Ex Parte 7258998 et al

Board of Patent Appeals and Interferences

Jul 6, 2012

90011025 (B.P.A.I. Jul. 6, 2012)

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.
90/011,025 06/03/2010 7258998 BJS-4145-64 6570
23117 7590 07/09/2012
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON, VA 22203
EXAMINER
KUNZ, GARY L
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
07/09/2012 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte LONZA BIOLOGICS PLC.
Appellant
____________

Appeal 2012-006123
Reexamination Control 90/011,025
Patent 7,258,998
Technology Center 3900
____________

Before, RICHARD E. SCHAFER, RICHARD M. LEBOVITZ, and
RAE LYNN P. GUEST, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal by the Patent Owner from the Patent
Examiner’s rejections of claims 1, 3-5, and 8-21 in an ex parte reexamination
of U.S. Patent No. 7,258,998 B2, issued August 21, 2007. The Board’s
jurisdiction for this appeal is under 35 U.S.C. §§ 6 and 134. We affirm.

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STATEMENT OF THE CASE
A request for ex parte reexamination of U.S. Patent 7,258,998 B2
(hereinafter, “the ‘998 patent) was made by a Third Party Requester on June
3, 2010 pursuant to 37 C.F.R. § 1.510. A Final Rejection (“Final Rej’n”)
rejecting all pending claims was mailed by the Examiner on April 27, 2011.
Patent Owner appealed the Examiner’s adverse decision to the Board of
Patent Appeals and Interferences. Notice of Appeal, dated August 22, 2011.
The Examiner rejected the claims as follows:
A. Claims 1-3, 8-12, and 15-21 under 35 U.S.C. § 103(a) as obvious in
view of Field1 and Bertheussen;2 and
B. Claims 4, 5, 13, and 14 under 35 U.S.C. § 103(a) as obvious in view
of Field, Bertheussen, and Bebbington.3
For Rejection B, Patent Owner argued that Bebbington did not
overcome the deficiencies of Field and Bertheussen. App. Br. 24.
Consequently, we have considered both rejections together.
Claim 1 is the only independent claim on appeal. We select it as
representative. Claim 1 reads as follows:

1 Raymond Paul Field, EP 0 239 292 B1 (pub. Sep. 29, 1993).
2 Kjell Bertheussen, U.S. 2002/0031825 A1 (pub. Mar 14, 2002).
3 Christopher Robert Bebbington et al., U.S. 5,891,693 (Apr. 6, 1999).
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1. A method of producing a product protein, wherein the
protein is expressed from a lymphoid cell, in cell culture at least
during a certain span of time during cell culture, comprising the
steps
a) preparing a cell culture inoculum comprising said
lymphoid cells in a serum-free growth medium comprising an
acetate salt selected from the group consisting of an alkali metal
salt, an alkaline earth metal salt and a metal salt, said acetate salt
being present in a concentration of 5 to 20 mM;
b) inoculating a serum-free cell culture growth medium
with said inoculum and culturing the lymphoid cells in the serum
free cell culture growth medium with concomittant [sic]
expression of the product protein, and
c) harvesting said protein from the serum free cell culture
growth medium,
said serum-free growth medium and said serum-free cell
culture growth medium being devoid of butyrate,
said alkali metal not being lithium,
said serum-free cell culture growth medium being devoid
of acetate salts in the range of more than 1 mM.

