Ex Parte Zlokovic

Board of Patent Appeals and Interferences

Sep 16, 2009

10296168 (B.P.A.I. Sep. 16, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/296,168 06/30/2003 Berislav V. Zlokovic GRT/5191-6 5656
23117 7590 09/17/2009
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON, VA 22203
EXAMINER
WANG, CHANG YU
ART UNIT PAPER NUMBER
1649
MAIL DATE DELIVERY MODE
09/17/2009 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte BERISLAV V. ZLOKOVIC
__________

Appeal 2009-002309
Application 10/296,168
Technology Center 1600
__________

Decided: September 17, 2009
__________

Before DONALD E. ADAMS, ERIC GRIMES, and RICHARD M.
LEBOVITZ, Administrative Patent Judges.

GRIMES, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of diagnosing Alzheimer’s disease. The Examiner has rejected the claims as
indefinite, nonenabled, and obvious, and provisionally rejected them for
obviousness-type double patenting. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm the provisional rejection for double patenting but reverse
the other grounds of rejection.
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STATEMENT OF THE CASE
The Specification discloses that “[d]eposition of amyloid-β protein
(Aβ) in brain occurs during normal aging and is accelerated in individuals
with Alzheimer’s disease (AD)” (Spec. 1: 26-27). “It has been suggested
that decreased clearance of Aβ from brain and CSF is the main cause of Aβ
accumulation in sporadic AD” (id. at 2: 13-14).
The Specification discloses that low-density lipoprotein receptor
related protein-1 (LRP-1) mediates transport of Aβ from the central nervous
system, across the blood-brain barrier, to the systemic circulation (id. at
1: 14-17).
Claims 1-3 and 15-22 are pending and on appeal. Claims 1 and 21,
the only independent claims, read as follows:
1. A method of at least diagnosing a human patient with Alzheimer’s
disease, said method comprising:
(a) measuring at least abundance of low-density lipoprotein receptor
related protein-1 (LRP-1), abundance of transcripts thereof, or LRP-1
receptor activity in a human patient,
(b) comparing the abundance of LRP-1 protein, abundance of
transcripts thereof, or activity of LRP-1 receptor in said human patient to at
least an age-matched control not affected by Alzheimer’s disease, and
(c) at least diagnosing said human patient with Alzheimer’s disease
when the abundance of LRP-1 protein, abundance of transcripts thereof, or
activity of LRP-1 receptor in said human patient is decreased relative to said
age-matched control not affected by Alzheimer’s disease;
wherein LRP-1 mediated removal of amyloid-β peptide (Aβ) at the
blood-brain barrier in the direction from brain to blood in said human patient
is decreased as compared to an age-matched control not affected by
Alzheimer’s disease.

21. A method of measuring low-density lipoprotein receptor related
protein-1 (LRP-1) in a human patient with Alzheimer’s disease, said method
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comprising measuring a decrease in LRP-1 mediated removal of amyloid-β
peptide (Aβ) at the blood-brain barrier in the direction from brain to blood in
said human patient relative to an age-matched control not affected by
Alzheimer’s disease.

The claims stand rejected as follows:
• Claims 1-3 and 15-20 under 35 U.S.C. § 112, second paragraph, as
indefinite (Ans. 9);
• Claims 1-3 and 15-20 under 35 U.S.C. § 112, first paragraph, as
nonenabled (Ans. 4); and
• Claims 1-3 and 15-22 under 35 U.S.C. § 103(a) as obvious in view
of Van Uden,1 Urmoneit,2 and Mackic3 (Ans. 11).
In addition, claims 1-3 and 15-20 have been provisionally rejected for
obviousness-type double patenting based on the claims of Applications
10/516,729 and 10/451,917 (Ans. 10).
DEFINITENESS
The Examiner has rejected claims 1-3 and 15-20 on the basis that they
are indefinite “because the claims recite ‘at least’ without specify[ing] what
other claimed subject matters are” (Ans. 9). The Examiner concludes that

