Ex Parte Manuelidis

Board of Patent Appeals and Interferences

Mar 10, 2011

11114411 (B.P.A.I. Mar. 10, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte LAURA MANUELIDIS
__________

Appeal 2010-001622
Application 11/114,411
Technology Center 1600
__________

Before MELANIE L. McCOLLUM, JEFFREY N. FREDMAN, and
STEPHEN WALSH, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a co-
culture of infected cell lines. The Examiner has rejected the claims as
anticipated or obvious. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm-in-part.

1 The two-month time period for filing an appeal or commencing a
civil action, as recited in 37 C.F.R. § 1.304, or for filing a request
for rehearing, as recited in 37 C.F.R. § 41.52, begins to run from
the “MAIL DATE” (paper delivery mode) or the
“NOTIFICATION DATE” (electronic delivery mode) shown on
the PTOL-90A cover letter attached to this decision.
Appeal 2010-001622
Application 11/114,411

2
Statement of the Case
Background
“The present invention relates to compositions and methods for
identifying suitable treatment protocols and treatment compositions for
transmissible spongiform encephalopathies (TSE)” (Spec. 1 ¶ 0003).
According to the Specification, the invention “relates to stable cell lines
which produce the pathological form of PrP (PrP-res) after infection with the
infectious agent for a human or other mammalian form of transmissible
spongiform encephalopathy” (Spec. 1 ¶ 0003).
The Claims
Claims 1-3 and 27-29 are on appeal. Claims 1 and 27 are
representative. The remaining claims have not been argued separately and
therefore stand or fall together with claims 1 and 27. 37 C.F.R. §
41.37(c)(1)(vii). Claims 1 and 27 read as follows:
1. A co-culture comprising a mammalian
neuronal cell line stably infected with a
mammalian transmissible spongiform
encephalopathy (TSE) agent and living non-
infected neuronal cells,
wherein said stably infected cell line is
infective to neuronal cells in co-culture therewith,
and wherein abnormal prion protein (PrP-res) is
present in said cell line, and the concentration of
PrP-res in said cell line shows less than 2 fold
change with progressive subculture over at least 15
passages.

27. A co-culture comprising at least one first
cell line stably infected with a first mammalian
TSE agent and at least one second cell line stably
infected with a second mammalian TSE agent, or a
Appeal 2010-001622
Application 11/114,411

3
tissue infected with said second mammalian TSE
agent wherein said second TSE agent is more
virulent than said first TSE agent.

The issues
A. The Examiner rejected claims 1-3 and 27 under 35 U.S.C. § 102(b) as
anticipated over Lehmann2 (Ans. 3-6).
B. The Examiner rejected claims 28 and 29 under 35 U.S.C. § 103(a) as
obvious over Lehmann and Enari3 (Ans. 7-8).
A. 35 U.S.C. § 102(b) over Lehmann
The Examiner finds that “Lehmann discloses a co-culture comprising
mammalian neuronal cell line GT1-7 comprising cells infected with the
abnormal prion protein PrP-res from Fukuoka strain and the non-infected
cells” (Ans. 3). The Examiner finds that “the subcloned cell lines contain
both infected and non-infected cells lines and therefore read on the presently
claimed co-culture” (id. at 4). The Examiner finds that “Lehman discloses a
co-culture comprising mammalian neuronal cell line N2a#58 comprising
cells infected with abnormal prion protein from Chandler extract and non-
infected cells” (id.).

2 Lehmann et al., Ex Vivo Transmission of Mouse-Adapted Prion
Strains to N2a and GT1-7 Cell lines, ALZHEIMER’S DISEASE:
ADVANCES IN ETIOLOGY, PATHOGENESIS AND THERAPEUTICS, 679-
686 (2001).
3 Enari et al., Scrapie prion protein accumulation by scrapie-
infected neuroblastoma cells abrogated by exposure to a prion
protein antibody, 98 PROC. NAT’L ACAD. SCI. USA 9295-9299
(2001).
Appeal 2010-001622
Application 11/114,411