REJECTION
Claim 1 is drawn to a method of producing a protein product which is
expressed from a lymphoid cell. The claimed method comprises three steps:
a) preparing a cell culture inoculum in a “serum-free growth medium”
comprising the lymphoid cells and an acetate salt in a concentration of 5 to 20
mM;
b) inoculating a “serum-free cell culture growth medium” with the
inoculum and culturing the cells with expression of the protein from the cells;
and
c) harvesting the protein.
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The “growth medium” in step a) and the “cell culture growth medium”
in step b) are devoid of butyrate. The “cell culture growth medium” in step b)
is also devoid of acetate salts in the range of more than 1 mM.
The Examiner found that Field describes a method of culturing
lymphoid cells in a growth medium with an alkanoate to produce a protein,
the same general method to which claim 1 is directed. Answer 5-6. Field’s
method comprises using serum free culture medium as claimed, with an
alkanoate, preferably a straight chain of 2-10 carbon atoms. Answer 6; Field,
p. 5, ll. 48-50. Acetate, as recited in claim 1, is a 2-carbon alkanoate. Answer
6.
The Examiner found that Field does not specifically exemplify acetate,
although it is within the scope of alkanoate compounds disclosed in Field.
Answer 6. The Examiner also found that Field does not describe a) preparing
a cell culture inoculum in a concentration of 5 to 20 mM and b) inoculating it
into a cell culture growth medium which, after the inoculation, is “devoid of
acetate salts in the range of more than 1 mM.”
The Examiner concluded that such differences would have been
obvious to one of ordinary skill in the art. The Examiner found the acetate
requirement of claim 1 obvious based on Bertheussen’s teaching of cell
culture medium with acetate. Answer 7-8. With respect to the specific
concentrations of acetate, and the transition from a high concentration of
acetate in step a) to a lower concentration in step b), the Examiner found that
Field teaches that suitable alkanoate concentrations can be selected by routine
optimization. Answer 7-8. The Examiner also reasoned that the step in
which the inoculum comprising 5 to 20 mM acetate was added to the cell
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culture growth medium as a conventional dilution step in which the inoculum
acetate is diluted to a final concentration of less than or equal to 1 mM acetate.
Final Rej’n 3.
The Examiner found that it would further have been prima facie
obvious
to have reduced the concentration of acetate during the culture
period of the hybridoma or lymphoid cells to a level equal to or
less than 1 mM to ensure adequate cell proliferation based on the
teachings in Field that the preferred concentration of alkanoate
salt during the culture period for hybridomas is from 0.1 - 0.9
mM and that concentrations of enhancing agent higher than the
optimal determined concentration will interfere with cell growth.
Answer 8.
The Examiner set forth fact-based reasoning for concluding that the
claims would have been prima facie obvious in view of Field and
Bertheussen. The Examiner also provided logical and fact-based responses to
Patent Owner’s arguments. We adopt the Examiner’s position with regard to
the rejection and response to arguments, and provide the following additional
discussion. The section titles below correspond to rebuttal arguments made
by Patent Owner in its Brief.

Addition of acetate to serum-free cell culture growth medium
Patent Owner contends that Field does not “not teach or suggest
inoculating a serum-free cell culture growth medium of the claimed invention
with an inoculum containing lymphoid cells, serum-free growth medium and
an acetate salt, as required by the claimed invention.” App. Br. 16-17.
However, Field describes diluting a suspension culture of cells into a
serum free-medium and then adding butyrate to a desired concentration.
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Field, p. 7, ll. 28-30. The final concentrations of 0.01mM, 0.5mM, and
1.0mM disclosed by Field are within the claimed range of step b). The
manner in which “sodium butyrate “was added at concentrations of 0.01mM,
0.5mM and 1.0mM” was not described by Field, indicating that it was within
the level of ordinary skill in the art to add the butyrate in any effective way,
including by diluting it from a medium containing the cells as claimed, similar
to the way in which the cells were diluted by Field to a final concentration.
Field, p. 7, 28-30. See also Answer 8, quoted above. The Examiner found
that Field teaches that appropriate concentrations of alkanoates can be
determined routinely and added at different times (Answer 12 & 15),
providing evidence that persons of ordinary skill in the art routinely added
enhancing agent to culture medium. Patent Owner contends that the claimed
steps achieved unexpected results, which is discussed in more detail below.

