Ex Parte Nagy

Board of Patent Appeals and Interferences

Jul 1, 2010

10659578 (B.P.A.I. Jul. 1, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ZSUZSANNA NAGY
__________

Appeal 2009-012158
Application 10/659,578
Technology Center 1600
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Decided: July 1, 2010
__________

Before DONALD E. ADAMS, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
for diagnosing Alzheimer’s Disease. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm.

Appeal 2009-012158
Application 10/659,578

Statement of the Case
The Claims
Claims 1-3, 5, 6, 8, 17, 30-32, and 34 are on appeal. Claim 1 is
representative and reads as follows:
1. A method for the diagnosis of a neurological
condition in a human subject, wherein said neurological
condition is selected from the group consisting of:
Alzheimer's Disease; incipient Alzheimer's Disease; possible
Alzheimer's Disease; and Alzheimer's Disease associated
with evidence of other type of dementia; wherein said
method comprises the steps of:
(A) determining the effectiveness of the G1/S cell
cycle checkpoint exhibited by a non-neuronal cell of said
subject; and
(B) comparing said determined G1/S cell cycle
checkpoint effectiveness with the G1/S cell cycle checkpoint
effectiveness exhibited by a non-neuronal reference cell of a
healthy individual or of an individual having said
neurological condition, to thereby diagnose whether said
subject has said neurological condition.

The prior art
The listing of the prior art relied upon by the Examiner is found in the
Examiner’s Answer (see Ans. 2-3).

The issues
A. The Examiner rejected claims 1-3, 5, 6, 8, 17, 30-32, and 34 under 35
U.S.C. § 112, first paragraph, enablement (Ans. 4-9).
B. The Examiner rejected claims 1-3, 5, 6, 8, 17, 30-32, and 34 under 35
U.S.C. § 112, first paragraph, new matter (Ans. 9-10).

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A. 35 U.S.C. § 112, first paragraph, Enablement
The Examiner finds that “merely assaying for a defect in the G1/S
checkpoint, or relative resistance to the effects of a G1 inhibitor such as
rapamycin, then diagnosing patients with such a G1/S defect as having AD
would misdiagnose many cancer patients as having AD” (Ans. 7). The
Examiner finds that:
Applicants provide no direction or guidance for diagnosing
AD, or any other neurological condition, by performing only
the method steps as instantly claimed (e.g. see claim 1). The
specification requires the skilled artisan to practice trial and
error experimentation to develop a reliable and effective
assay that differentiates AD from other dementias and
cancer by merely assaying for a G1/S checkpoint defect.

(Id. at 8.)
Appellant argues that, based on the Nagy Declaration, the diagnostic
method of the Specification “is as reliable as other diagnostic methods in the
art, there is no contradictory data, and there is sufficient guidance both in the
Application and in the general knowledge of those skilled in the art to enable
the diagnosis of the recited neurological diseases using the claimed
methods” (App. Br. 5). Appellant argues that the Specification teaches
“working examples describing the use of the claimed methods to diagnose
Alzheimer’s Disease and the other recited neurological diseases, which
diagnosis was confirmed by the independent diagnosis of the patients using
the NINCDS-ARDRA criteria” (id. at 6).
Appellant also argues, based on the Nagy Declaration, that “use of the
claimed methods would not lead to misdiagnoses” (id. at 7). Appellant
argues that “Dr. Nagy stated that those skilled in the art would recognize the
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ability of the claimed methods to predictably diagnose Alzheimer’s Disease
prior to death, at a reliability comparable to currently used diagnostic
methods” (App. Br. 9).
In view of these conflicting positions, we frame the enablement issue
before us as follows:
Does the evidence of record support the Examiner’s conclusion that
undue experimentation would have been required to perform the claimed
diagnostic test for Alzheimer’s Disease?
Findings of Fact (FF)
Breadth of Claims
1. Claim 1 is drawn to diagnosis in any human subject of
Alzheimer’s Disease, incipient Alzheimer’s Disease, possible Alzheimer’s
Disease and Alzheimer’s Disease associated with evidence of other types of
dementia (see Claim 1).
2. Claim 1 comprises a method of determining the effectiveness of
the G1/S cell cycle checkpoint in any non-neuronal cell of a subject relative
to healthy or diseased controls using any checkpoint inhibitor (see Claims 1
and 3).
Presence of Working Examples
3. The Specification teaches analyzing the lymphocytes of 104
subjects by treating the lymphocytes with or without rapamycin and
measuring “relative lengthening of the G1 phase of the cell cycle in treated
cultures relative to control cultures” (Spec. 24, ll. 24-26).
4. The Specification teaches that:
The highest values, indicating more effective G1 inhibition
by rapamycin, were found in subjects diagnosed as controls,
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dementia syndromes other than AD and possible
Alzheimer’s disease patients. Patients diagnosed as suffering
from AD (probable AD by NINCDS) and those with AD
and coexisting other pathology (ADM) were found to have a
significantly less effective G1 block than control subjects
and patients suffering from DNOS or possAD as diagnosed
by the NINCDS criteria.

