Ex Parte Andersen et al

Patent Trial and Appeal Board

Apr 10, 2017

13352393 (P.T.A.B. Apr. 10, 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
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/352,393 01/18/2012 Lars Dyrskj0t Andersen SRG-321-FAB-II 7412
35859 7590
Pierce Atwood LLP
100 Summer Street
Suite 2250
Boston, MA 02110
EXAMINER
HIBBERT, CATHERINE S
ART UNIT PAPER NUMBER
1636
NOTIFICATION DATE DELIVERY MODE
04/12/2017 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):
Patent @pierceatwood. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LARS DYRSKJ0T ANDERSEN and
TORBEN FALCK ORNTOFT
Appeal 2014-003417
Application 13/352,393
Technology Center 1600
Before JEFFREY N. FREDMAN, CHRISTOPHER G. PAULRAJ, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to methods
of using quantitative PCR to predict the likelihood of an individual’s bladder
cancer progression. The Examiner rejected the claims as indefinite, as
failing to comply with the enablement requirement, as directed to non-
statutory subject matter, and as anticipated. We have jurisdiction under
35 U.S.C. § 6(b). We affirm.
1 Appellants identify the Real Parties in Interest as Catalyst Assets
LLC and Aros Applied Biotechnology A/S (see App. Br. 3).
Appeal 2014-003417
Application 13/352,393
Statement of the Case
Background
“[U]rinary bladder cancer is the fourth most common malignancy in
males .... The disease basically takes two different courses: one where
patients have multiple recurrences of superficial tumors (Ta and Tl), and
one which progresses to a muscle invasive form (T2+) which can lead to
metastasis” (Spec. 1). “[I]t is often difficult to differentiate Ta from Tl
stage tumors, and the two stages are often confused. 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” (Spec. 2).
The Claims
Claims 13—28 are on appeal. Claim 13 is representative and reads as
follows:
13. A method of using a quantitative PCR (“QPCR”)
machine to determine gene expression levels of certain bladder
cancer progression markers in order to predict the likelihood of
an individual’s bladder cancer progression, said method
encompasses reducing sources of noise in said determination,
comprising:
a. Using QPCR to determine gene expression levels
of certain harmful and protective markers from an
individual with stage Ta or Tl bladder cancer wherein a
Ct value for said markers indicates the number of
amplification cycles until a signal threshold has been
reached in inverse relationship to the expression level for
said markers;
b. Calculating a value for the expression levels of
said protective markers by summing the Ct values of said
protective markers and dividing by the number of said
protective markers;
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Application 13/352,393
c. Calculating a value for the expression levels of the
said harmful markers by summing the Ct values of said
harmful markers and dividing by the number of said
harmful markers;
d. Subtracting one of the calculated values obtained
in steps b and c above from the other thereby obtaining a
score based on reduced sources of noise in the Ct values;
and
e. If the score signifies increased expression levels of
protective markers compared to expression levels of
harmful markers it indicates a decreased risk of the
individual’s bladder cancer progression; or, if the score
signifies increased expression levels of harmful markers
compared to expression levels of protective markers it
indicates an increased risk of the individual’s bladder
cancer progression.
The Issues2
A. The Examiner rejected claims 13—28 under 35 U.S.C. § 101, as being
directed to non-statutory subject matter (Ans. 2—9).
B. The Examiner rejected claims 13—28 under 35 U.S.C. § 112, second
paragraph, as indefinite (Ans. 9—10).
C. The Examiner rejected claims 16, 20, and 26 under 35 U.S.C. § 112,
first paragraph as failing to comply with the enablement requirement (Ans.
10-17).
D. The Examiner rejected claims 13—15, 17—19, 21—25, 27, and 28 under
35 U.S.C. § 102(b) as anticipated by Glinskii3 (Ans. 17—21).
2 The Examiner withdrew the provisional obviousness-type double
patenting rejections (see Ans. 21).
3 Glinskii, G., US 2009/0233279 Al, published Sept. 17, 2009 (“Glinskii”).
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Application 13/352,393
A. 35 U.S.C. § 101
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 101 as being directed to patent-ineligible subject matter. The Examiner
finds that “claim(s) 13—28 are determined to be directed to a law of
nature/natural principle” (Ans. 2). The Examiner reached this conclusion by
applying the test set out in Mayo Collaborative Services v. Prometheus
Laboratories, Inc., 132 S. Ct. 1289 (2012), as directed in a 2012 guidance
memo4 (Ans. 2—9).