Fields teaches a preference for butyrate and would not have led the
skilled worker to use another alkanoate which operates by a different
mechanism
As mentioned above, Field describes the addition of an alkanoate to a
serum-free growth medium in which lymphoid cells are cultured to produce a
protein, the same general method recited in claim 1. The alkanoate is
described to be an enhancing agent for protein expression. Field teaches that
the alkanoate is “preferably a straight chain C2-10, especially a C3-5 alkanoic
acid or a salt thereof and in particular is butyric acid or a salt thereof,
especially an alkali metal salt such as sodium butyrate.” Field, p. 5, ll. 48-50.
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Field’s examples and the bulk of discussion are directed to butyrate, which is
a 4-carbon alkanoate.
Butyrate and the alkanoates generally, are described by Field as
inducing or enhancing agents which induce or increase protein production in
cell lines cultured in growth medium. Field, p. 3, ll. 22-41. Field teaches that
butyrate appears to modify gene expression, enhancing the production of
protein from the genes expressed by the cells. Field, p. 3, l. 39 to p. 4, l. 42.
The claims are directed to acetate, a C2 alkanoate acid, which is said to
serve as an energy source and precursor for the synthesis of fatty acids,
cholesterol, etc. App. Br. 12. Acetate is a member of the straight chain C2-10
alkanoates disclosed by Field, but it is not specifically exemplified in the
experiments described in Field. Patent Owner contends that Field teaches a
preference for butyrate in cell culture and would not have suggested using
another alkanoate which operates by different mechanism. App. Br. 13.
Patent Owner argues that because acetate
would be recognized by one of ordinary skill in the art to not act
at a molecular level in a manner described by Field for butyrate,
which is the preferred “enhancing agent” described by Field, one
of ordinary skill would not have been led by Field - or any of the
cited art - to have used an acetate of the claimed invention in
place of the butyrate of Field.
App. Br. 13.
This argument is not persuasive. Field expressly describes using
alkanoates salts other than butyrate in its medium, including a C2 salt which
corresponds to the claimed acetate salt. Patent Owner contends that acetate
operates in cell culture by a different mechanism from butyrate. App. Br. 12-
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13. Patent Owner provided credible evidence4 that acetate serves an energy
source and fatty acid precursor to cells. However, even if acetate provided
these functions to a cell, such functions do not preclude acetate from acting as
a protein expression enhancing agent in the manner described by Field.
Patent Owner has not provided sufficient evidence that one of ordinary
skill in the art would doubt that an acetate salt would possess this additional
activity as a protein enhancing agent. As discussed above, Field expressly
stated that a straight chain C2-10 alkanoic acid or a salt thereof, which includes
acetate salts, could be utilized as an enhancing agent. Field, p. 5, ll. 48-50.
Field provided experimental evidence that other alkanoic acids could serve
this function. Field, p. 11, table 5.
Moreover, the claims do not require acetate to serve as an enhancing
agent. Even if acetate lacked such activity, the skilled worker would have had
reason to include it in a culture medium as a replacement for fatty acids,
necessary for cell growth as taught by Bertheussen at page 8, ¶¶ 150-151.
We additionally note that Field acknowledges prior art methods in
which proteins were produced without an enhancing agent. Field, p. 3, ll.
49-54. Thus, omitting butyrate would simply be practicing a method disclosed
in the prior art, albeit a less effective method. Practicing an inferior process
does not make an obvious process patentable. In re Gurley, 27 F.3d 551, 553
(Fed. Cir. 1994).

4 We considered the evidence cited in footnote 5 on page 12 of the Appeal
Brief, despite the Examiner’s position that it was not timely filed. Answer 13.

