Ex Parte Olson

Board of Patent Appeals and Interferences

May 22, 2008

10043658 (B.P.A.I. May. 22, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

Ex parte ERIC N. OLSON
____________

Appeal 2007-4153
Application 10/043,658
Technology Center 1600
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Decided: May 22, 2008
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Before DEMETRA J. MILLS, LORA M. GREEN, and
RICHARD M. LEBOVITZ, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal from the final rejection of claims 1, 4, and
9. We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

STATEMENT OF THE CASE
“Cardiac hypertrophy is an adaptive response of the heart to virtually
all forms of cardiac disease, including those arising from hypertension,
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Application 10/043,658

mechanical load, myocardial infarction, cardiac arrythmias, endocrine
disorders and genetic mutations in cardiac contractile protein genes. While
the hypertrophic response is initially a compensatory mechanism that
augments cardiac output, sustained hypertrophy can lead to dilated
cardiomyopathy, heart failure, and sudden death. In the United States,
approximately half a million individuals are diagnosed with heart failure
each year, with a mortality rate approaching 50%” (Spec. 2).
Myocyte enhancer factor-2 (MEF2) is a transcription factor expressed
in cardiac tissue which is described in the Specification as having an
important role in the control of cardiac hypertrophy (Spec. 4-5). The
Specification states that inhibiting the function of MEF2 can be used to treat
cardiac hypertrophy (Spec. 6-7). The claims in this appeal are directed to
methods of treating hypertrophy in a cardiomyocyte by inhibiting the
function of MEF2.
Claims 1, 4, and 9 are pending, stand rejected, and are appealed (App.
Br. 4). There is one rejection at issue: Claims 1, 4, and 9 under 35 U.S.C. §
112, first paragraph, for lack of enabling disclosure (App. Br. 4; Ans. 4).
Claims 1 and 9, which read as follows, are representative of the claimed
subject matter.
1. A method of treating hypertrophy in a cardiomyocyte cell
comprising the step of inhibiting the function of MEF2.

9. The method of [claim 1 further comprising inhibiting the
upregulation of a gene upregulated by MEF2] 4, wherein the
agent that inhibits the function of said genes is an antisense
construct.

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ISSUE ON APPEAL
The Examiner contends that claims contain subject matter which is
“not described in the specification in such a way as to enable one skilled in
the art . . . to make and/or use the invention” (Ans. 4). The Examiner finds
the following deficiencies in the Specification:
1) MEF2 is a class of transcription factors which include the MEF2A,
MEF2B, MEF2C, and MEF2D isoforms (Spec. 4: 1-4; 16-17). The
Specification, however, only provides evidence that MEF2C is involved in
cardiac hypertrophy, but not the other members of the MEF2 family
(Ans. 5-6);
2) The Specification shows a correlation between cardiac hypertrophy
and up-regulation of MEF2, but no direct evidence that MEF2 is a causative
factor of hypertrophy (Ans. 5);
3) The Specification is not enabled for the claimed method because
“no specific compounds are provided in the specification” (Ans. 12) to
achieve the claimed method of “treating hypertrophy in a cardiomyocyte
comprising the steps of . . . inhibiting the function of MEF2.”

