Ex Parte Hunt

Board of Patent Appeals and Interferences

Jun 22, 2009

10288738 (B.P.A.I. Jun. 22, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte TERRENCE J. HUNT
__________

Appeal 2009-001360
Application 10/288,738
Technology Center 1600
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Decided:1 June 22, 2009
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Before DEMETRA J. MILLS, ERIC GRIMES, and RICHARD M.
LEBOVITZ, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
BOTOX® composition containing recombinant human serum albumin.

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).
Appeal 2009-001360
Application 10/288,738

The Examiner has rejected the claims as obvious in view of the prior art.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
“BOTOX® consists of a purified botulinum toxin type A complex,
human serum albumin, and sodium chloride packaged in sterile, vacuum-
dried form” (Spec. 12: 15-16). Appellant discloses that he has
“surprising[ly] found that a botulinum toxin pharmaceutical composition
comprising a recombinant albumin has a greater potency than does a
botulinum toxin pharmaceutical composition comprising the same amount
(on a weight for weight basis) of a human serum albumin” (id. at 40: 6-10).
Claims 18 and 24-27 are pending and on appeal. The claims have not
been argued separately and therefore stand or fall together. 37 C.F.R.
§ 41.37(c)(1)(vii). Claim 18 is representative and reads as follows:
18. A pharmaceutical composition, comprising:
(a) a botulinum toxin, and;
(b) a recombinant human serum albumin.
OBVIOUSNESS
Issue
The Examiner has rejected claims 18 and 24-27 under 35 U.S.C.
§ 103(a) as obvious in view of either Goodnough2 and Fleer3 or Johnson4

2 Goodnough et al., Stabilization of Botulinum Toxin Type A during
Lyophilization, 58 APPLIED AND ENVT’L MICROBIOLOGY 3426-3428 (1992).
3 Fleer et al., EP 0 361 991 B1, issued December 15, 1999.
4 Johnson et al., US 5,756,468, issued May 26, 1998.
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and Fleer (Answer 3, 4).5 The Examiner finds that Goodnough and Johnson
disclose compositions comprising botulinum toxin and non-recombinant
human serum albumin (HSA) and Fleer discloses recombinant HSA
(Answer 3, 4-5). The Examiner concludes that it would have been obvious
to substitute Fleer’s recombinant HSA for the non-recombinant HSA in
Goodnough’s or Johnson’s composition because Fleer teaches that the
recombinant product provides improved purity without the possibility of
viral contamination (id. at 4, 5).
Appellant contends that the Examiner has not shown prima facie
obviousness (Appeal Br. 7-8) and that, even if prima facie obviousness were
shown, he has provided evidence of unexpected results that rebut a
conclusion of obviousness vel non (id. at 9-11).
The issues presented in this appeal are:
(1) Does the evidence of record support the Examiner’s conclusion
that the claimed composition would have been prima facie obvious? and,
(2) Has Appellant provided evidence of nonobviousness (unexpected
results) that outweigh the evidence of obviousness?
Findings of Fact
1. Goodnough discloses that commercial preparations of crystalline
type A botulinum toxin contain the toxin, sodium chloride, and HSA
(Goodnough 3426, left col.).