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Patent 7,258,998

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Field’s Table 1 in which butyrate was used alone. Id. at 8. For example,
Patent Owner states that Table 1 shows 0.5 mM butyrate producing 3.1 µg/105
per day, while Table 5 show values 7.00 µg/105 and 4.70 µg/105 in
Experiments 1 and 2, respectively, for the butyrate alone. Id. at 9. Because
the values are higher in Table 5 than would have been expected from Table 1,
Patent Owner contends that the butyrate experiment in Table 5 actually
contains a basal amount of butyrate in addition to a second butyrate amount.
Id. at 8-9. Thus, Patent Owner asserts the skilled worker would have
understood that butyrate was present along with the specifically listed
alkanoate in every condition (i.e., propionate + butyrate; pentanoate +
butyrate; hexanoate + butyrate). Id.
Patent Owner’s position is not supported by sufficient evidence. First,
Field expressly stated that other alkanoates could be used as enhancing agents
and Example 6 is titled “Effect of varying alkanoates and antibody production
from hybridoma cells,” logically suggesting that the table summarizes the
effect of different alkanoates on protein production. The description of
Example 6 does not indicate that butyrate was added on top of another
alkanoate: “Varying straight chain sodium alkanoate salts (propionate,
butyrate, pentanoate or hexanoate) were added to the inoculum at the
concentrations indicated in table 5.” Field, p. 10, ll. 40-42. Patent Owner has
no given sufficient reason to doubt this most logical interpretation of the data
in Table 5.
It is true that protein production was greater in Experiments 1 and 2 in
Example 6 as compared to the experiment summarized in Table 1. However,
Patent Owner did not provide sufficient evidence that these differences were
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significant, rather than expected experimental variability. For example, for
butyrate, Experiments 1 and 2 of Example 6 showed a difference of 1.5 fold
(7.0 and 4.7), indicating experiment to experiment variability in protein
production. The control with no butyrate in Table 1 was 2.6 (Field, p. 8,
between ll. 30-35), while in Table 5 it was 3.30 and 2.39, respectively, again
indicating experimental variability. Patent Owner did not provide objective
evidence that the skilled worker would have considered these differences to
establish that butyrate was present in each condition described in Example 6,
contrary to the example title that the alkanoates were being varied to
determine their effect on antibody production. The statements of the patent
counsel are insufficient because the patent counsel did not establish he is a
person of ordinary skill in the art.

Field requires the continuous presence of butyrate
Field describes “a process for the production of a protein which
comprises maintaining genetically manipulated or hybridoma cells which
constitutively produce said protein in culture in the continuous presence of an
alkanoic acid or salt thereof which enhances protein production.” Field, p. 6,
ll. 19-21. In Example 1 of Field, cells were grown to a viable density and then
aliquots of the cells “were dispensed into shake flasks and sodium butyrate
added at concentrations of 0.1mM, 0.3mM, 0.5mM and 1.0mM.” Field, p. 7,
ll. 29-30. The cells were incubated in the shake flasks for up to 207 hours.
Fields, p. 7, ll. 31-32.
Patent Owner contends:
The description of Field for the continuous presence of
butyrate in the culture medium would not have led one of
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ordinary skill to have made the presently claimed method
wherein the initial acetate salt in the serum-free growth medium
is not replenished in the subsequent serum-free cell culture
growth medium.
App. Br. 13.
Patent Owner therefore appears to construe claim 1 to exclude
replenishing acetate during the growth stage and, presumably, to exclude
growing cells continuously in an enhancing agent. We therefore must first
interpret claim 1 in light of the ‘998 patent specification.

