Ex Parte 6,777,231 et al

Patent Trial and Appeal Board

Jul 31, 2017

95001592 (P.T.A.B. Jul. 31, 2017)

UNITED STATES PATENT AND TRADEMARKOFFICE
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.
95/001,592 04/01/2011 6,777,231 606512800500 8338
23460 7590 11/30/2017
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO, IL 60601-6731
EXAMINER
PONNALURI, PADMASHRI
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
11/30/2017 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
____________

UNIVERSITY OF PITTSBURGH OF THE COMMOMWEALTH
SYSTEM OF HIGHER EDUCATION
(Patent Owner and Appellant)

v.

CELLERIX
(Requester and Cross-Appellant)
____________

Appeal 2016-008300
Reexamination Control 95/001,592
US Patent 6,777,231 B1
Technology Center 3900
____________

Before LORA M. GREEN, RICHARD M. LEBOVITZ, and
RAE LYNN P. GUEST, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

REQUEST FOR REHEARING
This is a request for rehearing under 37 C.F.R. § 41.79(a)(1) (“Req.
Reh’g”) of the 37 C.F.R. 41.77(f) Decision (“41.77f Dec.”) entered July 31,
2017. The request is made by the Requester in the above identified inter
partes reexamination. The patent under reexamination is US Patent No.
6,777,231 B1 (“the ’231 patent”).

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Patent 6,777,231 B1

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OBVIOUSNESS BASED ON HAUNER
Requester requests reconsideration of the decision not to adopt the
rejection of claims 11–15, 17, 18, and 21–24 based on the Hauner
publication.
Claims 11 and, representative of the appealed claims, are reproduced
below:
11. An isolated adipose-derived stem cell that can differentiate
into two or more of the group consisting of a bone cell, a
cartilage cell, a nerve cell, or a muscle cell, wherein the isolated
adipose-derived stem cell is substantially free of other adipose
tissue cells and extracellular matrix material, and which can be
cultured for at least 15 passages without differentiating,
wherein the cell is cultured in DMEM and 5-15% serum for the
at least 15 passages without losing the capacity to differentiate.
12. An isolated adipose-derived stem cell that differentiates into
two or more of the group consisting of a fat cell, a bone cell, a
cartilage cell, a nerve cell, or a muscle cell, wherein the isolated
adipose-derived stem cell is substantially free of other adipose
tissue cells and extracellular matrix material, and which can be
cultured for at least 15 passages without differentiating,
wherein the cell is cultured in DMEM and 5-15% serum for the
at least 15 passages without losing the capacity to differentiate.

Vivotecnia
In an attempt to demonstrate that Hauner describes cells which
anticipate the claimed adipose-derived stem cells, Requester provided a
report by Vivotecnia Research S.L. (Study Director is listed as Covadonga
Pañeda, Ph.D.), a test facility, which was said to have isolated cells by
Hauner’s protocol. 41.77f Dec. 17. In the 41.77f Decision, we did not find
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the report adequate to establish that Hauner’s cells inherently possessed all
the characteristics of the claimed cells. The Decision stated:
Vivotecnia did not perform experiments to determine whether
such cells were capable of differentiating into adipocyte cells
[claim 12] and one of the other cell types recited in the claims.
The ’231 patent, in Example 3 (col. 15, l. 36), showed that not
all cells isolated by its protocol retained the ability to
differentiate into all terminal cell types recited in . . . [the
claims]. As discussed in more detail below with respect to the
cells of Zilberfarb, there is sufficient evidence of record
regarding heterogeneity within the isolated cell populations to
explain the differences between the claimed stem cells, the
precursor cells of Hauner, and those isolated in the Vivotecnia
report.
41.77f Dec. 18.
Requester cites to a second declaration by Mario Delgado, Ph.D.
(executed Sept. 30, 2011) (“2nd Delgado Decl.”) as providing evidence that
the cells described in Vivotecnia were capable of differentiation into the
recited cell types. Req. Reh’g 3.
Dr. Delgado tested the cells after the second passage and found that
they differentiated into muscle and neuronal cells. 2nd Delgado Decl. ¶ 45
(“I understand that cells at passage 2 were sent by Vivotecnia to Cellerix.
Cellerix then provided me with the cells. . . . I then induced myogenic and
neuronal differentiation in the cells with my colleague by culturing cell
samples in differentiation media.”). However, the claims require the cells
“cultured for at least 15 passages without differentiating, wherein the cell is
cultured in DMEM and 5-15% serum for the at least 15 passages without
losing the capacity to differentiate.” Dr. Delgado did not show that the cells
did not lose the capacity to differentiate after 15 passages, but rather looked
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at passage 2. Thus, Dr. Delgado did not demonstrate that the cells meet all
the limitations in the claims.

