Ex Parte Smith

Board of Patent Appeals and Interferences

Mar 11, 2004

08137168 (B.P.A.I. Mar. 11, 2004)

The opinion in support of the decision being entered today was not written
for publication and is not binding precedent of the Board.
Paper No. 55
UNITED STATES PATENT AND TRADEMARK OFFICE
__________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________
Ex parte DAMON C. SMITH
__________
Appeal No. 2002-2209
Application No. 08/137,168
__________
HEARD: January 22, 2004
__________
Before WINTERS, WILLIAM F. SMITH, and MILLS, Administrative Patent Judges.
WILLIAM F. SMITH, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of claims 23
through 38 and 42 through 44. Claims 39 through 41 are pending and are allowed.
Claim 37 is representative of the rejected claims and reads as follows:
37. An isolated snake antivenom comprising a mixture of at least two
monospecific IgG, F(ab0)2 fragment, or Fab fragment populations obtained from at least
two antisera, wherein each antiserum is separately raised to a venom from a different
species or subspecies of snake, produced by the process of:
(a) immunizing a host with venom from one species or subspecies of snake;
(b) immunizing a second host with venom from a different species or subspecies
of snake;
(c) separately collecting blood from each host;
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(d) pooling said blood from each host; and
(e) obtaining the IgG, F(ab0)2 fragment, or Fab fragment populations from said
pool of blood.
Claim 39 is representative of the allowed claims and reads as follows:
39. An isolated snake antivenom comprising a mixture of four different
monospecific IgG, F(ab0)2 fragment, or Fab fragment populations each of which is
obtained from different ovine antisera, wherein each of said antisera is separately raised
to a different snake venom, and wherein said snake venom is selected from a group
consisting of A. piscivorus, C. adamanteus, C. atrox, and C. scutulatus.
The references relied upon by the examiner are:
Carroll 5,196,193 Mar. 23, 1993
Russell et al. (Russell), “Preparation of a New Antivenin by Affinity Chromatography,”
American J. Trop. Med. Hyg., Vol. 34, No. 1, pp. 141-150 (1985)
Berkow et al. (Berkow), “Venomous Bites and Stings,” The Merck Manual, Ch. 290, pp.
2565-2571 (15th ed., Merck & Co., Inc., Rahway, NJ 1987)
Goding et al. (Goding), “Generation of Conventional Antibodies,” Monoclonal
Antibodies: Principles and Practice, Ch. 8, pp. 250-261 (Academic Press Inc., Orlando,
FL 1983)
Dos Santos et al. (Dos Santos), “Purification of F(ab0)2 Anti-Snake Venom by Caprylic
Acid: A Fast Method for Obtaining IgG Fragments With High Neutralization Activity,
Purity and Yield,” Toxicon, Vol. 27, No. 3, pp. 297-303 (1989)
References relied upon by appellant are:
Theakston et al. (Theakston), “Therapeutic Antibodies to Snake Venoms,” Therapeutic
Antibodies, Ch. 6, pp. 109-133 (Springer-Verlag London Limited 1995)
Christensen, “The Preparation and Purification of Antivenoms,” Mem. Inst. Butantan
Simp. Internc., Vol. 33, No. 2, 245-250 (1966)
Claims 23, 25 through 30, 32 through 38, and 42 through 44 stand rejected under
35 U.S.C. § 103(a). As evidence of obviousness, the examiner relies upon Carroll,
Russell, and Berkow. Claims 24 and 31 stand rejected under 35 U.S.C. § 103(a). As
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Application No. 08/137,168
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evidence of obviousness, the examiner relies upon Carroll, Russell, and Berkow and in
addition, Goding. The examiner also maintains two other rejections under 35 U.S.C. §
103(a) which parallel the two rejections set forth above but, in addition, rely upon Dos
Santos as additional evidence of obviousness. We affirm.