Claim interpretation and analysis
Step a) of claim 1 comprises “preparing a cell culture inoculum
comprising said lymphoid cells in a serum free growth medium” comprising
an acetate salt “being present in a concentration of 5 to 20 mM.” In step b)
that concentration is reduced by “inoculating a serum-free cell culture growth
medium with said inoculum,” such that the growth medium contains no more
than 1 mM acetate (“being devoid of acetate salts in the range of more than 1
mM.”) Patent Owner characterizes the transition from step a) to step b) as a
decision not to replenish the acetate from step a), which apparently Patent
Owner interprets also to exclude the cells from being continuously grown in
the acetate as taught by Field. We are not persuaded.
Step b) is silent as to whether or not acetate may be replenished during
culture growth. The claim expressly recites in step b) that the cells are
cultured in a growth medium “being devoid of acetate salts in the range of
more than 1 mM.” Acetate is therefore permitted to be present in the medium
when the cells are cultured, albeit at a level which is not more 1mM, even if
replenished to an amount no more than 1mM. Thus, step b) includes
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embodiments in which the cells are grown continuously in acetate and permits
replenishment to a certain level.
The concentration of acetate in step b) is lower than the concentration
in the cell culture inoculum of step a). However, as long as there is some
acetate present in the growth medium, the cells are still exposed to the acetate
in both steps, and therefore are in the continuous presence of the acetate.
Thus, the cells are still continuously exposed to the acetate.
If Patent Owner is interpreting “devoid of acetate salts in the range of
more than 1 mM” to mean that no acetate is present, Patent Owner has not
identified any support for this narrow interpretation. To the contrary, such an
interpretation is unreasonable since the cells comprising acetate in step a) are
inoculated into a cell growth medium in step b), so there must be at least some
acetate present in the growth medium of step b) of claim 1.
The ‘998 patent specification is consistent with this interpretation of
claim 1. According to a passage in the ‘998 patent cited by Patent Owner for
steps a) and b):
Most preferably, acetate is added only directly to the culture
medium prior to culture onset, in the amounts stated above and in
particular at 6 to 9 mM and in the form of sodium acetate, and is
not replenished during cell cultivation via feed, preferably it is
not replenished during culture growth in a suitable medium such
as a high cell density growth medium.
‘998 Patent, col. 3, l. 63 to col. 4, l. 2.
Thus, when the patent refers to “replenishing,” it means that additional
acetate is not added after the initial addition of it. The cells, however, may
still be grown in the presence of the acetate added at the onset, even if the
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acetate is not replenished into the culture media and used during the culture
period.
The ‘998 patent also describes growing cells in a culture medium which
“is devoid of acetate salts in the >1 mM range,” which corresponds to the
range recited in step b) of claim 1. In this described embodiment, “only the
inocculum culture is treated with acetate.” ‘998 patent, col. 4, ll. 13-14.
‘Addition to the medium prior to starting cell culture’
according to the present invention means exposing cells at about
the time of inocculation which includes the initial lag-phase
before the onset of detectable growth or exposing them even
prior to inocculation of the culture medium to acetate or its
equivalents in the above stated amounts. Again, ‘prior to
inocculation’ means that the inocculum pre-culture itself is
grown in a medium comprising the acetate medium supplement
in the above stated amounts. It is also possible to combine both
aspects. In one particularly preferred embodiment, only the
inocculum culture is treated with acetate in the amounts stated
above whereas the cell culture growth medium used for large-
scale production culture is devoid of acetate salts in the >1 mM
range.
‘998 Patent, col. 4, ll. 3-16.
It appears from the passage reproduced above that treatment of the
inoculum culture would correspond to the cell’s exposure to acetate “prior to
inocculation of the culture medium,” where the latter phrase is specifically
defined to mean “that the inocculum pre culture itself is grown in a medium
comprising the acetate medium supplement.” Thus, this embodiment involves
growing cells first in a concentration of acetate to produce the inoculum, and
then putting them into a growth medium which is “devoid of acetate salts in
the >1 mM range.” Claim 1 is broad enough to include an embodiment where
step a) would correspond to the step of “prior to inocculation of the culture
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medium,” and step b) to the large scale production culture. As the latter step
permits acetate to be present, once again, this embodiment includes growing
cells continuously in the presence of acetate, although at different acetate
concentrations.
In sum, person of ordinary skill in the art would have reasonably
interpreted claim 1 in light of the ‘998 patent specification to include
embodiments in which the cells are grown in the continuous presence of
acetate. As Field teaches such growth conditions (p. 10, supra), we conclude
that the Examiner’s finding that Field describes or suggests the claimed steps
a) and b) to be supported by a preponderance of the evidence. Patent Owner
has not rebutted the Examiner’s fact-based findings and conclusion.