4
Appellant contends, regarding claim 1, that if “the Examiner were
correct that some of the cells are not infected by the agent, then there might
be present living, non-infected neuronal cells in the culture; however, the
culture would still lack a neuronal cell line stably transfected with a TSE as
defined in the claims” (App. Br. 7). Appellant contends that “absent having
survived several passages, they cannot be defined as a cell line. Lehmann's
cultures do not contain any cell line at all” (id. at 8).
Appellant contends, regarding claim 27, that “Lehmann conducted
experiments in which brain extracts from TSE infected brains were tested for
their ability to infect either N2a, N2a#58 or GT1-7 cells. These are
neuroblastoma cell lines that are not infected with TSE agents; they are
merely susceptible to such infection” (id. at 4). Appellant contends that “[i]t
is not seen how a culture of cells of an uninfected cell line in contact with a
brain extract that contains no living cells, but only one infectious agent could
possibly result in a co-culture that contains two - i.e. of, one cell line
infected with a stronger TSE agent and a second cell line infected with a
weaker one” (id. at 5).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that Lehmann teaches a “co-culture comprising a mammalian neuronal cell
line stably infected . . . and living non-infected neuronal cells” as required
by claim 1?
(ii) Does the evidence of record support the Examiner’s conclusion
that Lehmann teaches a co-culture infected with two TSE agents “wherein
Appeal 2010-001622
Application 11/114,411

5
said second TSE agent is more virulent than said first TSE agent” as
required by claim 27?

Findings of Fact
1. Figure 63.1 of Lehmann is reproduced below:

“Figure 63.1. General procedure of ex vivo transmission experiments”
(Lehmann 680).
2. Lehmann teaches that “[s]ubcloning of the infected cells was
sometimes performed, preferably at the first passage after inoculation to
maximize the chance of getting infected clones” (Lehmann 681).
Appeal 2010-001622
Application 11/114,411

6
3. Lehmann teaches that “it is essential after at least ten passages
to demonstrate by animal assay that the cells not only generated PrPSc but
actually carried the infectivity” (Lehmann 681).
4. The Examiner finds that the “subcloned cell lines contain both
infected and non-infected cell[] lines and therefore read on the presently
claimed co-culture” (Ans. 4).
5. Lehmann teaches that “[a]fter five passages (P5), the presence
of PrPSc was analyzed by Western blotting, after PK digestion. Only 22L,
Chandler, and 139A homogenates lead to the production of PrPSc by the
infected cell lines” (Lehmann 682, figure 63.2 legend).
6. The Specification teaches that “[c]ultures of stably transformed
cells, then, can be characterized as cultures containing target cells where the
effect on these target cells of various perturbations can be assessed” (Spec. 8
¶ 0034).
7. Dr. Manuelidis states that Lehmann’s “homogenate does not
contain living cells” (Manuelidis4 Dec. 2 ¶ 4).
8. Dr. Manuelidis states that Lehmann passages “the target cell
cultures 5-10 passages before assaying for abnormal PrP in order to avoid
false positives (p. 681). However, this would not result in a stably infected
cell line” (Manuelidis Dec. 2 ¶ 5).
Principles of Law
“[A] prima facie case of anticipation [may be] based on inherency.” In
re King, 801 F.2d 1324, 1327 (Fed. Cir. 1986). Once a prima facie case of

4 Declaration of Laura Manuelidis, filed Jun. 27, 2008.
Appeal 2010-001622
Application 11/114,411

7
anticipation has been established, the burden shifts to the Appellant to prove
that the prior art product does not necessarily or inherently possess the
characteristics of the claimed product. In re Best, 562 F.2d 1252, 1255
(CCPA 1977) (“Where, as here, the claimed and prior art products are
identical or substantially identical, or are produced by identical or
substantially identical processes, the PTO can require an applicant to prove
that the prior art products do not necessarily or inherently possess the
characteristics of his claimed product.”).
Analysis
Claim 1
The Examiner finds that “the subcloned cell lines contain
both infected and non-infected cells lines and therefore read on the
presently claimed co-culture” (Ans. 4).
Appellant contends, regarding claim 1, that if “the Examiner
were correct that some of the cells are not infected by the agent,
then there might be present living, non-infected neuronal cells in
the culture; however, the culture would still lack a neuronal cell
line stably transfected with a TSE as defined in the claims” (App.
Br. 7).
We find that the Examiner has the better position. There is
no reasonable dispute that Lehmann teaches a culture which
comprises mammalian neuronal cell lines which are infected with a
TSE agent (FF 1-3).
Further, Lehmann states that “[s]ubcloning of the infected cells was
sometimes performed, preferably at the first passage after inoculation to
Appeal 2010-001622
Application 11/114,411