Background
The present invention relates to an isolated snake antivenom. As explained:
Snake venoms, produced primarily for the procurement of prey or in a
defensive role, are complex biological mixtures of upwards of 50
components. Death of prey from a snake bite is due to respiratory or
circulatory failure caused by various neurotoxins, cardiotoxins (also called
cytotoxins), coagulation factors, and other substances acting alone or
synergistically. Snake venoms also contain a number of enzymes which
when injected into the prey start tissue digestion. The venoms thus
contain substances designed to affect the vital processes such as nerve
and muscle function, the action of the heart, circulation of the blood and
the permeability of membranes. Most constituents of snake venoms are
proteins, but low molecular weight compounds such as peptides,
nucleotides and metal ions are also present.
Specification, page 1 (reference citation omitted). Historically, snake antivenoms have
been prepared by inoculating animals with sublethal doses of venom followed by
injections of increasing doses to levels above those which would, if injected initially,
cause death. Id., page 5, lines 11-34. Appellant provides further perspective on the
preparation of snake antivenom, stating:
Most known antivenoms are refined concentrates of equine serum
globulins prepared in a liquid or dried form. The antivenoms are obtained
from horses that have been immunised against a single venom, to
produce a monospecific antivenom, or a mixture of a number of venoms,
to produce a polyspecific antivenom. Antivenoms have been prepared for
the treatment of most types of snake venom poisoning. Methods of
production have changed little since the pioneering times of the last
century. Immune horse serum may undergo a crude purification step
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usually employing ammonium sulphate to precipitate the globulin fraction
and in some cases this is the form of the final product. Since antivenoms
in this form can give rise to severe serum reactions, it is known to employ
pepsin digestion to remove the Fc part of the immunoglobulin which is
primarily responsible for such immunogenic reactions.
Id., paragraph bridging pages 5 and 6.
In considering the issues raised in this appeal, it is important to distinguish
between monospecific antivenoms that are raised against single venoms and a
polyspecific antivenom which has been raised against the spectrum of different venoms.
As explained:
In general, the more specific an antivenom the greater the likelihood
that it will neutralise the challenging venom. Monospecific antivenom,
raised against single venoms, are therefore most effective against their
homologous venom. However, such antivenoms are only of use in the
treatment of a snake bite when the species or subspecies of the offending
snake has been identified. When the offending snake has not been
identified, as is usually the case in a “field” situation, a polyspecific
antivenom, raised against a spectrum of different venoms, is preferred in
order to improve the likelihood of the antivenom being effective against the
venom of the unidentified snake. Conventional polyspecific antivenoms,
however, lack the specificity of monospecific antivenoms and are,
therefore, less effective in neutralising the pharmacological activity of a
venom.
Id., page 6, last paragraph.
The nature of snake venom and snake antivenom is further explained as follows:
Snake venoms are complex multicomponent mixtures of protein,
nucleotides and metal ions. These components differ in molecular weight,
in their degree of antigenicity and in their concentration in the venom.
When venom is injected into an animal to raise an antiserum a number of
antibody populations may be produced. The concentration and affinities
of the antibodies raised will vary according to various criteria, for example,
the number of epitopes on the surface of a component, the immuno-
genicity of each epitope, the concentration of each component. The
lethal, neurotoxic components of venoms (including, for example,
rattlesnake venoms) often comprise low molecular weight, poorly
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immunogenic components present only in low concentrations. Such
components are unlikely to elicit high titre antibodies.
Id., page 7, last full paragraph.
The present invention involves appellant’s “unexpected and surprising discovery
that an antivenom (herein referred to as a ‘mixed monospecific antivenom’) comprising
a mixture of different antisera raised separately to different venoms is more effective in
neutralising the pharmacological activity of a venom than a conventional polyspecific
antivenom prepared by raising a single antiserum to a spectrum of venoms, but retains
the broad specificity of polyspecific antivenoms.” Id., page 7. Appellant postulates that
a mixture of different antisera raised separately to different venoms is more effective
than a polyspecific venom produced by use of an immunization mixture comprising a
mixture of venoms because “the low concentration, low molecular weight and poorly
immunogenic components are further diluted by highly immunogenic components.” Id.,
paragraph bridging pages 7 and 8. Appellant further postulates that “[p]roduction of a
polyspecific antivenom therefore results in an antivenom in which antibodies to some
components do not exist or are in such low concentration that their effectiveness is
negligible.” Id. Finally, appellant states:
In contrast, the mixed monospecific antivenom of the present invention
comprises a mixture of antisera raised to different venoms in separate
groups of animals. By raising the antisera separately, the number of
possible antibody populations that is available for each antiserum is the
same but the number of epitopes in the immunogen is significantly less.
