Ex Parte Shin et al

Patent Trial and Appeal Board

Jul 21, 2016

12665007 (P.T.A.B. Jul. 21, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/665,007 08/30/2010
4743 7590 07/25/2016
MARSHALL, GERSTEIN & BORUN LLP
233 SOUTH WACKER DRIVE
6300 WILLIS TOWER
CHICAGO, IL 60606-6357
FIRST NAMED INVENTOR
Seung-Uon Shin
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www .uspto.gov
ATTORNEY DOCKET NO. CONFIRMATION NO.
32286/50556 7463
EXAMINER
AEDER, SEAN E
ART UNIT PAPER NUMBER
1642
NOTIFICATION DATE DELIVERY MODE
07/25/2016 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address( es):
mgbdocket@marshallip.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SEUNG-UON SHIN, JOSEPH DAVID ROSENBLATT,
and SHERIE L. MORRISON
Appeal2014-004500
Application 12/665,007 1
Technology Center 1600
Before FRANCISCO C. PRATS, JOHN G. NEW, and RYAN H. FLAX,
Administrative Patent Judges.
FLAX, Administrative Patent Judge.
DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) involving
claims directed to an isolated chimeric fusion protein with an anti-tumor
antigen binding domain from an anti-HER2 or anti-EGFR antibody and a
human endostatin protein (or fragment) with a proline to alanine amino acid
substitution at pos. 125 (and pharmaceuticals/kits therewith). Claims 20-23,
25-35, 45--47, 49-55, 57, 58, and 65 are on appeal as rejected under
35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
1 The Real Party in Interest is University of Miami. App. Br. 3.
Appeal2014-004500
Application 12/665,007
STATEMENT OF THE CASE
The Specification describes that the invention is generally directed to
compositions and methods of targeting and modulating, e.g., treating, tumor
cells, i.e., cancer. Spec. i-f 1. The focus of the Specification is a chimeric
fusion of two molecules, one of which being a tumor antigen targeting
domain (binding domain), e.g., anti-HER2/neu, and the other being an anti-
tumor effector function domain, e.g., endostatin. Spec. i-fi-1 1, 10-92. Fig. IA
illustrates such a chimeric molecule and is reproduced below:
«HER 2-hUEndo aH ER 2 .. m£ndo..f' 125A
!'IG. l.I\
Endostatin--
Endostatin ___ ·
{P125A}
Specification Figure IA shows "a schematic diagram showing anti-HER2
IgG 3-human endostatin fusion proteins [where t ]he endostatin domains []
are indicated by an arrow" and position 125 on a mutated P125A-endostatin
is shown by a darker line, indicated as "P125A." Spec. i-f 95. The
Specification explains, "[i]ntroduction of a point mutation into human
endostatin at position 125 (proline to alanine; huEndo-P125A) enhances
endothelial cell binding, anti-angiogenic activity, and anti-tumor activity as
compared to the wild type endostatin molecule." Spec. i-f 126.
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Application 12/665,007
The appealed claims can be found in the Claims Appendix of the
Appeal Brief. Claims 20, 45, and 65 are independent claims. Claim 45 is
representative and reads as follows:
45. An isolated chimeric fusion protein comprising an anti-
tumor antigen binding domain from an anti-HER2 or anti-EGFR
antibody and at least one human endostatin protein or fragment
thereof, wherein the at least one human endostatin protein or
fragment thereof comprises a proline to alanine amino acid
substitution at position 125 of human endostatin.
App. Br. 19 (Claims App'x).
The following rejection is on appeal:
Claims 20-23, 25-35, 45--47, 49-55, 57, 58, and 65 rejected under
35 U.S.C. § 103(a) over Shin, 2 Yokoyama-1, 3 and Yokoyama-2. 4
DISCUSSION
We adopt the Examiner's findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer. We identify the following only to highlight certain facts:
2 U.S. Patent Application Pub. No. US 2005/0008649 Al (published Jan. 13,
2005) (hereinafter "Shin").
