Pfizer Inc.

Patent Trials and Appeals Board

Jun 1, 2020

2019005827 (P.T.A.B. Jun. 1, 2020)

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.
14/352,740 04/18/2014 Wenge Wang PC52477A 7531
28940 7590 06/01/2020
Pfizer Inc.
Attn:Legal Patent Department, Chief IP Counsel
235 East 42nd Street
New York, NY 10017
EXAMINER
BARRON, SEAN C
ART UNIT PAPER NUMBER
1653
NOTIFICATION DATE DELIVERY MODE
06/01/2020 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):
PfizerPatentDocketing@pfizer.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte WENGE WANG, YEN-TUNG LUAN,
DENIS DRAPEAU, and RYAN P. NOLAN
__________

Appeal 2019-005827
Application 14/352,740
Technology Center 1600
__________

Before DONALD E. ADAMS, FRANCISCO C. PRATS, and
TAWEN CHANG, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL

Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1, 2, 7–9, 11, 13, 18, 21, 22, and 31.
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant states that the real party in interest is Pfizer Inc. of
New York, NY. Appeal Br. 3.
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STATEMENT OF THE CASE
The sole rejection before us for review is the rejection of claims 1, 2,
7–9, 11, 13, 18, 21, 22, and 31 under 35 U.S.C. § 103(a) as being
unpatentable over Krüger,2 Drapeau,3 and Blatný.4 Ans. 3–7.
Appellant’s claim 1, the sole independent claim on appeal, is
representative and reads as follows:
1. A method of increasing cell density, viability, and/or titer
in a cell culture medium comprising the steps of:
(a) providing cells in a cell culture medium of at least
10L to start a large-scale cell culture process, wherein said cell
culture medium comprises iron as a trace element wherein the
concentration of iron is less than 100 μM; and
(b) adding a composition comprising iron to said cell
culture medium during the cell culture process such that the
concentration of iron in the cell culture medium is increased
over the course of the cell culture process, wherein the
composition comprising iron is added on or after day 3 of the
cell culture process.
Appeal Br. 12.
DISCUSSION
The Examiner’s Rejection
The Examiner cited Krüger’s Example 7 as disclosing a process in
which, as recited in representative claim 1, iron was added 3 days after the
culturing process was initiated. Ans. 4–5. The Examiner found that