Thus, it is postulated that the component antisera contain a higher
proportion of protective antibodies against low molecular weight, poorly
immunogenic components than polyspecific antivenoms. Combination of
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the monospecific antisera to produce a mixed monospecific antiserum results in
an antivenom which has all the populations of the monospecific serum, and
therefore conveys better protection, but also has the advantages of a polyspecific
antivenom in that the cross reactivity of the antivenom has been maximised.
Id., page 8, lines 10 through 25.
Discussion
1. Separate Argument of Claims.
Appellant states “[t]he claims of each group of claims under rejection stand or fall
together. Indeed, . . . all the appealed claims stand or fall together across all four issues
for appeal.” Appeal Brief, page 8, VII. Grouping of Claims. Thus, appellant not only
fails to argue any claim separately but also fails to argue any rejection separately.
Under these circumstances, we shall select claim 37 as representative of the claims
under rejection and shall decide all issues in this appeal on the basis of the patentability
of claim 37. 37 CFR § 1.192(c)(7).
2. Claim Construction.
Claim 37 is a product-by-process claim. The product set forth in this claim is an
isolated snake antivenom comprising a mixture of at least two monospecific IgG, F(ab0)2
fragment, or Fab fragment populations obtained from at least two antisera. Each
antiserum is separately raised to a venom from a different species of subspecies of
snake. Claim 37 then goes on to describe how the IgG, F(ab0)2 fragment, or Fab
fragment populations are obtained.
The patentability of product-by-process claims is determined based on the
product itself. In re Thorpe, 777 F.2d 695, 697, 227 USPQ 964, 966 (Fed. Cir. 1985)
(“[t]he patentability of a product does not depend on its method of production”
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(reference citations omitted)).
Here the method steps set forth in claim 37 on appeal appear to be those steps
which have been historically performed to obtain monospecific and polyspecific
antivenoms. Specification, page 4, lines 26-30 (reference citation omitted) (“The
scientific study of antivenom began with the work of Henry Sewell in 1887 and has
progressed throughout the present century. Currently, a large number and diversity of
monospecific and polyspecific antivenoms are produced around the world.”). Thus,
claim 37 includes within its scope a mixture of two monospecific antivenoms as have
been historically produced.
3. Patentability of Claim 37.
The main issue presented in this appeal concerns whether the evidence of
nonobviousness the examiner considered in determining that claims 39 through 41 are
patentable is commensurate in scope with the remaining claims that stand rejected,
e.g., claim 37. That evidence appears in the working examples of the specification, the
data of which are graphically depicted in Fig. 2 of the application.
Specifically, assays were performed using four rattlesnake venoms. Id., page 16,
lines 32-34. The venoms used were a “mixed monospecific antivenom made up by
mixing equal volumes of equal concentrations of the monospecific IgG’s obtained by
immunising four groups of ewes against the venom of A. piscivorous, C. adamanteus,
C. atrox, and C. scutulatus.” Id., page 17, lines 4-8. Control studies were performed
using “monospecific antivenoms raised to each of the venoms and using polyspecific
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antivenom raised to a 1:1:1:1 mixture of the venoms.” Id., page 17, lines 13-16. The
data are described by appellant in the following manner:
The results are illustrated in Figure 2 which shows that the mixed
monospecific antivenom is of greater or equal potency than the
corresponding polyspecific antisera for neutralisation of venom PLA2
activity. Indeed, for three of the four venoms tested, significantly less
antivenom was required to achieve 50% neutralisation.
Id., page 17, lines 21-26. On the basis of these data, the examiner allowed claims 39
through 41 which are specific to the four rattlesnakes used in the examples.
In presenting their respective positions on appeal, appellant and the examiner
have argued why the data graphically depicted in Figure 2 of the application is or is not
commensurate in scope with the remaining claims, e.g., claim 37. However, we believe
this discussion is of little relevance when the strength of the prima facie case of
unpatentability for claim 37 is considered.