Unexpected results
A case of prima facie obviousness can be rebutted with a showing of
unexpected results. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (“One way
for a patent applicant to rebut a prima facie case of obviousness is to make a
showing of ‘unexpected results,’ i.e., to show that the claimed invention
exhibits some superior property or advantage that a person of ordinary skill in
the relevant art would have found surprising or unexpected.”). Those results
must be “surprising or unexpected” to one of ordinary skill in the art when
considered in the context of the prior art. Soni, 54 F.3d at 750; Iron Grip
Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1323 (Fed. Cir. 2004).
Here, Patent Owner contends that the inventor discovered an
“unexpected advantage in not replenishing the acetate salt of the claim
invention in the serum free cell culture grown medium,” for example, to the
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levels in step a). App. Br. 14. Patent Owner states that Figure 4 and Example
1 [Experiment 1 at columns 8-9] of the ‘998 patent demonstrate the claimed
method “unexpectedly provides an improvement in maximum viable cell
concentration, cumulative cell time (CCT), product concentration and single
cell productivity.” App. Br. 17.
As explained in more detail below, these results are not persuasive.
Under Soni, “the PTO must consider comparative data in the
specification in determining whether the claimed invention provides
unexpected results.” Soni, 54 F.3d at 750. “Mere lawyer's arguments and
conclusory statements in the specification, unsupported by objective evidence,
are insufficient to establish unexpected results.” In re Wood, 582 F.2d 638,
642 (CCPA 1978). In this case, the ‘998 patent specification provides factual
evidence of increase yield and single cell productivity. In the description of
Figure 4 of Experiment 1, it is stated:
Addition of acetate to the inocculum culture or at the time of
inocculation, meaning the use of an acetate supplemented culture
medium for production culture, was found to be the most
effective mode in view of increased yield and maximized single
cell productivity.
‘998 patent, col. 9, ll. 44-48.
However, “[m]ere improvement in properties does not always suffice to
show unexpected results.” Soni, 54 F.3d at 751. Rather, as explained in Soni
“when an applicant demonstrates substantially improved results” and “states
that the results were unexpected, this should suffice to establish unexpected
results in the absence of evidence to the contrary.” Id. In this case, ‘998
patent established that certain culture conditions were “the most effective
mode in view of increased yield and maximized single cell productivity,” but
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the ‘998 Patent Owner did not establish by sufficient evidence that a person of
ordinary skill in the art would have considered such data “unexpected” or
“surprising.”
In addition, Patent Owner describes several culture conditions in Figure
4, but did not identify which corresponded to the closest prior art. To establish
unexpected results, the claimed subject matter must be compared with the
closest prior art. In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir.
1991).
In sum, we have considered Patent Owner’s evidence of unexpected
results, but do not find it sufficient to overcome the obviousness rejection
when considered in view of the totality of evidence of record before us.

Claims 20 and 21
Patent Owner separately argued claims 20 and 21. Claim 20, depends
on claim 1, and recites that the “acetate salt is not replenished in the serum-
free cell culture growth medium during the culturing of the lymphoid cells.”
Claim 21 is dependent on claim 3, which in turn is dependent on claim 1, and
recites the same replenishing limitation as in claim 20.
Field clearly teaches culturing cells without replenishing the alkanoate
in the growth media. In Example 1 of Field, cells were grown to a viable
density and then aliquots of the cells “were dispensed into shake flasks and
sodium butyrate added at concentrations of 0.1mM, 0.3mM, 0.5mM and
1.0mM.” Field, p. 7, ll. 29-30. The cells were incubated in the shake flasks
for up to 207 hours. Fields, p. 7, ll. 31-32. There is no disclosure in Field that
the butyrate was replenished during the incubation period.
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SUMMARY
We affirm the Examiner’s determination that claims 1, 3-5, and 8-21
are unpatentable in view of the prior art cited in Rejections A and B. Claims
not separately argued fall together with claim 1. 37 C.F.R. 41(c)(1)(vii).

TIME PERIOD FOR RESPONSE
Requests for extensions of time in this ex parte reexamination
proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f).

AFFIRMED
ack

cc:
Patent Owner
NIXON & V ANDERHYE, PC
901 NORTH GLEBE ROAD, 11 TH FLOOR
ARLINGTON, V A 22203
Third Party Requester:

BARBARA A. MCDOWELL
ROSSI, KIMMS & MCDOWELL, LLP
20609 GORDON PARK SQUARE, SUITE 150
ASHBURN, VA 20147