Ex Parte Lebing et al

Board of Patent Appeals and Interferences

Sep 17, 2010

11873878 (B.P.A.I. Sep. 17, 2010)

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.
11/873,878 10/17/2007 Wytold R. Lebing 13281-00002-US1 1437
23416 7590 09/17/2010
CONNOLLY BOVE LODGE & HUTZ, LLP
P O BOX 2207
WILMINGTON, DE 19899
EXAMINER
MOSHER, MARY
ART UNIT PAPER NUMBER
1648
MAIL DATE DELIVERY MODE
09/17/2010 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 STATE S PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte WYTOLD R. LEBING, DOUGLAS C. LEE,
KLAUS-PETER RADTKE, SCOTT A. COOK,
HANNS-INGOLF PAUL, and PATRICIA ALRED
__________

Appeal 2010-008454
Application 11/873,878
Technology Center 1600
__________

Before ERIC GRIMES, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of preparing a purified, virally inactivated antibody preparation.2 The

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.
2 Oral Hearing held on September 14, 2010.
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Application 11/873,878

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Examiner rejected the claims as anticipated. We have jurisdiction under 35
U.S.C. § 6(b). We affirm.
Statement of the Case
The Claims
This is a reissue application of US 6,955,917, issued October 18,
2005. Claims 8 and 11, filed in the reissue application, are on appeal.
Claims 8 and 11 read as follows:
8. A method of preparing a purified, virally
inactivated antibody preparation from a starting
solution comprising antibodies and other
substances at an initial pH, the method comprising
the steps of:
(a) adding a source of caprylate ions to the
starting solution and adjusting the pH to form a
precipitate and a supernatant solution comprising
antibodies, and
(b) incubating the supernatant solution under
conditions of time, pH, temperature, and caprylate
ion concentration to inactivate substantially all
enveloped viruses to produce a purified, virally
inactivated antibody preparation.

11. A method of preparing a purified, virally
inactivated immunoglobulin preparation from a
starting material comprising immunoglobulin and
other substances, the method comprising the steps
of
(a) adjusting the starting material to
conditions of pH, temperature, and caprylate
concentration such that a first precipitate and a first
supernatant comprising immunoglobulin are
formed,
(b) separating the first supernatant from the
first precipitate,
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Application 11/873,878

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(c) incubating the first supernatant under
conditions of time, pH, temperature, and caprylate
concentration to inactivate substantially all
enveloped viruses, and such that a second
precipitate and a second supernatant comprising
immunoglobulin are formed, and
(d) separating the second supernatant from
the second precipitate to produce a purified, virally
inactivated immunoglobulin preparation.

The issue
The Examiner rejected claims 8 and 11 under 35 U.S.C. § 102(b) as
anticipated by Steinbuch3 as evidenced by Seng4 (Ans. 3-4).
The Examiner finds that Steinbuch “teaches a method of preparing
antibodies from a starting solution comprising other substances, which
comprises adjustment of the pH to 4.5 - 5.2 (optimally 4.8) and dropwise
addition of caprylic acid (6.8 g/100 ml) at room temperature for 30 minutes
to form a precipitate and a supernatant solution comprising antibodies” (id.
at 3). The Examiner finds that Seng evidences that “at pH 6.5 or less, virus
inactivation by caprylic acid is achieved almost instantaneously” (id.). The
Examiner concludes that “Steinbuch inherently anticipates the claimed
method, even though the reference does not expressly teach virus
inactivation” (id.).
Appellants contend that “Steinbuch teaches addition of caprylic acid.
. . . [U]se of caprylic acid, and particularly use at high levels as disclosed in

3 M. Steinbuch and R. Audran, The Isolation of IgG from
Mammalian Sera with the Aid of Caprylic Acid, 134 ARCHIVES
BIOCHEMISTRY BIOPHYSICS 279-284 (1969).
4 Seng et al., US 4,939,176, issued Jul. 3, 1990.
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Application 11/873,878

