Ex Parte Selden et al

Board of Patent Appeals and Interferences

Sep 20, 2010

10165060 (B.P.A.I. Sep. 20, 2010)

1

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte RICHARD F. SELDEN, MARIANNE BOROWSKI,
CAROL M. KINOSHITA, DOUGLAS A. TRECO,
MELANIE D. WILLIAMS, THOMAS J. SCHUETZ,
and PETER F. DANIEL
__________

Appeal 2010-000532
Application 10/165,060
Technology Center 1600
__________

Before DONALD E. ADAMS, DEMETRA J. MILLS, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL1

This is an appeal under 35 U.S.C. § 134. The Examiner has rejected
the claims for obviousness. We have jurisdiction under 35 U.S.C. § 6(b).

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.

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STATEMENT OF THE CASE
The following claim is representative and read as follows:
46. A method of treating a subject, comprising administering to a subject in
need thereof a human α-galactosidase A (α-Gal A) glycoprotein preparation,
wherein greater than 50% of the total glycans of the preparation are
complex-type glycans, the preparation has a specific activity of at least 2.0 x
106 units/mg protein, wherein protein concentration of the preparation is
measured by ultraviolet absorbance at 280 nm.

Cited References
The Examiner relies on the following prior art references:
Bergh et al. US 5,272,066 Dec. 21, 1993
Maras et al. US 5,834,251 Nov. 10, 1998

Desnick et al., Enzyme Therapy XVII: Metabolic and Immunologic
Evaluation of α- Galactosidase A Replacement in Fabry Disease, Birth
Defects: Original Article Series, 16 (1) pp. 393-413 (1980).

Bishop et al., Affinity Purification of α-Galactosidase A from Human Spleen,
Placenta, and Plasma with Elimination of Pyrogen Contamination, Journal
of Biological Chemistry, 256 (3) pp. 1307-1316 (1981).

Pierce, Extinction Coefficients, Tech Tip #6 pp. 1-3 (2006).

UniProtKB/Swiss-Prot-entry P00924 (1986).

Biochrom, Declaration of Conformity (2001).

Grounds of Rejection
1. Claims 46-50, 53-55, 57-65, and 76-88 are rejected under 35
U.S.C. §103(a) as being unpatentable over Desnick in view of Bishop.

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2. Claims 46-50, 53-55, 57-65, and 76-88 are rejected under 35
U.S.C. §103(a) as being unpatentable over Desnick in view of Bishop, Bergh
and Maras.
Discussion of Rejections 1 and 2
ISSUE
The Examiner concludes that “[a]s the use of highly purified enzymes
for the treatment of humans is well known in the art to be preferable, it
would have been obvious to one of skill in the art to use[ ] the purified
preparations of Bishop et al. in the treatments of Desnick et al.” (Ans. 9.)
The Examiner further concludes that using the data from Bishop Figure 4 to
calculate protein concentration using Pierce Tech Tip #6, one of ordinary
skill in the art would obtain a specific activity of 2.0 X 10 6 units for splenic
α-gal A. (Ans. 7-8.)
Appellants contend that “[n]either Bishop nor Desnick, alone or in
combination, teach or suggest an α-gal A preparation with these properties,
or the use of such a preparation in a method of treating a subject, and the
Office has failed to provide rational reasoning to show otherwise.” (App. Br.
3.) “Desnick does not disclose an α-gal A preparation having the requisite
level of specific activity.” (App. Br. 5 (underline font omitted).) “Desnick
describes a preparation of human α-gal A isolated from spleen having a
specific activity of 2.05 x 104 units/mg, and a preparation of α-gal A isolated
from human plasma having a specific activity of 1.45 x 103 units/mg (see
Table 1 at page 398). It does not describe a human α-gal A preparation
having a specific activity of at least 2.0 x 106 units/mg, with protein
concentration being measured by any particular assay, not to mention by
ultraviolet (UV) absorbance at 280 nm.” (App. Br. 5.) “Bishop does not
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calculate specific activity using a protein concentration measured by UV
absorbance at 280 nm.” (App. Br. 5 (underline font omitted).)
The issue is: Does the evidence support the Examiner’s conclusion
that the cited references teach or suggest a preparation having a specific
activity of at least 2.0 x 106 units/mg protein, wherein protein concentration
of the preparation is measured by ultraviolet absorbance at 280 nm?