As set forth above, claim 37 reads upon a simple mixture of two monospecific
snake antivenoms. The Carroll reference relied upon by the examiner establishes that
such a mixture is not novel.
Carroll describes a polyvalent snake antivenom comprising immunoglobulins
having two or more monovalent subpopulations. Preferably, the polyvalent antivenom
has reactivity to C. atrox and C. adamanteus. Carroll, column 8, lines 52-64.
Importantly, Carroll states:
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Polyvalent antivenom can be made either by a) immunizing with a
venom cocktail or b) immunizing with single venoms and mixing two or
more monovalent antivenoms. In either case, the reactivity of the
subpopulation(s) determine the spectrum of reactivity of the population,
i.e. the antivenom. Importantly, whether monovalent or polyvalent, the
purification of the present invention allows for the quantitative retention in
the purified antivenom of the spectrum of reactivity of the unpurified
antivenom.
Id., column 17, lines 52-61. In describing that the polyvalent antivenom of that invention
may be made by “mixing two or more monovalent antivenoms,” Carroll is describing the
subject matter of claim 37 on appeal. Thus, claim 37 lacks novelty.
This finding of lack of novelty is also supported by the two references relied upon
by appellant in pursuing this appeal, i.e., Theakston and Christensen. Theakston is a
chapter in a book directed to therapeutic antibodies that is co-authored by the present
appellant, D.C. Smith. While Theakston was published in 1995 and, thus, is not prior art
to claim 37, much of the work described in Theakston is prior art to claim 37. Of
particular interest is one reference cited in Theakston relied upon by appellant in
pursuing his position on appeal, i.e., Christensen. Specifically, Theakston states “[i]t is
assumed that polyspecific antisera should be produced by immunization of animals with
a mixture of venoms rather than by mixing of monospecific antivenoms, as the latter
method was thought to result in dilution of each component (Christensen 1966a); this,
however, may not be true in all cases (see ‘Antivenom composition’, p. 123).”
Theakston, page 111. Turning to the antivenom composition section Theakston
referenced in this passage, Theakston states:
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A second approach is to mix monospecific antisera, each produced in
separate animals. This method maximizes the possible number of
available antibody-producing cells and, in theory, should provide a wider
range of specific antibodies. However, because these antisera are then
mixed, a dilution effect is produced, the magnitude of which is dependent
on the number of monospecific antisera included in the product. Such
dilution should, in theory, reduce the effectiveness of such a product, but
because many venoms are highly cross-reactive (for the reasons given
above) the dilution effects are again much reduced. Experiments to
monitor the ability of both poly-, monospecific and mixed monospecific
antivenoms to neutralize the phospholipase activity of crotalid venoms
have shown that, as anticipated, monospecific products often offer the
best protection, while mixed monospecific antivenoms are in general
better than polyspecific antivenoms (Fig. 6.2).
Id., page 124. Figure 6.2 of Theakston appears to be a duplicate of Figure 2 of this
application. In other words, the conclusion reached by Theakston in this portion of the
document appears to be based upon the same data present in this application that is
graphically depicted in Figure 2. This is not surprising since, as noted above, present
appellant D.C. Smith is a co-author of the Theakston article.
These portions of Theakston are of interest since they state in a positive manner
that “a second approach is to mix monospecific antisera.” This is all that claim 37 on
appeal requires. Turning to Christensen, the source document relied upon for this prior
art knowledge, we find that Christensen acknowledges that “[s]ome laboratories prepare
polyvalent sera by blending several monovalent sera.“ While Christensen does state
that “others, including ourselves, prefer to immunize the horses with all the antigens,”
the fact remains that Christensen acknowledges that as of 1966 it was not novel to
blend “several monovalent sera.” Again, this is all that claim 37 on appeal
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requires. Thus, the statement set forth in Carroll in regard to blending several
monoseras in order to arrive at a polyspecific snake antivenom is entirely consistent
with other disclosures in the prior art, e.g., Christensen.
