Ex Parte Dimitrova et al

Patent Trial and Appeal Board

Aug 19, 2016

13140972 (P.T.A.B. Aug. 19, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/140,972 11/08/2011 Nevenka Dimitrova
24737 7590 08/23/2016
PHILIPS INTELLECTUAL PROPERTY & STANDARDS
465 Columbus A venue
Suite 340
Valhalla, NY 10595
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.
2008P01650WOUS 1421
EXAMINER
DAUNER, JOSEPH G
ART UNIT PAPER NUMBER
1634
NOTIFICATION DATE DELIVERY MODE
08/23/2016 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):
marianne.fox@philips.com
debbie.henn@philips.com
patti. demichele@Philips.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte NEVENKA DIMITROV A, CHET AN MITT AL,
And SITHARTHAN KAMALAKARAN 1
Appeal2015-001005
Application 13/140,972
Technology Center 1600
Before FRANCISCO C. PRATS, JOHN G. NEW, and TA WEN CHANG,
Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1Appellants state the real party-in-interest is Koninklijke Philips N.V. App.
Br. 1.
Appeal2015-001005
Application 13/140,972
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 1-17. Specifically, claims 1-3, 10,
and 11 stand rejected as unpatentable under 35 U.S.C. § 102(b) as being
anticipated by Esteban Ballestar et al., Methyl-CpG Binding Proteins
IdentifY Novel Sites of Epigenetic Inactivation in Human Cancer, 22 (23)
THE EMBO JOURNAL, 6335--45, (2003) ("Ballestar") or, alternatively, as
unpatentable under 35 U.S.C. § 103(a) as being obvious over Ballestar.
Claims 16 and 17 also stand rejected as unpatentable under 35 U.S.C. §
103(a) as being obvious over Ballestar.
Claims 4--9 and 12-14 stand rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Ballestar and Adorjan et
al. (US 2005/0003463 Al, January 6, 2005) ("Adorjan").
Claim 15 stands rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination ofBallestar and Berlin et al.
(US 2005/0021240 Al, January 27, 2005) ("Berlin").
Claims 1-3, 10, 11, 16, and 17 also stand rejected as unpatentable
under 35 U.S.C. § 103(a) as being obvious over Lidia Lopez-Serra et al., A
Profile of Methyl-CpG Binding Domain Protein Occupancy of
Hypermethylated Promoter CpG Islands of Tumor Suppressor Genes in
Human Cancer, 66 (17) CANCER REs. 8342--46 (2006) ("Lopez-Serra").
Claims 4--9 and 12-14 stand rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Lopez-Serra and Adorjan.
Claim 15 stands rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Lopez-Serra and Berlin.
We have jurisdiction under 35 U.S.C. § 6(b).
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We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellants' invention is directed to a method for the detection of a
DNA methylation signature associated with the presence of or the
predisposition to develop a disorder. The method comprises the
identification of one or more candidate genes exhibiting differential DNA
methylation in target and reference samples as well as the respective
determination of the nucleic acid sites in said candidate genes that are
differentially methylated and the recognition sites for DNA binding factors,
said DNA binding factors each recognizing such a differentially methylated
nucleic acid site, wherein the patterns of differentially methylated nucleic
acid sites and of DNA binding factor recognition sites obtained together
represent a DNA methylation signature that is indicative for the presence of
or the predisposition to develop a disorder in a target sample. Abstract.
REPRESENTATIVE CLAIM
Independent claim 1 is representative of the claim and recites:
1. A method, comprising:
(a) providing a plurality of matched samples, the plurality
comprising at least one target sample and at least one reference
sample;
(b) identifying one or more candidate genes/loci exhibiting
differential DNA methylation in the at least one target sample as
compared to the at least one reference sample;
( c) determining the nucleic acid sites comprised in the one
or more candidate genes/loci that are differentially methylated
and which are obtained in step (b );
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Application 13/140,972
( d) determining in the one or more candidate genes/loci
obtained in step (b) the presence of recognition sites for DNA
binding factors, wherein said DNA binding factors each
recognize a nucleic acid site determined in step ( c ); and
( e) detecting a DNA methylation signature which is
represented by a pattern of the differentially methylated nucleic
acid sites obtained in step (c) together with a pattern of the DNA
binding factor recognition sites obtained in step ( d), wherein the
DNA methylation signature is indicative for the presence of or
the predisposition to develop a disorder in the at least one target
sample.
