Ex Parte Mao et al

Board of Patent Appeals and Interferences

Nov 15, 2010

11611554 (B.P.A.I. Nov. 15, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte LI MAO, HENING REN, and JUN ZHANG
__________

Appeal 2010-006514
Application 11/611,554
Technology Center 1600
__________

Before ERIC GRIMES, DEMETRA J. MILLS, and LORA M. GREEN,
Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL1

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 2010-006514
Application 11/611,554

2
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s rejection of claims 59, 61, and 63-70.2 We have jurisdiction
under 35 U.S.C. § 6(b).

STATEMENT OF THE CASE
Claims 59 and 70 are representative of the claims on appeal, and read
as follows:
59. A monoclonal antibody which binds and neutralizes HDGF.
70. The antibody of claim 59, wherein the antibody is further defined as a
C1 (SEQ ID NO:32 and SEQ ID NO:34) or H3 (SEQ ID NO:36 and SEQ ID
NO:38) antibody.

The following grounds of rejection are before us on review:
I. Claim 70 stands rejected under 35 U.S.C. § 112, second paragraph,
as being indefinite.
II. Claim 70 stands rejected under 35 U.S.C. § 112, first paragraph, as
lacking enablement.
III. Claims 59, 61, and 63-69 stand rejected under 35 U.S.C. § 103(a)
as being rendered obvious by the combination of Hu3 and Thorpe.4

2 Claims 1, 9, 10, 13, 37, 43, and 59-74 are pending. (App. Br. 2.) Claims 1,
9, 10, 13, 37, 43, and 71-74 stand withdrawn from consideration, and claims
60 and 62 are objected to as depending from a rejected base claim. (Id.)
3 Hu et al., Expression of Hepatoma-Derived Growth Factor in
Hepatocellular Carcinoma A Novel Prognostic Factor, 98 CANCER 1444-
1456 (2003).
4 Thorpe, US 6,342,221 B1, Jan. 29, 2002.
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We affirm rejections I and III, and vacate rejection II.
ISSUE (Indefiniteness)
Does the recitation of both the antibody clone names and the SEQ ID
NO:s of only the variable regions of the clones render claim 70 indefinite?

FINDINGS OF FACT
FF1 The Specification teaches that “HDGF is a heparin-binding growth
factor.” (Spec. ¶10.)
FF2 According to the Specification:
HDGF may be used as a target for hyperproliferative cell, and
in particular cancer, therapies, and identifying that HDGF may
be employed as a diagnostic or prognostic marker; furthermore,
the present invention provides therapies that selectively target
and neutralize HDGF function. In certain embodiments, . . . an
antibody (e.g., a monoclonal antibody, an antibody fragment or
single chain antibody, or a humanized, fully human and/or
recombinant version of the foregoing) which selectively affects
HDGF (i.e., binds, reduces the function of and/or reduces the
expression of HDGF) may be used to treat such disorders.

(Id. at ¶15.)
FF3 The Specification notes that “all of the anti-HDGF antibodies known
to the present inventors, prior to the present invention, are not HDGF-
neutralizing . . ., likely because they do not recognize, or recognize only
poorly, native HDGF molecules.” (Id. at ¶21.)
FF4 The Specification teaches that monoclonal antibodies are preferred
because of “the ease of standard preparation of therapeutically acceptable
commercial amounts of monoclonal antibodies.” (Id.)
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FF5 The Specification also teaches that “HDGF selective antibodies may
be prepared using techniques well known in the art.” (Id. at ¶87.)
FF6 The Specification teaches that antibodies C1 and H3 are preferred.
(Id. at ¶24.) The Specification teaches further that:
Another embodiment of an HDGF-targeting agent is an isolated
nucleic acid that encodes the amino acid sequences of SEQ ID
NO: 32 and SEQ ID NO:34; or SEQ ID NO:36 and SEQ ID
NO:38.

(Id. at ¶23.)
FF7 The Examiner’s statement of the indefiniteness rejection may be
found at pages 4-5 of the Answer.
FF8 The Examiner concludes that the claims are “indefinite for reciting the
antibody clone names C1 and H3 accompanied by the variable region
sequences,” as it is unclear if Appellants intend to claim the cloned antibody,
including the constant regions, or only the variable regions defined by the
sequences contained within the parentheses. (Ans. 5.)

PRINCIPLES OF LAW
“[A]mbiguity in claim scope is at the heart of the definiteness
requirement of 35 U.S.C. § 112, ¶ 2.” Amgen, Inc. v. Hoechst Marion
Roussel, Inc., 314 F.3d 1313, 1342 (Fed. Cir. 2003).

ANALYSIS
Appellants argue that claim 70 is not indefinite as the claim recites
“specific sequences of antibodies C1 and H3 in terms of their heavy and
light chain sequences.” (App. Br. 5.)
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As noted by the Examiner, however, the sequences are only to the
variable regions of the heavy and light chains (see FF8), but not the constant
region. Thus, we agree with the Examiner that we are unable to ascertain
the scope of the claim, because it is unclear if Appellants are claiming the
entire C1 and H3 antibodies, or only their variable regions as defined by the
recited SEQ ID NO:s.
Finally, as we are unable to ascertain the scope of claim 70, we vacate
the enablement rejection of that claim.

