Ex Parte Kaisheva et al

Board of Patent Appeals and Interferences

Sep 27, 2010

10291528 (B.P.A.I. Sep. 27, 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.
10/291,528 11/08/2002 Elizabet A. Kaisheva 027782-012310US 3639
45308 7590 09/28/2010
TOWNSEND AND TOWNSEND AND CREW LLP
TWO EMBARCADERO CENTER, EIGHTH FLOOR
SAN FRANCISCO, CA 94111-3834
EXAMINER
KIM, YUNSOO
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
09/28/2010 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 STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte ELIZABET A. KAISHEVA, SUPRIYA GUPTA, SHANTI G.
DUVUR, AND MALATHY SUBRAMANIAN
____________________

Appeal 2009-003947
Application 10/291,528
Technology Center 1600
________________

Before JAMES T. MOORE, Vice Chief Administrative Patent Judge,
SALLY GARDNER LANE and MICHAEL P. TIERNEY, Administrative
Patent Judges.

MOORE, Vice Chief Administrative Patent Judge.

DECISION ON APPEAL1

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 2009-003947
Application 10/291,528

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This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 12, 15-16, 18-20. We have jurisdiction under 35 U.S.C. § 6(b)
(2006).
STATEMENT OF THE CASE
This appeal concerns a stable, liquid, high concentration antibody
formation. The invention is said to provide a high concentration of
Daclizumab, an anti-IL2 receptor antibody, suitable for parenteral
administration and stable for storage purposes. (Spec. at 3). Claim 12 is the
only independent claim in question and stands rejected under 35 U.S.C.
§ 103(a).
EVIDENCE
Salfeld 6,941,128 Jul. 5, 2005
ZENAPAX (Daclizumab) Product Information Sheet Dec. 1997
bioWORLD.com Biological Buffer List Oct. 10, 2006

Daugherty, Ann L. and Mrsny, Randall J, Formulation and Delivery Issues for
Monoclonal Antibody Therapeutics, Advanced Drug and Delivery News, (2006).

ISSUE
Whether the subject matter of claim 12 would have been obvious to
one of ordinary skill in the art at the time the invention was made in light of
Salfeld, the ZENAPAX product information sheet, and the bioWORLD.com
buffer list?
ANALYSIS
I. Findings of Fact
FF-01. Claim 12 reads as follows:
12. A stable liquid pharmaceutical formulation comprising:
20-60 mM succinate buffer, having pH of pH 5.5 to pH 6.5,
0.02% - 0.04% polysorbate,
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75-150 mM sodium chloride, and
a Daclizumab antibody, wherein said antibody has a
concentration of 50 mg/ml or more.
FF-02. Salfeld describes an injectible liquid or lyophilized
pharmaceutical composition of the IL-12 antibody, including:
- .01-250 mg/ml antibody;
- L-histidine as a buffer (1-50 mM, optimally 5-10 mM), at pH
5.0 – 7.0 (optimally pH 6.0);
- sodium chloride to modify toxicity (0-300 mM, optimally 150
mM for liquid form); and
- surfactants, namely polysorbate 80 (0 – 0.05%, optimally
0005 – 0.01%). (Final Rejection, 2; Salfeld 72:14-58).
FF-03. Salfeld additionally describes the usefulness of additives such
as stabilizers, bulking agents, preservatives, and cryoprotectants, which
enhance the shelf life or effectiveness of the antibody. (Salfeld 72:14-58)
FF-04 . Salfeld specifically describes sodium succinate in a list of
four additional buffers that are acceptable for the pharmaceutical
composition. (Final Rejection, 2; Salfeld 72:42-44).
FF-05. Salfeld describes that additional agents be combined with the
claimed antibodies, for therapeutic purposes or otherwise, including
antibodies to cell surface receptor CD25. (Final Rejection, 3;
Salfeld 75:49-65, 76:24-27).
FF-06. The ZENAPAX (Daclizumab) product information sheet
describes that Daclizumab is a monoclonal antibody that binds
specifically to the alpha subunit of CD25, human interleukin-2 receptor
at 5 mg/ml concentration with some restricted storage conditions and
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limits on the timeframe within which the prepared drug must be used.
(Final Rejection, 3; ZENAPAX product information sheet, p. 1).
FF-07. The ZENAPAX product information sheet describes that, in
addition to 5mg of Daclizumab, each milliliter contains 3.6 mg sodium
phosphate monobasic monohydrate (buffer), 11 mg sodium phosphate
dibasic heptahydrate (buffer), 4.6 mg sodium chloride, 0.2 mg
polysorbate 80, and may contain hydrochloric acid or sodium hydroxide
to adjust the pH to 6.9. (ZENAPAX product information sheet, p. 2).
FF-08. The bioWORLD.com biological buffer list lists the pKa value
and buffer range of important biological buffers. The list provides two
succinate buffers, one (pK1) with a range of 3.2-5.2, the other (pK2) with
a range of 5.5-6.5. (bioWORLD.com Buffer List, p.2).
FF-09. The Examiner found that a person of ordinary skill in the art
would know to select the pK2 succinate buffer because it is most
effective in the pH range of 5.5-6.5. (Final Rejection, 3).
FF-10. The Examiner found that it would be a matter of optimization
of the pH of interest to use pK2 succinate buffer because succinate is
most effective in the pH range of 5.5-6.5 (Final Rejection, 3.)
FF-11. The Examiner found that one of ordinary skill in the art would
have been motivated to combine the pharmaceutical composition taught
in Salfeld with the Daclizumab antibody to stabilize the antibody
formula. (Final Rejection, 4).
FF-12. The Examiner has concluded that it would have been obvious
to one of ordinary skill in the art at the time of invention to use the
teachings of Salfeld to formulate a stable pharmaceutical composition for
high concentrations of Daclizumab and that they would have been
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motivated to do so to increase shelf life and efficacy, as stated in Salfeld.
(Final Rejection, 4).
II. The Arguments on Appeal
The Appellants raise several arguments on appeal, asserting that: the
references cited by the Examiner do not disclose every element of the claims
(Br. 11); the Examiner has presented no reason to combine the references
(Br. 14); there is no reasonable expectation of success in combining the
references (Br. 18); and the Examiner used impermissible hindsight in
selecting references (Br. 22).
We find the presented arguments unpersuasive for the reasons set
forth in the Examiner’s Answer at pages 5-8, which we adopt as our own,
with the exception of the discussion of physiological pH discussed infra.
We add the following only for emphasis and to correct one harmless error of
the Examiner.
A. The Claimed Subject Matter Combines Known Elements
Performing Their Known Functions