App. Br. 10.
ISSUES AND ANALYSIS
We agree with, and explicitly adopt, the Examiner's findings and
conclusion that the appealed claims are prima facie obvious over the cited
prior art references. We address the arguments raised by Appellants on
appeal below.
A. Claims 1-3, 10, 11, 16, and 17 over Ballestar
Issue
Appellants argue the Examiner erred in finding Ballestar discloses, or
teaches or suggests, the limitation of claim 1 reciting "providing a plurality
of matched samples, the plurality comprising at least one target sample and
at least one reference sample." App. Br. 3.
Analysis
Appellants dispute the Examiner's finding characterizing the
lymphocytes and lymphoblastoid cell lines of Ballestar as reference samples
because, Appellants argue, the lymphocytes and lymphoblastoid cell lines
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are not "matched samples" as recited by claim 1. App. Br. 4 (citing Final
Act. 4). Appellants admit that "matched samples" are not restricted to the
analysis of pairs of samples; however, Appellants argue that the Examiner
has failed to establish that a person of ordinary skill in the art would have
understood breast cancer cell lines and lymphocytes and lymphoblastoid cell
lines to have been "matched samples," as recited in claim 1. Id.
Furthermore, Appellants argue, Ballestar teaches employing a global screen
for methyl-CpG binding protein ("MBD") targets in breast cancer cells and
subsequently subjecting the genes that were bound by MBDs to DNA
methylation. App. Br. 4. Appellants therefore assert Ballestar does not
teach or suggest a method including, inter alia, steps (b }---( e ), as specifically
recited in claim 1. Id.
The Examiner responds that Appellants' Specification
discloses:
[T]he term "plurality of matched samples", as used herein,
denotes any even or odd number of samples that is >2 (for
example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and so forth) as long as
the plurality of samples encompasses at least one target sample
and at least one reference sample.
Ans. 3 (quoting Spec. 9, 11. 24-27). The Examiner finds Appellants'
Specification also discloses:
The term "matched samples", as used herein, denotes a
plurality of at least two samples that relate to each other. For
example, a pair of samples to be analyzed may include one target
sample derived from a patient suffering from a disease (e.g.,
cancer) and one reference sample derived from a healthy subject.
However, the method of the invention is not restricted to the
analysis of pairs of samples. For example, it is also possible to
analyze four different target samples derived in comparison to
one reference sample, e.g., target samples from patients suffering
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Application 13/140,972
from the same disease but being affected to different extents
(e.g., three different pre-cancerous states and one cancer sample).
Ans. 4 (quoting Spec. 9, 11. 15-23). The Examiner further finds the
Specification discloses:
The term "target sample", as used herein, refers to a
sample being at least supposed to exhibit or to have a
predisposition to develop a disorder, whereas the term "reference
sample" (also referred to as "control sample") typically denotes
wild-type material (e.g., healthy cells) not having characteristics
of such a disorder. However, in some applications, the method of
the invention may be used to analyze and compare several
samples exhibiting characteristics of a disorder (e.g., pre-disease
and disease states), for example in order to monitor disease
progression. In such scenario, if no wildtype (healthy) control
sample is included, the sample having the less severe disease
characteristics is typically considered the "reference sample".
Id. (quoting Spec. 9, 11. 6-14).
Construing the claim language in view of these definitions, the
Examiner finds, the claimed "providing" step is interpreted to encompass
"matched samples," i.e., any two samples that are related. Ans. 4. The
Examiner finds the claim language encompasses providing a test sample
along with positive or negative control samples. Id. Negative control
samples are "related" to a test sample because they are used for comparison
purposes and verification of the results from the test sample. Id.