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Steinbuch, is not the same as ‘adding a source of caprylate ions’ as recited in
step (a) of claim 8” (App. Br. 11).
Appellants contend that the “anticipation rejection of claim 8 also fails
because the inherency of viral inactivation has not been established” (id. at
12). Appellants quote Seng’s teaching that “[s]urprisingly, at lower pHs
(6.5 or less) if caprylic acid is present at 0.07 to 0.001%, virus inactivation
is achieved almost instantaneously” (id., citing Seng 3). Appellants
calculate that “Figure 2 discloses using 6.8 g caprylic acid in 100 ml of 5%
human plasma and 200 ml acetate buffer. Assuming the solution has a
density of 1 mg/ml, caprylic acid is present at 2.267 % by weight, which is
far above where Seng teaches instantaneous viral inactivation occurs” (id.).
The issues with respect to this rejection are:
(i) Does the evidence of record support the Examiner’s conclusion
that the IgG isolation method of Steinbuch inherently adds caprylate ions?
(ii) Does the evidence of record support the Examiner’s conclusion
that the IgG isolation method of Steinbuch inherently functions to
“inactivate substantially all enveloped viruses”?
Findings of Fact
1. Steinbuch teaches “a procedure for the preparation of pure IgG
with good yield” (Steinbuch 279, col. 1).
2. Steinbuch teaches a starting solution where “[h]uman, equine,
ovine, and rabbit sera or ACD plasma were used in these experiments”
(Steinbuch 279, col. 1).
3. Steinbuch teaches that “the purity and yield of IgG were
dependent on the amount of caprylic acid, the pH of the reaction mixture, the
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Application 11/873,878

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dilution factor and the molarity of the buffer used for dilution” (Steinbuch
280, col. 1).
4. Steinbuch teaches that “[a]djustment of the pH to 4.8 ± 0.05
before adding the caprylic acid has been adopted as a standard procedure”
(Steinbuch 280, col. 2).
5. Steinbuch teaches that the “amount of caprylic acid necessary
to remove the proteins of 100 ml ACD plasma of about 5% protein
concentration (or equally diluted serum) was 6.8 g ± 5%” (Steinbuch 280,
col. 2).
6. Figure 2 of Steinbuch is reproduced below:

“Fig. 2. Flow sheet showing the isolation of IgG from human plasma”
(Steinbuch 281).
7. Figure 2 of Steinbuch shows that caprylic acid was added
dropwise into a 300 ml solution with a pH of 4.8 at a temperature of 20°C
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Application 11/873,878

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and then subjected to stirring for 30 minutes prior to centrifugation (see FF
6).
8. The Examiner finds that “an acid . . . will partially dissociate
into its ionized form in aqueous solution. At the pKa, one-half of the
dissolved molecules will be in ionized form” (Ans. 4).
9. Seng teaches that the “pKa of caprylic acid is 4.89 . . . The
Henderson-Hasselbalch equation:

gives the concentration of acid and its ionized form at various pHs” (Seng,
col. 4, ll. 1-9).
10. Seng teaches that “one can easily provide a given concentration
of caprylic acid by carefully controlling pH and caprylate concentration. For
example, if the caprylic acid concentration is kept constant at 0.07% (0.0035
M) and the ionized form (e.g., sodium caprylate) is varied between 0.06% at
pH 4.9 and 2.0% at pH=8, the amount of caprylic acid shown as FIG. 1 is
produced” (Seng, col. 4, ll. 9-16).
11. Seng teaches “varying the concentration of sodium caprylate
between 0.1% at pH 4.8 and 20% at about pH =9.0 to give instantaneous
inactivation of lipid-coated viruses. More preferably, the total concentration
is kept between 0.1% at pH 4.8 and linearly increasing to 2.0% at 6.5 to give
instantaneous virus inactivation” (Seng, col. 4, ll. 21-27).
12. Seng teaches that “caprylate can be kept at 2% between pH 6.5
and 9.5 for a longer period of time (e.g., 2 to 4 hours) to give an appropriate
caprylic acid concentration for virus inactivation” (Seng, col. 4, ll. 27-30).
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13. The Specification5 teaches that the “process involves
suspension of the antibodies at pH 3.8 to 4.5 followed by the addition of
caprylic acid (or other source of caprylate) and a pH shift to pH 5.0 to 5.2 . .
. . Sodium caprylate is again added to a final concentration of not less than
about 15 mM. This solution is incubated under conditions sufficient to
substantially reduce the titer of active virus” (Alred, col. 3, ll. 1-9).
Principles of Law
“Whether the rejection is based on ‘inherency’ under 35 U.S.C. § 102,
on ‘prima facie obviousness’ under 35 U.S.C. § 103, jointly or alternatively,
the burden of proof is the same, and its fairness is evidenced by the PTO’s
inability to manufacture products or to obtain and compare prior art
products.” In re Best, 562 F.2d 1252, 1255 (CCPA 1977).
Analysis
The Specification teaches that caprylic acid is a source of caprylate
(FF 13). Steinbuch teaches adding caprylate ions to a starting solution
which comprises antibodies, and adjusting the pH to form a precipitate,
followed by incubating the solution with caprylate (FF 1-6). Seng provides
evidence that a solution of caprylic acid at pH 8 will comprise caprylate ions
(FF 8-10) and that caprylic acid will instantaneously inactivate lipid coated
particles at pH 4.8 (FF 11-12).
We agree with the Examiner that Seng “provides reason to believe
that the conditions of time, pH, temperature and caprylate ion concentrations
present in Steinbuch were inherently sufficient to inactivate substantially all
enveloped viruses in the supernatant solution” (Ans. 4).