(Spec. 26, ll. 6-16.)
5. Figure 2 of the Specification is reproduced below:

“Figure 2 illustrates relative (left panel) and age- corrected relative (right
panel) lengthening of the G1 phase of the cell cycle under the influence of
rapamycin in cultured lymphocytes from preAD, AD, ADM, possAD,
DNOS and control subjects” (Spec. 21, ll. 21-25).
6. The Specification teaches that DNOS is defined as “patients
with dementia who do not meet the requirements of the NINCDS criteria for
probable Alzheimer’s disease” (Spec. 27, ll. 31-32).
Amount of Direction or Guidance Presented
7. The Specification teaches that when “the method of the
invention is used diagnostically, the presence of a defect in cell cycle
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regulation at the G1/S phase transition in a non-neuronal cell type is taken as
an indication that the subject has Alzheimer’s disease” (Spec. 4, ll. 25-29).
8. The Specification teaches screening lymphocytes as the non-
neuronal cell type (see Spec. 5, l. 9).
9. The Specification teaches methods of performing the
proliferation assay as well as calculating the lengthening of the G1 phase of
the cell cycle which results from exposure to a cell division inhibitor or
stimulus that induces cell cycle arrest (see Spec. 8-10).
State of the Prior Art and Unpredictability of the Art
10. The Specification teaches that a “definite diagnosis of
Alzheimer’s disease can only be made after post mortem examination”
(Spec. 5, ll. 4-6).
11. Wendel teaches that “rapamycin reverses the apoptotic defects
and drug resistance occurring in Akt lymphomas . . . although each
lymphoma studied contained an anti-apoptotic lesion, the chemosensitizing
effects of rapamycin were specific for tumours with constitutive Akt
signalling [sic]” (Wendel 334, col. 1).
12. Chan teaches that “mammalian cells display widely varying
sensitivities to the growth-inhibition of rapamycin. A typical target cell for
rapamycin is the activated T lymphocyte, which undergoes G1 to S phase
progression in response to IL-2 or T-cell growth-promoting cytokines”
(Chan 1421, col. 1).
13. Chan teaches that a “study of a panel of breast cancer cell lines
showed differences in the sensitivity to the antiproliferative effects of CCI-
779 [a rapamycin analogue]” (Chan 1421, col. 2).
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14. The Examiner finds that “in Fig. 1A of Nagy et al (2002), the
DNOS group is less responsive to rapamycin than the control. According to
the instantly claimed methods, this would lead to a misdiagnosis of these
patients as having AD, which is clearly not correct” (Ans. 6).
15. Figure 1, panel A of Nagy (2002) is reproduced below:

This figure shows the relative lengthening of the G1 phase in control
patients and patients with various Alzheimer’s disease diagnoses and DNOS
patients, who have dementia but do not meet the requirements of the
NINCDS criteria for probable Alzheimer’s disease.
16. Nagy (2002) teaches that “while the rapamicin [sic] induced a
significant lengthening of the G1 phase after 24 h, the effects on cell
numbers are not robust enough to discriminate between AD patients and
control subjects” (Nagy (2002) 83, col. 2).
17. Ichimura teaches that “[a]bnormalities of genes involved in G1-
S transition and the p53 pathway are frequently found in different human
tumors” (Ichimura 422, col. 2).
Quantity of Experimentation
18. The Examiner finds that the “specification requires the skilled
artisan to practice trial and error experimentation to develop a reliable and
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effective assay that differentiates AD from other dementias and cancer by
merely assaying for a G1/S checkpoint defect” (Ans. 8).
Skill in the art
19. The Examiner finds that “[w]hile the level of skill in the art of
assaying for cell cycle defects is high, the level of skill in the art of
diagnosing AD by assaying for such defects is low” (Ans. 9).
Principles of Law
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.