Specifically, the Examiner finds, the breast cancer cell lines exhibit
characteristics of breast cancer cells and the isolated lymphocytes and
lymphoblastoid cell lines of Ballestar are "reference samples" in accordance
with the description in the instant specification because they denote "wild-
type material not having characteristics of such as disorder." Ans. 5. The
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Examiner finds the latter cells do not have the characteristics of breast
cancer and in particular, lack the MBDs found in the breast cancer cell lines.
Id. Therefore, the Examiner finds Ballestar discloses providing at least one
target sample and at least one reference sample, and thus provides a
"plurality of matched samples" that is within the scope of the claims in view
of Appellants' Specification. Id.
We agree with the Examiner. Ballestar teaches:
To investigate the involvement of MBDs in epigenetic
repression, we initially adopted a candidate gene approach to
study genes known to be hypermethylated in a breast tumour
model, specifically in the breast cancer cell lines MCF7 and
MDA-MB-231. [Chromatin immunoprecipitation ("ChIP")]
analyzes were performed using antibodies raised against epitopes
unique to each MBD protein (MeCP2, MBD 1, MBD2 and
MBD3) . . . . Additionally, normal lymphocytes, representing
non-tumoural non-cultured cells, and non-transformed
lymphoblastoid cell lines were also used as negative controls.
Ballestar 6336. Ballestar fhrther teaches:
Whilst MeCP2 and MBD2 were both present in the methylated
GSTPJ promoter, for RASSFJA and RARB2 only MeCP2 was
bound, and for BRCAJ and MGMT the only MBD present was
MBD2 (Figure 1 C). In none of the six selected promoters did we
find any association with MBD 1 or MBD3. In contrast, these six
promoters are unmethylated in lymphocytes and lymphoblastoid
cell lines and do not exhibit any binding of MBDs in these
normal cells (Figure 1 C).
Id. 2 We agree with the Examiner that Ballestar teaches "a plurality of
matched samples," defined in Appellants' Specification as comprising at
2 GSTP1, RASSFJA, RARB2, BRCAJ, and MGMT refer to certain tumor
suppressor genes explored in Ballestar. Ballestar 6336.
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least two samples, as long as the plurality of samples encompasses at least
one target sample and at least one reference sample. See Spec. 9. We
further agree that Ballestar teaches the tumor suppression gene promoter
regions in breast cancer cell lines, which we interpret as "target samples" as
defined by Appellants' Specification, because they exhibit or have a
predisposition to develop a disorder (i.e., a carcinoma). We also agree that
the lymphocytes taught by Ballestae are "reference samples" because they
constitute "wild-type material (e.g., healthy cells)," also as disclosed by
Appellants' Specification. Moreover, we agree that the explicit comparison
by Ballestar of the cancer cell lines and the lymphocytes constitutes "a
plurality of matched samples, the plurality comprising at least one target
sample and at least one reference sample" as required by claim 1. Id.
Finally, Appellants argue:
Moreover, to the best of Appellant's understanding,
Ballestar utilized a global screen for MBD targets in breast
cancer cells and then subjected the genes that \Vere bound by
MBDs to DNA methylation. Thus, Ballestar has not been shown
to have described or made obvious a method including, inter alia,
steps (b )-( e ), as specifically recited in claim 1.
App. Br. 4. The Examiner has explained how Ballestar discloses steps (b }-
( e) of claim 1. Ans. 5-8. Appellants have not pointed to any error in the
Examiner's reasoning; nor have Appellants adduced persuasive evidence to
support their contention that Ballestar fails to teach steps (b }-( e) beyond a
bare assertion of the alleged purpose of Ballestar's teaching. Attorney
argument unsupported by evidence is insufficient to overcome the
Examiner's prima facie conclusion of obviousness. See In re De Blauwe,
736 F.2d 699, 705 (Fed. Cir. 1984). We therefore agree with the Examiner's
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conclusion that Balle star anticipates and/ or teaches or suggests Appellants'
claims 1-3, 10, 11, 16, and 17, and we affirm the rejection of those claims
over Ballestar.
