Ex Parte Tang

Patent Trial and Appeal Board

Apr 16, 2013

11676042 (P.T.A.B. Apr. 16, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JORDAN TANG
__________

Appeal 2011-010598
Application 11/676,042
Technology Center 1600
__________

Before DEMETRA J. MILLS, FRANCISCO C. PRATS, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to processes for
inhibiting amyloid-β protein (Aβ) production in human neuronal cells in
vitro, as well as in subjects suffering from Alzheimer’s disease (AD). The
Examiner entered rejections for lack of written description and enablement.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

STATEMENT OF THE CASE
The Specification explains that “amyloid ‘plaques,’ and tangled
bundles of fibers, now called neurofibrillary ‘tangles[]’ . . . are considered
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hallmarks of AD [Alzheimer’s disease]” (Spec. 2-3). “The production,
aggregation, and accumulation of amyloid β-protein (Aβ), the major
constituent of the amyloid plaque, in the brain are initial steps in the
pathogenesis of AD” (id. at 3).
The Specification explains that when the lipid carrier protein
apolipoprotein E (ApoE) binds to its receptor (ApoER2), the resulting
complex is transported into cells (see id.). The Specification notes that three
different forms of ApoE are present in humans: ApoE2, ApoE3, and ApoE4
(see id.).
The Specification further explains that, although the association
between AD and ApoE is “unclear,” “ApoE polymorphism is linked to AD
as people with ApoE4 have higher incidence of the disease” (id. (citation
omitted)).
Appellant’s invention is thus directed to a process of reducing Aβ
production in a neuronal cell expressing an ApoER2 receptor by providing
to the cell an agent “that inhibits the binding of ApoE to ApoER2. In
another embodiment . . . there is provided a method of blocking the
progression of one or more symptoms of Alzheimer’s Disease in a subject
comprising providing to subject an agent that inhibits the binding of ApoE to
ApoER2” (id. at 4).
The Specification discloses that the agent which reduces Aβ
production “may preferentially inhibit the interaction of ApoE4 binding to
ApoER2” (id.). The Specification states that such agents include peptides
which are subsequences of the known ApoE4 protein sequence (see id. at
14-15), and which are six to forty amino acids in length (see id. at 17). “Of
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particular interest are peptides that span the region of polymorphism in
ApoE4, namely, residue 112” (id.).
Claims 1, 6, 13-15, and 20-22 stand rejected and appealed (App. Br.
2). Claims 1, 20, and 21 illustrate the appealed subject matter and read as
follows:
1. A method of inhibiting Aβ production in a human neuronal cell
expressing a human ApoER2 receptor comprising providing to
said cell a human ApoE4 peptide of 6 to 40 amino acids that
inhibits the binding of ApoE4 to ApoER2.

20. The method of claim 19 [sic, 1?], wherein said human neuronal
cell is in a living subject.

21. The method of claim 20, wherein said living subject suffers
from Alzheimer’s Disease.

The following rejections are before us for review:
(1) Claims 1, 6, and 13-15, under 35 U.S.C. § 112, first paragraph, as
failing to comply with the written description requirement (Ans. 4-7); and
(2) Claims 1, 6, 13-15, and 20-22, under 35 U.S.C. § 112, first
paragraph, as failing to comply with the enablement requirement (Ans. 8-
13).1

1 The Examiner entered a new ground of rejection for lack of enablement as
to claims 20-22, based on a rationale previously applied in office actions
entered July 6, 2009, and March 12, 2010 (see Ans. 11-13). In response,
Appellant contends that the new ground “improperly . . . resurrects” the
previously withdrawn rejection (Reply Br. 6), but also argues the merits of
the new rejection (see id. at 6-7). Because the Reply Brief alleges no
specific procedural defect as to the new ground, and because the Reply Brief
addresses the new ground and does not request that prosecution be reopened,
Appellant has in effect requested this appeal to be maintained. See 37
C.F.R. § 41.39(b)(1) and (b)(2).
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WRITTEN DESCRIPTION
The Examiner initially notes that the rejected claims recite inhibiting
Aβ production in human neuronal cells using “a genus of peptide molecules
defined by functional activity and length, namely, any ApoE4 peptide of 6-
40 amino acids that is able to inhibit binding of ApoE4 to ApoER2” (Ans.
4).
The Examiner finds, however, that it is not clear from the
Specification “what molecules that are 6-40 residues in length are
considered ApoE4 peptides capable of inhibiting the binding of ApoE4 to
ApoER2 as there is no structure-to-function description or a representative
number of species within the genus of peptides” (id. at 6). In particular, the
Examiner finds that the Specification “does not provide any partial or
complete structure of a conserved domain necessary for said activity, and
fails to provide a representative number of example inhibitory peptides
within the genus claimed” (id.).
Appellant argues that a “computer program could quickly spit out
each and every peptide within the scope of the present claims, and though
that number might be rather large, size alone is not grounds for lack of
written description” (App. Br. 5; see also Reply Br. 3). Appellant argues
that, “in the field of protein biology, it is quite common to make peptides
from a given molecule and randomly screen for their activity. To argue that
one of ordinary skill in the art could not envision each and every one of the
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peptides falling within the scope of the claims simply is not credible” (id.
(citing Koelsch Declaration)).2
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.