DISCUSSION
No evidence that all MEF2 isoforms are involved in cardiac hypertrophy
The MEF2 family of transcription factors includes four different
isoforms, MEF2A, MEF2B, MEF2C, and MEF2D (Spec. 4: 1-4; 16-17).
Claim 1 is directed to treating cardiac hypertrophy by “inhibiting the
function of MEF2” and thus covers inhibition of any one (or all) of the four
known isoforms. The Examiner asserts that the Specification provides
evidence that only one of these isoforms, MEF2C, is involved in cardiac
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hypertrophy and thus concludes that the Specification is not enabled for the
full scope of the claim (Ans. 5).
In response to the Examiner’s objection, Appellant provides several
lines of evidence which he asserts establishes “that the extrapolation from
MEF2C to other isoforms is indeed warranted, and . . . that simply alleging
unpredictability . . . cannot shift the burden to appellant to provide clinical
evidence of efficacy” (App. Br. 5). That evidence, which is discussed in
more detail below, includes pre- and post-filing publications, and a
declaration by Dr. Tim Kinsey, an employee of the licensee of the instant
application.
“[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 (Fed. Cir.
1993). “When rejecting a claim under the enablement requirement of
section 112, the PTO bears an initial burden of setting forth a reasonable
explanation as to why it believes that the scope of protection provided by
that claim is not adequately enabled by the description of the invention
provided in the specification of the application; this includes, of course,
providing sufficient reasons for doubting any assertions in the specification
as to the scope of enablement. If the PTO meets this burden, the burden then
shifts to the applicant to provide suitable proofs indicating that the
specification is indeed enabling.” Wright, 999 F.2d at 1561-1562. In making
our determination, we apply the preponderance of the evidence standard.
See Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427 (Fed. Cir. 1988) (explaining
the general evidentiary standard for proceedings before the Office).
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We agree with the Examiner there would have been reasonable basis
at the time of filing to doubt that all the identified MEF2 isoforms are
involved in cardiac hypertrophy. Wright, 999 F.2d at 1561-1562. The
Specification states that “[o]f the four mammalian MEF2 genes, three
(MEF2A, MEF2B and MEF2C) can be alternatively spliced, which have
significant functional differences” (Spec. 16-17). Thus, Appellant admits
that there are “significant functional differences” between the different
isoforms (id.). This statement is consistent with experiments described in
the Specification showing that “a subset of cardiac genes is dependent on
MEF2C” for expression, while certain other cardiac genes which “also
contain essential MEF2 binding sites in their promoters” are “MEF2C-
independent” (Spec. 74). Based on these experiments, the Specification
concluded that “it is likely that another member of the MEF2 family can
support . . . expression [of the MEF2C-independent genes] in the absence of
MEF2C” (id.). Thus, direct evidence is provided in the Specification that
not all members of the MEF2 family have the same function. In our
opinion, these facts establish a reasonable basis to doubt that each of
MEF2A, MEF2B, and MEF2D would have the same functional role as
MEF2C in cardiac hypertrophy.
Appellant provides several lines of evidence to rebut the Examiner’s
finding of reasonable doubt, none of which we conclude is sufficient to
overcome the rejection.
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Appellant relies on two post-filing publications – Xu1 and Mora2 – to
show “that extrapolation from MEF2C to other isoforms is indeed
warranted” (App. Br. 5).
He characterizes Xu as reporting “that MEF2A behaves [as] much as
does MEF2C in terms of sarcomeric disorganization, focal elongation,
altered gene expression, extracellular matrix remodeling, and ion handling.”
Appellant concludes “[t]hus, there is indeed evidence to indicate that
MEF2A, like MEF2C, is involved in hypertrophic signaling” (App. Br. 6).
This evidence is not convincing. Appellant does not explain how the
disclosure that MEF2A’s behavior is like that of MEF2C in certain cellular
processes establishes that MEF2A is also a player in hypertrophic signaling
(App. Br. 6). In particular, Appellant does not state how these cellular
processes predict that MEF2A, like MEF2C, would have a role in cardiac
hypertrophy.
Mora, Appellant states, shows that “MEF2A and MEF2D form a
heterodimer, further suggesting a common role for these two proteins” (App.
Br. 6). Once again, Appellant has not explained how this activity would
compel persons of skill in the art to believe that MEF2A and MEF2D
function similarly to MEF2C – making it reasonable to extrapolate that they
would have the same function in hypertrophy as does MEF2C. For example,
Mora does not state that the heterodimer occurs in hypertrophy; rather, Mora