GPDH (glycerol-3-phosphate dehydrogenase)
Requester, without citing any objective evidence, contends that the
“Board has misinterpreted the GPDH data in Hauner as meaning cells could
not differentiate into adipose cells.” Req. Reh’g 4.
The 41.77f Decision cited disclosure from Hauner that, after a second
subculture, GPDH was not detected in cells. 41.77f Dec. 16–17 (citing
FF9). In other words, the cells had lost the ability to differentiate. The
41.77f Decision explained, citing Hauner’s Abstract, that GPDH is a marker
for adipose cell differentiation and thus the lack of GPDH would indicate the
failure of cells to differentiate. Id. Hauner’s Abstract makes it clear that
GPDH was used as a marker for adipose differentiation, as well as lipid
accumulation, and one other enzyme marker: “cells were able to undergo
terminal adipose differentiation within 18 d, as assessed by lipid
accumulation and the expression of lipoprotein lipase (LPL) and glycerol-3-
phosphate dehydrogenase (GPDH) activities.” Thus, we do not agree with
Requester that the GPDH data was misinterpreted.
The original Decision on Appeal (“DOA”) (entered Nov. 27, 2013)
referenced both markers and cited Hauner’s disclosure on page 1666 for its
teaching that exposure of the cells to serum resulted in loss of differentiation
capacity. DOA 20–21. Requester did not identify a defect in the findings
nor the conclusion based upon it, other than to deny them. Reply Br. 4–5.
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Requester also states that the Board failed to address the differences in
conditions for adipocyte differentiation between Hauner and the ’231 Patent.
Req. Reh’g 4. Request contends that the conditions disclosed in the ’231
patent would have resulted in adipocyte differentiation using the cells of
Hauner. Id., 5. Requester also cited the second declaration of Dr. Marion
Delgado stating:
As can be seen from a comparison of Hauner and Zuk 2001,
Hauner at most used three adipogenic induces (insulin, cortisol
and IBMX), while Zuk 2001 uses four adipogenic inducers
(insulin, dexamethasone, IBMX, and indomethacin).
Moreover, Zuk 2001 used adipogenic inducers at
concentrations that were higher than that used in Hauner. For
example, Zuk 2001 used 10 µM insulin, which is 20 times more
than the 0.5 µM insulin used by Hauner. Moreover, Zuk 2001
used 0.5 mM IBMX, which is twice as much as the 0.25 mM
IBMX used by Hauner. Based on these differences, it is my
opinion that a skilled artisan would have concluded that the
differences in the number and amounts of adipogenic inducers
could have accounted for the differences in adipogenic lineage
differentiation capacity rather than the length of time that the
cells were cultured in serum.
2nd Delgado Decl. ¶ 44.
Requester states that, in contrast to Hauner, the ’231 patent “uses four
adipogenic inducers at significantly higher concentrations.” Req. Reh’g 4.
This argument is not persuasive.
Requester has the burden to show that the claim is unpatentable.
Requester did not meet that burden. Based on the teaching in Hauner that its
cells lost the ability to differentiate after two passages, there is reasonable
factual basis to conclude that the cells in Hauner do not meet the limitation
of claim 11 and others that the cells must be “cultured in DMEM and 5-15%
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serum for the at least 15 passages without losing the capacity to
differentiate.” (Emphasis added.) Requester did not provide sufficient
factual evidence to rebut or undermine this reasonable belief that the cells
are different based on the explicit factual teaching in Hauner.
Although Dr. Delgado stated that the differences in adipogenic
inducers “could have accounted for the differences in adipogenic lineage
differentiation capacity rather than the length of time that the cells were
cultured in serum,” he did not provide evidence that the inducers, in fact, did
account for the difference, but rather merely conjectured – with no
supporting evidence – they “could have” made a difference. 2nd Delgado
Decl. ¶ 44. Dr. Delgado also stated that “the induction method used by Zuk
is a much more potent inducer of adipogenisis [sic, adipogenesis] than that
used by Hauner,” but Dr. Delgado merely identified the differences in
chemicals and concentrations used between the publications without
demonstrating or providing scientific reasoning that such differences
affected a cell’s differentiation capacity. Id., ¶¶ 43, 44. Absent such
evidence or scientific explanation, we conclude that Requester did not meet
the burden of establishing that Hauner’s cells are the same as those which
are claimed.
Secondly, if the claims are interpreted to require that the cells were
actually “cultured in DMEM and 5-15% serum for the at least 15 passages
without losing the capacity to differentiate” (41.77f Dec. 10, 16–17), then
the claimed cells cannot be anticipated by Hauner’s cells which were
passaged only twice and then found to have lost their capacity to
differentiate. Id. Under this interpretation, even if Dr. Delgado’s opinion
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testimony is adopted (2nd Delgado Decl. ¶ 44), it is irrelevant whether the
induction protocol is responsible for the differences in cell capability
because the actual and only protocol used by Hauner resulted in the loss of
differentiation capability after two passages.
Requester also contends:
Hauner measures differentiation capacity by detecting glycerol-
3-phosphate dehydrogenase (GPDH) activity, while the ‘231
specification measures differentiation capacity by looking at the
accumulation of lipid droplets by staining with Oil red O (see
‘231 patent at Col. 14, line 60). One of skill in the art would not
assume that different metrics would yield similar outcomes, but
instead would expect different outcomes when using different
metrics.
Req. Reh’g 4.
Requester has provided no evidence that different “metrics” would
lead to different outcomes. . However, again, Requester provides no
scientific evidence or reasoning to support this statement about different
metrics having different outcomes. To the contrary, Hauner reports using
both lipid accumulation and GPDH to determine a cell’s ability to undergo
adipose differentiation (Hauner, Abstract), and noted the consistency of both
markers:
It must be recalled that a good correlation between the
proportion of differentiated triacylglycerol-containing cells and
the specific activity of GPDH occurred both for human stromal-
vascular cells (12) and mouse Ob17 cells (20). Furthermore,
histochemical staining of GPDH was only observed in clusters
of lipid-containing cells (13).
Hauner 1666.
Thus, Requester’s argument is contrary to the actual teaching in
Hauner.
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In sum, Requester did not persuasively identify an error in the
decision not to adopt the anticipation rejection based on Hauner.

