Ex Parte Andersen et al

Patent Trial and Appeal Board

Jun 13, 2016

13316821 (P.T.A.B. Jun. 13, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/316,821 12/12/2011
93599 7590
Eric P, Mirabel, JD, LLM
3783 Darcus Street
Houston, TX 77005
06/15/2016
FIRST NAMED INVENTOR
Lars Dyrskjot Andersen
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.
SRG-321-FAB 1078
EXAMINER
HIBBERT, CATHERINE S
ART UNIT PAPER NUMBER
1636
NOTIFICATION DATE DELIVERY MODE
06/15/2016 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):
emirabel@comcast.net
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LARS DYRSKJOT ANDERSEN and
TORBEN FALCK ORNTOFT1
Appeal2013-008129
Application 13/316,821
Technology Center 1600
Before ERIC B. GRIMES, ROBERT A. POLLOCK, and
JACQUELINE T. HARLOW, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating bladder cancer, which have been rejected as nonenabled and
lacking written description. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
The Specification states that bladder cancer can take the form of either
recurring superficial tumors (stages Ta and T 1 ), or it can progress to a
1 Appellants identify the Real Parties in Interest as Catalyst Assets LLC and
Aros Applied Biotechnology A/S. (Appeal Br. 3.)
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Application 13/316,821
muscle invasive form (stages T2 and up). (Spec. 1.) "The ability to predict
which tumors are likely to recur or progress would have great impact on the
clinical management of patients with superficial disease, as it would be
possible to treat high-risk patients more aggressively (e.g. with radical
cystectomy or adjuvant therapy)." (Id. at 2.)
"The invention relates to determining expression levels of certain
markers associated with progression or death from bladder cancer. More
particularly, expression levels of markers MBNL2, F ABP4, UBE2C, and
BIRCS have been associated with progression or death from bladder
cancer." (Id. at 3.)
Claims 1 and 13 are on appeal. Claim 1 is illustrative and reads as
follows:
1. A method for treating stage Ta or Tl bladder cancer, comprising:
determining the likelihood of progression of an individual's bladder cancer,
by, determining in a bladder tumor sample biopsied from the individual:
a. the level of gene expression from the markers MBNL2 and
F ABP4 wherein if the expression level determined for both
MBNL2 and F ABP4 is increased as compared to their
expression levels in a control or different bladder cancer
sample, it indicates a decreased risk of progression relative to
said control or different bladder cancer sample; and wherein if
the expression level for both MBNL2 and F ABP4 is decreased
as compared to their expression levels in a control or different
bladder cancer sample, it indicates an increased risk of
progression relative to said control or different bladder cancer
sample; and
b. administering a chemotherapeutic agent to the individual if the
expression levels determined for both MBNL2 and F ABP4 are
decreased as compared to their expression levels in a control or
different bladder cancer sample.
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Claim 13 is identical to claim 1 except that step (b) recites
"performing cystectomy on said individual," rather than administering
chemotherapy.
The claims stand rejected as follows:
Claims 1 and 13 stand rejected under 35 U.S.C. § 112, first paragraph,
based on both the written description requirement (Ans. 2) and the
enablement requirement (Ans. 3).
I
The Examiner has rejected both of the claims on appeal on the basis
that they include new matter. The Examiner finds that "[t]he specification as
originally filed does not provide support for the invention as now claimed: a
method for treating stage Ta or Tl bladder cancer by administering a
chemotherapeutic agent or performing cystectomy if the expression levels
for both MBNL2 and F ABP4 are decreased compared to a control." (Ans.
2.)
Appellants respond by pointing to several passages in the
Specification that, in their opinion, describe the treatments recited in the
claims. (Appeal Br. 10-11.) Appellants also argue that, although the
Specification does not refer to chemotherapy, its reference to "a more
standard treatment" would be recognized as showing possession of the
claimed method because "[o]ne skilled in the art would certainly know (as
would the majority of the general public) that chemotherapy is a standard
treatment for tumors and cancers, including bladder cancer." (Id. at 11.)
