Marie-Caroline Dieu-Nosjean et al.

Patent Trials and Appeals Board

Aug 2, 2019

14373246 - (D) (P.T.A.B. Aug. 2, 2019)

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.
14/373,246 07/18/2014 Marie-Caroline Dieu-Nosjean 11450280US 1311
30743 7590 08/02/2019
W&C IP
11491 SUNSET HILLS ROAD
SUITE 340
RESTON, VA 20190
EXAMINER
AKHOON, KAUSER M
ART UNIT PAPER NUMBER
1642
MAIL DATE DELIVERY MODE
08/02/2019 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte MARIE-CAROLINE DIEU-NOSJEAN,
WOLF HERVE FRIDMAN, ROMAIN REMARK,
and CATHERINE SAUTES-FRIDMAN1
____________

Appeal 2018-008321
Application 14/373,246
Technology Center 1600
____________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
DAVID COTTA, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The claims in this appeal are directed to a method of treating a patient
with a solid tumor containing tumor-induced lymphoid structures. The
Examiner rejected the claims under 35 U.S.C. § 103 as obvious. Pursuant to
35 U.S.C. § 134, Appellant appeals the Examiner’s determination that the

1 The Appeal Brief (“Appeal Br.” entered Feb. 15, 2018) lists INSERM
(INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE
MEDICALE) of Paris, France; UNIVERSITE PARIS DESCARTES of
Paris, France; UNIVERSITE PARIS DIDEROT - PARIS 7 of Paris, France;
UNIVERSITE PIERRE ET MARIE CURIE - PARIS VI of Paris,
France; and ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS of Paris,
France as the Real Parties in Interest. Appeal Br. 3.
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claims are unpatentable. We have jurisdiction for the appeal under
35 U.S.C. § 6(b). The Examiner’s decision is AFFIRMED.

STATEMENT OF THE CASE
Claims 14–21 stand rejected by the Examiner under pre-AIA
35 U.S.C. § 103(a) as obvious in view of Ladanyi et al. (Cancer Immunol.
Immunother., 2011, 60:1729–1738) (“Ladanyi”), Galon et al. (U.S. Pat.
Appl. Publ. 2009/0215053 A1, published Aug. 27, 2009) (“Galon”), and
Dieu-Nosjean et al. (J. Clin. Oncol., 2008, 26: 4410–4417) (“Dieu” or
“Dieu-Nosjean”). Ans. 3.
Claim 14, the only independent claim on appeal, is reproduced below:
14. A method of treating a patient with a solid tumor
containing tumor-induced lymphoid structures, comprising
a) obtaining a sample of the solid tumor that contains
tumor-induced lymphoid structures from the patient;
b) quantifying, within B-cell follicles in the tumor-
induced lymphoid structures of the sample, a cell density of
follicular B cells;
c) comparing the cell density of follicular B cells with a
predetermined reference value; and
d) providing the patient with chemotherapy and/or
radiotherapy when the cell density of follicular B cells is lower
than the predetermined reference value.

REJECTION
The claims in this appeal are directed to a method treating a patient
with a solid tumor. The treatment is based on determining “when the cell
density of follicular B cells [in a tumor-induced lymphoid structure] is lower
than the predetermined reference value.”
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As found by the Examiner (Final Act. 5), Ladanyi describes
“investigat[ing] the prevalence of CD20+ B cells . . . in primary melanoma.”
Ladanyi 1729 (Abstract). Ladanyi found “B cells clustered in dense
aggregates resembling follicles (Fig. 1b)” in 26% of the samples (Ladanyi
1732 (left col.)), although the density of these aggregates were not measured
(Ladanyi 1731).
The Examiner also found that Ladanyi reported (Final Act. 6) “that an
increased density of B lymphocytes infiltrating primary cutaneous
melanomas was associated with a lower occurrence of distant metastases and
longer survival of patients.” Ladanyi 1736 (right col.). The Examiner found
(Final Act. 6) that Ladanyi calculated “[t]he proportion of patients with
significant density of CD20+ [B] cells . . . using cutoff values set up
separately for intra- and peritumoral localization.” Ladanyi 1731 (right
col.). Thus, the Examiner found that Ladanyi describes “quantifying” B-
cells and “comparing the cells density” of the B cells to a reference value as
recited in steps b) and c) of claim 14, but not in “B-cell follicles” in tumor-
induced lymphoid structure as required by the claim. Final Act. 6.
The Examiner cited Dieu-Nosjean for its teaching of the prognostic
value of measuring the density of mature dendritic cells in Ti-BALT (tumor-
induced bronchus-associated lymphoid tissue) and that “increased density of
mature dendritic cells positively correlated with increased survival.” Final
Act. 7. Ti-BALT comprise B-cell follicles as required by all the rejected
claims in this appeal. Dieu-Nosjean 4410 (“As in lymph nodes, Ti-BALTs
were composed of mature dendritic cell (DC)/T-cell clusters adjacent to B-
cell follicles and had features of an ongoing immune response.”).

