Ex Parte Cook et al

Board of Patent Appeals and Interferences

Sep 9, 2010

10741611 (B.P.A.I. Sep. 9, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte MARK E. COOK, MINGDER YANG, and DAVID M. BARNES
__________

Appeal 2010-002890
Application 10/741,611
Technology Center 1600
__________

Before CAROL A. SPIEGEL, LORA M. GREEN, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL1
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s final rejection of claims 1-6, 8-12, and 40-45.

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 2010-002890
Application 10/741,611

2
We have jurisdiction under 35 U.S.C. § 6(b).

STATEMENT OF THE CASE
Claim 1 is representative of the claims on appeal, and reads as
follows:
1. A method for enhancing growth, improving feed efficiency, or both in
a human or non-human animal, the method comprising the step of:
administering to the animal an agent that can reduce formation of a
complex on cellular surface of a cell in the gastrointestinal tract of the
animal wherein the complex comprises endotoxin, toll-like receptor 4
(TLR4) and CD14 and wherein the agent comprises a member selected from
(i) an antibody to the extracellular domain of TLR4 or CD14 and (ii) a
soluble peptide that can compete with TLR4 or CD14 to form a complex
with endotoxin wherein the soluble peptide comprises said extracellular
domain of TLR4 or CD14.

The following ground of rejection is before us for review:
Claims 1-6, 8-12, and 40-45 stand rejected under 35 U.S.C. § 103(a)
as being rendered obvious by the combination of Cook,2 Abreu,3 Cario,4 and
Anker.5
We reverse.

2 Cook, US 6,213,930 B1, issued Apr. 10, 2001.
3 Abreu et al., Decreased Expression of Toll-Like Receptor-4 and MD-2
Correlates with Intestinal Epithelial Cell Protection Against Dysregulated
Proinflammatory Gene Expression in Response to Bacterial
Lipopolysaccharide, 167 THE JOURNAL OF IMMUNOLOGY 1609-1617 (2001).
4 Cario et al., Lipopolysaccharide Activates Distinct Signaling Pathways in
Intestinal Epithelial Cell Lines Expressing Toll-Like Receptors, 164 THE
JOURNAL OF IMMUNOLOGY 966-972 (2000).
5 Anker, WO 00/53224, published Sept. 14, 2000
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ISSUE
Has the Examiner established by a preponderance of the evidence that
the combination of Cook, Abreu, Cario, and Anker renders obvious a
method of enhancing growth, improving feed efficiency, or both in a human
or non-human animal by administering an agent that interferes with
formation of a complex between TLR4 and CD14?