3 Y. Yokoyama & S. Ramakrishnan, Improved Biological Activity of a
Mutant Endostatin Containing a Single Amino-Acid Substitution, 90 BRITISH
J. CANCER 1627-35 (2004) (hereinafter "Yokoyama-I").
4 Yumi Yokoyama & S. Ramakrishnan, Addition of Integrin Sequence to a
Mutant Human Endostatin Improves Inhibition of Tumor Growth, 111 INT. J.
CANCER 839--48 (2004) (hereinafter "Yokoyama-2").
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Application 12/665,007
FINDINGS OF FACT
FF 1. Shin disclosed "[ c ]himeric molecules comprising endostatin
and all or a portion of an lg (lg) molecule are used to treat tumors. A
chimeric molecule, including endostatin fused to an lg domain of an anti-
HER2/neu antibody exhibited longer serum half-life and stability than native
endostatin[,] ... preferentially localized to CT26-HER2 tumors[, and
exhibited c]learance ... 6 fold faster than ... anti-HER2/neu IgG3 ....
Anti-HER2/neu IgG3-endostatin inhibited tumor growth more effectively
than endostatin alone, anti-HER2/neu IgG3 antibody, or the combination of
antibody and endostatin." Shin Abstract; see also Final Action 3, 7-8, 11
and Ans. 2-3, 7, 11-13 (discussing Shin).
FF2. Shin disclosed "[i]n another embodiment of the invention, the
chimeric polypeptide of the invention, e.g., a endostatin construct, is a fusion
constn.1ct of a modified or an unmodified endostatin with a modified or an
unmodified modulatory or cytotoxic molecule." Shin i-f 136; see also Final
Act. 3 (discussing Shin); cf Reply Br. 11 (contending Shin neither provides
motivation to alter its constructs to result in claimed invention nor teaches to
apply its fusion proteins to endostatin P125A).
FF3. Shin disclosed that it was within the ordinary skill in the art to
produce and characterize a chimeric anti-HER2/neu IgG3-endostatin fusion
molecule. Shin i-fi-1275-276 (Example 5); see also Final Action 2
(discussing Shin).
FF 4. Y okoyama-1 disclosed:
Human endostatin has an internal Asn-Gly-Arg (NGR) motif at
position 126-128 following a proline at position 125. Asn-Gly-
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Arg contammg peptides have been shown to target tumour
vasculature and inhibit aminopeptidase N activity. We
previously compared the in vitro and in vivo biological activities
of native endostatin and endostatin with a proline to alanine
mutation (P125A-endostatin). P125A-endostatin exhibited
greater inhibition of both endothelial cell proliferation and
human ovarian cancer growth compared to native endostatin. . ..
P125A-endostatin bound to endothelial cells more efficiently
than native endostatin and exhibited greater inhibition of not only
proliferation but also migration of endothelial cells. P125A-
endostatin also localised into tumour tissue to a higher degree
than the native protein, and displayed greater inhibition of
growth of colon cancer in athymic mice. Both proteins inhibited
tumour cell-induced angiogenesis effectively. Real-time PCR
analysis showed that both native and P125A-endostatin
decreased expression of key proangiogenic growth factors.
Vascular endothelial growth factor and angiopoietin I were
downregulated more by the mutant. These studies suggest that
the region around P 125 can be modified to improve the
biological activity of endostatin.
Yokoyama-I 1627 (Abstract); see also Final Action 3-5, 7-13 and Ans. 4--
11 (discussing Yokoyama).
FF5. Y okoyama-1 disclosed:
In order to determine whether the mutant protein was folded
properly, gross secondary structural analysis of the P125A
mutant was compared to the native protein made in the same
expression system. The CD spectra of native and P125A human
endostatin showed identical profiles, indicating that the two
proteins have similar gross secondary structures (Figure IB).