CONCLUSION OF LAW
We conclude that the recitation of both the antibody clone names and
the SEQ ID NO:s of only the variable regions of the clones render claim 70
indefinite. We thus affirm the rejection of claim 70 under 35 U.S.C. § 112,
second paragraph, as being indefinite.
As we are unable to ascertain the scope of claim 70, we vacate the
rejection of that claim under 35 U.S.C. § 112, first paragraph, as lacking
enablement.

ISSUE (Obviousness)
Has the Examiner established by a preponderance of the evidence that
the combination of Hu and Thorpe renders the antibody of claim 59
obvious?

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FINDINGS OF FACT
FF9 The statement of the obviousness rejection may be found at pages 9-
12 of the Examiner’s Answer. As Appellants do not argue the claims
separately, we focus our analysis on claim 59, and claims 61 and 63-69 stand
or fall with that claim.
FF10 We initially note that the Examiner interprets “neutralizing antibody”
as “one that would inhibit the activity of HDGF when bound by the
antibody.” (Ans. 16.)
FF11 The Examiner cites Hu for teaching that “HDGF is overexpressed in
hepatocellular carcinoma and is associated with tumor progression,” and
also for suggesting that “elevated HDGF expression may stimulate
angiogenic activity and promote tumor progression.” (Id. at 9-10.)
FF12 The Examiner also notes that Hu teaches Western blots,
immunofluorescence, and immunohistochemistry, and thus teaches an
antibody to HDGF. (Id. at 17 (citing Hu, Figures 1-5).)
FF13 Specifically, Hu teaches that “[r]ecombinant 6x-histidine-tagged
HDGF was purified to near homogeneity for the generation of HDGF
antibodies.” (Hu, p. 1447, second column.) According to Hu, the generated
antibodies specifically detect HDGF in human cells. (Id.)
FF14 Hu also teaches that “HDGF antisense oligonucleotides were shown
to block HDGF expression and inhibit the proliferation of hepatoma cells to
varying degrees,” with the inhibitory effect being the greatest in hepatoma
cells with the highest endogenous HDGF levels. (Id. at p. 1450, second
column.)
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FF15 The Examiner notes that Hu does not teach “a monoclonal antibody
that neutralizes HDGF.” (Ans. 10.)
FF16 Thorpe is cited for teaching blocking or neutralizing antibodies to
VEGF, a growth factor involved in tumor angiogenesis and growth. (Id.)
FF17 Specifically, the invention of Thorpe “is based on antibodies that
specifically inhibit VEGF binding to only one (VEGFR2) of the two primary
VEGF receptors.” (Thorpe, col. 3, ll. 2-4.) According to Thorpe, “[s]uch
antibodies inhibit angiogenesis and induce tumor regression as effectively as
other anti-VEGF antibodies, including those already in clinical trials, and yet
have improved safety due to their specific blocking properties.” (Id. at col.
3, ll. 4-8.)
FF18 The Examiner concludes that it would have been obvious to produce a
blocking or neutralizing antibody to HDGF “for therapeutic benefit in
hepatocellular carcinoma patients.” (Ans. 11.)
FF19 The Examiner further notes that Hu concludes that “‘our findings
indicate that HDGF may be a candidate gene for the development of
diagnostic and therapeutic strategies for HCC.’” (Id. at 17 (quoting Hu, p.
1454, second column) (emphasis added by Examiner).)
FF20 The Examiner thus concludes that one would have been motivated to
target HDGF for the treatment of HCC by neutralizing the gene product, i.e.,
HDGF. (Ans. 17.)
FF21 The Examiner also concludes that Thorpe provides a reasonable
expectation of success by providing “evidence that blocking or neutralizing
an angiogenic and tumor promoting growth factor with a monoclonal
antibody effectively inhibits tumor growth in vivo.” (Id. at 12.)
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FF22 The Examiner further cites Campbell5 for its teaching “that it is
customary for any group working on a macromolecule to both clone the
genes coding for it and make monoclonal antibodies to it.” (Ans. 17.)
FF23 Lepourcelet,6 cited by Appellants, teaches that “HDGF expression is
dramatically increased in human colorectal cancers.” (Lepourcelet,
Abstract.)
FF24 Lepourcelet teaches that antibodies to HDGF were provided as gifts,
and used in immunostaining. (Lepourcelet, p. 416, second column, and p.
422, Fig. 4.)
FF25 Lepourcelet also studied HDGF function by attempting to isolate
proteins that associate with HDGF that have established cellular function.
(Id. at 423, first column.) Lepourcelet recovered peptides corresponding to
hnRNPK, hnRNPI, and TLS/Fus. (Id. at 423, paragraph bridging first and
second columns.)
FF26 As to immunopreciptation, Lepourcelet teaches:
Available antibodies against the putative HDGF-
associated proteins lack immunoprecipitating ability, which
precludes independent assessment of protein interactions.
Instead, we resolved nuclear extracts from HeLa cells and from
E13 mouse intestine by glycerol gradient sedimentation.
Specific antibodies against hnRNPK and TLS/Fus (hnRNPI
antibody is not readily available) revealed partial co-
sedimentation with HDGF . . . . These results support the idea

5 Alisa M. Campbell, MONOCLONAL ANTIBODY TECHNOLOGY 1-32 ( Elsevier
Science Publishers, Chapter 1) (1984).
6 Lepourcelet et al., Insights into developmental mechanisms and cancers in
the mammalian intestine derived from serial analysis of gene expression and
study of the hepatoma-derived growth factor (HDGF), 132 DEVELOPMENT
415-427 (2005).
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that nuclear HDGF associates, probably substoichiometrically,
with these factors.