5 Citation is to Alred et al., US 6,955,917 B2, issued Oct. 18, 2005.
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Application 11/873,878

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Appellants contend that “Steinbuch teaches addition of caprylic acid.
. . . [U]se of caprylic acid, and particularly use at high levels as disclosed in
Steinbuch, is not the same as ‘adding a source of caprylate ions’ as recited in
step (a) of claim 8” (App. Br. 11).
We are not persuaded. Appellants’ own Specification teaches
addition of caprylic acid as a source of caprylate (FF 13). Seng teaches the
Henderson-Hasselbalch equation, which shows the equilibrium equation for
a compound in acid and ionized forms (FF 9). Seng teaches this equilibrium
for caprylic acid and its ionized form (FF 10). Seng teaches that at pH 4.9
the solution comprises 0.0035 M caprylic acid, where 0.06% is in the
ionized form (FF 10). Thus, there can be no reasonable dispute that at pH
4.8 as taught in Steinbuch, the caprylic acid will be found in both caprylic
acid and ionized forms, as required by the Henderson-Hasselbalch equation
(FF 9-11).
Appellants contend that “the suspensions involved in Steinbuch et al.
are not ideal solutions . . . Thus the arguments based on pK in an ideal
aqueous solution do not apply, because the mixture in Steinbuch et al. is far
from an idealized aqueous solution” (Reply Br. 3).
We are not persuaded. Seng clearly relies upon the Henderson-
Hasselbalch equation as representative of the ionization of caprylic acid in
solution (FF 9-11). The Examiner reasonably relies upon this evidence to
demonstrate inherency in the absence of any rebuttal evidence.
Appellants contend that the “anticipation rejection of claim 8 also fails
because the inherency of viral inactivation has not been established” (App.
Br. 12). Appellants quote Seng’s teaching that “[s]urprisingly, at lower pHs
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Application 11/873,878

9
(6.5 or less) if caprylic acid is present at 0.07 to 0.001%, virus inactivation
is achieved almost instantaneously” (id., citing Seng 3). Appellants
calculate that Steinbuch’s “Figure 2 discloses using 6.8 g caprylic acid in
100 ml of 5% human plasma and 200 ml acetate buffer. Assuming the
solution has a density of 1 mg/ml, caprylic acid is present at 2.267 % by
weight, which is far above where Seng teaches instantaneous viral
inactivation occurs” (id. at 12).
Steinbuch teaches the dropwise addition of caprylic acid to the
antibody solution which will inherently and necessarily result in increasing
concentrations of both caprylic acid and the ionized form as more drops are
added, until the final concentration is reached (FF 6-7). As these
concentrations increase from zero to Appellants’ calculated 2.267% (App.
Br. 12), during Steinbuch’s process, the concentrations will necessarily fall
within Seng’s instantaneous inactivation range of 0.07 to 0.001%.
Further, Seng does not teach that higher concentrations of caprylic
acid and caprylate ions do not inactivate virus, but rather that the lower
concentration range of 0.07 to 0.001% is preferred (see Seng, col. 3, ll. 24-
26). In fact, Seng teaches that “caprylate can be kept at 2% between pH 6.5
and 9.5 for a longer period of time (e.g., 2 to 4 hours) to give an appropriate
caprylic acid concentration for virus inactivation” (Seng, col. 4, ll. 27-30; FF
12). This 2% range is close to the 2.267% value calculated for Steinbuch by
Appellants (see App. Br. 12).
Appellants have provided no direct evidence clearly showing that the
amount of caprylic acid added by Steinbuch does not inherently comprise
caprylate ions or that the amount, time, pH value and temperature used by
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Application 11/873,878

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Steinbuch would not inherently result in inactivating the virus as required by
claims 8 and 11. “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 [A]pplicant to
prove that the prior art products do not necessarily or inherently possess the
characteristics of his claimed product.” In re Best, 562 F.2d 1252, 1255
(CCPA 1977).
Conclusions of Law
(i) The evidence of record supports the Examiner’s conclusion that
the IgG isolation method of Steinbuch inherently adds caprylate ions.
(ii) The evidence of record supports the Examiner’s conclusion that
the IgG isolation method of Steinbuch inherently functions to “inactivate
substantially all enveloped viruses.”
SUMMARY
In summary, we affirm the rejection of claims 8 and 11 under 35
U.S.C. § 102(b) as anticipated by Steinbuch as evidenced by Seng.
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)(2006).

AFFIRMED

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CONNOLLY BOVE LODGE & HUTZ, LLP
P O BOX 2207
WILMINGTON, DE 19899