8
maximize the chance of getting infected clones” (Lehmann 681; FF 2). This
statement directly teaches that in the initial culture, some cells were infected
and some cells were not infected. Lehmann also demonstrates that some
further passaged cultures resulted in infected cells and some in non-infected
cells, teaching that “[a]fter five passagess (P5), the presence of PrPSc was
analyzed by Western blotting, after PK digestion. Only 22L, Chandler, and
139A homogenates lead to the production of PrPSc by the infected cell lines”
(Lehmann 682, figure 63.2 legend; FF 5).
We therefore find that the Examiner has reasonably established that
Lehmann inherently demonstrates, in the initially infected cell culture, a co-
culture which comprises some cells which were infected and some cells
which were not infected (FF 1-5).
Appellant contends that “absent having survived several passages,
they cannot be defined as a cell line. Lehmann’s cultures do not contain any
cell line at all” (App. Br. 8).
We are not persuaded. We recognize that Dr. Manuelidis states that
Lehmann passages “the target cell cultures 5-10 passages before assaying for
abnormal PrP in order to avoid false positives (p. 681). However, this would
not result in a stably infected cell line” (Manuelidis Dec. 2 ¶ 5; FF 8). This
statement, while itself evidence, does not, however, define what constitutes a
“cell line stably infected.” Further, there is no direct evidence which rebuts
the Examiner’s inherency argument that a cell line, infected with a TSE
agent, which remained infected after five passages, would not reasonably
inherently satisfy the requirement for a stably infected cell line (see FF 5).
For example, unlike HIV infected cells which would require integration of
Appeal 2010-001622
Application 11/114,411

9
the HIV genome into the cellular genome in order to be “stably infected,”
the TSE agent is a protein which would reasonably have identical properties
in the cell after initial infection as compared to the properties in a cell
passaged 15 times. Appellant has identified no change in the cells or in the
TSE agent which results from progressive subculture and 15 passages, much
less provided evidence to support such a change.
Claim 27
Appellant contends that “[i]t is not seen how a culture of cells of an
uninfected cell line in contact with a brain extract that contains no living
cells, but only one infectious agent could possibly result in a co-culture that
contains two - i.e. of, one cell line infected with a stronger TSE agent and a
second cell line infected with a weaker one” (App. Br. 5).
We agree with Appellant. We find unpersuasive the Examiner’s
interpretation that “the claim only refers to the agents as the first and second
agent, which is broadly interpreted as two different prion agents from the
same strain” (Ans. 12). Claim 27 requires more than two different agents,
and also requires that one of the agents is more virulent than the other (see
Claim 27). There is no reasonable basis to conclude that the same prions in
Lehmann’s extract would exhibit different virulence without evidence
showing such a difference in virulence. The Examiner lacks such evidence.
Conclusion of Law
(i) The evidence of record supports the Examiner’s finding that
Lehmann teaches a “co-culture comprising a mammalian neuronal cell line
stably infected . . . and living non-infected neuronal cells” as required by
claim 1.
Appeal 2010-001622
Application 11/114,411

10
(ii) The evidence of record does not support the Examiner’s finding
that Lehmann teaches a co-culture infected with two TSE agents “wherein
said second TSE agent is more virulent than said first TSE agent” as
required by claim 27.

B. 35 U.S.C. § 103(a) over Lehmann and Enari
Having reversed the anticipation rejection of claim 27 over Lehmann
for the absence of a teaching of two TSE agents “wherein said second TSE
agent is more virulent than said first TSE agent,” we necessarily reverse the
obviousness rejections as the Enari reference does not remedy the
deficiencies of Lehmann.

SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. §
102(b) as anticipated over Lehmann. Pursuant to 37 C.F.R. §
41.37(c)(1)(vii)(2006), we also affirm the rejection of claims 2-3, as these
claims were not argued separately.
We reverse the rejection of claim 27 under 35 U.S.C. § 102(b) as
anticipated over Lehmann.
We reverse the rejection of claims 28 and 29 under 35 U.S.C. § 103(a)
as obvious over Lehmann and Enari (Ans. 7-8).

AFFIRMED-IN-PART

Appeal 2010-001622
Application 11/114,411

11

cdc

MORRISON & FOERSTER LLP
12531 HIGH BLUFF DRIVE
SUITE 100
SAN DIEGO, CA 92130-2040