In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993). “[T]he question of
undue experimentation is a matter of degree. The fact that some
experimentation is necessary does not preclude enablement; what is required
is that the amount of experimentation ‘must not be unduly extensive.”’ PPG
Indus., Inc. v. Guardian Indus. Corp., 75 F.3d 1558, 1564 (Fed. Cir. 1996).
Factors to be considered in determining whether a
disclosure would require undue experimentation … include
(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 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).

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Analysis
Claim interpretation is at the heart of patent examination because
before a claim is properly interpreted, its scope can not be compared to the
prior art. In this case, a central aspect of the dispute centers on the claim
requirement for “diagnosis.”
During prosecution, claim terms are given their broadest reasonable
interpretation as they would be understood by persons of ordinary skill in the
art in the light of the Specification. Therefore, we first turn to the
Specification to determine whether the scope of the term “diagnosis” can be
discerned. The Specification teaches that the invention is “early diagnosis of
Alzheimer’s disease, especially detection of individuals who are in pre-
clinical stages of the disease, and for identification of individuals who have
not yet developed Alzheimer’s disease as such but are ‘at risk’ of doing so
because of the presence of the cell cycle regulatory defect” (Spec. 5, ll. 11-
17).
Therefore, we interpret the “diagnosis” in the context of Claim 1 as
identifying individuals with clinical, pre-clinical, or possible Alzheimer’s
Disease.
The Examiner’s argument is that a method for “diagnosis of a
neurological condition . . . selected from . . . Alzheimer’s Disease; incipient
Alzheimer’s Disease; possible Alzheimer’s Disease; and Alzheimer’s
Disease associated with evidence of other types of dementia” requires that
the method function to reliably distinguish individuals with Alzheimer’s
based neurological conditions from individuals with cancer or dementia
other than Alzheimer’s Disease (see Ans. 5-6). The Examiner explains that
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there is “no certain way to differentiate such a result between a diagnosis of
cancer or one of the recited neurological conditions” (Ans. 5). The
Examiner also finds that “the DNOS group is less responsive to rapamycin
than the control. According to the instantly claimed methods, this would
lead to a misdiagnosis of these patients as having AD, which is clearly not
correct” (id. at 6).
Appellant argues, based on the Nagy Declaration, that the diagnostic
method of the Specification “is as reliable as other diagnostic methods in the
art, there is no contradictory data, and there is sufficient guidance both in the
Application and in the general knowledge of those skilled in the art to enable
the diagnosis of the recited neurological diseases using the claimed
methods” (App. Br. 5).
We find that the Examiner has the better position. The evidence of
record supports the Examiner’s conclusion that the claimed method does not
distinguish between the DNOS patient population and the various
Alzheimer’s patient populations (FF 4-16). Both Figure 2 of the
Specification (FF 5) and Figure 1, Panel A of Nagy (2002) (FF 16) show that
the DNOS patient population, a group defined by the Specification as having
non-Alzheimer’s disease dementia, would be diagnosed by the method of the
instant claims as having Alzheimer’s Disease (FF 5-6, 15-16).
The evidence of record also supports the Examiner’s conclusion that
the claimed method would not reliably distinguish between non-neuronal
cells of certain cancers and Alzheimer’s Disease, as shown by Wendel, Chan
and Ichimura (FF 11-13, 17-18).
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Thus the Examiner has reasonably concluded that undue
experimentation would be required to use the instantly claimed method for
“diagnosis of a neurological condition . . . selected from . . . Alzheimer’s
Disease; incipient Alzheimer’s Disease; possible Alzheimer’s Disease; and
Alzheimer’s Disease associated with evidence of other types of dementia”
since the method will not reliably distinguish the spectrum of Alzheimer’s
Disease patients from DNOS patients or certain cancer patients.
Appellant argues that “because cancer does not produce the cell cycle
effects used in the claim methods in non-cancerous cells, use of the claimed
methods would not lead to misdiagnoses” (Ans. 7). Appellant cites the
Nagy Declaration, which states that “like any other diagnostic method, the
claimed method enables (but does not mandate) the diagnostic practitioner
skilled in the art to make a diagnostic conclusion based on the results of the
method” (Nagy Dec. B-7 ¶ 18).
We are not persuaded since the argument is inconsistent with the
express scope of the claims as written. That is, Claim 1 does not state that
the method is “indicative of a neurological condition . . .” or that the method
shows “increased risk of a neurological condition . . .,” but directly mandates
(to use the Nagy Declaration’s term) that if there is decreased effectiveness