Appellants argue that the claims require the use of QPCR, which is an
additional element that is significantly more than the natural principle of
correlating protective or harm fill gene expression levels with the likelihood
of bladder cancer progression (App. Br. 12). Appellants also claim the
“method of reducing noise is ‘significantly more than the natural principle
itself” {id.). Appellants also argue that the claims do not preempt the
natural principle because “[n]o one is foreclosed from correlating gene
expression with bladder cancer progression by other processes or means”
{id. at 13). Finally, Appellants argue that the calculations recited in the
claims are not conventional and routine steps because no reference has been
cited that teaches these steps {id. at 14).
We agree with the Examiner that, under the two-step test of Mayo, the
claims are not directed to patent-eligible subject matter. In Mayo, the
Supreme Court applied its test to claims that are similar to those of the
instant application and found them patent-ineligible under § 101.
4 2012 Interim Procedure for Subject Matter Eligibility Analysis of
Process Claims Involving Laws of Nature (July 3, 2012).
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Specifically, the claimed invention at issue in Mayo was a “method of
optimizing therapeutic efficacy for treatment of an immune-mediated
gastrointestinal disorder” comprising administering a certain class of drug
and then determining the level of 6-thioguanine (6-TG) in a patient, where a
level of 6-TG below or above certain amounts indicated a need to increase or
decrease, respectively, the drug dosage. Mayo, 122 S. Ct. at 1295.
Claim 13 of the instant application is similar, in that it is directed to a
method of predicting whether a given patient’s bladder cancer is or is not
likely to progress from an early, superficial stage to a muscle-invasive stage,
by measuring the gene expression of particular harmful and protective
markers and comparing the result to a control.
The Mayo Court concluded that the claims at issue in that case “set
forth laws of nature—namely, relationships between concentrations of
certain metabolites in the blood and the likelihood that a dosage of a
thiopurine drug will prove ineffective or cause harm.” Id. at 1296.
Similarly here, claim 13 on appeal sets forth a law of nature—namely,
a relationship between the level of expression of particular harmful and
protective markers and the likelihood that a bladder cancer will progress to a
more invasive form. Under the first step of the Mayo test claim 13 on appeal
is directed to a law of nature or natural phenomenon.
The Mayo Court next turned to the question “[w]hat else is there in
the claims before us?” Id. at 1297. The claims in Mayo included an
“‘administering’” step, a “‘determining’” step, and a “‘wherein’” clause. Id.
The Court concluded that “[t]he upshot is that the three steps simply tell
doctors to gather data from which they may draw an inference in light of the
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correlations.” Id. at 1298. In other words, “the claims inform a relevant
audience about certain laws of nature; any additional steps consist of well-
understood, routine, conventional activity already engaged in by the
scientific community; and those steps, when viewed as a whole, add nothing
significant beyond the sum of their parts taken separately.” Id. The Court
concluded that “the steps are not sufficient to transform unpatentable natural
correlations into patentable applications of those regularities.” Id.
Like the steps of the claims in Mayo, the manipulative steps of claim
13 on appeal also “consist of well-understood, routine, conventional activity
already engaged in by the scientific community.” Id. “Using QPCR” to
measure the expression level of a given gene is conventional, as shown by
Mack5 and Glinskii: “Often, amplification-based assays are performed to
measure the expression level of bladder cancer-associated sequences. . . .
Methods of quantitative amplification are well known to those of skill in the
art” (Mack 1153); “Q-PCR reactions and measurements were performed . . .
. The results were normalized to the relative amount of expression of an
endogenous control gene GAPDH” (Glinskii 191). Our reviewing court has
also recognized that the use of PCR was a “well-understood, routine, and
conventional activity” that is insufficient to confer patent eligibility. See
Genetic Techs. Ltd. v. MerialL.L.C., 818 F.3d 1369, 1377 (Fed. Cir. 2016)
(“[T]he physical steps of DNA amplification and analysis of the amplified
DNA to provide a user with the sequence of the non-coding region do not,
individually or in combination, provide sufficient inventive concept to
render claim 1 patent eligible.”); Ariosa Diagnostics, Inc. v. Sequenom, Inc.,
5 Mack et al., US 2004/0076955 Al, published Apr. 22, 2004 (“Mack”).
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788 F.3d 1371, 1377 (Fed. Cir. 2015) (“Using methods like PCRto amplify
and detect cffDNA was well-understood, routine, and conventional activity
in 1997.”).
