Ex Parte Gunaratne

Patent Trial and Appeal Board

Jul 20, 2017

13437128 (P.T.A.B. Jul. 20, 2017)

United States Patent and Trademark Office
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
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/437,128 04/02/2012 Preethi H. Gunaratne D7026 6505
27851 7590
BENJAMIN A. ADLER
8011 CANDLE LANE
HOUSTON, TX 77071
EXAMINER
SHIN, DANA H
ART UNIT PAPER NUMBER
1674
NOTIFICATION DATE DELIVERY MODE
07/24/2017 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):
Ben@ adlerandassociates.com
Colleen @ adlerandassociates.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PREETHI H. GUNARATNE1
Appeal 2016-006640
Application 13/437,128
Technology Center 1600
Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
RYAN H. FLAX, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to a method of improving therapeutic response for ovarian cancer treatment
by administering an agent that enhances the expression of microRNA 29a.
The Examiner rejects the claims as obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We AFFIRM.
1 According to Appellant, the real party in interest is University of Houston
System. Br. 3.
Appeal 2016-006640
Application 13/437,128
STATEMENT OF THE CASE
Claims 2, 4, 5, 7, 8, 15, 17, 18, and 20-25 are on appeal, and can be
found in the Claims Appendix of the Appeal Brief. Claims 2 and 15 are
representative of the claims on appeal, and read as follows:
Claim 2: A method of improving a therapeutic response to
ovarian cancer treatment, in a subject, the method comprising:
administering to the subject an effective amount of an
agent that enhances the expression of microRNA 29a or an
agent that mimics the effects of microRNA 29a to suppress the
growth of the ovarian cancer or to increase sensitivity of the
ovarian cancer to the treatment, thereby improving the
therapeutic response.
Claim 15: A method of treating ovarian cancer in a subject in
need of such treatment comprising the step of:
administering an effective amount of an agent that
enhances the expression of microRNA 29a or an agent that
mimics the effects of microRNA 29a[.]
Appellant seeks review of the Examiner’s rejection of claims 2, 4, 5,
7, 8, 15, 17, 18, and 20-25 under pre-AIA 35 U.S.C. § 103(a) over Flavin,2
Croce,3 Nielson,4 Park,5 in further view of Li6 and Leu.7
2 Flavin et al., miR-29b Expression Is Associated With Disease-Free
Survival in Patients With Ovarian Serous Carcinoma, 19 Int. J. Gynecol.
Cancer 641^17 (2009) (“Flavin”).
3 Croce et al., US 2011/0179501 Al, published July 21, 2011 (“Croce”).
4 Nielson et al., US 2007/0014768 Al, published Jan. 18, 2007 (“Nielsen”).
5 Park et al., miR-29 miRNAs activatep53 by targetingp85a and CDC42, 16
Nat. Struct. & Mol. Biology 23-29 (“Park”).
6 Li et al., Integrated analysis of DNA methylation and gene expression
reveals specific signaling pathways associated with platinum resistance in
ovarian cancer, 2 BMC Medical Genomics (2009) (“Li”).
7 Leu et al., Double RNA Interference of DNMT3b and DNMT1 Enhances
DNA Demethylation and Gene Reactivation, 63 Cancer Research 6110—
115 (2003) (“Leu”).
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Application 13/437,128
The issue is: Does the evidence of record support the Examiner’s
conclusion that the combination of references renders obvious a method of
administering an agent that that enhances expression of microRNA 29a for
improving therapeutic response to ovarian cancer treatment, and if so has
Appellant presented sufficient rebuttal evidence to overcome the prima facie
case?
Findings of Fact
We adopt the Examiner’s findings of fact and reasoning regarding the
scope and content of the prior art as set out in the Answer and Final Action
mailed March 18, 2015. For emphasis only we highlight the following:
FF1. Flavin teaches “that decreased miR-29b expression may help cancer
cells evade cell death, a cardinal hallmark of tumor cells.” Flavin
646.
FF2. Flavin teaches “that miR-29b is down-regulated in a proportion of
ovarian serous carcinomas and is associated with some
clinicopathological features of ovarian serous carcinoma.” Flavin
646. Flavin teaches that down regulation of miR-29b in ovarian
cancer cells provides “a rationale for developing epigenetic therapies
for cancers aberrantly expressing miR-29b alone or in combination
with other treatments to reactivate tumor suppressor genes and
normalize aberrant patterns of methylation in cancer.” Flavin 646.