1 Xu et al., “MEF2A and MEF2C Induce Dilated Cardiomyopathy in
Transgenic Mice”, J. Biol. Chem., M5:10217, Feb. 6, 2006.
2 Mora and Pessin, “The MEF2A Isoform is Required for Striated Muscle-
specific Expression of the Insulin-responsive GLUT4 Glucose Transporter”,
J. Biol. Chem., 275(21): 16323-328, 2000.
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describes the occurrence of MEF2A and MEF2D in insulin-stimulated
glucose uptake (Mora, at 16323, Abstract; see Ans. 9).
There is an additional reason why we find this evidence insufficient.
Enablement is determined as of the application filing date. In re Hogan, 559
F.2d 595, 604 (CCPA 1977). Xu was published in 2006; Mora was
published in 2000. The instant application claims the benefit of an
application having a filing date of Nov. 10, 1999 and provisional
applications filed Nov. 10, 1998 and Nov. 12, 1998 (Bibliographic Data
Sheet). Thus, it appears that both scientific articles were published after the
filing date of the instant application.
[A] later dated publication cannot supplement an insufficient
disclosure in a prior dated application to render it enabling. . . .
[However, a later publication can be used] as evidence of the
level of ordinary skill in the art at the time of the application
and as evidence that the disclosed device would have been
operative. Compare In re Hogan, 559 F.2d 595, 605 (CCPA
1977) (‘This court has approved use of later publications as
evidence of the state of the art existing on the filing date of an
application.’ (footnotes omitted) (emphasis in original)) with In
re Glass, 492 F.2d 1228, 1232 (CCPA 1974) (later publications
which add to the knowledge of the art cannot be used to
supplement an insufficient disclosure).
Gould v. Quigg, 822 F.2d 1074, 1078 (Fed. Cir. 1987).
In this case, there is no evidence that the facts disclosed about
MEF2A and MEF2D as described in Xu and Mora were available to those
skilled in the art (“existing on the filing date”) as of the filing date of the
instant application. Thus, under Gould, the later dated publications cannot
be used to supplement the disclosure.
Our analysis is consistent with Rasmusson v. SmithKline Beecham
Corp., 413 F.3d 1318 (Fed. Cir. 2005). Rasmusson had filed a chain of nine
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patent applications, each claiming a method of treating prostate cancer by
administering finasteride. The Board found that there would have been
reason to doubt as of the application filing dates of the first eight
applications that finasteride could be used to treat prostate cancer. It wasn’t
until the ninth application was filed that evidence because available that
finasteride was effective to treat prostate cancer.
[N]one of the applications filed before the ninth application
“would have enabled a person of ordinary skill in the art as of
each of the respective filing date[s] to treat human prostate
cancer by administering a therapeutically effective amount of
finasteride to a human in need thereof without undue
experimentation.” The Board based that finding on its
determination that a person of ordinary skill in the art would
have had no basis as of the filing date of the eighth application
for believing that finasteride could be used to treat prostate
cancer [as required by the claims] in light of the state of the art
and in light of Rasmusson’s failure to provide any data to
demonstrate the effects of finasteride in treating prostate cancer.
Rasmusson, 413 F.3d at 1322.
Although Rasmusson provided post-filing evidence that the
finasteride actually worked in treating prostate cancer, the Federal Circuit
concurred with the Board that this evidence was only effective to establish
enablement as of the date when the evidence become known to persons of
skill in the art – at which time it would have become effective to dispel the
reasonable doubt about the adequacy of the enabling disclosure.
Black,3 however, was available prior to the application filing date.
Appellant states that this reference provides “additional studies indicating