We agree with Appellants that the Specification would have been
recognized, by those of ordinary skill in the art, to show possession of the
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Application 13/316,821
claimed methods. The Specification describes determining a bladder cancer
patient's likelihood of cancer progression based on the expression level of
certain markers, including MBNL2 and FABP4. (Spec. 3, 2nd full i-f.) The
Specification also states that "[d]etection of expression levels of some or all
of these markers in early-stage bladder cancer patients can be used to predict
patient outcomes and/or tailor treatments." (Id. at 3, 3rd full i-f.) Thus, the
Specification describes tailoring treatments-administering different forms
of treatment-to patients based on expression levels of the disclosed
markers.
The Specification also states that patients at high risk of progression
"may also be good candidates for cystectomy or other more aggressive
treatment options." (Spec. 10, 2nd full i-f.) We agree with Appellants that
this disclosure would be recognized by those skilled in the art to describe
performing cystectomy on a patient with an increased risk of bladder cancer
progress10n.
Finally, the Specification states that "[i]ntermediate risk patients
might follow a more standard treatment and monitoring protocol." (Id.)
Appellants argue that those skilled in the art would know that chemotherapy
is a standard treatment for cancer. (Appeal Br. 11.) We agree; it is common
knowledge that chemotherapy is one of the standard treatments for various
types of cancer.
The Examiner responds that "' [ c ]hemotherapy' is a term of art which
is different in scope from 'standard treatment', and/or 'aggressive
treatment'. 'Adjuvant therapy' may encompass or exclude the term
'chemotherapy' depending on the context." (Ans. 12.)
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However, "[i]n order to satisfy the written description requirement,
the disclosure as originally filed does not have to provide in haec verba
support for the claimed subject matter at issue." Purdue Pharma L.P. v.
Faulding, Inc., 230 F.3d 1320, 1323 (Fed. Cir. 2000). The test of adequate
written description is whether the disclosure conveys with reasonable clarity
to those skilled in the art that the inventor was in possession of the invention.
See id.
In this case, the Specification's description of "standard" treatment
would be recognized as showing possession of administering chemotherapy,
even though standard treatments for cancer might also include, for example,
surgery or radiation therapy, because those skilled in the art would recognize
that each of these approaches is a standard treatment of cancer.
For the reasons discussed above, we reverse the rejection of claims 1
and 13 for lack of adequate written description.
II
The Examiner has rejected both of the claims on appeal for
nonenablement. The Examiner finds that the claims are broad, in that they
only require assaying two marker genes and do not recite any specific
expression levels. (Ans. 4.) The Examiner cites several references as
evidence that "contrary to the instantly claimed methods, the MBNL2
marker is associated with increased likelihood of progression of cancer."
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(Id. at 4---6 (citing Mack2, Clarke,3 and Bignotti4).) The Examiner also cites
several references as evidence that biomarkers must be validated before they
can be used. (Id. at 6-7 (citing Wagner,5 Frank,6 Feng,7 and Dyrskj0t8).)
The Examiner cites Sanchez-Carbayo9 as evidence of unpredictability
(id. at 8), and notes that the Specification does not include a working
example of the claimed method (id. at 9). The Examiner concludes that "the
basic premise underlying the claimed invention is no more than a theoretical
possibility" and "it would require undue experimentation to practice the
invention as presently claimed." (Id. at 9-10.)
Appellants argue that they have provided evidence showing that the
correlation between MBNL2 and F ABP4 expression levels and either
progression or non-progression of bladder cancer is statistically significant.
(Appeal Br. 12-13.) Appellants also argue that the references cited by the
2 US 2004/0076955 Al published April 22, 2004.
3 US 2006/0019256 Al published January 26, 2006.
4 Bignotti et al., Gene expression profile of ovarian serous papillary
carcinomas: identification of metastasis-associated genes, 196 American
Journal of Obstetrics & Gynecology 245.el-245.el l (2007).
5 Wagner, Overview of biomarkers and surrogate endpoints in drug
development, 18 Disease Markers 41--46 (2002).
6 Frank et al., Clinical biomarker in drug discovery and development, 2
Nature Reviews 566-580 (2003).
7 Feng et al., Research issues and strategies for genomic and proteomic
biomarker discovery and validation: a statistical perspective, 5
Pharmacogenomics 709-719 (2004).