We select claim 1 as representative of the claims subject to this
ground of rejection. See 37 C.F.R. § 41.37(c)(1)(vii).
Appellant’s arguments do not persuade us that a preponderance of the
evidence fails to support the Examiner’s prima facie case of lack of written
description as to claim 1.
“The written description requirement . . . ensures that when a patent
claims a genus by its function or result, the specification recites sufficient
materials to accomplish that function - a problem that is particularly acute in
the biological arts.” Ariad Pharms., Inc. v. Eli Lilly and Co., 598 F.3d 1336,
1352-53 (Fed. Cir. 2010) (en banc).
Thus, a “sufficient description of a genus . . . requires the disclosure
of either a representative number of species falling within the scope of the
genus or structural features common to the members of the genus so that one
of skill in the art can ‘visualize or recognize’ the members of the genus.” Id.
at 1350 (quoting Regents of the University of California v. Eli Lilly & Co.,
119 F.3d 1559, 1568-69 (Fed. Cir. 1997)).

2 Declaration of Gerald Koelsch under 37 C.F.R. § 1.132 (declaration
executed December 3, 2008).
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Accordingly, “merely drawing a fence around the outer limits of a
purported genus is not an adequate substitute for describing a variety of
materials constituting the genus and showing that one has invented a genus
and not just a species.” Id.
Ultimately, the “test for sufficiency is whether the disclosure of the
application relied upon reasonably conveys to those skilled in the art that the
inventor had possession of the claimed subject matter as of the filing date.”
Id. at 1351.
In the instant case, it appears that the sequence of ApoE4 was known
at the time this application was filed (see Spec. 14-15). The Examiner thus
does not dispute Appellant’s assertion (see App. Br. 5; see also Koelsch
Dec. ¶ 5), that it would have been a routine matter to ascertain all possible
subsequences of ApoE4 that are 6 to 40 amino acids in length.
Claim 1, however, also requires the peptides having those sequences
to be capable of inhibiting binding of ApoE4 to ApoER2 to the extent that
Aβ production in a human neuronal cell is also inhibited. As Examiner
points out, the Specification simply does not demonstrate that any peptide
meeting the structural requirements of claim 1 also meets the functional
requirements of the claim.
Specifically, the Specification asserts that it “show[s] that ApoER2
mediates the increase of Aβ40 production by ApoE, especially ApoE4, in
neuronal cells” (Spec. 12; see also id. at 43, 47-49). The Specification
asserts that “[t]his discovery also predicts that small molecular antagonists
that interfere with the binding of ApoER2 to ApoE, especially ApoE4, will
reduce the production of Aβ” (id. at 12).
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The Specification does not, however, describe any experiments that
confirm the accuracy of this prediction. Rather than verifying that peptides
consisting of ApoE4 subsequences, as recited in claim 1, can inhibit the
observed ApoE4-induced increase in Aβ production, the Specification
merely directs practitioners to determine for themselves whether such
peptides will inhibit Aβ production, and if so, which ones possess the
inhibitory activity (see id. at 18-19):
Short peptide sequences, or libraries of overlapping peptides,
usually from about 6 up to about 35 to 50 amino acids, which
correspond to the selected regions described herein, can be
readily synthesized and then screened in screening assays
designed to identify reactive peptides. Alternatively,
recombinant DNA technology may be employed wherein a
nucleotide sequence which encodes a peptide of the invention is
inserted into an expression vector, transformed or transfected
into an appropriate host cell and cultivated under conditions
suitable for expression.