FF3. Croce teaches a link between DNA methyltransferase (DNMT) and
miR-29 expression. Reduction in “global DNA methylation, restores
expression of TSGs [(tumor suppressor genes)] and inhibits
tumorigenicity both in vitro and in vivo.” Croce 1210.
“Overexpression of individual miR-29s[, either miR-29a, miR-29b, or
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Application 13/437,128
miR-29c, showed] marked reduction of DNMT3A and DNMT3B
mRNA levels . . . , whereas silencing of miR-29s with antisense
molecules, induced up-regulation of DNMT3A and DNMT3B mRNA
levels.” Croce 1193; see Ans. 3^4.
FF4. Park teaches a link between p53 levels and miR 29 expression. “The
p53 pathway is inactivated in most human cancers, highlighting the
crucial role of p53 as a tumor suppressor.” Park 23. “Each of the
miR-29 family members alone as well as a mixture of all three miR-
29 RNAs (miR-29mix) increased p53 protein levels of transfected
HeLa cells by two-fold to three-fold, indicating that miR-29a, miR-
29b and miR-29c have similar effects on p53.” Park 24.
Principle of Law
“If the claim extends to what is obvious, it is invalid under § 103.”
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007).
Analysis
We agree with the Examiner’s factual findings and conclusion, as set
out in the Final Action and Answer which we adopt and incorporate herein
by reference. To summarize, the Examiner finds that Flavin suggests “to
enforce expression of miR-29b in ovarian serous cancer so as to reduce
global DNA methylation, restore tumor suppressor genes, and inhibit
tumorigenicity, because Flavin expressly taught that ovarian serous
carcinoma samples isolated from 50 patients show reduced expression levels
of miR-29b.” Ans. 2—3; see FF1, FF2. The Examiner finds that it would be
obvious to substitute miR-29a for the miR-29b taught in Flavin because
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Application 13/437,128
these micro RNAs have been shown to be functional equivalents. See Ans.
3—6; FF2, FF4. The Examiner relies on Croce and Park to support the
finding of functional equivalents between the miR-29 isoforms. “Croce
expressly demonstrates that miR-29 family members, miR-29a, miR- 29b,
and miR-29c isoforms, share about 90% sequence homology and all three
isoforms bind and reduce DNMT3B mRNA expression.” Ans. 3; FF2.
Based on the teachings of both Croce and Park that show miR-29a, miR-
29b, and miR-29c have similar effects in the various cell systems tested, we
find no error with the Examiner’s conclusion that substituting one miR 29
family member for another member of the same family would be obvious.
See Ans. 4, 5, 8; FF1—FF4. Because the family members are shown to have
similar effects in different cell systems there is a reasonable expectation that
they would behave similarly in ovarian tumor tissue. See FF1—FF4.
We conclude that the Examiner has met the burden of presenting a
prima facie case based on the combination of references. “When prima facie
obviousness is established and evidence is submitted in rebuttal, the
decision-maker must start over.” In re Rinehart, 531 F.2d 1048, 1052
(CCPA 1976); In re Hedges, 783 F.2d 1038, 1039 (Fed. Cir. 1986) (“If a
prima facie case is made in the first instance, and if the applicant comes
forward with reasonable rebuttal, whether buttressed by experiment, prior art
references, or argument, the entire merits of the matter are to be
reweighed”). “After a prima facie case of obviousness has been made and
rebuttal evidence submitted, all the evidence must be considered anew.” In
re Eli Lilly & Co., 902 F.2d 943, 945 (Fed. Cir. 1990) (citing In re Piasecki,
745 F.2d 1468, 1472 (Fed. Cir. 1984)). Because the Examiner presents a
prima facie case of obviousness, we consider whether Appellant submits
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Application 13/437,128
sufficient evidence or argument in rebuttal to overcome the prima facie
finding of obviousness.