(Id. at paragraph bridging pp. 423-424.)

PRINCIPLES OF LAW
“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).
If a person of ordinary skill can implement a predictable
variation, § 103 likely bars its patentability. For the same
reason, if a technique has been used to improve one device, and
a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using the
technique is obvious unless its actual application is beyond his
or her skill.

Id. at 417. It is proper to “take account of the inferences and creative steps
that a person of ordinary skill in the art would employ.” Id. at 418. See also
id. at 421 (“A person of ordinary skill is also a person of ordinary creativity,
not an automaton.”).

ANALYSIS
As to Hu, Appellants assert that Hu teaches that HDGF expression is
correlated with hyperproliferative states of hepatocellular carcinoma (HCC),
and is a “‘novel prognostic factor for HCC who have undergone surgery.’”
(App. Br. 6 (citing Hu, Abstract).) Hu, Appellants argue, only mention
therapy in the last sentence of the article, where it is states that “‘HDGF may
be a candidate gene for the development of diagnostic and therapeutic
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strategies for HCC.’” (App. Br. 6.) Thus, Appellants argue, Hu focuses on
the HDGF gene, but does not teach or suggest the use of neutralizing
antibodies. (Id. at 6-7.) Appellants argue further that Hu teaches polyclonal
antibodies for detection of HDGF, thus further teaching away “from
developing neutralizing monoclonal antibodies for therapeutic applications.”
(Id. at 7.)
Appellants’ arguments have been carefully considered, but are not
convincing. We agree with the Examiner that Hu provides a reason for
developing antibodies that block the function, i.e., neutralize, the activity of
HDGF. That is, Hu teaches that HDGF expression is correlated with
hyperproliferative states of hepatocellular carcinoma, as well as being a
prognostic factor for HCC who have undergone surgery. Lepourcelet, cited
by Appellants, also teaches that HDGF is involved in cancerous states,
specifically teaching that HDGF expression is greatly increased in human
colorectal cancers. (FF23.)
Moreover, like our appellate reviewing court, “[w]e will not read into
a reference a teaching away from a process where no such language exists.”
DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464
F.3d 1356, 1364 (Fed. Cir. 2006). Thus, the fact that Hu only produces
polyclonal antibodies to HDGF does not teach away from the production of
monoclonal antibodies, because, as noted by the Examiner, it is customary
for any group working on a macromolecule to make monoclonal antibodies
to it. (FF22.)
Appellants argue further that there is no reasonable expectation of
success of generating neutralizing antibodies. (App. Br. 7.) Appellants cite
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Lepourcelet, which stated that available antibodies against HDGF lacked
immunoprecipitating ability, asserting that an “antibody that is unable to
immunoprecipitate an antigen would certainly not be expected to have
neutralizing activity.” (Id.) Appellants state that the relevance of Thorpe is
unclear, but note that the reference states that it was “surprising” that
blocking antibodies against VEGF could be produced. (Id. at 8.)
Again, Appellants’ arguments are not found to be convincing. First,
we note that all that is required is a reasonable expectation of success, not
absolute predictability of success. In re O’Farrell, 853 F.2d 894, 903 (Fed.
Cir. 1988). Second, the Specification specifically teaches that HDGF
antibodies may be prepared using techniques well known in the art, and
Appellants have not argued or presented evidence that the antibodies have
unexpected properties or that it did require more than standard techniques
and screening methods to produce the claimed antibodies. Third, we
conclude that Lepourcelet does not teach away, as Lepourcelet teaches that
“[a]vailable antibodies against the putative HDGF-associated proteins lack
immunoprecipitating ability,” not that available antibodies to HDGF itself
lacked immunoprecipitating ability. (FF26.) Finally, Thorpe did not teach
that it was “surprising” that neutralizing antibodies against VEGF could be
produced, but that it was surprising that antibodies that specifically inhibit
VEGF binding to only one of the two primary VEGF receptors could be
produced. (See Thorpe, col. 4, ll. 8-11.)

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CONCLUSION OF LAW
We conclude that the Examiner has established by a preponderance of
the evidence that the combination of Hu and Thorpe renders the antibody of
claim 59 obvious. We thus affirm the rejection of claims 59, 61, and 63-69
under 35 U.S.C. § 103(a) as being rendered obvious by the combination of
Hu and Thorpe.

TIME PERIOD FOR RESPONSE
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)(2006).

AFFIRMED

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