
not read them as stating that the link between TNF-α and NEC is tenuous.
As noted above, Eibl ’984 goes on to teach that endotoxin challenge
and administration of TNF-α has induced bowel necrosis in an experimental
model of neonatal necrotizing enterocolitis. Wolf also teaches that
endotoxin challenge and administration of TNF-alpha induced bowel
necrosis in a rat model of neonatal NEC. As to Muguruma, Appellants are
reading that example of Muguruma out of context of the reference as a
whole. Muguruma recognizes that previous studies in which the

3 All references to the Reply Brief (Reply Br.) are to the Reply Brief dated
May 3, 2007.
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administration of TNF-α and lipopolysaccharide (LPS) have caused
necrotizing enterocolitis in an animal model. As to their results, Muguruma
states that it “is not clear why the necrosis did not develop as previously
reported,” but states further that the hemorrhage observed may be
“associated with the subsequent development [of necrosis] in these cases.”
(Muguruma, p. 578, first column.) Thus, the ordinary artisan, would not
understand Muguruma as casting doubt on the association between the link
between TNF-α and NEC, especially in view of the teachings of Eibl ’984
and Wolf.
Finally, we note that the Specification discloses that the prior art
recognizes the link between TNF-α and NEC. Specifically, the Specification
teaches:
Recent studies have suggested that certain
proinflammatory molecules including PAF, LPS and cytokines
such as, TNF and IL-6 play an important role in the
development of NEC in the newborn. Patients with NEC were
reported to have higher levels of TNF, IL-1 and IL-6. D. Birk
et al., "Is the elimination of endotoxin and cytokines with
continuous lavage an alternative procedure in necrotizing
enterocolitis?" Acta Paediatr Suppl. 396:24 (1994). Animal
models for NEC indicate that the pathology associated with
NEC can be generated by the administration of PAF, as well as
various endotoxins and cytokines. W. Hsueh et al, "Platelet-
activating factor: an endogenous mediator for bowel necrosis
in endotoxemia," FASEB J. 1 :403-405 (1987). X. Sun and W.
Hsueh, "Bowel Necrosis Induced by Tumor Necrosis Factor in
Rats Is Mediated by Platelet-activating Factor," J. Clin. Invest.
81: 1328 (1988).

(Specification 4.)

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CONCLUSION
In summary, we find that the Examiner has set forth a prima facie case
of obviousness that has not been rebutted by Appellants. Thus the rejection
of claims 1-5, and 7 under 35 U.S.C. § 103(a) over the combination of Le,
Eibl 984, Wolf, Muguruma, Eibl (1998) and Williams, is affirmed.
TIME PERIOD

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED

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