Yokoyama-I 1629 (right col.), 1630 (Figure IB); see also Final Action 3--4,
8 and Ans. 4, 7-8 (discussing the structural similarities between native
human endostatin and P125A human endostatin).
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FF6. Yokoyama- I disclosed "In spite of the nonconservative
substitution of a proline to alanine, the mutant protein was expressed in
soluble form and was biologically active. The CD spectrum showed that
PI25A-mutation did not cause major structural change." Yokoyama-I I633
(right col.); see also Final Action 3--4, 8, and Ans. 4, 7-8 (discussing the
structural similarities between native human endostatin and PI25A human
endostatin).
FF7. Yokoyama-I disclosed PI25A-endostatin was more effective at
binding endothelial cells (HUVEC) (7I %) than native endostatin (38.5%).
Yokoyama-I I629 (right col.), I630 (Figure IC); see also Final Action, e.g.,
4 and Ans., e.g., 3, 7 (discussing Yokoyama-I).
FF8. Yokoyama-I disclosed, "PI25A-endostatin inhibited
endothelial cell proliferation more efficiently than native endostatin."
Yokoyama-I I629 (right col.); see also Final Act., e.g., I I (discussing
Yokoyama-I).
FF9. Yokoyama- I disclosed "[ t ]umour localisation is improved by
PI25A-mutation [of endostatin]." Yokoyama-I I630 (both col. and Figure
IE); see also Final Action, e.g., 4 (discussing improved localization with
mutation).
FFIO. Yokoyama-I disclosed "neither the native nor the PI25A
mutant showed any inhibition of aminopeptidase N activity even at 5 µM
concentration." Yokoyama-I I 63 I (right col.); see also Reply Br. 4--8
(contending Yokoyama- I did not show improved antitumor effect of mutant
endostatin).
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FFI 1. Yokoyama-I disclosed "both endostatin and PI25A-endostatin
treatment significantly inhibited angiogenesis in vivo (Figure 3H, I and
Figure 4)." Yokoyama-I I63I (right col.); see also Reply Br. 4--8
(contending Yokoyama-I did not show improved antitumor effect of mutant
endostatin).
FF I 2. Yokoyama- I disclosed:
mRNA levels of major proangiogenic growth factors (tumour
cell derived) and receptors expressed on host endothelial cells
were downregulated by endostatin or PI25A-endostatin
treatment. Moreover, VEGF and AngI expression were
significantly decreased by PI25A-endostatin when compared to
native endostatin. Angiopoietin 2 transcript was not detected in
any of the samples analysed. Basic FGF-related transcript levels
were equally decreased by both the native and mutant endostatin.
Yokoyama-I I 632 (left col.); see also Reply Br. 6 (contending inconsistent
effects of mutant endostatin reported by Yokoyama- I).
FF13. Yokoyama-I disclosed "alginate beads of Pl25A-endostatin
was more effective in inhibiting MAI48 ovarian cancer growth when
compared to the native protein given under similar condition (Calvo et al,
2002). These results were confirmed in a human colon cancer model system
(Figure 6)." Yokoyama-I I632 (right col.) (75% vs 30%. tumor growth
inhibition, respectively); see also Reply Br. 4 (contending no data on
improvement using mutant endostatin in bolus form).
FF I 4. Yokoyama- I disclosed:
cell attachment assays showed that PI25A-endostatin bound
more avidly than native endostatin. Enhanced binding to
endothelial cells led to improved biological activity, indicated by
the results of endothelial cell proliferation and migration assays.
In both the assays, the PI25A-mutation increased bioactivity of
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endostatin. Enhanced binding to endothelial cells also led to
improved tumour localisation of endostatin. The homing
specificity of endostatin to tumours compared to lung or liver
tissue was also improved by PI25A-mutation.
Yokoyama-I I 634 (paragraph spanning left and right cols.); cf Reply Br. 7
(contending cited references teaching of PI25A endostatin tumor inhibition
based solely on impermissible hindsight).