Thus, as the Specification does not specifically identify a single
peptide which has the functional attributes required by claim 1, we are not
persuaded that the Specification meets the test of demonstrating possession
of the claimed subject matter. The fact that the Specification identifies a
potentially “rather large” group of peptides (App. Br. 5) which might include
a peptide having the inhibitory activity required by claim 1 does not, in our
view, demonstrate possession.
It may be true, as Appellant seems to argue, that a skilled practitioner
could determine, through a routine test of every peptide meeting the
structural requirements of claim 1, whether the Specification’s prediction of
inhibiting Aβ production was accurate. That fact does not, however, negate
the Specification’s failure to verify the propounded theory by identifying,
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that is, by specifically describing, at least one peptide within the structural
limits of claim 1 that also has the required activity of inhibiting ApoE4
binding to ApoER2 so as to inhibit Aβ production.
Given the teachings in the Specification, an ordinary artisan might
have considered it an obvious matter to determine which of the peptides
structurally named in claim 1 also possessed the claimed inhibitory activity.
As the court pointed out in Ariad, however, “a description that merely
renders the invention obvious does not satisfy the requirement.” Ariad v.
Lilly, 598 F.3d at 1352; see also University of Rochester v. G.D. Searle &
Co., Inc., 358 F.3d 916, 927-928 (Fed. Cir. 2004) (although claims specified
a broad category of drugs (NSAIDS) that an ordinary artisan could readily
envision and test, court found lack of written description in view of the
patentees’ failure to provide any specific examples of embodiments that met
the desired functional property recited in the claims).
In sum, Appellant’s arguments do not persuade us, for the reasons
discussed, that a preponderance of the evidence fails to support the
Examiner’s prima facie case of lack of written description as to claim 1. We
therefore affirm the Examiner’s rejection of that claim, as well as claims 6,
and 13-15, which were not argued separately. See 37 C.F.R.
§ 41.37(c)(1)(vii).
ENABLEMENT
The Examiner acknowledged that it was known in the art that
“peptides, in general, may inhibit protein-protein interactions,” but
contended nonetheless that “there are no generalizations about such
interactions; rather, these inhibitions require specific confirmation on an
individual peptide-to-protein basis” (Ans. 8).
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The Examiner found that Appellant’s Specification “fails to provide
such guidance, by failing to provide a single example of any single specific
peptide that inhibits, with a reasonable expectation of success, the
interaction between ApoE4 and ApoER2” (id.). In particular, as to claim 1,
the Examiner found that the Specification “had not provided a single
representative example of a peptide of ApoE4 that is 6 to 40 amino acids
long and which specifically inhibits binding of ApoE4 to ApoER2” (id.).
In contrast to the inhibitory activity required by claim 1, the Examiner
noted the Specification’s disclosure that ApoE4 itself “increases Aβ
production” (id.). Noting the Specification’s failure to provide in vivo or in
vitro representative working examples, the Examiner reasoned:
Given the unpredictability within the art; the fact that the
instant claims are based upon a theory that inhibition of the
interaction of ApoE4 with ApoER2 leads to an inhibition of Aβ
production, a theory for which there is no suggestion or
evidence in the specification or the art at filing; and taking into
consideration the evidence at the time of filing that specific
domains within ApoE4 actually mediate an increase[d] Aβ
production, then one of ordinary skill in the art would have to
make a substantial inventive contribution in order to practice
the method as claimed.

(Id. at 9; see also id. at 18 (citing Ye)).3
As to claims 20-22, which recite inhibiting Aβ production in neuronal
cells within a living subject either suffering from AD, or who is at risk of
developing AD, the Examiner again contended that the Specification lacked
guidance explaining which ApoE peptides “within the broad genus claimed

3 Shiming Ye et al., Apolipoprotein (apo) E4 enhances amyloid β peptide
production in cultured neuronal cells: ApoE structure as a potential
therapeutic target, 102 PNAS 18700-18705 (2005).
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actually inhibit Aβ production with a reasonable expectation of success. Nor
is there any guidance as to how contact of neuronal cells in vivo is to be
achieved, or how individuals having Alzheimer’s disease or at risk of
Alzheimer’s disease are identified” (id. at 12). The Examiner urged that,
given the recognition in the art as to the unpredictability in diagnosing and
predicting AD, “one of ordinary skill would not know how to practice the
method without undue further experimentation” (id.).
Appellant argues that it is “a well-known scientific fact that peptides
are effective inhibitors of protein-protein interactions, particularly where the
peptide is derived from portion of one of the two interacting proteins. Thus,
the present claims are grounded in both scientific fact, as well as highly
credible scientific theory” (App. Br. 8; see also Reply Br. 5-6). Appellant
points to the Koelsch Declaration as support for that argument (see App. Br.
9-10). In particular, the declaration states that it is “well known that
receptor ligand interactions can be effectively blocked by peptides that
mimic the binding motif of the ligand. In fact, many FDA-approved drugs
are peptides which are either agonists or antagonists to their native
counterpart” (Koelsch Dec. ¶ 5).
Appellant further argues that an ordinary artisan would not have had
to experiment unduly to “assess various ApoE4 peptides falling within the
scope of the instant claims for their ability to block ApoE4 binding to its
receptor” (App. Br. 10). Rather, Appellant argues, “[g]iven the nature of the
invention (identifying inhibitory peptides) and the skill of those in the art at
the time of filing, even considerable experimentation would not be
considered undue” (id.).
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Facts that should be considered in determining whether a specification
is enabling, or if it would require an undue amount of experimentation to
practice the invention include: (1) the quantity of experimentation necessary
to practice the invention, (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. See In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
We again find that Appellant’s arguments do not persuade us that a
preponderance of the evidence fails to support the Examiner’s prima facie
case of lack of enablement. Appellant has not shown by a preponderance of
the evidence that upon consideration of the Wands factors that it would not
have required undue experimentation on the part of one of ordinary skill in
the art to practice the claimed invention and identify peptides which have the
functional properties required by the claims.
As noted above, although Appellant’s Specification proposes a theory
by which a practitioner might inhibit in vitro and in vivo Aβ production by
neuronal cells expressing ApoER2, the Specification does not provide any
working examples of peptides having the structure required by claim 1,
which also have the functional properties required by the claim.
Appellant’s Specification thus resembles that discussed in In re ‘318
Patent Infringement Litigation, 583 F.3d 1317 (Fed. Cir. 2009), in which a
proposed theory of therapeutic efficacy was held as failing to enable
treatment methods because of the absence of any specific in vivo or in vitro
data. See id. at 1327 (“[A]t the end of the day, the specification, even read
in the light of the knowledge of those skilled in the art, does no more than
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state a hypothesis and propose testing to determine the accuracy of that
hypothesis. That is not sufficient.”).
As the court stated in In re ‘318 Patent Infringement Litigation:
If mere plausibility were the test for enablement under section
112, applicants could obtain patent rights to ‘inventions’
consisting of little more than respectable guesses as to the
likelihood of their success. When one of the guesses later
proved true, the ‘inventor’ would be rewarded the spoils instead
of the party who demonstrated that the method actually worked.
That scenario is not consistent with the statutory requirement
that the inventor enable an invention rather than merely
proposing an unproved hypothesis.