Salfeld provides the general teaching that certain conditions are
necessary for a pharmaceutical composition of an antibody that is suitable
for patient administration. (Salfeld 72:14-33). These include buffers (at an
optimal pH) tonicity modifiers, and other additives, such as surfactants and
preservatives, to enhance the stability, shelf life, or effectiveness of the
antibody. (Id.) Salfeld also teaches specific parameters for a pharmaceutical
composition suitable for the IL-12 antibody. (See Salfeld 72:34-58; FF-04).
Daugherty, cited as evidence of nonobviousness by the Appellants
(Br., Evidence Appx.), teaches that formulating a stable and effective
pharmaceutical composition is difficult in the antibody art, especially with a
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high antibody concentration. (Daugherty 3). Daugherty specifically
mentions that different antibodies have different “personalities” and
therefore each antibody drug requires a specific formulation to maximize
stability and preserve efficacy. (Id. at 5). However, Daugherty, like Salfeld,
explains that every antibody formulation needs certain basic components and
that the challenge is determining the correct concentrations of the
components to maximize the stability and efficacy of a pharmaceutical
composition. (Id. at 8).
Salfeld teaches specific ranges and conditions for the IL-12 antibody
that may also be effective for other antibodies or therapeutic agents.
(Ans. 7-8). Daclizumab is a known antibody, which, in its pharmaceutical
formulation as ZENAPAX, has a very short shelf life after preparation and
has storage and handling restrictions due to its unstable nature. (ZENAPAX
product information sheet, p. 1). A person of ordinary skill in the art would
be motivated to combine these references to achieve a more stable and
effective pharmaceutical formulation for the Daclizumab antibody. (Final
Rejection, 4).
The Appellant has not provided persuasive evidence otherwise.
B. Optimization

“Discovery of an optimum value of a result effective variable in a
known process is ordinarily within the skill of the art.” In re Peterson, 315
F.3d 1325, 1330 (Fed. Cir. 2003) (quoting In re Boesch, 617 F.2d 272, 276
(CCPA 1980)). As such, a prior art reference that discloses a range
encompassing a narrower claimed range is sufficient to create a rebuttable
presumption of obviousness. The burden then shifts to the applicant to show
the invention is not obvious. (Id.). One way to demonstrate nonobviousness
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is to provide evidence of unexpected results. In re Soni, 54 F.3d 746, 750
(Fed. Cir. 1995). However, Appellants have provided no persuasive
evidence of unexpected results to support a finding of nonobviousness.
Appellants stress, and assert that Daugherty supports, the fact that it is
difficult to achieve stability and maintain effectiveness with higher
concentrations of antibody. (Br. 19-20). However, difficult does not
necessarily mean nonobvious. As the Examiner correctly notes, “it is not
inventive to discover the optimum . . . ranges by routine experimentation
where the general conditions of a claim are disclosed in the prior art.”
(Ans. 8).
The Appellants urge that there was no reasonable expectation of
success in combining the references. (Br. 18 et seq.). Within that argument,
the Appellants argue that the process included optimization of pH and
buffer. (Br. 20). Several formulations were made up which resulted in a
formula which counsel for appellant states was “remarkably” stable (Br. 21).
We have been unable to find the term “remarkably” or “unexpected”
within the specification, nor a sufficient evidentiary basis to support the
Appellants’ argument that one of ordinary skill in the art would doubt there
was a reasonable expectation of success in combining the references. The
Appellants were working with known compounds used for their known
purposes and effects. See, e.g., Estee Lauder Inc. v. L'Oreal, S.A., 129 F.3d
588, 595 (Fed. Cir. 1997)(Attorney argument can not take the place of
evidence in the record.).
C. Physiological pH
The Appellants are correct that physiological pH is in the range of
about 7.3 to 7.4, a fact of which we take official notice. However, that
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inaccuracy does not affect the outcome of the final conclusion of
obviousness. Succinate buffer is known to effectively work at a pH range of
5.5-6.5. (Final Rejection 3, Ans. 7).

CONCLUSION
The rejection of claims 12, 15-16, 18-20 under 35 U.S.C. § 103(a)
over the combination of Salfeld, the ZENAPAX product information sheet,
and the bioWORLD.com buffer list is AFFIRMED.
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)(2007).

AFFIRMED

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