2 WO 2009/087087 A1 (published July 16, 2009).
3 WO 2006/026447 A2 (published Mar. 9, 2006).
4 Pavel Blatný et al., Trace determination of iron in water at the μg/1 level
by on-line coupling of capillary isotachophoresis and capillary zone
electrophoresis with UV detection of the EDTA-Fe(III) complex, 757 J.
CHROMATOGR. A 297–302 (1997).
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Krüger’s process differed from the process of Appellant’s claim 1 in two
respects: (1) “Krüger does not teach a cell culture medium of at least 10L or
a cell culture apparatus capable of holding at least 10L” and (2) “Krüger is
silent regarding any trace (i.e. non-added and less than 100 μM) iron in the
aqueous culture media.” Id. at 5. The Examiner cited Drapeau and Blatný
as evidence that the process of Appellant’s claim 1 would have been obvious
despite the differences between Krüger’s process and the claimed process.
Id. at 5–7.
In particular, the Examiner cited Drapeau as evidence that it would
have been obvious to use a cell culture apparatus with a volume of 10 L or
more, to scale up Krüger’s process allowing the cells to produce large
quantities of proteins and/or polypeptides. Ans. 5–6. In particular, the
Examiner reasoned that “mere scaling up of a prior art process capable of
being scaled up, if such were the case, would not establish patentability in a
claim to an old process so scaled.” Id. at 6 (citing In re Rinehart, 531 F.2d
1048 (CCPA 1976)). The Examiner cited Blatný as evidence that Krüger’s
initial culture medium, prior to the addition of iron, actually contained trace
amounts of iron encompassed by step (a) of Appellant’s claim 1. Id.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant in
response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
Having carefully considered the evidence and arguments advanced by
Appellant and the Examiner, Appellant does not persuade us that a
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preponderance of the evidence does not support the Examiner’s conclusion
that the process of representative claim 1 would have been obvious.
As the Supreme Court explained in KSR Int’l Co. v. Teleflex Inc., 550
U.S. 398 (2007), “when a patent ‘simply arranges old elements with each
performing the same function it had been known to perform’ and yields no
more than one would expect from such an arrangement, the combination is
obvious.” Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273, 282
(1976)).
In the present case, representative claim 1 recites an arrangement of
elements which the Examiner has established were known in the prior art.
In particular, as recited in representative claim 1, Krüger’s Example 7
describes a process in which CHO cells were cultured for three days in a
medium without added iron, after which iron and, in certain instances,
spermine are added:
The inoculum cells were cultured three days in a polyamine and
iron free medium to deplete the intracellular iron and polyamine
pool. Then the so conditioned cells are used as inoculum. The
experiment is performed in fed-batch modus. All cultures were
fed with a feeding medium containing substrates for cell growth
and viability, such as amino acids and glucose. The feeding
medium is without polyamines and contains iron (III) citrate at
a concentration of 3200 mg/l. Figure 7 demonstrates that the
positive effect of spermine is also seen with other iron sources.
Furthermore, cells tolerate very high iron concentration up to
800 mg/l in the presence of spermine.
Krüger 28; see also id. at 21 (all experiments in Krüger used a CHO cell
line); id. at Fig. 7 (showing higher cell concentrations culturing in 800 mg/L
Fe-Citrate with or without 40 mg/L spermine).
As the Examiner found, and Appellant does not dispute, although
Krüger describes the initial culture medium in its Example 7 as “iron free”
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(Krüger 28), Blatný shows that a skilled artisan would have understood the
initial culture medium in Krüger’s Example 7 to contain trace amounts of
iron encompassed by the recitation in step (a) of representative claim 1. See
Blatný 301 (tap water has 85 ± 19 μg/L iron (Table 1)).
Although Krüger does not describe using a cell culture medium of at
least 10 L as recited in representative claim 1, Drapeau discloses that when
culturing cells to produce desired proteins and/or polypeptides, it is useful to
do so in volumes larger than 10 L. See Drapeau ¶ 5 (“The present invention
provides an improved system for large scale production of proteins and/or
polypeptides in cell culture. For example, the present invention provides
commercial scale (e.g., 500 L or more) culture methods . . . .”); id. ¶ 91
(disclosing “bioreactor” as vessel with volume of “at least 1 liter and may be
10, 100, 250, 500, 1000, 2500, 5000, 8000, 10,000, 12,000[] liters or more”
and “production bioreactor” as vessel with volume of at least 500 liters and
may be 1000, 2500, 5000, 8000, 10,000, 12,000[] liters or more”); id. ¶ 144
(“In a particularly preferred embodiment, the present invention is used in the
culturing of and expression of polypeptides and proteins from CHO cell
lines.”).
Drapeau discloses, moreover, that the initial cell culture medium,
ultimately used to provide cells for the production medium, “can be of any
size, but is often smaller than the culture volume of the production
bioreactor used in the final production of the polypeptide or protein of