B. Claims 4--9 and 12-14 over Ballestar and Adorjan
Appellants rely upon the same arguments presented with respect to
claims 1-3, 10, 11, 16, and 17 supra, arguing that Adorjan does not cure the
alleged deficiencies of Ballestar. App. Br. 5. We have explained our
reasoning as to why we are not persuaded by Appellants' arguments with
respect to Ballestar. We consequently affirm the Examiner's rejection of
claims 4--9 and 12-14 over Ballestar and Adorjan.
C. Claim 15 over Ballestar and Berlin
Appellants rely upon the same arguments presented with respect to
claims 1-3, 10, 11, 16, and 17 supra, arguing that Berlin does not cure the
alleged deficiencies of Ballestar. App. Br. 5. We have explained our
reasoning as to why we are not persuaded by Appellants' arguments with
respect to Ballestar. We consequently affirm the Examiner's rejection of
claim 15 over Ballestar and Berlin.
D. Claims 1-3, 10, 11, 16, and 17 over Lopez-Serra
Appellants argue Lopez-Serra teaches "'select[ing] promoters of
different tumor suppressor genes for which [5 '-C-phosphate-G-3' ("CpG")]
island promoter hypermethylation has been described previously in human
cancer."' App. Br. 7 (quoting Lopez-Serra 8344). Appellants contend a
person of ordinary skill in the art would not have understood Lopez-Serra to
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teach or suggest a method including "providing a plurality of matched
samples comprising at least one target sample and at least one reference
sample; [and] [ ] identifying one or more candidate genes/loci exhibiting
differential DNA methylation in the at least one target sample as compared
to the at least one reference sample," as recited in claim 1. Id.
Appellants also argue Lopez-Serra neither teaches nor suggests
"detecting a DNA methylation signature which is represented by a pattern of
the differentially methylated nucleic acid sites obtained in step ( c) together
with a pattern of DNA binding factor recognition sites obtained in step ( d),"
as recited in claim 1. App Br. 7. According to Appellants, the non-
methylated promoter CpG islands of Lopez-Serra have not been shown to be
hypomethylated or to have exhibited differential DNA methylation from that
of a reference sample. Id. at 8. Therefore, Appellants argue, a person of
ordinary skill in the art would not have understood Lopez-Serra to teach or
suggest detection of a DNA methylation signature, because the MBD
occupancy data of Lopez-Serra includes both methylated and unmethylated
promoters. Id.
The Examiner responds that, although Lopez-Serra teaches the
analysis of promoters that have been previously identified as being
hypermethylated as compared to normal tissues (i.e., a reference sample), an
artisan of ordinary skill would recognize that additional differentially-
methylated candidate genes/loci could reasonably be identified through
providing target samples of interest, such as samples of cancer tissues, and
comparing the level of methylation in the provided target samples to the
level of methylation in normal tissues. Ans. 9. The Examiner therefore
concludes it would have been obvious to a person of ordinary skill in the art
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to provide target samples and reference samples for the purpose of
identifying additional candidate genes/loci. Id.
The Examiner further finds Lopez-Serra teaches the use of 10 human
cancer cell lines. Ans. 9 (citing Lopez-Serra 8343). The Examiner finds
Figure 3 of Lopez-Serra demonstrates any one of the 10 cells lines may be
used as a reference to determine whether the gene promoters of another cell
line are differentially methylated. By way of example, the Examiner finds
H-1299 cell line target samples are hypermethylated in regions of the
CDH13 gene and are hypomethylated in regions of the RARB2 gene when
compared to HeLa cells as a reference sample. Id. The Examiner finds
Lopez-Serra describes comparing the different cell lines in order to identify
relative differences between them. Id. (citing Lopez-Serra 8343).
We are not persuaded by Appellants' arguments. Lopez-Serra
teaches:
One of the key achievements in cancer epigenetics has
been the recognition of profiles of aberrant CpG
hypermethylation that are specific to the tumor type . . . . . The
existence of these profiles provides a powerful set of markers for
outlining the disruption of critical pathways in tumorigenesis and
for deriving sensitive molecular detection strategies for virtually
every human tumor type.
In this report, we address the question of [ methyl-CpG
binding domain ("MBD")] occupancy in aberrantly methylated
promoters in the context of cancer cells. We have
comprehensively analyzed a panel of transformed cells
corresponding to different tumor types and selected tumor
suppressor genes that are known to undergo CpG island promoter
hypermethylation. Our results prove that MBDs are a common
feature of all methylated genes in cancer with a profile of MBD
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distribution and occupancy that exhibits gene promoter- and cell
type-dependent specificity.
Lopez-Serra 8342 (internal references omitted). Lopes-Serra thus teaches
that comparisons between the various cell lines exhibits a differential
distribution ofMBDs depending upon the tumor (i.e., cell line) type. See
Lopez-Serra Figure 3).
When making such comparisons between at least two samples from
different cell lines, the cell line examined may be considered to be the target
sample and the cell line being compared against considered as the reference
sample, per the Examiner's example. This is consistent with Appellants'
Specification, which discloses: "in some applications, the method of the
invention may be used to analyze and compare several samples exhibiting
characteristics of a disorder (e.g., pre-disease and disease states), for
example in order to monitor disease progression." Spec. 9, 11. 9-12. Lopez-
Serra teaches comparison of, inter alia, different breast cancers (MCF7 and
MDA-MR-231), colon cancer (HCT15, Lo Vo, SW48), and lymphoma (Raji
and U937) cell lines. Lopez-Serra 8342--43. We find a comparison of MBD
distribution and occupancy between, e.g., two different breast cancer lines or
three different colon cancer lines, with one designated as the reference
sample, would be consistent with the Specifications' characterization of
target and reference samples quoted in the passage above, i.e., "analyz[ing]
and compar[ing] several samples exhibiting characteristics of a disorder."
For the same reasons, we agree with the Examiner that Lopez-Serra
teaches "detecting a DNA methylation signature which is represented by a
pattern of the differentially methylated nucleic acid sites obtained in step ( c)
together with a pattern of DNA binding factor recognition sites obtained in
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step ( d)," as required by claim 1. As we have explained, Lopez-Serra
explicitly teaches analysis of differentially distributed MBDs, which can act
as methylated DNA-binding recognition sites. See Lopez-Serra 8342
("Current evidence indicates that, in mammals, only MeCP2, MBD 1, and
MBD2 are bona fide methylated DNA-binding proteins"). We consequently
agree with the Examiner's findings that Lopez-Serra teaches or suggests the
disputed limitations of claim 1 and we affirm the Examiner's rejection of
claims 1-3, 10, 11, 16, and 17 upon this ground.
E. Claims 4--9 and 12-14 over Lopez-Serra and Adorjan
Appellants rely upon the same arguments presented with respect to
claims 1-3, 10, 11, 16, and 17 supra, arguing that Adorjan does not cure the
alleged deficiencies of Lopez-Serra. App. Br. 5. We have explained our
reasoning as to why we are not persuaded by Appellants' arguments with
respect to Lopez-Serra. We consequently affirm the Examiner's rejection of
claims 4--9 and 12-14 over Lopez-Serra and Adorjan.
F. Claim 15 over Lopez-Serra and Berlin
Appellants rely upon the same arguments presented with respect to
claims 1-3, 10, 11, 16, and 17 supra, arguing that Berlin does not cure the
alleged deficiencies of Lopez-Serra. App. Br. 5. We have explained our
reasoning as to why we are not persuaded by Appellants' arguments with
respect to Lopez-Serra. We consequently affirm the Examiner's rejection of
claim 15 over Lopez-Serra and Berlin.
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DECISION
The Examiner's rejection of claims 1-3, 10, and 11 as unpatentable
under 35 U.S.C. § 102(b) is affirmed
The Examiner's rejection of claims 1-17 as unpatentable under 35
U.S.C. § 103(a) is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l). See 37 C.F.R.
§ 1.136(a)(l )(iv).
AFFIRMED
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