Id. (quoting Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1325
(Fed. Cir. 2005)).
We thus acknowledge the evidence in the Specification supporting the
proposition that the ApoE4-induced increase in Aβ production involves the
interaction between ApoE4 and its receptor, ApoER2 (see, e.g., Spec. 12, 43,
47-49). Again, however, the Specification simply does not provide a single
example of a peptide consisting of a subsequence of ApoE4, six to forty
amino acids in length, that inhibits ApoE4 binding to ApoER2 to the extent
that Aβ production is also inhibited.
While Appellant urges that the inventive concept is based on well
known scientific fact, neither Appellant nor the declarant points to a single
specific prior art example where a subsequence of a receptor-binding protein
was found to block an undesired downstream physiological effect of
receptor binding. Moreover, because ApoE4’s interaction with ApoER2
increases Aβ production, we perceive no error in the Examiner’s finding that
an ordinary artisan would have equally surmised that binding of an
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appropriate subsequence of that stimulatory protein, as recited in claim 1,
would increase rather than inhibit Aβ production. Also, as noted above,
mere plausibility is not an adequate substitute for presenting a working
enabled invention. See In re ‘318 Patent Infringement Litigation, 583 F.3d
at 1327.
We are also not persuaded that Ye supports a conclusion that the
Specification enables claim 1. We note that the ApoE4 (Thr-61) mutant of
ApoE4 did not elicit an increase in Aβ production to the same extent as
ApoE4 (see Ye 18704 (Fig. 5B)). The ApoE4 (Thr-61) protein, however,
appears to be a full length version of the ApoE4 molecule with threonine
substituted for the amino acid normally occurring at position 61 (see id. at
18700 ((“the Thr-61 mutant of apoE4 (apoE4-Thr-61)”)).
Thus, the ApoE4 (Thr-61) protein not only has a different sequence
than ApoE4, it is not a subsequence of ApoE4 which is six to forty amino
acids in length, as claim 1 requires. Moreover, rather than being used as a
blocking agent like the small molecules whose inhibitory effect is shown in
Figure 5C of Ye, Ye merely compares the Aβ production-inducing effect of
the ApoE4 (Thr-61) protein to ApoE4, to show the effect of the domain
interaction property of ApoE4 (see id. at 18703).
In sum, Appellant’s arguments do not persuade us, for the reasons
discussed, that a preponderance of the evidence fails to support the
Examiner’s prima facie case of lack of enablement as to claim 1. We
therefore affirm the Examiner’s rejection of that claim, as well as claims 6
and 13-15, which were not argued separately. As the in vivo methods
recited in claims 20-22 ultimately rely on the same unverified theory of
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inhibiting Aβ production underlying claim 1, we affirm the Examiner’s
enablement rejection as to claims 20-22 as well.

SUMMARY
We affirm the Examiner’s rejection of claims 1, 6, and 13-15, under
35 U.S.C. § 112, first paragraph, for failure to comply with the written
description requirement.
We also affirm the Examiner’s rejection of claims 1, 6, 13-15, and 20-
22, under 35 U.S.C. § 112, first paragraph, as failing to comply with the
enablement requirement.

TIME PERIOD
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

msc