Ex Parte Finkbeiner

Board of Patent Appeals and Interferences

Oct 31, 2007

09922483 (B.P.A.I. Oct. 31, 2007)

The opinion in support of the decision being entered today
is not binding precedent of the Board.

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte STEVEN FINKBEINER
__________

Appeal No. 2007-0859
Application No. 09/922,483
Technology Center 1600
__________

Decided: October 31, 2007
__________

Before DEMETRA J. MILLS, LORA M. GREEN, and NANCY J.
LINCK, Administrative Patent Judges.

MILLS, Administrative Patent Judge.

DECISION ON APPEAL
The Appellant appeals the examiner’s final rejection of claims 10-13 and 28-
30 for lack of enablement.
We have jurisdiction under 35 U.S.C. § 6(b) (2006).

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Representative claim 10 reads as follows:
10. A method of determining whether an agent is capable of modulating the
binding interaction between a protein comprising a polyglutamine expansion and a
cellular target of said protein, said method comprising:
(a) contacting said protein or a binding fragment or mimetic thereof with:
(i) said agent; and
(ii) an antibody that recognizes a protein comprising a polyglutamine
expansion or binding fragment or mimetic thereof, wherein said antibody
has greater affinity for said polyglutamine expansion than a 1C2 monoclonal
antibody;
(b) detecting the presence of binding complexes comprising said protein and
said antibody; and
(c) comparing the results of step (b) with a control;
wherein the ability of an agent to modulate the binding interaction between said
protein and said antibody indicates that the ability of said agent to modulate the
binding interaction between said protein and a cellular target of said protein.

Cited References
South et al. “Identification of Novel Peptide Antagonists for von Willebrand
Factor Binding to the Platelet Glycoprotein Ib Receptor from a Phage
Epitope Library, Vol. 73, Journal of the Intenational Society on Thrombosis
and Haemostasis, pp. 144-150 (1995)

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Heiser et al. “Inhibition of huntingtin fibrillogenesis by specific antibodies
and small molecules: Implications for Huntington’s disease therapy,”
Vol. 97, No. 12, Proceeding of the National Academy of Science,
pp. 6739-6744 (2000)

Kaji et al. “Peptide Mimics of Monocyte Chemoattractant Protein-1
((MCP-1 with an Antagonistic Activity,” The Journal of Biochemistry,
Vol. 129 No. 4 pp. 577-583 (2001)

Grounds of Rejection
Claims 10-13 and 28-30 stand rejected under 35 USC 112, first paragraph
for lack of enablement.

DISCUSSION
Background
Huntington's Disease (HD) is a devastating neurological disease which
usually presents in mid adult life … HD is associated with expansion of a CAG
repeat within the HD gene. … The HD gene encompasses 67 exons, spans over
200 kb and is associated with two transcripts of 10.3 kb and 13.6 kb, differing with
respect to their 3' untranslated regions. [T]he HD gene encompasses a highly
polymorphic CAG repeat (polyglutamine) which varies in number from 8 to 35 in
normal individuals. CAG expansion beyond 36 CAG repeats is seen in persons with
HD. (Specification 1.)
The Specification, pages 17-18, discloses Appellant found 6 monoclonal
antibodies specific for the mutant polyglutamine, designated 1F11E5, 4H7H7,
3A2D3, 4F1B5, 3C4A6, 3B5H10 which differ from a known antibody, 1C2,
specific for the polyglutamine repeat in HD by at least one of specificity, affinity
and avidity. The Specification further describes binding fragments of the
antibodies and binding mimetics which share the binding characteristics of the
Comment [d1]: Should any of the text
be in quotes?
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antibodies for the polyglutamine expansion protein, mutant huntingtin protein.
(Specification 8.)
The subject antibodies, binding fragments and mimetics thereof
… find use in screening applications designed to identify agents or
compounds that are capable of modulating, e.g. inhibiting, the binding
interaction between the protein to which the antibody binds and a
cellular target. For example, the subject antibodies find use in
screening assays that identify compounds capable of modulating the
interaction between mutant huntingtin protein and its cellular targets.
In such assays, the subject antibody is contacted with mutant
huntingtin protein in the presence of a candidate modulation agent and
any resultant binding complexes between the antibody and the mutant
huntingtin protein are detected. The results of the assay are then
compared with a control. Those agents which change the amount of
binding complexes that are produced upon contact are identified as
agents that modulate the binding activity of mutant huntingtin protein
and therefore are potential therapeutic agents. Of interest in many
embodiments is the identification of agents that inhibit, at least to
some extent, the binding of mutant huntingtin protein with its target.

(Specification 11-12.)

Enablement
Claims 10-12, and 28-30 stand rejected under 35 U.S.C. § 112, first
paragraph, for lack of enablement.
The Examiner contends that the "preamble of the claim is directed to
identifying compounds capable of modulating the interaction between mutant
huntingtin protein and its cellular targets. Yet the method steps outlined in the
claim will only measure the interaction between mutant huntingtin protein and an
antibody." (Answer 3.) Thus, the Examiner argues, that "the specification does
not teach a method of screening agents that will interfere with the interaction of
mutant huntingtin protein with the normal cellular target of the huntingtin protein"
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and that the "normal cellular target of the hungtingtin protein is not known."
(Answer 4.) The examiner argues the claimed methods cannot distinguish whether
the agent binds to the antibody or the polyglutamine containing protein itself and
argues that if the agent binds the antibody it would not be useful to prevent the
binding of the huntingtin protein to the undisclosed and unidentified cellular
receptor. (Answer 4.) Therefore, as we understand it, the Examiner's position
appears to be that Appellant has not disclosed in the specification information
about the specific cellular target recited in claim 10, i.e., specific information about
a cellular receptor or target for mutant huntingtin protein, and has not described
agents which interfere with the binding reaction claimed. For these reasons, the
Examiner finds enablement is lacking for the claimed subject matter.
Appellant contends that the Examiner has failed to establish a reasonable
basis to question enablement. (Br. 8.) In particular, Appellant argues that "[t]he
Examiner has apparently misunderstood the claimed invention" and that "[t]he
antibodies in the claimed method do not serve to prevent the binding of the
polyglutamine expansion-containing protein to its cellular target. Instead, the
antibodies serve as surrogates for the cellular target." (Br. 11.) Appellant argues
that "those skilled in the art would find it reasonable that a polyglutamine
expansion-containing protein binds to an antibody specific for the polyglutamine
expansion of the polyglutamine expansion-containing protein in a manner similar
to the binding of a cellular target of the polyglutamine expansion-containing
protein." (Br. 11.)
Thus, Appellant takes the position that "those skilled in the art would also
find it reasonable to use an antibody as a surrogate for the cellular target(s) of a
polyglutamine expansion-containing protein in a screening method to identify
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agents that modulate binding interaction between a polyglutamine expansion-
containing protein and a cellular target of the protein." (Id.)
Enablement is a question of law, based on underlying findings of fact. See,
e.g., In re Wands, 858 F.2d 731, 735, 8 USPQ2d 1400, 1402 (Fed. Cir. 1988).
“[T]o be enabling, the specification . . . must teach those skilled in the art how to
make and use the full scope of the claimed invention without ‘undue
experimentation.’” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513
(Fed. Cir. 1993) (emphasis added), quoted in Genentech, Inc. v. Novo Nordisk, A/S,
108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997). Thus, “there must
be sufficient disclosure, either through illustrative examples or terminology, to
teach those of ordinary skill how to make and use the invention as broadly as it is
claimed.” In re Vaeck, 947 F.2d 488, 496 & n. 23, 20 USPQ2d 1438, 1445 & n. 23
(Fed. Cir. 1991), quoted in Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362,
1372, 52 USPQ2d 1129, 1138.
Factors to be considered in determining whether a disclosure
would require undue experimentation . . . the quantity of
experimentation necessary, (2) the amount of direction or guidance
presented, (3) the presence or absence of working examples, (4) the
nature of the invention, (5) the state of the prior art, (6) the relative
skill of those in the art, (7) the predictability or unpredictability of
the art, and (8) the breadth of the claims. [Id. at 737, 8 USPQ2d at
1404.]
“Patent protection is granted in return for an enabling disclosure . . . , not for
vague intimations of general ideas that may or may not be workable.” Genentech,
108 F.3d at 1365, 42 USPQ2d at 1005. “Tossing out the mere germ of an idea
does not constitute enabling disclosure. While every aspect of a generic claim
certainly need not have been carried out by an inventor, or exemplified in the
specification, reasonable detail must be provided in order to enable members of
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the public [skilled in the art] to understand and carry out the invention.” Id., 42
USPQ2d at 1005 (emphasis added).
In the present case, the quantity of experimentation necessary to determine
whether an agent is capable of modulating the binding interaction between a
protein comprising a polyglutamine expansion and a cellular target of the protein is
great. The Specification does not provide a clear correlation between an antibody
that binds a polyglutamine expansion protein and the actual cellular target for the
polyglutamine expansion. The Specification does not define or characterize any
agents which interfere with the claimed binding reaction. The lack of direction or
guidance presented in the Specification concerning the cellular target for the
polyglutamine expansion and the absence of working examples of compounds
which modulate the binding interaction between a protein comprising the
polyglutamine expansion and the cellular target is evident upon review of the
Specification.
The nature of the invention is such that the art has a high level of
unpredictability. The state of the prior art is indicated in Heiser, which evidences
that the formation of insoluble protein aggregates (fibrillar proteins) plays an
important role in the cellular distortions underlying HD and the related glutamine-
repeat disorders. (Heiser, col. 1, p. 6739.) Heiser further evidences that antibody
1C2 was known to recognize the conformation of an elongated polyQ tract in
soluble proteins but not the array of glutamine residues in insoluble protein
aggregates with fibrillar morphology. (Heiser, col. 2 p. 6740.) Heiser further
indicates that "the causal relationship between aggregate formation and disease has
not been proven", but genetic, neuropathological, and biochemical evidence
indicates that the formation of insoluble protein aggregates plays an important role
in the cellular distortions underlying HD. (Heiser, col. 1, p. 6739.) Thus, the state
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of the art as reflected by Heiser, does not recognize or provide information about
the function or nature of the normal cellular target for the mutant huntingtin
protein. (Answer 5.) Finally, the claims are broadly drawn to a method of
determining whether an agent is capable of modulating the binding interaction
between a protein comprising a polyglutamine expansion and a cellular target of
said protein. The Specification does not describe any agent, chemical or protein,
capable of modulating the claimed binding interaction. The Specification does not
provide guidance as to the nature of the actual cellular target for polyglutamine
expansion protein.

According to the Appellant

[a]ll that claim 10 requires is that the polyglutamine expansion
containing protein be contacted with the agent and an antibody that
recognizes the polyglutamine expansion of the polyglutamine
expansion-containing protein (where the antibody has greater affinity
for the polyglutamine expansion than a 1C2 monoclonal antibody);
and that the presence of a binding complex between the antibody and
the polyglutamine expansion-containing protein be detected and
compared to a control. The ability of the agent to modulate the
binding interaction between the polyglutamine expansion containing
protein and the antibody indicates the ability of the agent to modulate
binding interaction between the polyglutamine expansion-containing
protein and a cellular target of the polyglutamine expansion
containing protein. Thus, the antibody in the claimed method serves
as a surrogate for the cellular target(s) of the polyglutamine
expansion-containing protein.

(Br. 7.)

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Appellant further argues that

[t]he instant specification provides ample description of
antibodies to be used in a subject method; as well as ample description
as to how to determine whether an agent modulated binding of an
antibody to a polyglutamine expansion of a polyglutamine expansion-
containing protein. The specification describes antibodies, and
binding fragments and mimetics of such antibodies, which specifically
bind to polyglutamine expansion-containing proteins, such as mutant
huntingtin protein. Specification, page 3, lines 23-25; page 4, line 20
to page 6, line 26; and page 8, line 25 to page 9, line 11; and page 18,
line 28-page 19, line 1. The specification describes how to determine
whether an agent modulated binding of an antibody to a
polyglutamine expansion of a polyglutamine expansion-containing
protein. Specification, page 11, line 24 to page 12, line 30. Given the
description in the specification, those skilled in the art could readily
practice the method as claimed without undue experimentation.

(Br. 7.)

Appellant concludes that

[t]he person skilled in the art would find it reasonable that
cellular target(s) for polyglutamine expansion-containing protein
include proteins. The person skilled in the art would find it reasonable
that a polyglutamine expansion containing protein binds to an
antibody specific for the polyglutamine expansion of the
polyglutamine expansion-containing protein in a manner similar to the
binding of the cellular target of the polyglutamine expansion-
containing protein.

(Br. 7.)
In support of this position regarding enablement, Appellant puts for the
Declaration under 37 C.F.R. 1.132 of Ross Stein. As explained in the Declaration
of Stein, "the antibody used in the assay has a specific binding site for a toxic
conformation of polyglutamine. Declaration ¶4. The Declarant speculates that
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"[t]he binding site on the antibody might have structural features and binding
properties for polyglutamine that are similar to binding sites on the cellular
proteins that mediate the toxic effects of polyglutamine. Small drug-like
molecules that bind to the site on the antibody might also bind to the cellular
proteins." Declaration, ¶4.
We are not persuaded by the speculative conclusions drawn in the
Declaration. The Declaration speculates that the antibody binding site might have
structural features and binding properties for polyglutamine that are similar to
binding sites on the cellular proteins that mediate the toxic effects of
polyglutamine, but this remains a hypothesis and is no evidence that the both the
antibody and the cellular target share a similar conformation.
Appellant also relies on Kaji and South as teaching that it is known in the art
to use antibodies as surrogates for a cellular target in a manner similar to that
claimed. Appellant argues that Kaji describes the screening of a phage display
library with monoclonal antibodies that inhibit the chemotactic activity of
monocyte chemoattractant protein (MCP-1). (Br. 10.) The method identified two
peptides that bound to THP-1 cells (which are responsive to MCP-1), and it was
determined that the binding was competitively inhibited by MCP-1. Id. From this
Kaji concluded that the peptides mimic the MCP-1 binding domain that is
recognized by the MCP-1 receptor. Kaji, col. 2, p. 577. Appellant argues Kaji
used the antibodies as a surrogate for the MCP-1 receptor and found that peptides
that bound the antibody also bound the receptor CC chemokine receptor 2 (CCR2).
Br. 10. (Kaji, col. 2, p. 577.) However, Kaji could draw no evidentiary
conclusions that its phage clones shared binding properties with the CCR2
receptor. Kaji describes that the binding region of MCP-1 to its receptor CCR2
had been identified by mutational analysis. Kaji, col. 1, p. 582. Kaji found a
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sequence with low sequence similarity to the binding region of MCP-1 in its
synthetic peptides C25 and C27. Id. Kaji stated that, "it is conceivable that both
phage clones may bind to the structure of CCR2 shared with other MCP-1
receptors. The precise binding specificity of these phage clones remains to be
studied." (Kaji, col. 1, p. 582.)
Appellant argues South screened a phage display library for inhibitors of the
von Willebrand factor (vWF) platelet Glycoprotein Ib (GPIb) interaction. (Br. 11.)
The phage display library was screened with a monoclonal antibody that
recognizes GPIb binding domain of vWF. (South, Abstract.) In particular, South
screened an epitope library with a monoclonal antibody that neutralizes the
biological activity of a GPIb receptor/ligand interaction. (South, col. 2, p. 144.)
South used a well characterized antibody to von Willebrand factor that disrupts
vWF binding to the platelet GPIb receptor. (South, col. 2, p. 144.) The Examiner
indicates that the "critical difference between the cited paper [South] and the
instant specification is that in the South et al. paper the authors actually knew that
the antibody binds to the GPIb domain that recognizes the vWF. (Final Rejection
3.) In the present case, unlike South, the natural target for the polyglutamine
repeat is unknown, and it is unverified that the antibodies share the same binding
specificity with a known receptor. Thus we do not find either Kaji or South to be
convincing evidence that one of ordinary skill in the art would haven been enabled
to practice the claimed method without undue experimentation.
A preponderance of the evidence exists when it suggests that it is
more likely than not that the assertion in question is true. Herman v.
Huddleston, 459 U.S. 375, 390 (1983). In the present case we find that
Appellant has not established by a preponderance of the evidence that the
claimed invention is enabled primarily because the nature of the cellular
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target of mutant huntingtin protein is not known or described in the
Specification. Therefore the rejection of the claims for lack of enablement is
affirmed.

CONCLUSION
The rejection of claims 10-13 and 28-30 under 35 U.S.C. § 112, first
paragraph, for lack of enablement are 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).
AFFIRMED

dm

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