interest, and frequently cells are passaged several times in bioreactors of
increasing volume prior to seeding the production bioreactor.” Drapeau
¶ 160.
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Given Drapeau’s disclosures regarding the desirability of culturing
cells such as CHO cells in large volume bioreactors to produce desired
proteins and/or polypeptides, we agree with the Examiner that a skilled
artisan had a good reason for, and a reasonable expectation of success in,
performing the process described in Krüger’s Example 7, including the
initial 3-day iron depleted culturing step, in a medium with a volume of at
least 10 L. We therefore also agree with the Examiner that the process
recited in Appellant’s representative claim 1 would have been prima facie
obvious to a skilled artisan.
Appellant’s arguments do not persuade us to the contrary. In
particular, we are not persuaded that the combined teachings of Krüger and
Drapeau fail to suggest performing the initial 3-day iron free inoculum
culturing step of Krüger’s Example 7 in a volume of at least 10 L. See
Appeal Br. 8–9; Reply Br. 2–3.
It might be true, as Appellant contends, that Krüger viewed alone
distinguishes its initial smaller volume inoculum from the production
medium used to produce proteins. As noted above, however, Drapeau
discloses that when producing proteins on a large commercial scale,
although the initial pre-production culture medium is “often smaller than the
culture volume of the production bioreactor,” the pre-production culture
medium “can be of any size.” Drapeau ¶ 160. Given this teaching, and the
overall advantages of large scale cultures taught in Drapeau, Appellant does
not persuade us that the Examiner erred in finding that a skilled artisan had a
sufficient reason to perform the initial 3-day iron free inoculum culturing
step of Krüger’s Example 7 in a volume of at least 10 L, as recited in
representative claim 1.
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Appellant also does not persuade us that, because the iron depletion in
the initial 3-day culturing step of Krüger’s Example 7 was solely for
experimental purposes to evaluate the effects of iron addition, and because
Krüger assigned no specific benefit to 3 days of initial iron depletion, a
skilled artisan lack motivation for performing that step when producing
proteins in a scaled-up process such as Drapeau’s. See Appeal Br. 9–10;
Reply Br. 3–4. Nor are we persuaded that, because Krüger discloses that
adding iron at the initial stages of culturing was beneficial, a skilled artisan
had no reason to perform the initial 3 day iron depletion step of Appellant’s
representative claim 1. See Appeal Br. 10–11; Reply Br. 4–5.
We acknowledge that, as to Krüger’s Example 7, “[t]he goal was to
test if the positive effect of polyamines is visible on cell growth with another
iron source as well.” Krüger 27. We acknowledge also that Figure 1 of
Krüger appears to show improved concentrations of cells in culture even at
initial stages of the culture prior to 3 days.
Nonetheless, as discussed above, a skilled artisan knew from Krüger’s
Example 7 that one suitable way of producing CHO cells for generating
proteins was a process in which the cells were cultured for three days in a
medium without added iron, after which iron was added. See Krüger 28; see
also id. at Fig. 7 (showing higher cell concentrations culturing in 800 mg/L
Fe-Citrate with or without 40 mg/L spermine). And, as also discussed
above, a skilled artisan knew from Drapeau that when using CHO cells to
produce desired proteins, it was useful to culture the cells in large volumes,
including at the initial stage of culturing.
Thus, even if a skilled artisan would have considered it preferable,
based on the teachings of Krüger, to add iron to the initial medium used for
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maintaining a stock of cells, a skilled artisan would have recognized,
nonetheless, that the process of Krüger’s Example 7 was a suitable method
of culturing cells which would be useful in large scale culturing methods
such as those described in Drapeau. Appellant does not persuade us,
therefore, that a skilled artisan had no reason for performing the entire
process of Krüger’s Example 7 on the large commercial scale taught in
Drapeau.
In sum, for the reasons discussed, Appellant does not persuade us that
the Examiner erred in finding, based on the teachings in Krüger, Drapeau,
and Blatný, that a skilled artisan had a sufficient reason for, and a reasonable
expectation of success in, performing a process having all of the steps and
features recited in Appellant’s representative claim 1. Because Appellant
does not identify any unexpected result or other objective evidence of
nonobviousness coming from the claimed process, we find that the
preponderance of the evidence supports the Examiner’s conclusion of
obviousness as to claim 1. We therefore affirm the Examiner’s rejection of
claim 1 over Krüger, Drapeau, and Blatný. Because they were not argued
separately, claims 2, 7–9, 11, 13, 18, 21, 22, and 31 fall with claim 1.

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/
Basis
Affirmed Reversed
1, 2, 7–9,
11, 13, 18,
21, 22, 31
103(a) Krüger,
Drapeau,
Blatný
1, 2, 7–9,
11, 13, 18,
21, 22, 31

Appeal 2019-005827
Application 14/352,740

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

AFFIRMED