The step of comparing gene expression levels is also routine, as also
shown by Mack and Glinskii. Mack states that its “invention provides
nucleic acid and protein sequences that are differentially expressed in
bladder disease or cancer relative to normal tissues” (Mack 1104). Glinskii
teaches “[mjolecular signatures can then be identified from these sets of
transcripts exhibiting concordant expression changes between metastatic
tumor and stem cell samples” (Glinskii | 60). The final step of claim 13
simply preserves and informs others of the correlation. See Genetic Tech.,
818 F.3d at 1379 (finding “instruction to undertake a simple comparison step
does not represent an unconventional, inventive application sufficient to
make the claim patent-eligible”).
Thus, when claim 13 is considered as an ordered combination, it
informs a relevant audience of certain laws of nature: specifically, that the
expression level of particular genes can be used to distinguish between
bladder cancer patients whose cancer is more likely or less likely to
progress. All of the additional steps of claim 13 consist of well-understood,
routine, conventional activity already engaged in by the scientific
community such as Mack or Glinskii.
We conclude that, under the Mayo test, claim 13 is directed to patent-
ineligible subject matter. The rejection of claim 13 under 35 U.S.C. § 101 is
affirmed. Independent claims 17 and 23 add more data manipulation steps,
but those steps merely determine the accuracy of the levels of expression
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relative to other (protective or harmful) markers, in order to determine the
likelihood of bladder cancer progression. These claims also add nothing
more than routine and conventional steps of data manipulation that are
required to inform the relevant audience of the natural principle itself. We
therefore conclude that all of the claims on appeal are directed to patent-
ineligible subject matter.
B. 35 U.S.C. § 112, second paragraph
The Examiner finds “Claims 13,17 and 23 recite ‘using’ QPCR but
since the claims do not set forth any positive steps involved in the process of
using, it is unclear what process applicant is intending to encompass by the
term ‘using’” (Ans. 9).
Appellants contend:
The independent claims set forth a number of steps “in the
process of using,” including: determining “gene expression
levels of certain harm fill and protective markers” [claims 13,17
and 23]; “calculating a value for the expression levels of’
harmful and protective markers [claims 13,17 and 23];
“subtracting one of the calculated values” [claims 13,17 and
23]; and “assigning weights to said markers according to the
significance of each marker” [claims 17 and 23].
(App. Br. 14).
We find that Appellants have the better position. The Examiner has
not pointed to evidence showing that those skilled in the relevant art would
not understand what process is referred to as quantitative PCR (QPCR) and
in fact argues, in the context of the § 101 rejection, that QPCR is “old,
conventional, and routine in the art of differential gene expression
determination” (Ans. 5). As already noted, Glinskii teaches “Q-PCR
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Application 13/352,393
reactions and measurements were performed with the SYBR-Green and
ROX as a passive reference, using the ABI 7900 HT Sequence Detection
System” (Glinskii 191). Thus, the evidence supports Appellants’ position
that the ordinary artisan would understand the process steps involved in
“using QPCR.” We reverse this rejection.
C. 35 U.S.C. § 112, first paragraph, enablement
The Examiner finds “the combination of the breadth of the claims
which encompass a four-gene signature in combination with the limitation
that one of the four genes must be MBNL2 as a ‘protective marker’ is
unpredictable” (Ans. 12). The Examiner finds that the prior art references
“teach that the MBNL2 gene marker is considered to be a harmful marker
rather than a protective marker as currently claimed and that the MBNL2
gene marker would be predictive of poor prognosis” {id.). The Examiner
finds there is no working example and “[cjonflicting information regarding
the status of the MBNL2 marker as being a ‘protective’ marker versus a
‘harmful’ marker associated with progression or death from bladder cancer
is found in the specification” {id. at 15). The Examiner concludes “it would
require undue experimentation to practice the invention as presently
claimed” {id. at 17).
Appellants contend “Table 4 of Application Serial Nos. 13/316733
and 13/316765 (see Evidence Appendix) shows ... the correlation with
progression/non-progression events for both MBNL2 levels expression
levels was statistically significant” (App. Br. 15). Appellants contend,
regarding the cited art, that the results “do not indicate anything about
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Application 13/352,393
whether MBNL2 is or is not a progression marker for bladder cancer” (App.
Br. 17).
We find that Appellants have the better position. The data from the
Evidence App’x regarding MBNL2 and FABP4 is reproduced, in part,
below:
24 MONTHS
Marker Tvpe
(P or
nr
T Test Witeexem
sigeed-
raok test
KS Test Cox Regression
Analysis
ROC
P~wiiw P~vaim
('t Hjfk ICtif
ALL
MBM.2 P 0.000 0.000 0,000 0,000 0.757 i
FABP4 P 0,001 0.001 Oivn 0.195 0.001 0.705 i
“Table 4 — Markers selected for their correlation with clinical determination
of bladder cancer progression or non-progression” (see App. Br. 28)
(emphasis omitted).