of a G1/S cell cycle checkpoint relative to a normal control, the patient is
diagnosed with Alzheimer’s Disease (see Claim 1). Claim 1 includes no
language to suggest the use of other diagnostic information to determine the
required “diagnosis.” “[L]imitations are not to be read into the claims from
the specification.” In re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir. 1993)
(citing In re Zletz, 893 F.2d 319, 321 (Fed. Cir. 1989)).
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Thus Claim 1 encompasses the situation where a patient with DNOS
or with cancer would submit a sample for analysis, which analysis would
reasonably result in a misdiagnosis based upon the claimed method (FF 10-
18).
Appellant argues regarding the issue of the Nagy (2002) data and the
data in the Application that the “Examiner dismisses these arguments set
forth in the Nagy Declaration with little explanation” (App. Br. 11).
We disagree. The Examiner directly addressed the Nagy
Declaration’s data analysis (see Final Rej. 5). More importantly, the data in
the Nagy Declaration does not detract from the Examiner’s fundamental
point, which is that based upon the data presented using the claimed method,
the skilled artisan would not reasonably be able to reliably distinguish
DNOS patients from other patient populations which are diagnosed as
“Alzheimer’s Disease” or “possible Alzheimer’s Disease” (see App. Br. 11,
Nagy Dec. ¶¶ 12-15).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that undue
experimentation would have been required to perform the claimed diagnostic
test for Alzheimer’s Disease.
B. 35 U.S.C. § 112, first paragraph, New Matter
The Examiner finds that “[t]here is no mention or teachings of a
method step of diagnosing a subject as having one of the neurological
conditions recited in claim 1 by merely comparing a G1/S cell cycle
checkpoint effectiveness of subject cells to those of ‘an individual having
said neurological condition’” (Ans. 10). The Examiner finds that there is
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“no support for the method step of diagnosing one of the neurological
conditions in claim 1 by comparing a determined G1/S cell cycle checkpoint
effectiveness with ‘the G1/S cell cycle checkpoint effectiveness exhibited
by... an individual having said neurological condition’. Thus, the amended
claims include impermissible New Matter” (Ans. 10).
Appellant argues that “the Examiner is arguing that no possession of
the invention is shown because the exact claim language is not used in the
specification, but such argument goes beyond what is required by the law. It
is well-settled that the description of a claimed invention need not be in ipsis
verbis” (App. Br. 13). Appellant argues that the Specification “at page 28,
line 11 through page 29, line 3 describes a comparison between patient
controls (healthy elderly individuals) and patients with Alzheimer's disease,
and then describes an assay based on these results that can be used to
diagnose patients at risk for developing Alzheimer' s disease” (id.).
In view of these conflicting positions, we frame the New Matter issue
before us as follows:
Does the evidence of record support the Examiner’s conclusion that
Claim 1 fails to comply with the written description requirement as
incorporating new matter?
Findings of Fact
20. Claim 1 teaches two alternative modes of diagnosis, one by
comparing G1/S cell cycle checkpoint effectiveness of the subject with the
effectiveness of a healthy individual and one by comparing effectiveness
with an individual having said neurological condition (see Claim 1).
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21. The Specification teaches that the “presence, of a cell cycle
regulatory defect at the G1/S phase transition is indicated by a reduced
relative lengthening of the G1 phase in the presence of the cell division
inhibitor substance or stimulus in cells from the test subject, as compared to
control cells not having a cell cycle regulatory defect at the G1/S phase
transition” (Spec. 10, ll. 9-15).
22. The Specification teaches that the “highest values, indicating
more effective G1 inhibition by rapamycin, were found in subjects
diagnosed as controls, dementia syndromes other than AD and possible
Alzheimer's disease patients” (Spec. 26, ll. 6-10).
23. The Specification teaches that the “results of the first set of
experiments indicate that G1 inhibitor-induced cell cycle arrest, as indicated
by the lengthening of the G1 phase of the cell cycle, is significantly less
effective in patients suffering from Alzheimer's disease than in control
individuals” (Spec. 28, ll. 11-16).
24. The Specification teaches that
the results of this study indicate that the response of
activated lymphocytes to G1 inhibition is significantly
altered in Alzheimer’s disease sufferers. In addition these
alterations appear early before the onset of a fully developed
dementia syndrome identifying subjects who are likely to
develop Alzheimer’[s] disease later. The results indicate that
a diagnostic test relying on the detection of the integrity of
the G1/S transition checkpoint may allow the identification
of subjects who are at risk from developing AD later.