FF I 5. Yokoyama- I disclosed:
In summary, these studies show that human endostatin can be
genetically modified to improve its ability to bind and inhibit
endothelial cells. Higher binding also coincided with changes in
potency in inhibiting cell proliferation and migration, and in
homing to tumours. Such differences in tumour-homing
properties can contribute to improved antitumour activity of
mutant endostatin.
Yokoyama-I I 634 (right col.); cf Reply Br. 7 (contending cited references
teaching of PI25A endostatin tumor inhibition based solely on
impermissible hindsight).
FF I 6. Y okoyama-2 disclosed "the PI 25A mutation did not affect the
biologic activity of endostatin but in fact had better antiangiogenic activity
when compared to the native molecule. Further modification of PI25A-
endostatin with the RGD motif showed specific and increased binding to
endothelial cells, and the increased binding coincided with improved
antiangiogenic properties." Yokoyama-2 839 (Abstract); cf Reply Br. 7
(contending cited references teaching of PI 25A endostatin tumor inhibition
based solely on impermissible hindsight).
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ANALYSIS
We agree that the evidence of record supports the Examiner's prima
facie case that the claims would have been obvious over the cited prior art
combination. The issue presented is whether the Appellants' evidence
supporting their contentions of secondary indicia of nonobviousness, i.e.,
unexpected results, is sufficient to overcome the established prima facie case
of obviousness. 5 We find it is not sufficient. We address Appellants'
arguments below.
"[B]y definition, any superior property must be unexpected to be
considered evidence of non-obviousness. Thus, in order to properly evaluate
whether a superior property was unexpected, the [fact-finder must]
consider[] what properties were expected." Pfizer, Inc. v. Apotex, Inc., 480
F.3d 1348, 1371 (Fed. Cir. 2007) (emphasis original; internal citations
omitted herein unless otherwise indicated). Here, the Appellants present
not-insubstantial evidence of significant experimental results relating to the
claimed invention (see generally, App. Br. 8-13); however, on the current
record, these results were not "unexpected."
5 See Declaration of Dr. Seung-Uon Shin under 37 C.F.R. § 1.132 dated Apr.
15, 2013 (hereinafter the "Shin Deel.") and Declaration of Dr. Louis Weiner
under 37 C.F.R. § 1.132 dated Aug. 13, 2013 (hereinafter the "Weiner
Deel."); see also Bookman et al., Evaluation of Monoclonal Humanized
Anti-HER2 Antibody, Trastuzumab, in Patients With Recurrent or
Refractory Ovarian or Primary Peritoneal Carcinoma With Overexpression
of HER2: A Phase II Trial of the Gynecologic Oncology Group, 21 J.
CLINICAL ONCOLOGY 283-90 (Jan. 15, 2003) (hereinafter "Bookman").
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As determined by the Examiner, Shin showed synergy in combining
an anti-HER2/neu IgG3 and a native endostatin into a fused chimeric
molecule. 6 FF 1. Moreover, Shin disclosed that its fused chimeric molecule
"inhibited tumor growth more effectively" than its components individually
or merely combined. Id. As also determined by the Examiner, Yokoyama-I
showed P125A human endostatin was structurally similar to, but better at
treating cancer than native human endostatin because the former exhibited
greater inhibition of endothelial cell proliferation, more efficient binding to
endothelia cells, greater inhibition of endothelial cell migration, higher
degree of localization in tumor tissue, and better inhibition of colon cancer
growth. FF4-FF6, FF15. In substituting a P125A endostatin for the native
endostatin of Shin, a skilled artisan would have sought and expected the
improvements offered by the P125A endostatin mutant in addition to the
anti-tumor synergy of the Shin chimeric fusion. Expected beneficial results
are not evidence of nonobviousness, they are evidence of obviousness. See
In re Skoner, 517 F.2d 947, 950 (CCPA 1975).