WRITTEN DESCRIPTION
Patent Owner again contends that ’231 patent fails to describe or
enable an “isolated adipose-derived stem cell” which, inter alia, “can be
cultured for at least 15 passages without differentiating, wherein the cell is
cultured in DMEM and 5-15% serum for the at least 15 passages without
losing the capacity to differentiate.” In other words, the cells do not lose the
capacity to differentiate after being passaged at least 15 times.
The 41.77f Decision cited disclosure in the ’231 patent stating “the
cells can be passaged at least five times in such medium without
differentiating, while still retaining their developmental phenotype” and
“without losing developmental phenotype.” 41.77f Dec. 5. Requester
appears to question whether retaining “developmental phenotype” is the
same as “without losing the capacity to differentiate.” Req. Reh’g 5.
However, this was explained in the original Decision on Appeal:
The stem cells of claims 11 and 25 can be cultured in DMEM
and 5-15% serum “without losing the capacity to differentiate.”
The latter phrase is explained in the ‘231 Patent. According to
the patent, “[a] stem cell is a pluripotent cell that has the
capacity to differentiate in accordance with at least two discrete
developmental pathways.” (‘231 Patent, col. 18, ll. 10-12;
emphasis added.) A cell that has differentiated along a
“developmental pathway” is one that differentiated into a given
developmental phenotype (id. at col. 6, ll. 25-33). “A
developmental phenotype is the potential of a cell to acquire a
particular physical phenotype through the process of
differentiation.” (Id. at col. 18, ll. 3-5.) In other words, the
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“capacity to differentiate” means the ability of the claimed stem
cell to differentiate into two or more of the cell types (a
“physical phenotype”) selected from the group consisting of a
fat cell, a bone cell, a cartilage cell, a nerve cell, or a muscle
cell.
DOA 4.
With respect to the reference to original claims 1, 2, and 3 as
supporting the written description (41.77f Dec. 5–6), we have considered
Requester’s argument, but do not find it persuasively demonstrates an error
in the Decision. Claim 2 clearly recites the ability to differentiate after 15
passages and claim 3, which depends from it, as clearly lists the
developmental phenotypes of the cell. Since claim 3 adds a limitation to
claim 2, the skilled worker would understand that the cell of claim 3 has the
attributes of claim 2 (“can be cultured in DMEM + about 10% fetal bovine
serum for at least 15 passages without differentiating”) and claim 3 (the
recited developmental phenotypes). Requester misapprehends original claim
3 by asserting “[o]ne of skill in the art would read the developmental
phenotypes of claim 3 as applying to the cell of claim 2, not the
multitudinous offspring of the cell of claim 2 after undergoing 15 passages.”
Req. Reh’g. 6. Requester’s construction of the claim ignores and reads out
the express limitation that claim 2 covers cells which have been passaged 15
times.
In addition, we have considered Requester’s contention that the
inventors did not test their cells for differentiation capacity after passaging
15 times in the claimed medium. Id. We find this argument to be
unpersuasive. The recited passages (see DOA 4; 41.77f Dec. 5–6); and
claims convey that the inventors possessed the idea of passaging cells for 5,
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10, 15, and 20 times without differentiating and without losing
developmental potential. If the cells did not lose developmental potential,
the inventors clearly had to test to determine that the potential was not lost.

REHEARING DENIED

PATENT OWNER:
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO, IL 60601-6731

THIRD PARTY REQUESTER:
ROBERT A. SALTZBERG
MORRISON & FOERSTER LLP
425 MARKET STREET
SAN FRANCISCO, CA 94105-2482