FINDINGS OF FACT
FF1 According to the Specification, the “invention relates to a method for
enhancing growth or improving feed efficiency in a human or non-human
animal by reducing the binding between bacterial endotoxin and its cellular
receptors in the gastrointestinal tract of the animal.” (Spec. 1.)
FF2 The Specification teaches that “[r]ecent evidence further suggests that
toll-like receptor 4 (TLR4) and CD14 act together as the cellular receptor for
endotoxin to transduce signals.” (Id. at 1-2.)
FF3 The Examiner’s rejection may be found at pages 3-6 of the Answer.
FF4 Specifically, the Examiner cites Cook for teaching a “method for
enhancing growth, improving feed efficiency in animals, comprising
administering an agent that reduces gastrointestinal inflammation.” (Ans.
4.) The Examiner finds that Cook teaches administration of anti-
phospholipase A2 [anti-PLA2] antibody. (Id.)
FF5 Cook is drawn to “a method for modulating the activity of one or
more enzymes that produce precursors of lipid metabolites associated with
gastric inflammation, to reduce the deleterious effects of gastric
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inflammation and to enhance animal and human growth or improve feeding
efficiency.” (Cook, col. 1, ll. 15-20.)
FF6 Cook teaches that the “anti-PLA2 antibodies limit availability of
arachidonic acid, a precursor to inflammatory lipid metabolites such as
leukotrienes and prostaglandins.” (Id. at col. 2, ll. 35-37.)
FF7 The Examiner notes that Cook does not teach a “method for
enhancing growth, improving feed efficiency in animals, comprising
administering an agent that reduce[s] formation of a complex, wherein the
complex comprises endotoxin, toll-like receptor and CD14.” (Ans. 4.)
FF8 The Examiner finds that Abreu teaches that binding of endotoxin to
CD14 activates TLR4, which “induces a cascade of downstream event[s]
that results in gastrointestinal inflammation.” (Id.)
FF9 Abreu teaches that the “lumenal surface of the colonic epithelium is
continually exposed to Gram-negative commensal bacteria and LPS.”
(Abreu, Abstract.)
FF10 Abreu teaches further that “[r]ecognition of LPS by Toll-like receptor
(TLR)-4 results in proinflammatory gene expression in diverse cell types.”
(Id.)
FF11 Abreu teaches further that “LPS-mediated activation of TLR4
culminates in NF-κB transcriptional activity and inflammatory cytokine
production,” and that “LPS-dependent TLR4 signaling requires the presence
of LPS-binding protein . . . or soluble CD14.” (Id. at 1610, first column.)
FF12 Thus, Abreu “investigated the potential mechanism(s) by which IEC
protect themselves against massive amounts of bacteria and bacterial LPS
present in the intestinal lumen and do not initiate acute inflammatory
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responses as would be elicited along other mucosal surfaces such as the
bronchial or uroepithelium in response to bacterial LPS.” (Id. at 1613,
second column.)
FF13 Abreu found that IEC lines do not respond to purified LPS and
express low levels of TLR4 mRNA, noting that the results were
corroborated in primary human IEC, which also had low levels of TLR4
expression. (Id. at paragraph bridging pp. 1613-1614.)
FF14 Abreu notes further that “increased TLR4 expression in the mucosa of
patients with inflammatory bowel disease suggests that aberrant TLR
expression may play an important role in the loss of tolerance to enteric
bacteria.” (Id. at 1614, first column.)
FF15 Abreu teaches:
In idiopathic inflammatory bowel disease, Cario and Podolsky .
. . have demonstrated increased TLR4 expression by IEC.
Increased TLR4 expression as a primary defect or secondary to
the inflammatory milieu might initiate or perpetuate chronic
inflammation in the presence of commensal bacteria. We
suggest that MD-2 expression may be another critical point of
regulation in the intestinal innate immune response to
commensal organisms. Absent or low MD-2 expression may
protect against dysregulated innate immune responses, whereas
increased expression of MD-2 in idiopathic inflammatory
bowel disease may contribute to the inflammatory cascade.
Thus, careful regulation of both TLR4 and MD-2 is necessary
to maintain homeostasis in an organ that is continuously
exposed to high concentrations of bacteria. An understanding
of the mechanisms used in health to limit deleterious activation
of TLR pathways in the presence of bacteria may help in
understanding the pathogenesis of inflammatory bowel disease
and guiding therapy.

(Id. at 1614, second column.)
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FF16 The Examiner finds that Cario teaches that lipopolysaccharide [LPS]
can induce an inflammatory response in intestinal epithelial cells [IEC].
(Ans. 4.)
FF17 According to the Examiner, Cario teaches “that . . . [‘]the pathogenic
toxin LPS itself is an effective inducer of NF-κB expression in the IEC
lines.’” (Id. at 5 (quoting Cario, p. 971) (emphasis added by Examiner).)
Thus, the Examiner reasons that “[i]t would be immediately obvious to one
[of] skill in the art that NF-κB expression is . . . central to inflammatory
responses, and thus would conclude that LPS does elicit an inflammatory
response[ ] in intestinal epithelial cells.” (Ans. 5.)
FF18 Cario looked for membrane-bound CD14 (mCD14) expression in IEC
lines, but found that none of the cell lines used expressed constitutive
mRNA for CD14. (Cario, p. 969, second column.)
FF19 Cario also notes that IEC do not constitutively express CD14, which
may allow the cells to be “hyporesponsive and tolerant to the constant
luminal exposure of resident miroflora and nondangerous amounts of
pathogenic baterial toxin.” (Cario, p. 971, second column.)
FF20 Cario notes that in “active inflammatory bowel disease, CD14 is
highly up-regulated in recruited monocytes of the intestinal mucosa,” but
that “[i]n vivo studies are needed to clarify the role of CD14 and TLR
proteins in the intestinal epithelium as well as inflammatory cells in the
pathogenesis of inflammatory bowel diseases.” (Id. at 970, paragraph
bridging columns 1 and 2.)
FF21 Cario postulates that high concentrations of LPS may produce mCD14
expression, or that soluble CD14 may be released when the intestinal
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epithelial monolayer is disrupted and invaded by pathogens. (Id. at 970, first
column.) Cario also postulates that injury of intestinal mucosa may lead to
cleavage of mCD14 to produce soluble CD14. (Id.)
FF22 The Examiner relies on Anker for teaching the use of an antibody to
reduce complex formation between TLR4 and CD14 in endotxin-mediated
cardiovascular diseases. (Ans. 5.)
FF23 The Examiner concludes that it would have been obvious to the
ordinary artisan to perform the claimed method because the references as
combined suggest that endotoxin (LPS) binding to CD14, which further
forms a complex with TLR4, “induces a cascade of downstream event[s]
that results in gastrointestinal inflammation.” (Id.)