The evidence proffered by Appellants consists of two witness'
declarations and a publication directed to research on anti-HER2 antibody
therapy. See note 5, supra. The Shin Deel., while offering impressive data
on the successful treatment of tumors using the invention, as a whole merely
indicates that combining anti-HER2/neu and P125A endostatin, as suggested
by Shin and Y okoyama-1, was as successful as these references would lead
6 See Shin i-f 14 7, which teaches "[ t ]he constructs of the present invention
may comprise domains originating from one species, e.g., from mammals,
such as human." See also id. i-f 297 (identifying human endostatin).
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one to believe. "Synergism, in and of itself, is not conclusive of
unobviousness in that synergism might be expected." In re Kollman, 595
F.2d 48, 55 n.6 (CCPA 1979). Here, it was expected and its confirmation by
the Appellants' experimental data and witness's opinion is not evidence of
nonobviousness.
The Weiner Deel. is directed to the witness's opinion that, as of the
date of invention, a skilled artisan would not be enthusiastic about using or
researching the use of endostatin and related molecules for tumor inhibition.
Other than personal knowledge, the witness bases this opinion on the lack of
any "explicit or implicit suggestion in any of these references to modify any
of the references to result in the claimed invention, and [the afore-discussed]
unexpected results." Weiner Deel. i-fi-13, 7. As discussed above, the Shin
and Yokohama-I references teach both fusing anti-HER2/neu and endostatin
and substituting P125A endostatin for the native to gain improved anti-
tumor effects. Thus, we are not persuaded by this testimony.
Also, Appellants contend the Bookman reference would dissuade the
skilled artisan from looking to anti-HER2 antibodies for cancer treatment.
App. Br. 8. Even if this were so, Shin is explicit that combining anti-
HER2/neu with endostatin offers significant advantages over the antibody
alone. FF 1. Therefore, we are not persuaded by this evidence.
Appellants also contend the Examiner failed to provide acceptable
reasoning why one of ordinary skill in the art would have found it obvious to
modify the references as proposed. App. Br. 6. Appellants also contend the
claimed chimeric fusion proteins would not have been expected because an
expert in the field aware of the cited references would not have been
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motivated to develop a chimeric fusion protein including the endostatin
P125A mutation and an antibody/fragment against HER2. Id. The
reasoning set forth above shows these arguments to be without merit as the
references themselves provide ample motivation for their combination.
Appellants also contend that it was unexpected that incorporating the
mutant endostatin into the claimed fusion would result in a working protein
because proper folding and secondary structure of the resultant chimeric
fusion would be unexpected. App. Br. 7. As the Examiner determined,
Y okoyama-1 is explicit that the mutant endostatin has essentially the same
structure/shape as the native endostatin, which combined and functioned in
the chimeric fusion disclosed by Shin. FF5, FF6. Therefore, the Appellants'
argument is not persuasive.
"[W]hen a patent claims a structure already known in the prior art that
is altered by the mere substitution of one element for another known in the
field, the combination must do more than yield a predictable result." KSR
Int'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). "The combination of
familiar elements according to known methods is likely to be obvious when
it does no more than yield predictable results." Id. We are confronted with
precisely this circumstance here. The chimeric fusion of anti-HER2/neu and
endostatin for cancer therapy was known in the art. FF 1. The fact that the
P125A mutant endostatin offered the same biologic activity of native
endostatin, but with improved anti-tumor benefits was likewise known.
FF4, FF16. Merely substituting the mutant for the native endostatin to yield
the predictable result of improved anti-tumor properties would have been
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obvious and, so, the preponderance of the evidence supports the Examiner's
rejection.
For the above reasons, we find claims 20-23, 25-35, 45--47, 49-55,
57, 58, and 65 would have been obvious over Shin, Yokoyama-I, and
Yokoyama-2, therefore, the respective rejection is affirmed.
SUMMARY
The rejection of claims 20-23, 25-35, 45--47, 49-55, 57, 58, and 65
under 35 U.S.C. § I03(a) over Shin, Yokoyama-I, and Yokoyama-2 is
affirmed.
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. § I. I36(a).
AFFIRMED
I3