PRINCIPLES OF LAW
An invention “composed of several elements is not proved obvious
merely by demonstrating that each of its elements was, independently,
known in the prior art.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418
(2007). “Often, it will be necessary . . . to look to interrelated teachings of
multiple [references] . . . and the background knowledge possessed by a
person having ordinary skill in the art, all in order to determine whether
there was an apparent reason to combine the known elements in the fashion
claimed[.]” Id. at 418. “[T]his analysis should be made explicit” (id. at 418),
and it “can be important to identify a reason that would have prompted a
person of ordinary skill in the relevant field to combine the elements in the
way the claimed new invention does” (id.). “[T]here must be some
articulated reasoning with some rational underpinning to support the legal
conclusion of obviousness.” In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006).
Moreover, “obviousness requires a suggestion of all limitations in a
claim.” CFMT, Inc. v. Yieldup Int’l. Corp., 349 F.3d 1333, 1342 (Fed. Cir.
2003) (citing In re Royka, 490 F.2d 981, 985 (CCPA 1974)).
When evaluating claims for obviousness, “the prior art as a whole
must be considered. The teachings are to be viewed as they would have
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been viewed by one of ordinary skill.” In re Hedges, 783 F.2d 1038, 1041
(Fed. Cir. 1986).

FINDINGS OF FACT
1. “Desnick et al. teach the treatment of two Fabry's disease
patients with two preparations of human alpha-galactosidase A
isolated from human plasma and human spleen tissue.” (Ans. 5.)
2. “Desnick et al. teach that the two preparations differ in purity and in the
extent of sialylation with the spleen tissue preparation being
substantially purer and the plasma preparation having a higher
degree of sialylation.” (Id.)
3. The Examiner finds that the methods of the claims “differ from the
methods of Desnick et al. only in the level of purity of the human spleen
derived alpha-galactosidase A protein preparations used.” (Ans. 6.)
4. “Bishop et al. teach the purification of human plasma and spleen derived
alpha-galactosidase A to very high levels of purity (i.e., apparent
homogeneity and a specific activity of between 1.9 x 106 units/mg protein
and 4.1 x 106 units/mg protein depending on the method of determining total
protein which was used for the spleen enzyme and to a specific activity of
2.3 x 105 units/mg protein for the plasma enzyme. . .. The values of 1.9 x 106
units/mg protein and 4.1 x 106 units/mg protein cited by Bishop et al. for the
specific activity of the spleen-derived preparation were calculated based on
determination of total protein by Lowry assay and fluorescamine assay
respectively, while the instant claims recite that the preparation should have
a specific activity of at least 2 x 106 units/mg protein when total protein is
measured by UV absorbance at 280 nm. (A280).” (Ans. 6-7.)
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5. “Bishop et al. report a total protein concentration of the spleen-derived
preparation as measured by A280 of 1.2 mg/ml. Bishop et al. also disclose
the UV spectra of the spleen-derived preparation in Figure 4 which shows
that the A280 of this preparation is 1.0 and teach that the extinction
coefficient of a 1% solution (E1%) is 18.” (Ans. 7.)
6. The Examiner finds that “[u]sing standard methods in the art for
calculating protein concentration from an A280 (see for example Pierce Tech
Tip #6 which shows that the concentration in mg/ml = (A280/El%)10) gives a
protein concentration of 0.55 mg/ml for the splenic α-gal preparation using
the A280 shown in Figure 4 and the extinction coefficient disclosed by
Bishop et al. Using the protein concentration of 0.55 mg/ml (calculated from
the A280 shown in Figure 4 and extinction coefficient of 18 reported by
Bishop et al.) for the splenic α-gal preparation yields a specific activity for
this preparation of 2.0 X 106 units/mg [503,000 unit/0.253 mg protein,
0.55mg/ml x 0.46 ml = .253 mg protein].” (Ans. 7-8.)
7. The Examiner finds that “The discrepancy appears to have been the
result of the fact that Bishop et al. did not directly calculate the
concentration from the raw A280 data and the extinction coefficient but
instead Bishop et al. state that the value of 1.2 mg/ml was obtained by the
method of Warburg and Christian. This appears to be the use of the equation
protein concentration in mg/ml = 1.55 (A280) - 0.76 (A260) (See pages 12-13
of the Biochrom Declaration of Conformity). However it is noted that this