3 Black et al., “Cooperative transcriptional activation by the neurogenic
basic helix-loop-helix protein MASH1 and members of the myocyte
enhancer factor-2 (MEF2) family”, J. Biol. Chem., 271(43): 26659-26663,
1996.
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that MEF2A, MEF2C and MEF2D have similar functions with respect to
interactions with MASH1 and E12” (App. Br. 6). This argument is not
convincing. According to Black, each of MEF2A, MEF2C, and MEF2D
interact with the MASH1/E12 heterodimer (Black, at 26663, col. 1).
Appellant has not explained why the ability to interact with MASH1/E12
would predict that these isoforms would have the same functional
involvement with cardiac hypertrophy as does MEF2C.
As acknowledged by Appellant, the different MEF2 isoforms are
“alternatively spliced” and have “significant functional differences” between
them (Spec. 16-17). Figure 1 of the Specification shows the isoforms to
share the same DNA binding domain, but to vary in the regions involving
transactivation. The Specification explicitly states that the transcription
activation domain (“transactivation”) of MEF2C “is a nuclear target for
hypertrophic signaling pathways” (Spec. 23). Thus, we find that persons of
ordinary skill in the art would have had reason to believe that differences
between the various isoforms in their transcription activation domains could
lead to functional differences in their role in cardiomyocyte hypertrophy.
A declaration under 37 C.F.R. § 1.132 (dated Sept. 14, 2006) by Dr.
Tim McKinsey (“McKinsey II Dec.”) was provided during prosecution in
which he described experiments using one-month old MEF2D knockout
mice (McKinsey II Dec. ¶ 3). The results showed that thoracic aortic
banding (TAB) produced cardiac hypertrophy in wild-type mice, but not in
animals lacking a functional MEF2D gene (id.)
This evidence does not persuade us that the Examiner erred in
rejecting the claims as non-enabled. First, Appellant does not identify
support in the Specification for making and using the MEF2D knockout
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mice (Ans. 10). Although the Specification describes methods of making
transgenic knockout mice (see Spec. 19-23), there is no explicit statement in
the Declaration that these methods were followed; consequently, it is not
clear that the experiments described in the McKinsey II Declaration were
enabled as of the application filing date.
In addition to this, there is a discrepancy between the function of
MEF2C and MEF2D in the knockout mice. According to the Specification,
mice lacking MEF2C (“knockout”) die at the embryonic stage from severe
cardiovascular defects (Spec. 73-74). However, MEF2D knockout mice
apparently do not die as embryos, but live at least one month after birth
(McKinsey II Dec. ¶ 3). These results hardly support Appellant’s contention
that the results for MEF2C can be extrapolated to MEF2D; in fact, MEF2C
appears to be an embryonic lethal, whereas MEF2D is not.
We also note that Appellant has not made arguments regarding the
reasonableness of extrapolating from MEF2C to MEF2B. This issue was
not addressed in the Appeal Brief nor in the McKinsey II Declaration.
For the foregoing reasons, we conclude that the preponderance of the
evidence supports the Examiner’s conclusion that claim 1 is not enabled for
its full scope, i.e., for treating cardiac hypertrophy by inhibiting all isoforms
of the MFE2 family.

No evidence that inhibiting MEF2 would be effective to treat hypertrophy in
cardiomyocytes
The Examiner acknowledges that “there is evidence that MEF2C
plays a role in the signal transduction pathway that is activated during
conditions that cause hypertrophy” in cardiac cells, but argues that there is
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no direct evidence that MEF2 is a causative factor (Ans. 5, 7). The
Examiner finds that cardiac “hypertrophy is a complex process of signal
transduction” suggesting that “simply inhibiting MEF2 will have no effect
(id. at 5). As evidence of this, the Examiner relies on two post-filing
references, Olson and Prassier.4 The Examiner also cites the Specification
for its statement on page 82 that “[c]ardiac hypertrophy has been shown to
be controlled by a signaling pathway involving calcineurin and the
transcription factor NFAT3, but there is evidence for alternate pathway”
involving “activation of MEF2 by CaMK-dissociation of HDAC” as
evidence that multiple pathways control cardiac hypertrophy.
Appellant contends that the Examiner erred. “The only specific attack
on MEF2 gene therapy is that inhibiting MEF2 generally would not be
believed to inhibit cardiac hypertrophy. . . . [A]ppellants have submitted an
expert declaration (McKinsey Declaration A; Exhibit 4) and a recently
published paper on this precise point (Xu et al., 2006; Exhibit l), both
documents supporting the position that down-regulating MEF2 would
indeed be therapeutic of cardiac hypertrophy” (App. Br. 8).
The Examiner bears the initial burden of setting forth a reasonable
explanation as to why the claims are not adequately enabled by the
Specification. A number of factors may be considered in making this
determination, including: (1) 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

4 Both are post-filing publications. The Examiner has not established that
the facts in Olson and Prassier were available as of the instant application
filing date. See Gould supra. Thus, we have not considered them in our
analysis.
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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. In re Wands,
858 F.2d 731, 737 (Fed. Cir. 1988). Here, the Examiner states that the
absence of working examples, the lack of a direct link between MEF2
inhibition and treatment of hypertrophy, and the finding that multiple
pathways are involved cardiac hypertrophy (generally, “unpredictability”)
together constitute a reasonable basis for doubting that the invention could
be carried out as claimed (see Ans. 4). As we find no defect in the
Examiner’s reasoning, we turn to Appellant’s response.
To rebut the Examiner’s conclusion, Appellant relies on additional
evidence (App. Br. 7-9): Xu and a declaration by Dr. McKinsey dated Apr.
4, 2005 (“McKinsey I Dec.”). However, Xu, as discussed previously, was
published after the application’s filing date and is therefore relevant only as
to those facts known on the application’s filing date. Likewise, Dr.
McKinsey bases his opinion on post-published references: Zhang5 in 2002
and his own post-filing reference6 (McKinsey, 2002).
As we stated previously, enablement is determined as of the
application filing date. Hogan, 559 F.2d at 604. Appellant has not
addressed the pivotal issue: whether persons of ordinary skill in the art
would have reasonably believed at the time of filing that the claimed method
was enabled in light of the evidence in the Specification coupled with the