8 Dyrskj0t et al., IdentifYing distinct classes of bladder cancer using
microarrays, 33 Nature Genetics 90-96 (2003). The Examiner refers to this
reference as "Andersen."
9 Sanchez-Carbayo, Use of High-Throughput DNA Microarrays to IdentifY
Biomarkers for Bladder Cancer, 49 Clinical Chemistry 23-31 (2003).
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Examiner as evidence that MBNL2 expression is associated with increased
likelihood of progression are either unreliable or not on point. (Id. at 13-
14.) Finally, Appellants argue that the evidence does not show the claimed
method to be unpredictable, and that "decreased expression levels of both
MBNL2 and F ABP4 have been validated as progression markers for bladder
cancer." (Id. at 14--15.)
We agree with Appellants that the Examiner has not shown, by a
preponderance of the evidence, that undue experimentation would be
required to practice the claimed method.
[T]he PTO bears an initial burden of setting forth a reasonable
explanation as to why it believes that the scope of protection
provided by that claim is not adequately enabled by the
description of the invention provided in the specification of the
application; this includes, of course, providing sufficient reasons
for doubting any assertions in the specification as to the scope of
enablement.
In re Wright, 999 F.2d 1557, 1561---62 (Fed. Cir. 1993). "After evidence or
argument is submitted by the applicant in response, patentability is
determined on the totality of the record, by a preponderance of evidence
with due consideration to persuasiveness of argument." In re Oetiker, 977
F.2d 1443, 1445 (Fed. Cir. 1992).
In this case, the Examiner has cited several references as evidence that
practicing the claimed method would require undue experimentation because
(a) MBNL2 expression has been associated by others with an increased,
rather than decreased, likelihood of cancer progression; (b) biomarkers
require validation; and ( c) using gene expression data for cancer prognosis
was unpredictable at the time of the invention. (Ans. 4--8.)
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In response, Appellants cite evidence that they submitted in
application 13/316,733, which was published as US 2012/0082994. (Appeal
Br. 12.) The evidence describes the methodology used to determine whether
increased expression of certain genes was correlated with increased or
decreased likelihood of bladder cancer progression, and shows that the
results indicated that both MBNL2 and F ABP4 were found to be "protective
markers" that correlated with non-progression. (Appeal Br. 17-19,
Evidence App'x.)
The Examiner's position, on the other hand, is that the evidence
shows that biomarkers must be validated in order to be clinically useful.
(Ans. 6-7, citing Wagner, Frank, Feng, and Dyrskj0t.) The Examiner does
not explain, however, why validating the two biomarkers recited in the
claims would be considered to be undue experimentation to those skilled in
the art, especially in view of the data disclosed in the instant Specification
and in Appellants' application 13/316,733 (US 2012/0082994). In fact,
Wagner, Frank, and Feng seem to contemplate validating a large number of
biomarkers for their clinical implications, and Dyrskj0t is specifically
addressed to classifying different types of bladder cancer tumors based on
gene express10n.
The Examiner cites Sanchez-Carbayo as evidence of the
unpredictability of using gene expression data in prognosis of bladder
cancer. (Ans. 8.) Sanchez-Carbayo, however, states that "[n]umerous
markers have been described to correlate to some extent with tumor stage
and prognosis of patients with bladder cancer." (Sanchez-Carbayo 23,
Background.) The Examiner has not explained how Sanchez-Carbayo
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indicates unpredictability in using known biomarkers, such as MBNL2 and
FABP4, in the claimed method.
The Examiner also cites Mack, Clarke, and Bignotti as evidence that
others have found increased MBNL2 expression to be associated with an
increased, not decreased, likelihood of cancer progression. (Ans. 4---6.) We
conclude that, while the Examiner's evidence shows some unpredictability,
it is insufficient to outweigh the evidence submitted by Appellants. Clarke
addresses "gene expression profiles associated with solid tumor stem cells."
(Clarke, i-f 8.) Clarke also discloses "providing a prognosis to [a] subject"
based on "at least one stem cell cancer marker ... from Table 8" (id. at
i-f 11), but Table 8 does not include MBNL2 (or MBLL39, which the
Examiner states is synonymous (Ans. 5)).