equation was derived from the protein yeast enolase (see page 12 of the
Biochrom Declaration of Conformity) and the value preceding the A280 is
dependent on the extinction coefficient of the protein (see page 13 of the
Biochrom Declaration of Conformity). As shown in Pierce Tech Tip #6 a
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theoretical value for the molar extinction coefficient (Emolar) can be
calculated from the amino acid sequence of any protein using the equation
Emolar = (the number of tryptophan residues X 5500) + (the number of
tyrosine residues X 1490) + (the number of cysteine residues X 125) and the
molar extinction coefficient can be converted to El% using the equation
(Emolar) 10 = (El%) X the molecular weight of the protein. Using the amino
acid sequence of yeast enolase (UniProt Accession No. P00924) the El% of
yeast enolase is 8.8 and using the known amino acid sequence of human α-
Gal (SEQ ID NO:4) the El% of human α-Gal is 22.4. Thus the extinction
coefficient of yeast enolase is less than half than that of human α-gal and the
method of Warburg and Christian clearly provides a poor means of
estimating protein concentration of human α-gal and the calculated value of
1.2 mg/ml reported by Bishop et al. is likely the value that is incorrect.”
(Ans. 8-9.)
8. The Examiner finds that “the value calculated using the raw data of
Figure 4 and the extinction coefficient reported by Bishop et al. is believed
more reliable and thus the spleen derived preparation meets the limitation of
having a specific activity of at least 2 x 106 units/mg protein when total
protein is measured by UV absorbance at 280 nm.” (Ans. 9.)
ANALYSIS
Appellants contend that neither Bishop nor Desnick, alone or in
combination, teach or suggest an α-gal A preparation with the claimed
properties, or the use of such a preparation in a method of treating a subject,
and the Office has failed to provide rational reasoning to show otherwise.
(App. Br. 3.) Appellants further argue that “Desnick describes a preparation
of human α-gal A isolated from spleen having a specific activity of 2.05 x
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104 units/mg, and a preparation of α-gal A isolated from human plasma
having a specific activity of 1.45 x 103 units/mg (see Table 1 at page 398).
It does not describe a human α-gal A preparation having a specific activity
of at least 2.0 x 106 units/mg, with protein concentration being measured by
any particular assay, not to mention by ultraviolet (UV) absorbance at 280
nm.” (Id. at 5.) “Bishop does not calculate specific activity using a protein
concentration measured by UV absorbance at 280 nm.” (App. Br. 5
(emphasis omitted).)
Appellants argue that protein purification is unpredictable for α-gal A
(Br. 9-10), referencing the Declaration of Carol Kinoshita primarily
discussing purification issues associated with purification of plasma α-gal A.
Appellants argue that the specific activity for splenic α-gal A is 9.11x105 not
2.0x106 (Br. 4, 6.), using the Bishop protein concentration of 1.2 and the UV
absorbance at 280 nm.
We are not persuaded by Appellants’ arguments. The Examiner
concludes that there is enough raw data in Bishop to calculate protein
concentration by UV absorbance and a specific activity for splenic α-gal A
of 2.0 x 106 and the Examiner provides an evidentiary basis for this
calculation. (Ans. 7-8.) The Examiner does not ignore the fact that Bishop
report protein concentration values of 1.2 mg/ml for splenic α-Gal A but
instead uses the Fig. 4 UV absorbance value disclosed in Bishop. (Ans. 17.)
In sum, the Examiner has provided articulate reasoning and a very
thorough evidentiary basis for her specific activity calculations for splenic α-
gal A based on the disclosure of Bishop which have not been sufficiently
rebutted by Appellants. With regard to the Kinoshita Declaration, it does
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not address the Examiner’s position that Bishop’s splenic α-gal A has the
claimed specific activity.
We find no error in the Examiner’s calculations of specific activity for
splenic α-gal A of 2.0 x 106. We do not find that Appellants’ have provided
persuasive evidence or argument that rebuts the Examiner’s prima facie
case. Appellants argue the rejection over Desnick in view of Bishop, Bergh
and Maras in the same manner as the rejection of Desnick in view of Bishop.
Thus we adopt the Examiner’s fact finding, statement of the rejection and
responses the Appellants’ arguments as our own.
CONCLUSION OF LAW
The cited references support the Examiner’s obviousness rejection.

AFFIRMED

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