We recognize that the examiner’s rejection before us for review is premised upon
§ 103(a) of the statute, not § 102. However, it has been held that finding one of the
references relied upon by the examiner as evidence of obviousness is in fact an
anticipation of a claim “does not constitute a new ground of rejection; lack of novelty is
the epitome of obviousness.” In re May, 574 F.2d 1082, 1089, 197 USPQ 601, 607
(CCPA 1978). At the same time, we are aware that the CCPA subsequently stated that
use of such phrases as “anticipation is the epitome of obviousness” is “nothing more
than the recognition of the commonsense fact that a rejection for obviousness under §
103 can be based on a reference which happens to anticipate the claimed subject
matter. Those cases do not provide a license for the board to shift the statutory basis of
rejection from § 103 to § 102 while denying appellant the procedural due process
provided by 37 CFR 1.196(b).” In re Meyer, 599 F.2d 1026, 1031 n. 14, 202 USPQ 175,
179 n. 14 (CCPA 1979) (citations omitted).
The sole issue raised in the briefing in this appeal is directed to whether the
evidence based upon four specific venoms which won allowance of claims 39 through
41 is commensurate in scope with the claims which remain under rejection. This issue,
of course, presupposes that claim 37 is novel with the issue being one of obviousness.
As explained above, this is an incorrect assumption.
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Under these circumstances, appellant has in essence, conceded that the applied
references would establish a prima facie case of obviousness, the only issue being
directed to the weight and force of the proffered evidence of nonobviousness. Having
considered appellant’s evidence of nonobviousness, we agree with the examiner that it
is not commensurate in scope with claim 37 and, thus, to the extent, the applied
references also establish a prima facie case of obviousness, the prima facie case
stands unrebutted.
The evidence of nonobviousness relied upon by appellant are the data set forth
in the specification and graphically depicted in Figure 2 of this application. Clearly,
these data represent a single data point generated on the basis of venom obtained from
four related rattlesnakes. Claim 37 is much broader in scope. Appellant’s attempt to
extend this single data point throughout the scope of claim 37 hinges on a single
statement appearing in Theakston, i.e., Theakston’s conclusion that “‘mixed
monospecific antivenoms are in general better than polyspecific antivenoms.’
‘[Theakston et al., at page 124 (emphasis added).]’” Appeal Brief, page 13. Appellant
places great weight figuratively and literally on the phrase “in general” that appears in
this quote from Theakston. Appellant would interpret the phrase “in general” as
meaning that the results obtained the single data point involving four related
rattlesnakes should be extended to reach the conclusion that mixed monospecific
antivenoms will be better than polyspecific antivenoms across the board. We disagree.
In reviewing the Appeal Brief and Reply Brief, it does not appear that appellant in
pursuing this argument acknowledges that he is a co-author of the Theakston article.
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As such, the Theakston article is less than an independent review of the single data
point and any interpretation and extension of that single data point must be viewed in
the context of appellant’s co-authorship of the article. Furthermore, Theakston itself
sets forth the reason why the single data point should not be extended in the manner
appellant desires. Theakston states that the so-called dilution effect which appellant
argues teaches away from mixing monovalent serums as required by claim 37 on
appeal to produce a polyvalent sera is minimized because many venoms are highly
cross reactive. Thus, experimental work relied upon to establish that mixed monovalent
sera is more effective than polyvalent sera must be evaluated in light of the specific
snake venoms used and their cross reactivity. The greater the cross reactivity, the less
the so-called dilution effect would be expected to occur which undercuts appellant’s
argument in regard to unexpected results. Clearly, comparing the vast scope of claim
37 on appeal with the single data point relied upon by appellant based upon four related
rattlesnakes, we agree with the examiner’s conclusion that the proffered data is not
commensurate in scope with claim 37.
Summary
As explained above, we have decided all four of the pending rejections based
upon the patentability of claim 37. Having found that claim 37 lacks novelty and that
examiner’s case of prima facie obviousness stands unrebutted, we affirm all four of the
examiner’s rejections.
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No time period for taking any subsequent action in connection with this appeal
may be extended under 37 CFR § 1.136(a).
AFFIRMED
)
Sherman D. Winters )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
William F. Smith )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
Demetra J. Mills )
Administrative Patent Judge )
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Application No. 08/137,168
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Finnegan, Henderson, Farabow,
Garrett & Dunner
1300 I Street, NW
Washington, DC 20005
dem