Bignotti lists MBNL2 as among the genes that are up-regulated at
least two-fold in metastatic, as compared to primary, OSPC. (Bignotti
245.e5.) However, "OSPC" is short for "ovarian serous papillary
carcinoma." (Id. at 245.el.) The Examiner has not provided evidence that a
gene that is overexpressed in metastatic ovarian carcinoma would be
expected to predictive of cancer progression for bladder cancer.
Finally, the Examiner cites Mack as evidence that MBNL2 expression
shows a higher, not lower, likelihood of bladder cancer progression. (Ans.
4--5.) The Examiner points out that Mack includes MBNL2 10 in its list of
"Genes predictive of bladder cancer progression," although it includes
10 There is no dispute that MBNL2 is the same as the gene referred to by
Mack as PR02032. (Ans. 5, Appeal Br. 13 (acknowledging that Mack's
Table 8A includes MBNL2).)
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Application 13/316,821
F ABP4 in its list of "Genes predictive of no bladder cancer progression."
(Id. at 5.)
Mack, unlike Bignotti and Clark, directly addresses the prognostic
value of MBNL2 in bladder cancer progression. Mack also discloses that
increased expression of MBNL2 leads to the opposite prognosis than is
recited in the claims on appeal. However, the Examiner has not persuasively
explained why Mack's conclusion should be considered more likely to be
accurate than Appellants'.
As Appellants point out (Appeal Br. 13), Mack provides little detail in
how the genes that are up-regulated in tumors that later progressed were
identified. Appellants argue that the only relevant description is provided in
Mack's paragraph 347. (Id.) The Examiner does not point to any additional
disclosure regarding methodology in Mack. (See Ans. 18-19.)
Mack states that "[ m ]olecular profiles of various normal and
cancerous tissues were determined and analyzed using gene chips. RNA
was isolated and gene chip analysis was performed as described" in prior art
references. (Mack i-f 347.) As Appellants point out, "Mack et al. do not
describe how many patients were studied, how long the study extended,
when samples were taken, and there is no statistical analysis of the
correlation between up or down regulation and progression." (Appeal Br.
13.)
By contrast, Appellants' evidence (or the published application from
which it came), states that RNA ('994 publ., i-f 94) from 205 patients with
stage Ta or Tl bladder cancer (id. at i-f 91) was converted to cDNA (id. at
i-f 94) and analyzed by QPCR (id. at i-f 95). The '994 published application
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also states that " [a ]nal ysis of these results led to selection of markers of
interest, which appeared to have high or low expression levels that
correlated well with the clinical determinations of either progression
(including death from bladder cancer) or non-progression." (Id. at i-f 97 .)
Appellants' evidence states that sets of markers of interest were then
identified, and statistical analysis was carried out for each marker: "the
Pearson correlation coefficient ... was calculated" (id. at i-f 101) and "a
t-test, Wilcoxon signed rank test P<0.01, Kolmogorov-Smimov (KS) test,
P<0.01, and Chi-squared test, P<0.01, were run" (id. at i-f 102). Appellants'
evidence states that "the markers that performed the best in all or most of the
above criteria" were separated into groups based on whether higher
expression correlated with progression or non-progression. (Id. at i-f 104.)
Appellants' evidence is specific to the expression of MBNL2 and
FABP4 in bladder cancer cells and their correlation with progression or non-
progression of the cancer. And Appellants provided a detailed explanation
of how the data were derived and the statistical methods that were used to
correlate changes in expression with progression or non-progression of the
cancer. We conclude that Appellants' evidence is entitled to greater weight
than the evidence cited by the Examiner.
The Examiner responded that Appellants' evidence "is not a study of
the MBNL2 and F ABP4 markers (i.e., called a two-gene signature) but is a
study of a twelve-gene signature, specifically the twelve marker genes listed
in Table 4 of [the] Evidence Appendix." (Ans. 18.) Appellants' evidence,
however, states that calculation of the Pearson correlation coefficient and
statistical analyses were performed "for each marker." (Appeal Br. 17.) We
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therefore agree with Appellants (Reply Br. 2-3) that the Examiner's position
is not consistent with the evidence presented.
SUMMARY
We reverse both of the rejections on appeal.
REVERSED
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