(Spec. 29, ll. 25-35.)

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Principles of Law
[T]he hallmark of written description is disclosure. . . . the
test requires an objective inquiry into the four corners of the
specification from the perspective of a person of ordinary
skill in the art. Based on that inquiry, the specification must
describe an invention understandable to that skilled artisan
and show that the inventor actually invented the invention
claimed.

Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1351 (Fed.
Cir. 2010).
“[T]he written description requirement does not demand either
examples or an actual reduction to practice; a constructive reduction to
practice that in a definite way identifies the claimed invention can satisfy the
written description requirement” id. at 1352. “[I]t is the specification itself
that must demonstrate possession. And while the description requirement
does not demand any particular form of disclosure, . . . or that the
specification recite the claimed invention in haec verba, a description that
merely renders the invention obvious does not satisfy the requirement” id.
(citations omitted).
It is the Examiner's “initial burden [to] present [ ] evidence or reasons
why persons skilled in the art would not recognize in the disclosure a
description of the invention defined by the claims.” In re Wertheim, 541
F.2d 257, 263 (CCPA 1976).
Analysis
There is no dispute that the Specification teaches comparison of the
tested non-neuronal cells to controls. The issue is whether the Specification
demonstrates possession of a control using cells “of an individual having
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said neurological condition” as introduced by Appellant’s amendment of
August 6, 2007.
Appellant points to page 10 of the Specification, which teaches that
the “presence, of a cell cycle regulatory defect at the G1/S phase transition is
indicated by a reduced relative lengthening of the G1 phase in the presence
of the cell division inhibitor substance or stimulus in cells from the test
subject, as compared to control cells not having a cell cycle regulatory defect
at the G1/S phase transition” (Spec. 10, ll. 9-15; FF 21). Appellant points to
similar teachings throughout the Specification (see, e.g, FF 22-24).
However, none of these teachings reasonably suggests or
demonstrates possession of the use of affected individuals as positive
controls (see FF 21-24). While the use of positive controls from affected
individuals would reasonably be understood as obvious based upon the
disclosure of the Specification, “a description that merely renders the
invention obvious does not satisfy the [written description] requirement.”
Ariad, 598 F.3d at 1352.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that Claim
1 fails to comply with the written description requirement as incorporating
new matter.
SUMMARY
In summary, we affirm the rejection of claim 1 under 35 U.S.C. § 112,
first paragraph, enablement. Pursuant to 37 C.F.R. § 41.37(c) (1)(vii)(2006),
we also affirm the rejection of claims 2, 3, 5, 6, 8, 17, 30-32, and 34, as these
claims were not argued separately.
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We affirm the rejection of claim 1 under 35 U.S.C. § 112, first
paragraph, new matter. Pursuant to 37 C.F.R. § 41.37(c) (1)(vii)(2006), we
also affirm the rejection of claims 2, 3, 5, 6, 8, 17, 30-32, and 34, as these
claims were not argued separately.
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).
AFFIRMED

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