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The Examiner also cited Galon for its teaching of “the correlation of a
favorable prognosis or poor prognosis based on immune response” by
specifically “quantifying biomarkers that are indicative of the presence or
level of immune response of the patient against the cancer.” Final Act. 6.
The Examiner concluded that it would have been obvious to one of
ordinary skill in the art at the time of the invention to have measured B cell
density in B-cell follicles as recited in the claims to correlate to survival
time, as described in Ladanyi, in patients suffering from lung cancer as
described in Dieu-Nosjean and Galon. Final Act. 7. As indicated above,
Dieu-Nosjean measured dendritic cell density, but not B-cell density, in the
same Ti-BALT structure which is claimed.
Appellants argue that “Ladanyi teaches a correlation between B-cell
density and survival time, however, Ladanyi also teaches that there is no
correlation between follicular B-cells and survival.” Appeal Br. 12.
Appellants further argues “Galon teaches methods for the prognosis of
cancer but is completely silent regarding B-cell follicles or tumor-induced
lymphoid structures.” Id. Appellants acknowledge that “Dieu-Nosjean
teaches a correlation between the density of mature dendritic cells and
survival time, but is completely silent regarding follicular B-cells.” Id.
Appellants state that “[w]hile the densities of T and B cells in BALT were
also quantified, Dieu-Nosjean found that the quantities of T and B cells were
not associated with patient outcome (see the 3rd line of column 2 of page
4413 of Dieu-Nosjean.” Id. at 14. Appellants state that Ladanyi and Dieu-
Nosjean “teach[ ] away from using B cells numbers in BALT to
prognosticate cancer outcomes, as required in the presently claimed
method.” Id.
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DISCUSSION
The principal issue in this appeal is whether the combination of
Ladanyi, Galon, and Dieu-Nosjean suggest the claimed step of “b)
quantifying, within B-cell follicles in the tumor-induced lymphoid structures
of the sample, a cell density of follicular B cells.”
As discussed by Appellants, Ladanyi did not quantify the areas of B-
cell aggregates, when present in samples, “because of the difficulty of the
accurate determination of B-cell number in these areas, resulting from the
extremely high cell density and overlapping cell borders.” Ladanyi 1731
(right col.). However, Ladanyi, as admitted by Appellants (Appeal Br. 12),
found
both intra- and peritumoral CD20+ cell densities were
found associated with the outcome of the disease, with
significantly higher values in cases that did not develop
visceral metastases during the 5-year follow-up period.
Consequently, infiltration by B lymphocytes correlated
with patient survival in univariate analysis.
Ladanyi 1736 (left col.) Thus, while Ladanyi did not measure the density of
B-cells in the aggregates, it discloses that infiltration of B-cells into the
tumor is associated with patient survival. Thus, the importance of B-cell
density was identified by Ladanyi, but not in the claimed tumor-induced
lymphoid structure.
Ladanyi specifically discussed the same Dieu-Nosjean publication
cited in the rejection (reference 32) and related publications, stating:
In a recent publication, the potential importance of
tertiary lymphoid structures, consisting of clusters of T
lymphocytes with adjacent B-cell follicles was
emphasized in lung carcinoma [32]. Moreover, mature
dendritic cells (DCs) were shown to localize
preferentially to these lymphoid structures, and their
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density was found to be associated with patients’
survival. Similar structures or B-cell follicles have also
been observed in a number of tumor types such as
colorectal, hepatocellular, breast and ovarian carcinoma
and uveal melanoma [7, 14, 15, 27, 28, 33], but this
phenomenon has not been described in cutaneous
melanoma. In our patient group, we observed the
presence of B lymphocytes organized in follicle-like
structures in 26% of samples. The presence of B-cell
aggregates was more prevalent in thick melanomas, in
tumors of axial location and in patients over 53 years, but
no correlation was observed with the metastatic pattern
or with patients’ survival.
Ladanyi 1735 (left col.).
Thus, while Ladanyi did not describe a correlation between survival
and the appearance of B-cell aggregates in melanoma, Ladanyi specifically
discussed B-cell aggregates in lung carcinoma and their potential
importance, and indicated cutaneous melanoma may be different that the
other cancers in which B-cell aggregates have been identified.
Dieu-Nosjean, as discussed by Ladanyi, describes “the presence of
tertiary lymphoid structures composed of mature DC/T-cell clusters and B-
cell follicles.” Dieu-Nosjean 4414 (in “Discussion”). Dieu-Nosjean states