5 Zhang et al., “Class II Histone Deacetylases act as signal-responsive
repressors of cardiac hypertrophy”, Cell, 110: 479-88, 2002.
6 Dr. McKinsey provided only the abstract of his publication. The abstract
was incomplete: the right-hand margin was cut off, deleting the last few
letters and words of every line. Because of the defect in the abstract and the
failure to provide the complete publication, we have not considered it in our
analysis.
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knowledge of the ordinary skilled artisan. What is lacking is evidence from
Appellant that the information disclosed in the Specification would have led
persons of ordinary skill in the art to reasonably believe that the claimed
method of inhibiting MEF would work to treat cardiac hypertrophy. The
evidence provide by Appellant is all post-filing (see Ans. 9; see supra. at p.
7) and thus does not address the sufficiency of the Specification.
In reaching this determination, we note that the Specification provides
explicit evidence for a role of MEF2 in cardiac hypertrophy (see
Specification; Examples 2, 3, 4, and 7). The Specification also provides
evidence that CaMK and calcineurin pathways “synergize to active MEF2”
(Spec. 8; see Fig. 2), in contrast to the Examiner’s assertion to the contrary.
The Specification also describes experiments involving several MEF2
isoforms which show their interaction with HDAC (Spec. 79-81). However,
Appellant does not explain how this information would have been sufficient
to enable the full scope of claim 1, which is drawn to inhibiting the function
of MEF2—including all of its isoforms—to treat hypertrophy in a
cardiomyocyte cell, but instead rely only post-filing evidence. Appellant
also does not clarify how their results concerning the effects of CaMK and
calcineurin on MEF2 are consistent with other statements in the
Specification indicating the pathways are alternatives to each other (Spec.
82).

The Specification does not disclose specific compounds to be used in the
claimed method
The Examiner contends that at the time of filing the Specification was
not enabled for decreasing expression of MEF2 to achieve treatment of
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hypertrophy in cardiomyocytes (Ans. 12). The Examiner states that “no
specific compounds” are disclosed in the Specification to treat hypertrophy
(id.). The Examiner also states that antisense as a therapeutic agent “is not a
routine art accepted method” (id. at 13).
Appellant contends that the Specification provides “a detailed
explanation of how one can achieve inhibition of MEF2 signaling” (App. Br.
9), as well as disclosing specific compounds useful for this purpose, such as
antisense polynucleotides and antibodies (id. at 10).
With respect to antisense technology, we find there is sufficient
guidance in the Specification to utilized antisense polynucleotides to treat
hypertrophy in a cardiomyocyte. See instant claim 9. The Specification
provides detailed guidance on how to design antisense polynucleotides
(Spec. 24-37), as well as methods of introducing the polynucleotides into
cells (Spec. 36-52). The Examiner states that antisense technology “is not a
routine art accepted method” (Ans. 13), but does not identify a specific
defect in the Specification disclosure. Nor does the Examiner explain why it
would involve undue experimentation to utilize antisense polynucleotides in
view of the guidance in the Specification.
We do not find this same level of disclosure for antibodies. The
Specification states that antibodies can be used “to block the function of an
MEF2 polypeptide” (Spec. 27-28), but does not explain how antibodies
would be introduced into a cardiomyocyte to treat hypertrophy as required
by claim 1. Thus, the enabling disclosure is not commensurate with the full
scope of claim 1. In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993).

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CONCLUSION
In summary, we affirm the rejection of claim 1under 35 U.S.C. § 112,
first paragraph, as lacking an enabling disclosure. Claims 4 and 9 fall with
claim 1 because they were not separately argued. See 37 C.F.R. §
41.37(c)(vii)(1).
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)(1)(iv)(2006).

dm

Steven L.Highlander, Esq.
Fulbright & Jaworski L.L.P.
600 Congress Avenue, Suite 2400
Austin, TX 78701

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