Appellant does not contest that Flavin “analyzed and characterized
miR-29b expression in ovarian serous carcinoma and demonstrated that
miR-29b is downregulated in a significant portion of ovarian serous
carcinomas.” Br. 5. The claims, however, are directed to administering
miR-29a and not miR-29b. Appellant contends that observations showing
“that miR-29b is down-regulated in both lung cancer and ovarian serous
tumor” does not provide reasonable expectation to “predict the effects of
administering any microRNA 29 mimic to ovarian cancer subjects.” Id. at 7.
In other words, Appellant contends that one of skill could not “extrapolate
therapeutic results from one cancer type to another with any reasonable
expectation of success.” Id. at 8; see also 11 (“a reasonable expectation that
miR-29a would have a similar effect as there can be significant differences
in effects between microRNAs of the same family”).
We are not persuaded by Appellant’s contention that there is no
reasonable expectation of success because, as the Examiner explained, “all
three miR-29 family members (miR-29a, miR-29b, and miR-29c) were
demonstrated to provide downregulation of DNMT3B and upregulation of
p53 as demonstrated by Croce and Park.” Ans. 7; FF2, FF4. The miR-29
family members have “been recognized to play a tumor suppressor role as
demonstrated by Croce showing reduced lung cancer cell growth both in
vitro and in vivo by all three isoforms and further evidenced by the cancer
cell apoptosis induced by all three miR-29 family members as disclosed by
Park.” Ans. 9.
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Appellant contends that microRNA belonging to the same family do
not necessarily work similarly. Relying on the teaching of Holland8 and
Lin,9 Appellant contends “miR-26a acts as an oncogene in glioma and miR-
26b acts as a tumor suppressor in glioma,. . . demonstrating] that
microRNAs of the same family can have opposing effects in the same type
of cancer.” Br. 12.
We are not persuaded. The evidence provided by Appellant is
directed to a different microRNA and that evidence provides no insight into
the workings of any of the miR-29 family members. More is known about
miR-29 family members than just their sequence similarity. The Examiner
relies on Croce and Park to establish that the miR-29 family members are
functionally equivalent because they behave similarly in the various cell
systems tested. “[A]ll three miR-29 family members (miR-29a, miR-29b,
and miR-29c) were demonstrated to provide downregulation of DNMT3B
and upregulation of p53.” Ans. 7; FF2, FF4. The Examiner finds that
“Croce demonstrates that all of miR-29a, miR-29b, and miR-29c inhibit lung
tumor cell growth . . . and Park [also] demonstrates that all three miR-29
members induce cancer cell apoptosis .... Hence, both miR-29a and miR-
8 Huse et al., The PTEN-regulating microRNA miR-26a is amplified in high-
grade glioma and facilitates gliomagenesis in vivo, 23 Genes &
Development 1327—37 (2009). We note that during prosecution the
Appellant refers to the reference as Holland even though the first named
author is Huse. For consistency we will continue to refer to this reference as
Holland.
9 Wu et al., Role of MicroRNA-26b in Glioma Development and Its
Mediated Regulation on EphA2, 6 PloS One 1—11 (2011). We note that
during prosecution the Appellant refers to the reference as Fin even though
the first named author is Wu. For consistency we will continue to refer to
this reference as Fin.
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Application 13/437,128
29b were known to be tumor-suppressors, unlike miR-26a and miR-26b.”
Ans. 9. In addition, “Croce[’s] showing reduced lung cancer cell growth
both in vitro and in vivo by all three isoforms and further evidenced by the
cancer cell apoptosis induced by all three miR-29 family members as
disclosed by Park” demonstrate how similarly they function. Ans. 9. We
agree with the Examiner’s conclusion that the evidence provided by
Appellant, that is directed to a different micro RNA family, is not sufficient
to overcome the teachings in Croce and Park that show that the miR-29
family members all behave similarly as tumor suppressors.
Upon reconsideration of all the evidence in light of Appellant’s
contention that one cannot extrapolate the teaching of one microRNA to the
reminder of the family, we find that the weight of the evidence supports the
Examiner’s conclusion of obviousness. Appellant’s evidence with respect to
miR-26 is not sufficient to establish that the teachings of Flavin, Croce,
Nielson, Park, Li, and Leu are incorrect or inconsistent or that the
Examiner’s conclusions and inferences drawn from those teachings are
unreasonable. On balance, we conclude that Appellant’s evidence does not
outweigh the evidence favoring obviousness.
SUMMARY
We affirm the rejection of all claims.
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
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