that these structures, also known as Ti-BALT, have the “features of an
ongoing immune response.” Id. While Dieu-Nosjean did not measure the
density of B-cells in the T-BALT, it did so for the dendritic cells and found
“through univariate analysis that the density of mature DCs, a cell
population that homes exclusively to Ti-BALT, is highly predictive of
survival (OS, DSS, and DFS) in early-stage NSCLC [non-small cell lung
cancer].” Id.
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Dieu-Nosjean further disclosed that B cells accumulate in the Ti-
BALT:
In particular, the densities of T and B cells, although
correlated with the density of mature DCs, were not
associated with clinical outcome. In contrast with mature
DCs, lymphocytes do not home exclusively to Ti-BALT.
Our data suggest that the more tumors are infiltrated by
mature DCs, the more T and B cells are organized and
proliferated in Ti-BALT. However in the absence of
mature DCs, infiltrating lymphocytes neither cluster nor
proliferate because of the absence of lymphoid structures.
Dieu-Nosjean 4415.
In other words, when B-cells were measured in the tumor, their
density alone was not correlated with “clinical outcome.” Id. However,
when the DC cells infiltrated the tumor and formed clusters, the B-cells
subsequently “organized and proliferated in Ti-BALT.” Id.
Dieu-Nosjean further suggested a role for the B-cells in the Ti-BALT.
Dieu-Nosjean states that the “presence of proliferating GC [germinal center]
B cells in some Ti-BALTs suggests that they may be an active partner in the
local initiation of potential antitumoral immunity.” Dieu-Nosjean 4416.
Further, Dieu-Nosjean discloses that “Ti-BALT GCs may support antigen
driven clonal expansion and extensive diversification. Ti-BALT B cells may
also play an important role in T-cell-mediated immunity against the tumor.”
Id. Thus, while Dieu-Nosjean did not measure the density of B-cells in T-
BALT, Dieu-Nosjean suggests the significance of B-cells in this structure,
providing a reason to have measured their density in Ti-BALT.
While Ladanyi found that B-cell aggregates did not show an
association with survival as argued by Appellants (Appeal Br. 13), as
discussed above, Ladanyi recognized that its finding for cutaneous
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melanoma was apparently different from lung cancer and several other
cancers. In view of the teaching in Dieu-Nosjean of the significance of B-
cells in anti-tumor immunity and their presence in T-BALT, we conclude
that one of ordinary skill in the art would not have been deterred from
measuring the density of B-cells in T-BALT, and would have reasonably
expected their correlation with outcome, consistent with Ladanyi’s teaching
that B-cells are “correlated with patient survival” (Ladanyi 1736 as
reproduced above).
Appellants refer to Dieu-Nosjean’s statement that T and B cells were
not associated with patient outcome (Appeal Br 14), but this statement, as
explained above, refers to the appearance of these cells in the tumor
generally. When DC cells form the lymphoid Ti-BALT structures, Dieu-
Nosjean teaches that the B cells proliferate in these regions (Dieu-Nosjean
4415, 4416), providing a reason to measure their density in Ti-BALT.
Specifically, Dieu-Nosjean teaches:
The presence of proliferating GC [germinal center] B cells in
some TI-BALTs suggests that they may be an active partner in
the local initiation of potential antitumoral immunity. As
previously described in chronic inflammatory diseases, Ti-
BALT GCs may support antigen-driven clonal expansion and
extensive diversification. Ti-BALT B cells may also play an
important role in T-cell-mediated immunity again.st the tumor.
Dieu-Nosjean 4416.
Thus, we do not find Appellants’ argument supported by adequate
evidence that Dieu-Nosjean teaches away from quantifying B cells in Ti-
BALT to prognosticate cancer outcome. Appeal Br. 14.
The claims merely extend the observation of Dieu-Nosjean that the
presence of DC cells in Ti-BALT are associated with better survival
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outcomes, by measuring the density of B-cells in those regions, as well,
motivated by the express suggestion that the B-cells are involved in the anti-
tumor immune response (see Dieu-Nosjean 4416). Dieu-Nosjean 4410
(Abstract) (“Ti-BALTs were composed of mature dendritic cell (DC)/T-cell
clusters adjacent to B-cell follicles and had features of an ongoing immune
response.” “Univariate analysis showed that the density of mature DCs was
highly associated with a favorable clinical outcome (overall, disease-
specific, and disease-free survival), suggesting that Ti-BALT may
participate in antitumoral immunity.”).
For the foregoing reasons, the obviousness rejection of claim 14 is
affirmed. Claims 15–21 were not argued separately, and fall with claim 14.
37 C.F.R. § 41.37(c)(1)(iv).

TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED