Ex Parte Gilchrest et al

Board of Patent Appeals and Interferences

Feb 13, 2009

10785924 (B.P.A.I. Feb. 13, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte BARBARA A. GILCHREST and MINA YAAR1
__________

Appeal 2008-5035
Application 10/785,924
Technology Center 1600
__________

Decided:2 February 13, 2009
__________

Before DONALD E. ADAMS, ERIC GRIMES, and MELANIE L.
McCOLLUM, Administrative Patent Judges.

McCOLLUM, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of inhibiting β-amyloid binding to the p75 nerve growth factor receptor.

1 The real party in interest is the Trustees of Boston University (App. Br. 3).
2 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).
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The Examiner has rejected the claims as anticipated, nonenabled, and/or not
supported by an adequate written description. We have jurisdiction under 35
U.S.C. § 6(b). We affirm.
STATEMENT OF THE CASE
Alzheimer’s disease “is characterized by progressive dementia
together with neuropathological findings of ‘senile plaques’ in the brain
formed by deposits of β-amyloid protein, surrounded by clusters of
degenerating neurons” (Spec. 1: 15 to 2: 1).
“[N]euronal cells express a high affinity (p140trkA) and a low affinity
receptor (p75NTR) for nerve growth factor (NGF)” (id. at 6: 16-17). The
Specification discloses that “these nerve growth factor receptors are also
expressed on melanocytes and that β-amyloid binds to the low affinity nerve
growth factor receptor, p75NTR, expressed on the melanocyte surface” (id. at
6: 17-20). In addition, the Specification discloses that “binding of
β-amyloid to the p75NTR activates the receptor, resulting in apoptotic cell
death of the melanocytes” (id. at 6: 20-22). The Specification also discloses
that “β-amyloid mediated-apoptosis can be competitively blocked by
providing nerve growth factor or a biologically active fragment, analog or
derivative thereof” (id. at 6: 22-24).
Claims 56-77 are on appeal.3 We will focus on claim 74, which reads
as follows:
A method of inhibiting β-amyloid-mediated activation of p75 nerve
growth factor receptor of a target cell, comprising contacting the target cell
with a small organic molecule, wherein the target cell expresses p75 nerve

3 Claims 48-55 are also pending but have been withdrawn from
consideration by the Examiner (App. Br. 3).
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growth factor receptor, and wherein β-amyloid is present at a concentration
sufficient to mediate activation of the p75 nerve growth factor receptor,
wherein the small organic molecule binds to the p75 nerve growth factor
receptor with at least about half the affinity as nerve growth factor and
competitively inhibits binding of β-amyloid to the p75 nerve growth factor
receptor, thereby inhibiting β-amyloid protein or β-amyloid peptide
activation of the p75 nerve growth factor receptor of a cell.
The Examiner relies on the following reference:
Shahrooz Rabizadeh et al., Expression of the low-affinity nerve
growth factor receptor enhances β-amyloid peptide toxicity, 91 PROC. NATL.
ACAD. SCI. USA 10703-10706 (1994) (hereinafter “Rabizadeh”).
Appellants rely on the following references:
David C. Horwell, The ‘peptoid’ approach to the design of non-
peptide, small molecule agonists and antagonists of neuropeptides, 13
TRENDS BIOTECHNOL. 132-134 (1995) (hereinafter “Horwell”);
Gerhard Klebe and Thomas Mietzner, A fast and efficient method to
generate biologically relevant conformations, 8 J. COMPUT. AIDED MOL.
DES. 583-606 (1994) (hereinafter “Klebe”);
Neil Q. McDonald et al., New protein fold revealed by a 2.3-Å
resolution crystal structure of nerve growth factor, 354 NATURE 411-414
(1991) (hereinafter “McDonald”); and
B. S. Chapman and I. D. Kuntz, Modeled structure of the 75-kDa
neurotrophin receptor, 4 PROTEIN SCI. 1696-1707 (1995) (hereinafter
“Chapman”).
Claims 56-77 stand rejected under 35 U.S.C. § 112, first paragraph, as
failing to comply with the enablement and written description requirements
(Ans. 4 & 8).
Claims 56, 57, 61-63, 65-67, 69, 70, and 74-77 stand rejected under
35 U.S.C. § 102(b) as anticipated by Rabizadeh (Ans. 10).
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ENABLEMENT
The Examiner contends that the Specification “does not enable any
person skilled in the art to which it pertains, or with which it is most nearly
connected, to make or use the invention commensurate in scope with these
claims” (Ans. 4).
Issue
Did the Examiner err in concluding that the Specification does not
enable the full scope of the claim term “small organic molecule”?
Findings of Fact
1. The Specification discloses:
Activation of the p75 nerve growth factor receptor can be
determined by measuring the β-amyloid activation of the p75
nerve growth factor receptor of neural crest-derived cells, in
culture or in a tissue sample, in the presence of the test
substance and comparing the results with the β-amyloid
activation of the p75 nerve growth factor receptor of neural
crest-derived cells in a control culture or sample without the
test-substance. A decrease of β-amyloid activation of the p75
nerve growth factor receptor of neural crest-derived cells in the
test sample compared to β-amyloid activation of the p75 nerve
growth factor receptor of neural crest-derived cells in the
control sample is indicative of a substance that inhibits
β-amyloid-mediated apoptosis in neural crest-derived cells.
(Spec. 4: 20 to 5:2.)
2. The Specification also discloses that “[b]inding of NGF to
p75NTR is mediated through amino acid residues 29-36, TDIKGKEV (SEQ
ID NO: 2), that are part of the β-hairpin loop of NGF” (id. at 19: 1-2).
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3. In addition, the Specification discloses that, “[i]f lysine (K) at
position 34 is replaced by alanine (A), the resulting mutant NGF molecule
still binds p75NTR but with 50% lower affinity” (id. at 19: 3-4).
4. The Specification also discloses that “in β-amyloid the amino
acid residues 28-30 . . . are KGA, a sequence that appears to permit p75NTR
binding by β-amyloid” (id. at 19: 5-7).
5. In addition, the Specification discloses that the “amino acid
sequences of the NGF fragments, analogues, derivatives, variants and
mutants of the present invention can be altered to optimize NGF binding to
p75NTR, by methods known in the art by introducing appropriate nucleotide
changes into native or variant DNA encoding the NGF, or by in vitro
synthesis of the desired NGF” (id. at 21: 9-12).
6. The Specification also discloses:
[T]he melanocyte culture model can be used to identify
substances that block the p75NTR binding of β-amyloid, and thus
block β-amyloid-mediated neuronal apoptosis. Several assay
methods are available in the art to measure p75 nerve growth
factor receptor activation by β-amyloid protein or β-amyloid
peptide and include an assay to determine melanocyte cell
yield, an assay to determine the inducement of Bax protein
expression; an assay to determine the onset of melanocyte
apoptosis or an assay to determine the presence of plaque-like
structures in the melanocyte culture.
(Id. at 22: 1-7.)
7. In addition, the Specification discloses that “candidate
substances that inhibit the binding of amyloid protein/peptide can also be
identified using in vitro binding assays well known in the art, such as surface
plasmon resonan[ce] (SPR). For example, peptide libraries and other small
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organic molecule libraries can be screened using proximity assays or
Biospecific Interaction Analysis (BIA).” (Id. at 22: 22-26.)
8. The Specification also states:
[T]he tripeptide lysine-glycine-alanine [KGA] is a candidate
substance for use as a therapeutic to alleviate the symptoms of
Alzheimer’s disease. The melanocyte culture model system can
be used to identify and evaluate other peptides containing the
KGK or KGA sequence, or various analogs of the KGK or
KGA tripeptide, to determine an optimum conformation and
composition that will bind p75NTR and, thus, block the binding
of the apoptosis-inducing β-amyloid ligand without interfering
with NGF binding that is beneficial. Because evaluation of
candidate substances is made with melanocytes obtained
specifically from the individual at risk, or with the diagnosis of
[Alzheimer’s disease], the probability of identifying an
effective candidate substance is very high.
(Id. at 23: 13-22.)
9. In addition, the Specification discloses administering “a
substance, e.g., a cyclic peptide comprising KGK or KGA, or an analog
thereof” (id. at 24: 7-8).
10. In particular, the Specification discloses synthesizing “the
pentapeptide CKGAC (SEQ ID NO: 3)” and that the “cysteine residues
flanking the ends of the pentapeptide can be linked, e.g., by a disulfide bond,
to maintain the conformation required for binding of the peptide to the
p75NTR, thus inhibiting, or preventing apoptosis” (id. at 24: 9-14).
11. The Specification also states that the “length of the peptide can
be longer than a pentapeptide, as long as the KGA, or analog peptide is
maintained in a configuration suitable for binding activity” (id. at 24: 14-16).
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12. Specifically, the Specification discloses a cyclic decapeptide
(SEQ ID NO: 4) “synthesized by attaching two cysteine residues to the
beginning and the end of the β-amyloid fragment consisting of amino acids
24-31: VGSNKGAI (SEQ ID NO: 1)” and that this peptide “competitively
inhibited 125I-β-amyloid binding” and blocked cell loss (id. at 12: 23-28; see
also Spec. 24: 17 & 30: 4-19).
Principles of Law
“The first paragraph of 35 U.S.C. § 112 requires, inter alia, that the
specification of a patent enable any person skilled in the art to which it
pertains to make and use the claimed invention . . . without ‘undue
experimentation.’” In re Vaeck, 947 F.2d 488, 495 (Fed. Cir. 1991) (citing
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988)). Some experimentation,
even a considerable amount, is not “undue” “if it is merely routine, or if the
specification . . . provides a reasonable amount of guidance with respect to
the direction in which the experimentation should proceed.” In re Wands,
supra. In particular, “sufficient disclosure . . . to teach those of ordinary
skill how to make and how to use the invention . . . means that the disclosure
must adequately guide the art worker to determine, without undue
experimentation, which species among all those encompassed by the
claimed genus possess the disclosed utility.” In re Vaeck, 947 F.2d at 496.
“Whether undue experimentation is needed is not a single, simple
factual determination, but rather is a conclusion reached by weighing many
factual considerations.” In re Wands, supra. Factors to be considered
include:
(1) the quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of
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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.
In re Wands concerned a claim directed to a method utilizing an
antibody to assay for a substance comprising hepatitis B-surface antigen
(HBsAg) determinants, wherein the antibody is a monoclonal high affinity
IgM antibody having a particular binding affinity for the HBsAg
determinants. 858 F.2d at 734. The issue was “whether the specification
enables one skilled in the art to make the monoclonal antibodies that are
needed to practice the invention.” Id. at 735.
In Wands, the Specification disclosed “a procedure for immunizing
mice against HBsAg, and the use of lymphocytes from these mice to
produce hybridomas that secrete monoclonal antibodies specific for
HBsAg.” Id. at 734. “Hybridoma cells that secrete the desired antibodies
then must be isolated from [an] enormous number of other cells in the
mixture[, which] is done through a series of screening procedures.” Id. at
737. “The PTO [did] not question that the screening techniques used by
Wands were well known in the monoclonal antibody art.” Id. at 738.
Finding that “[p]ractitioners of this art are prepared to screen negative
hybridomas in order to find one that makes the desired antibody,” the
Federal Circuit concluded that the record indicates that “the amount of effort
needed to obtain [the] antibodies is not excessive.” Id. at 740.
“[T]he PTO bears an initial burden of setting forth a reasonable
explanation as to why it believes that the scope of protection provided by
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that claim is not adequately enabled by the description of the invention
provided in the specification of the application.” In re Wright, 999 F.2d
1557, 1561-62 (Fed. Cir. 1993). “If the PTO meets this burden, the burden
then shifts to the applicant to provide suitable proofs indicating that the
specification is indeed enabling.” Id. at 1562. In meeting Appellants’
burden, “[a]ttorney’s argument in a brief cannot take the place of evidence.”
In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974).
Analysis
In the present case, the Examiner finds:
[T]he specification, while being enabling for methods of
inhibiting p75 nerve growth factor receptor (p75NGFR—also
referred to in the specification as p75NTR) mediated apoptosis
of cells expressing p75NGFR comprising administering NGF or
compounds comprising the polypeptides of amino acid
sequences 1, 2, 3 or 4, does not reasonably provide enablement
for methods of inhibiting p75NGFR mediated apoptosis of cells
expressing p75NGFR comprising administering any small
organic molecule as broadly claimed.
(Ans. 4.) In particular, the Examiner finds that “the claim covers every
conceivable structure for achieving the stated property (the ability to inhibit
p75NGFR mediated apoptosis) while the specification discloses at most only
those structures known by the inventor to achieve the stated result, which is
NGF or one of the peptides of SEQ ID NOs: 1-4” (id. at 15).
The Examiner concludes:
[D]ue to the large quantity of experimentation necessary to test
for all possible small molecules capable of inhibiting p75NGFR
mediated apoptosis in cells expressing p75NGFR, the lack of
direction/guidance presented in the specification and the
absence of working examples directed to administration of any
small molecule save NGF (SEQ ID NOs: 1-4), the complex
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nature of the invention, the unpredictability of the effects of
mutation on protein structure and function, and the breadth of
the claims which fail to recite limitations on all possible small
molecules that would be capable of inhibiting p75NGFR
mediated apoptosis of cells expressing p75NGFR, undue
experimentation would be required of the skilled artisan to
make and/or use the claimed invention in its full scope.
(Id. at 16.) We agree with the Examiner.
Claim 74 recites contacting the target cell with a “small organic
molecule [that] binds to the p75 nerve growth factor receptor with at least
about half the affinity as nerve growth factor and competitively inhibits
binding of β-amyloid to the p75 nerve growth factor.” As noted by the
Examiner, the term “‘small organic molecule’ . . . includes organic ring
structures, peptides, nucleic acids, sugars, lipids, etc.” (Ans. 18). The
Specification discloses peptides that “bind[] to the p75 nerve growth factor
receptor” (Findings of Fact (FF) 2, 10, & 12). In addition, the Specification
describes assays that can be used to identify molecules having this property
(FF 1 & 6-8). However, the Specification does not provide sufficient
guidance as to which non-peptide small organic molecules should be
subjected to these assays in order to identify such molecules. Therefore, we
agree that the Examiner has set forth a prima facie case that it would require
undue experimentation to make and use small organic molecules within the
full scope of claim 74.
Appellants argue that “the methods of the present invention utilize
small organic molecules that are functionally described in a very narrow
way. These small organic molecules inhibit p75 nerve growth factor
receptor mediated apoptosis and/or β-amyloid binding to p75 nerve growth
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factor receptor of target cells that express the p75 nerve growth factor
receptor.” (App. Br. 8.)
Furthermore, the assays for identifying the small organic
molecules of the invention are well described and involve routine
steps known by those of skill in the art. Identification of these
small organic molecules that function as described is simply a
matter of repeating one or more of the described assays until a
desirable small organic molecule is found. For one of skill in the
art, performing the assays described in the present application is
a matter of routine experimentation. Such experimentation is
neither undue nor burdensome.
(Id.) Thus, Appellants argue:
Just as in In re Wands, the specification describes in great detail
the assays for identifying the small organic molecules used in
the claimed methods of the invention. Furthermore, one of
ordinary skill in the art, when identifying the small organic
molecules would be prepared to screen libraries, such as those
that have been described in specification on page 22, lines 24-
26, in order to determine which small organic molecules exhibit
the desired characteristics for use with the claimed methods of
the invention . . . . The fact that the instant application is drawn
to a more expansive pool of molecules than was the application
of In re Wands does not negate that assertion that one of skill in
the art, using the Applicants’ specification would be able to
make and use the claimed invention.
(Id. at 9.)
We are not persuaded. As noted by Appellants, practicing the full
scope of the invention in Wands requires the use of screening assays. Wand,
858 F.2d at 737. However, Wands’ Specification disclosed a method for
producing antibody-secreting cells to be subjected to these screening assays.
Id. at 734. In contrast, in the present case, the compounds to be subjected to
the screening assays are “small organic molecules.” The Specification does
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not provide sufficient guidance as to which small organic compounds should
be subjected to the assays. In addition, Appellants have not provided
sufficient evidence that practitioners in this art would be enabled, without
further guidance, to screen the full scope of the broad category of small
organic molecules in order to find ones that have the desired binding. Thus,
we do not agree that the holding in In re Wands demonstrates that the
present enablement rejection should be reversed.
Conclusion
Appellants have not shown that the Examiner erred in concluding that
the Specification does not enable the full scope of the claim term “small
organic molecule.” We therefore affirm the enablement rejection of
claim 74. Claims 56-73 and 75-77 have not been argued separately and
therefore fall with claim 74. 37 C.F.R. § 41.37(c)(1)(vii).
WRITTEN DESCRIPTION
The Examiner contends that the claims contain “subject matter which
was not described in the specification in such a way as to reasonably convey
to one skilled in the relevant art that the inventor(s), at the time the
application was filed, had possession of the claimed invention” (Ans. 8).
Issue
Did the Examiner err in concluding that the Specification does not
provide adequate written description to support the claim term “small
organic molecule”?
Findings of Fact
13. Horwell “describes a rationale and strategy for the design of
low molecular weight, non-peptide ligands (peptoids), using the chemical
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structure of mammalian neuropeptides as a starting point” (Horwell,
Abstract).
14. Horwell defines “peptoid” as “a non-peptide agent that has been
designed using the chemical structure of mammalian neuropeptides as the
starting point, and may act as either a pharmacological functional agonist or
an antagonist” (id. at 132).
15. Horwell states that “[t]here are classical precedents for the use
of small molecule hormone and neurotransmitters as ‘chemical leads’ to
therapeutically useful agonists and antagonists” (id.).
16. However, Horwell states that “[p]olypeptides are more complex
chemical leads than the small molecule hormones” (id. at 133).
17. In particular, Horwell states that “[p]eptides are polyfunctional
ligands and have a large degree of conformational freedom associated with
the many freely rotatable bonds found in the polyamide backbone and in the
amino acid side chains” (id.).
18. Horwell discloses “a hypothesis that the ‘problem’ of a large,
flexible polypeptide can be reduced to a small-molecule surrogate as a
synthetic ‘device’ if three or fewer amino acid residues are identified as
critical for receptor recognition” (id.).
19. Horwell also indicates that its “ideas and rationale . . . have
been put into practice . . . , resulting in the rational design of antagonists and
agonists for several neuropeptides” (id.).
20. In addition, Horwell states that “[w]e hope that this approach
will provide other peptoids that are able to bind at the active site of the
protein target with specific interactions that may endow members of a
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congeneric peptoid series with either antagonistic or agonistic properties”
(id. at 134).
21. Klebe discloses that “reliance on just the crystal structures of a
ligand itself may not, in most cases, be an infallible and reliable indicator of
a biologically active conformation” (Klebe 584).
22. Therefore, Klebe discloses “a knowledge-based approach
toward conformational analysis. This ‘knowledge’ . . . is not stored in terms
of ‘rules’, but incorporated into an extended set of conformational libraries
which are directly derived from crystal data by a statistical evaluation of
conformational preferences.” (Id. at 585.)
23. Klebe also discloses that the “produced conformers possess
some probability to represent geometries that are likely to resemble those
actually adopted at the binding site of a protein” (id. at 604).
24. McDonald discloses the crystal structure of the murine NGF
dimer (MacDonald, Abstract).
25. McDonald also discloses the presence of a β–hairpin turn at
residues 30-33 (id. at 412).
26. Chapman discloses “a molecular model of NTR, also called
p75NGFR” (Chapman, Abstract).
27. Chapman also discloses that “NTR appears to bind in the dimer
interface of NGR, making two sets of contacts” (id.).
28. Chapman states that an “application of this study might be to
discover small molecule agonists that mimic the ability of [neurotrophins] to
prevent cell death induced by the NTR” (id. at 1704).
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Principles of Law
The first paragraph of 35 U.S.C. § 112 “requires a ‘written description
of the invention’ which is separate and distinct from the enablement
requirement.” Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir.
1991). An adequate written description of a chemical invention “requires a
precise definition, such as by structure, formula, chemical name, or physical
properties.” University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d
916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co.,
Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164,
1171 (Fed. Cir. 1993). “A description of what a material does, rather than of
what it is, usually does not suffice.” Rochester, 358 F.3d at 923; Eli Lilly,
119 F.3d at 1568. Instead, the “disclosure must allow one skilled in the art
to visualize or recognize the identity of the subject matter purportedly
described.” Id. However, not all functional descriptions “necessarily fail as
a matter of law to meet the written description requirement; rather, the
requirement may be satisfied if in the knowledge of the art the disclosed
function is sufficiently correlated to a particular, known structure.” Amgen
Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1332 (Fed. Cir. 2003).
In addition, possession of a genus “may be achieved by means of a
recitation of a representative number of [compounds] . . . falling within the
scope of the genus.” Eli Lilly, 119 F.3d at 1569. Possession may not be
shown by merely describing how to obtain possession of members of the
claimed genus. See Rochester, 358 F.3d at 927.
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Analysis
The Examiner finds that, “[w]ith the exception of NGF or compounds
comprising the polypeptides of amino acid sequences 1, 2 . . . , 3, and 4 . . . ,
the skilled artisan cannot envision the detailed chemical structure of the
encompassed small organic molecules” (Ans. 9). The Examiner also finds
that “NGF and the peptide[s] of SEQ ID NOS: 1-4 are not representative of
the vast genus of molecules encompassed by the term ‘small organic
molecules’” (id. at 27). We agree with the Examiner.
Claim 74 recites contacting the target cell with a “small organic
molecule [that] binds to the p75 nerve growth factor receptor with at least
about half the affinity as nerve growth factor and competitively inhibits
binding of β-amyloid to the p75 nerve growth factor receptor.” As noted by
the Examiner, “‘small organic molecules’ . . . are not limited to peptides or
proteins, but encompass any small carbon containing molecule capable of
carrying out the required functions” (Ans. 30). However, the Specification
does not describe any non-peptide small organic molecules that bind to the
p75 nerve growth factor receptor, nor does the Specification disclose the
physical properties or provide another precise definition of these molecules.
Therefore, we agree with the Examiner that the Specification does not
adequately describe species representative of the genus of small organic
molecules recited in claim 74.
Appellants argue that “it is axiomatic in patent law that an inventor
can establish reduction to practice in one of two ways: 1) by demonstrating
actual reduction to practice or 2) by filing an enabling patent application and
thus establishing constructive reduction to practice” (App. Br. 10).
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Therefore, Appellants argue that, “[b]ecause . . . the specification is
enabling, the filing of the specification represents constructive reduction to
practice, and thus, demonstrates that Applicants were in possession of the
invention at the time of filing” (id.).
We are not persuaded. First, as discussed above, we do not agree that
Appellants have overcome the Examiner’s prima facie case that the claims
are not enabled. In addition, the first paragraph of 35 U.S.C. § 112 “requires
a ‘written description of the invention’ which is separate and distinct from
the enablement requirement.” Vas-Cath Inc. v. Mahurkar, supra. Thus,
even if the Specification enabled claim 74, it would not necessarily follow
that the Specification provided written description support for claim 74.
Appellants also argue that the “specification clearly describes the
structure required for binding p75NTR” (App. Br. 10). To support this
statement, Appellants refer to the Specification at page 21, line 9, to page 23,
line 22 (id.).
We are not persuaded. The cited portion of the Specification indicates
that assays for identifying substances having the claimed properties are
known, that “peptide libraries and other small organic molecule libraries can
be screened,” and that “the probability of identifying an effective candidate
substance is very high” (FF 6-8). However, describing how to identify
molecules having the claimed function is not a description of “the structure
required for binding p75NTR,” as argued by Appellants. See Rochester, 358
F.3d at 927.
The cited portion of the Specification also discloses that the “amino
acid sequences of the NGF fragments, analogues, derivatives, variants and
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mutants of the present invention can be altered to optimize NGF binding to
p75NTR” (FF 5), that “the tripeptide lysine-glycine-alanine [KGA] is a
candidate substance,” and that “other peptides containing the KGK or KGA
sequence, or various analogs of the KGK or KGA tripeptide, [can be
evaluated] to determine an optimum conformation and composition that will
bind p75NTR and, thus, block the binding of the apoptosis-inducing
β-amyloid ligand” (FF 8). However, claim 74 is directed to a method that
uses a “small organic molecule” that has the claimed function. The
molecules are not limited to NGF fragments, analogues, derivatives,
variants, and mutants or even to peptides containing the tripeptide KGA or
KGK, or analogs thereof. Thus, these disclosures are not representative of
the claimed genus.
Referring to Horwell and Klebe, Appellants additionally argue that,
“at the time of the invention, there were well known methods in the art to
design molecules and test their biological activity once a few naturally
occurring or synthetic molecules having a desired function were identified”
(App. Br. 10).4 We are not persuaded. Horwell “describes a rationale and
strategy for the design of low molecular weight, non-peptide ligands
(peptoids), using the chemical structure of mammalian neuropeptides as a

4 This argument appears to be more relevant to the enablement rejection.
However, this argument does not persuade us to reverse the enablement
rejection. In particular, both Horwell and Klebe describe the difficulties
associated with designing non-peptide equivalents to peptides (FF 15-17 &
21). Although they propose techniques to deal with these difficulties (FF 13,
18, 19, & 22), we do not agree that the disclosure of techniques that may or
may not work is sufficient to demonstrate that non-peptide equivalents can
be uncovered without undue experimentation (see FF 20 & 23).
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starting point” (FF 13). In addition, Klebe discloses “a knowledge-based
approach toward conformational analysis[, where the] ‘knowledge’ . . . is not
stored in terms of ‘rules’, but incorporated into an extended set of
conformational libraries which are directly derived from crystal data by a
statistical evaluation of conformational preferences” (FF 22). However,
neither reference describes the physical properties or another precise
definition of molecules that bind to the p75 nerve growth factor receptor.
Referring to McDonald and Chapman, Appellants also argue that, “at
the time of the invention, receptor-ligand binding models existed for
designing analogs of the highly conserved protein NGF and its relatives”
(App. Br. 11). McDonald discloses the crystal structure of the murine NGF
dimer (FF 24) and Chapman discloses a molecular model of p75 nerve
growth factor receptor (FF 26). However, Appellants have not shown that
the crystal structure of NGF or the molecular model of the p75 nerve growth
factor receptor provides sufficient information about molecules other than
NGF that bind to the p75 nerve growth factor receptor to describe these
molecules.
Conclusion
Appellants have not shown that the Examiner erred in concluding that
the Specification does not provide an adequate written description to support
the claim term “small organic molecule.” We therefore affirm the written
description rejection of claim 74. Claims 56-73 and 75-77 have not been
argued separately and therefore fall with claim 74. 37 C.F.R.
§ 41.37(c)(1)(vii).
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Application 10/785,924

20
ANTICIPATION
The Examiner finds that Rabizadeh teaches “a method of inhibiting
p75NGFR mediated apoptosis in PC12 cells transfected to express
p75NGFR . . . by administering NGF in the presence of βAP” (Ans. 11).
The Examiner also finds that the “NGF used by Rabizadeh et al. meets the
limitation of ‘small organic molecule’ absent a specific definition in the
spec[i]fication or claims, since peptides are small and organic” (id. at 12).
Appellants argue that “one of skill in the art would not consider the
term ‘small organic molecule’ to include a protein such as NGF. Instead,
one of skill in the art would describe a protein such as NGF as a
macromolecule.” (App. Br. 13.)
Issue
Did the Examiner err in concluding that NGF is a “small organic
molecule”?
Findings of Fact
29. Rabizadeh discloses that the “low-affinity nerve growth factor
receptor (NGFR) p75NGFR induces apoptosis in the absence of nerve growth
factor (NGF) binding but enhances neural survival when bound to NGF”
(Rabizadeh, Abstract).
30. In particular, Rabizadeh discloses that “cells that express
p75NGFR . . . were sensitive to [β-amyloid peptide] toxicity, with a LD50 of
≈5 µM, but that the LD50 increased to ≈50 µM in the presence of NGF” (id.
at 10705).
31. The term “macromolecule” is defined as a “molecule, usually
organic, composed [of] an aggregation of hundreds or thousands of atoms”
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Hawley’s Condensed Chemical Dictionary, 14th ed. (2002) (definition
attached). The definition goes on to state:
Such giant molecules are generally of two types. (1) Individual
entities (compounds) that cannot be subdivided without losing
their chemical identity. Typically these are proteins, many of
which have molecular weights running into the millions.
(2) Combinations of repeating chemical units (monomers)
linked together into chain or network structures called
polymers; each monomer has the same chemical constitution as
the polymer, e.g., isoprene (C5H8) and polyisoprene (C5H8)n. . . .
(Id.)
32. “NGF is a dimeric molecule, with 118 amino acids per
protomer” (McDonald 411).
Principles of Law
“A claim is anticipated only if each and every element as set forth in
the claim is found, either expressly or inherently described, in a single prior
art reference.” Verdegaal Bros., Inc. v. Union Oil Co., 814 F.2d 628, 631
(Fed. Cir. 1987).
“It is axiomatic that, in proceedings before the PTO, claims in an
application are to be given their broadest reasonable interpretation consistent
with the specification.” In re Sneed, 710 F.2d 1544,1548 (Fed. Cir. 1983).
However, claim language must be interpreted according to how it would
have been understood by those skilled in the art at the time the application
was filed. See Schering Corp. v. Amgen Inc., 222 F.3d 1347, 1353 (Fed. Cir.
2000). In addition, if an Applicant wants to be his own lexicographer and
give a term other than its ordinary meaning, the Specification must clearly
redefine the term so as to put one skilled in the art on notice that the term has
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22
been redefined. Process Control Corp. v. HydReclaim Corp., 190 F.3d
1350, 1357 (Fed. Cir. 1999).
Analysis
Rabizadeh discloses contacting, in the presence of β-amyloid, a cell
that expresses p75 nerve growth factor receptor with an organic molecule,
NGF, that “binds to the p75 nerve growth factor receptor with at least about
half the affinity as nerve growth factor and competitively inhibits binding of
β-amyloid to the p75 nerve growth factor receptor,” as recited in claim 74
(emphasis added) (FF 29-30). However, we do not agree that the Examiner
has set forth a prima facie case that NGF would be considered a “small
organic molecule.”
In particular, we agree with Appellants that one of ordinary skill in the
art would consider NGF to be a “macromolecule” (FF 31-32). In the
attached definition, a macromolecule is referred to as a “giant” molecule.
Thus, although we recognize that “small” is a relative term and that NGF is
small relative to many objects, we do not agree that the Examiner has set
forth a prima facie case that one of ordinary skill in the art would consider
NGF to be a “small” molecule.
The Examiner argues that “[n]owhere in the specification is NGF or
other larger polypeptides clearly excluded in a definition of molecules that
could be used in the claimed methods” (Ans. 34). Therefore, the Examiner
argues that “the plain meaning defined in Appellants’ arguments is
inconsistent with the specification, which does not exclude macromolecules”
(id. at 35).
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We agree with the Examiner that the Specification does not clearly
exclude NGF or other large polypeptides from being substances that could
be used in the methods described therein. However, the Examiner has not
pointed to a passage in the Specification suggesting that the term “small
organic molecule” should be interpreted to include NGF and other large
polypeptides. Therefore, we agree with Appellants that the term “small
organic molecule” should be interpreted as it would be by one of ordinary
skill in the art.
Conclusion
The Examiner has not set forth a prima facie case that NGF would be
considered a “small organic molecule.” We therefore reverse the
anticipation rejection of claim 74 and of claims 56, 57, 61-63, 65-67, 69, 70,
and 75-77, which recite or depend from a claim that recites a “small organic
molecule.”
ORDER
We affirm the enablement and written description rejections of
claims 56-77. However, we reverse the anticipation rejection of claims 56,
57, 61-63, 65-67, 69, 70, and 74-77.
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

LP
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24
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P.O. BOX 9133
CONCORD, MA 01742-9133