The Specification teaches “for each group of patients weight the
preferred protective markers, for example MBNL2 and/or FABP4; and
weight the preferred harm fill markers, for example UBE2C” (Spec. 11).
Mack lists the protein identified by the Examiner as MBNL2 in a list
of “Genes predictive of bladder cancer progression” (Mack 133), Clarke6
lists MBLL39 in a table titled “Up Regulated in UPTG versus UPNTG”
(Clarke 12), while Bignotti7 lists MBNL2 in a table titled “Up-regulated
genes expressed at least 2-fold higher in metastasis vs primary OSPC
6 Clarke et al., US 2006/0019256 Al, published Jan. 26, 2006 (“Clarke”).
7 Bignotti et al., Gene expression profde of ovarian serous papillary
carcinomas: identification of metastasis-associated genes, 196 Am. J.
Obstet. Gynecol. 245.el-245.ell (2007) (“Bignotti”).
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[ovarian serous carcinomas]” (Bignotti 245.e5). Sanchez-Carbayo8 9teaches
issues relevant to microarray analyses (see Sanchez-Carbayo 29, col. 2).
As we balance the Wands9 factors evidence, we find that the evidence
supporting enablement of MBNL2 and FABP4 as progression markers
including the disclosure in the evidence appendix and Specification
outweighs both the unclear teachings in Mack and Clarke regarding MBNL2
and bladder cancer progression as well as the unrelated teachings of Bignotti
drawn to ovarian cancer and the general concerns of Sanchez-Carbayo. We
note the narrow nature of claims 16, 20, and 26, limited to analysis of
particular genes as protective and harmful for bladder cancer, as well as the
acknowledged high level of skill in the art (see Ans. 16). We conclude that
the evidence of record does not support a finding that undue experimentation
would have been required to use the invention.
D. 35 U.S.C. § 102(b) over Glinskii
The Examiner finds Glinskii teaches “a method comprising: (a)
determining gene expression levels of certain harm fill and protective
markers from an individual with early stage bladder cancer” (Ans. 18). The
Examiner finds:
Glinskii report that in paragraph 0072 that “[s]imilar types of
methods (e.g., Kaplan-Meier methods) can also be used to
determine a signature’s prediction capabilities of a short relapse
survival after therapy in patients with an early stage disease”.
Therefore, Glinskii teaches (c) calculating a value for the
8 Sanchez-Carbayo, M., Use of High-Throughput DNA Microarrays to
Identify Biomarkers for Bladder Cancer, 49 Clinical Chemistry 23—31
(2003) (“Sanchez-Carbayo”).
9 In re Wands, 858 F.2d 731, 737 (Fed. Cir. 2008).
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expression levels of the said protective markers, (d) calculating
a value for the expression levels of the said harm fill markers,
and especially per claim section (e), subtracting one of the
calculated values obtained in steps (c) and (d) above from the
other thereby obtaining a score.
(Ans. 20).
Appellants contend:
The claims also all require “subtracting” one of these sums of
Ct values (i.e., either the sum corresponding to harmful marker
gene expression level or the sum corresponding to protective
marker gene expression level) from the other, “thereby
obtaining a score based on reduced sources of noise in the Ct
values.” This step is also not disclosed in Glinskii
(App. Br. 18).
We find that Appellants have the better position. Although Glinskii
teaches the use of QPCR (Glinskii 191) for predicting clinical outcomes of
diseases including bladder cancer (Glinskii, claims 10, 14) using expression
profile data (Glinskii 138), the Examiner does not identify a teaching in
Glinskii for a “subtracting” step where the summed values of protective
markers is subtracted from the summed value of harmful markers as required
by claims 13, 17, and 23. We have reviewed paragraphs 71, 72, and 87 of
Glinskii, identified by the Examiner (see Ans. 33—34), and find no specific
teaching that either the “Kaplan-Meier methods” or “weighted survival score
analysis” and normalization of the gene expression values necessarily
involved any subtraction of protective marker values from harmful marker
values as required by the claims. We reverse this rejection.
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SUMMARY
In summary, we affirm the rejection of claims 13—28 under 35 U.S.C.
§ 101, as being directed to non-statutory subject matter.
We reverse the rejection of claims 13—28 under 35 U.S.C. § 112,
second paragraph, as indefinite.
We reverse the rejection of claims 16, 20, and 26 under 35 U.S.C.
§112, first paragraph as failing to comply with the enablement requirement.
We reverse the rejection of claims 13—15, 17—19, 21—25, 27, and 28
under 35 U.S.C. § 102(b) as anticipated by Glinskii.
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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