PRINCIPLES OF LAW
While the analysis under 35 U.S.C. § 103 allows flexibility in
determining whether a claimed invention would have been obvious, KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007), it still requires showing
that “there was an apparent reason to combine the known elements in the
fashion claimed by the patent at issue.” Id. “We must still be careful not to
allow hindsight reconstruction of references to reach the claimed invention
without any explanation as to how or why the references would be combined
to produce the claimed invention.” Innogenetics, N.V. v. Abbott Labs., 512
F.3d 1363, 1374 n.3 (Fed. Cir. 2008).

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ANALYSIS
Appellants argue that the rejection is based on hindsight, asserting that
the Examiner has not articulated “a sound reason why the rejected claims
would be obvious in light of the cited references as a whole.” (App. Br.6
14.) Specifically, Appellants assert, “Abreu . . . teaches that endotoxin
(LPS) in fact does not elicit an inflammatory response in normal intestinal
epithelial cells,” and thus there would be no reason to inhibit “the binding
between endotoxin and its receptor . . . to reduce inflammation in the gut.”
(Id. at 5.)
We agree with Appellants that the Examiner has not provided a reason
as to why it would have been obvious to administer an agent that interferes
with the formation of a complex between TLR4 and CD14 in a method of
enhancing growth or improving feed efficiency in a human or an animal
given the fact that, as taught by Abreu, normal IEC express only low levels
of TLR4. (See FF13.)
It is noted by the Examiner in response to the Appellants’ argument
“that the instant claims do not recite normal intestinal lumen condition in the
claimed method for enhancing growth and improving feed efficiency in
human or non-human animals.” (Ans. 9.) According to the Examiner,
“Appellant[s] acknowledge that prior art teaches that in certain conditions,
i.e. acute infection or in inflammatory bowel diseases, LPS can induce[ ]
stimulation [sic., inflammation?] in intestinal epithelial cells.” (Id.)

6 All references to the Appeal Brief (App. Br.) are to “Appellants’ Amended
Brief on Appeal,” dated June 5, 2009.
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The Examiner has not provided any reason, evidence, or argument as
to why the ordinary artisan would have expected interfering with formation
of a complex between TLR4 and CD14 in a method of enhancing growth or
improving feed efficiency in a human or an animal that suffers from acute
infection or inflammatory bowel diseases would have been obvious. While
Abreu teaches that there is increased TLR4 expression in the mucosa of
patients with inflammatory bowel disease, and Cario teaches that in active
inflammatory bowel disease, CD14 is highly upregulated in recruited
monocytes of the intestinal mucosa, both Abreu and Cario note that more
study is required to determine the roles of TLR4 and CD14 in inflammatory
bowel disease. Specifically, Cario teaches that “[i]n vivo studies are needed
to clarify the role of CD14 and TLR proteins in the intestinal epithelium as
well as inflammatory cells in the pathogenesis of inflammatory bowel
diseases” (FF20), and Abreu teaches that expression of MD-2 is also
increased in inflammatory bowel disease, and that further understanding of
the mechanisms involved “may help in understanding the pathogenesis of
inflammatory bowel disease and guiding therapy.” (FF15.) Thus, the art
relied upon by the Examiner does not establish that interfering with
formation of a complex between TLR4 and CD14 would result in a method
of enhancing growth or improving feed efficiency in a human or an animal
that suffers from acute infection or inflammatory bowel disease.

Appeal 2010-002890
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CONCLUSION OF LAW
We conclude that Examiner has not established by a preponderance of
the evidence that the combination of Cook, Abreu, Cario, and Anker renders
obvious a method of enhancing growth, improving feed efficiency, or both
in a human or non-human animal by administering an agent that interferes
with formation of a complex between TLR4 and CD14. The rejection of
claims 1-6, 8-12, and 40-45 under 35 U.S.C. § 103(a) is reversed.

REVERSED

alw

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