5 Although the rejections are set out separately, the Examiner relies on
Goodnough and Johnson for the same disclosure and provides the same
rationale for combining the references. Appellant relies on the same
argument for both rejections. We will consider the rejections together.
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2. Johnson teaches that the “commercial type A botulinal toxin
product is made by combining up to 500 ng/ml of type A toxin complex in
5.0 mg/ml human serum albumin (HSA) with 9.0 mg/ml sodium chloride at
a pH of 7.3” (Johnson, col. 1, ll. 62-66).
3. Fleer discloses “a microbiological method for the preparation of
human serum albumin (HSA) by culturing a yeast, especially of the genus
Kluyveromyces, modified by the use of recombinant DNA techniques”
(Fleer 2: 3-4).
4. Fleer discloses that “[u]p to now, HSA is generally produced by
conventional techniques of fractionation of plasma” (id. at 2: 54).
5. Fleer discloses that the “development of genetic engineering and of
new extraction and purification techniques has opened up the possibility of
obtaining improved products of higher purity and better stability without
viral contamination (e.g., hepatitis B and AIDS) and at lower cost” (id. at 3:
1-3).
6. Fleer discloses that recombinant HSA “is secreted by K. lactis in a
mature form and in its native configuration; it is not distinguishable from
human serum albumin extracted from plasma with respect to any of the
criteria applied” (id. at 21: 34-35).
7. The Specification discloses that a “commercially available
botulinum toxin containing pharmaceutical composition is sold under the
trademark BOTOX® (available from Allergan, Inc., of Irvine, California).
BOTOX® consists of a purified botulinum toxin type A complex, human
serum albumin, and sodium chloride.” (Spec. 12: 13-16.)
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8. The Specification discloses a “botulinum toxin pharmaceutical
composition wherein the primary stabilizer present in the formulation is a
recombinantly made albumin” (id. at 25: 28-29).
9. The Specification states that “[s]tabilizing’, ‘stabilizes’, or
‘stabilization’ mean that a pharmaceutical active ingredient (‘PAI’) retains at
least 20% and up to 100% of its biological activity . . . in the presence of a
compound which is stabilizing, stabilizes or which provides stabilization to
the PAI” (id. at 31: 5-9).
10. The Specification discloses a preferred embodiment containing a
botulinum toxin, a primary stabilizer such as recombinant HSA (r-HSA),
and a secondary stabilizer (id. at 33: 9-13). “[S]uitable secondary stabilizers
can include caprylate (octanoate) and NAT” (id. at 33: 13-14).
11. The Specification discloses that “sodium caprylate, Zinc and P80,
can also be present as further stabilizers of the botulinum toxin active
ingredient” (id. at 45: 7-8).
12. The Specification states that Appellant
unexpectedly . . . discovered that a pharmaceutical composition
comprising a botulinum toxin (as the active ingredient) and a
recombinant albumin (as the primary protein stabilizer) has a
greater potency than does a pharmaceutical composition
comprising a botulinum toxin (as the active ingredient) and a
human serum albumin (as the primary protein stabilizer).
(Id. at 41: 13-17.)
13. The Specification presents data comparing the potency of several
compositions containing botulinum toxin, along with either recombinant or
non-recombinant HSA and other ingredients, as shown in Table 1
(reproduced below):
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Table 1 shows the ingredients in Formulations A through F.
14. The Specification’s Figure 3 is reproduced below:

Figure 3 shows the potency of Formulations A through F, measured at
times T0 (reconstituted after less than one week of storage; Spec. 61: 6-7)
and time T6 (reconstituted after storage for six months, id. at 61: 11-14).
15. Appellant submitted a declaration under 37 C.F.R. § 1.132
presenting a comparison of the potency of two other formulations of
botulinum toxin (Hunt Declaration, executed May 15, 2006). The table from
Appellant’s declaration is reproduced below:
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The table shows the potency of Formulations H and I; the declaration
does not state that the toxin was stored for any length of time before being
reconstituted.
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “[W]hen the
question is whether a patent claiming the combination of elements of prior
art is obvious,” the answer depends on “whether the improvement is more
than the predictable use of prior art elements according to their established
functions.” Id. at 417.
“[A]ny need or problem known in the field of endeavor at the time of
invention and addressed by the patent can provide a reason for combining
the elements in the manner claimed.” Id. at 420.
“It is well settled that unexpected results must be established by
factual evidence. Mere argument or conclusory statements in the
specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed.
Cir. 1984).
“Mere improvement in properties does not always suffice to show
unexpected results. . . . [H]owever, when an applicant demonstrates
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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.” In re Soni, 54 F.3d 746, 751 (Fed. Cir. 1995)
(emphasis in original).
Analysis
Johnson and Goodnough both disclose compositions comprising
botulinum toxin and HSA. Fleer discloses recombinant HSA and states that
recombinant products are an improvement over non-recombinant products
because, among other things, they avoid the possibility of viral
contamination. We agree with the Examiner that these teachings would
have made it obvious, to a person of ordinary skill in the art, to substitute the
recombinant HSA taught by Fleer for the non-recombinant HSA used by
Goodnough and Johnson.
Appellant argues that the statement in Fleer that the Examiner relies
on “is nothing more than a generalized statement about the broad field of
genetic engineering. Neither that statement, nor any other statements, by
Fleer et al. actually compare characteristics of recombinant product with
non-recombinant product.” (Appeal Br. 8.)
This argument is not persuasive. Those skilled in the art would
recognize that Fleer’s statement – that recombinant products are better
because they eliminate the possibility of viral contamination – would apply
to any recombinant product, and provide a motivation to replace any non-
recombinant, blood-derived protein with the equivalent recombinant protein.
Fleer expressly discloses recombinant HSA, so those skilled in the art would
recognize that Fleer’s statement applies especially to HSA.
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Appellant also argues that the Specification and the Hunt Declaration
provide evidence that compositions containing recombinant HSA have
superior potency compared to compositions comprising non-recombinant
HSA (Appeal Br. 9, 10-11). Appellant argues that those of skill in the art
would have expected the two types of HSA to have the same properties and
that the superior potency of the recombinant HSA-containing compositions
was unexpected, thus rebutting any prima facie conclusion of obviousness
(id.).
We agree with Appellant that Fleer would have led a skilled worker to
expect that recombinant HSA would have the same properties as non-
recombinant HSA, since Fleer found that the two were indistinguishable on
the basis of several assays. However, we do not agree with Appellant that
the evidence of record shows that a composition containing recombinant
HSA has unexpectedly superior potency compared to an otherwise identical
composition containing non-recombinant HSA.
The Specification’s Figure 3 shows that certain compositions
containing recombinant HSA have higher potency than certain compositions
containing non-recombinant HSA. However, the Specification’s Table 1
shows that the compositions differ in more than simply a substitution of
recombinant HSA for non-recombinant HSA. All of the compositions
containing recombinant HSA (“r-HSA”) also contain 13 µg of octanoate and
0.04 µg of P80, while the compositions containing non-recombinant HSA
contain only 7 µg of octanoate and no P80.
The Specification discloses that both octanoate and P80 are
stabilizers. Thus, the Specification’s data provide no basis for distinguishing
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which part of the difference in potencies shown in Figure 3 is due to
recombinant HSA and which part is due to the increased amounts of
octanoate and P80 in the recombinant HSA-containing compositions.
The Hunt Declaration includes data on a composition containing non-
recombinant HSA, octanoate, and P80 (Formulation H). Formulation H,
therefore, is identical to Formulation C shown in Table 1 except for the
inclusion of non-recombinant HSA in Formulation H and recombinant HSA
in Formulation C. Formulation C has a potency of 100 at time T0 (see
Figure 3). Formulation H has a potency of 97. (The Hunt Declaration does
not state that Formulation H was stored for any length of time before
reconstitution, so the disclosed potency apparently also corresponds to time
T0.) Thus, when the data of the Hunt Declaration and of the Specification
are considered together, they show that recombinant HSA appears to cause
only a 3% increase in potency, all other things being the same.
Appellant has not provided evidence to show that a 3% increase in
potency in the assay used is an unexpectedly superior result. In fact, the
evidence tends to show the opposite. The Hunt Declaration includes data for
Composition I, which is identical to Composition C. Composition C has a
potency of 100; Composition I has a potency of 122. Neither the
Specification nor the Hunt Declaration state that the results shown represent
the average of repeated experiments, so apparently each composition was
tested only once. Compositions C and I show that the assay used in the
Specification and in the Hunt Declaration provides results that can vary by at
least 22% for the same composition.
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Because the evidence shows that the results of the assay used in the
Specification and in the Hunt Declaration can vary by 22% for an identical
composition when tested more than once, we find that the 3% difference
attributable to substituting recombinant HSA for non-recombinant HSA does
not represent a showing of unexpectedly superior results for the claimed
composition when compared to the closest prior art.
CONCLUSIONS OF LAW
The evidence of record supports the Examiner’s conclusion that the
claimed composition would have been prima facie obvious, and Appellant
has not provided evidence of nonobviousness (unexpected results) that
outweighs the evidence of obviousness.
SUMMARY
We affirm the rejection of claims 18 and 24-27 under 35 U.S.C.
§ 103(a) as obvious in view of either Goodnough or Johnson, combined with
Fleer.
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).

AFFIRMED

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cdc
STEPHEN DONOVAN
ALLERGAN, INC.
2525 Dupont Drive, T2-7H
Irvine CA 92612

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