1 Emily Van Uden et al., Aberrant Presenilin-1 Expression Downregulates
LDL Receptor-Related Protein (LRP): Is LRP Central to Alzheimer’s
Disease Pathogenesis?, 14 Neurosci. 129-140 (1999)
2 Britta Urmoneit et al., Cerebrovascular Smooth Muscle Cells Internalize
Alzheimer Amyloid Beta Protein via a Lipoprotein Pathway: Implications
for Cerebral Amyloid Angiopathy, 77 Lab. Invest. 2157-2166 (1997)
3 Jasmina B. Mackic et al., Cerebrovascular Accumulation and Increased
Blood-Brain Barrier Permeability to Circulating Alzheimer’s Amyloid β
Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy, 70 J.
Neurochem. 210-215 (1998)
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“the term ‘at least’ is open language. It is unclear what Applicant intended
to include in the claims.” (Id.)
Appellant contends that the “phrase ‘at least’ is open language, but
one of ordinary skill in the art would not find its use to be indefinite just as
the use of ‘comprising’ is proper in the claims” (Appeal Br. 8). “Even if ‘at
least’ as used in claim 1 is considered to be redundant in construing the other
claim limitations, this phrase is not capable of being construed in a
confusing manner in the context of the pending claims” (id.).
We will reverse this rejection. The phrase “at least,” like the
transitional term “comprising” opens the claims to any method that includes
the recited steps, no matter what else they may include. Cf. Invitrogen Corp.
v. Biocrest Mfg., L.P., 327 F.3d 1364, 1368 (Fed. Cir. 2003) (“The transition
‘comprising’ in a method claim indicates that the claim is open-ended and
allows for additional steps.”); SanDisk Corp. v. Memorex Products, Inc, 415
F.3d 1278, 1284 (Fed. Cir. 2005) (“As a patent term of art, ‘includes’ means
‘comprising.’ . . . Neither includes, nor comprising, forecloses additional
elements that need not satisfy the stated claim limitations.”).
The Examiner has not asserted that there is anything indefinite about
the manipulative steps that are positively recited in the claims. The phrase
“at least” therefore makes the claims broad but it does not make them
indefinite. In re Miller, 441 F.2d 689, 693 (CCPA 1971) (“breadth is not to
be equated with indefiniteness”).
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ENABLEMENT
Issue
The Examiner has rejected claims 1-3 and 15-20 under 35 U.S.C.
§ 112, first paragraph, for lack of enablement. The Examiner finds that “the
cause of AD is complex and undetermined, and therefore a skilled artisan
cannot diagnose . . . AD based on the decreased expression level of a single
gene (i.e. LRP-1)” (Ans. 5). The Examiner finds that LRP-1-mediated
clearance is not the only proposed mechanism for Aβ clearance (id. at 6) and
“many molecules have been shown to be involved in clearance of Aβ. . . .
Thus, it is unpredictable whether detection of the decrease of LRP can be
used to diagnose . . . AD as claimed” (id. at 7)
The Examiner acknowledges that the “working examples in the
specification show that the levels of LRP-1 are decreased in human brain
sections of patients who died of AD” (id.). The Examiner concludes,
however, that the Specification does not enable diagnosing AD in a patient
not previously known to have the disease because “Appellant fails to provide
guidance as to what level of LRP immunostaining in an individual not yet
been determined (i.e. a naïve patient) would be considered as a decrease of
LRP or how variable it is in naïve patients, and thus to conclude that a said
specific individual is with AD” (id. at 8).
Appellant contends that the Specification discloses that a decrease in
LRP-1 is diagnostic of Alzheimer’s disease and the Examiner has not
provided evidence or reasoning that contradicts that disclosure (Appeal Br.
5). Appellant also contends that methods for measuring the abundance of
LRP-1 protein or transcripts, and for measuring LRP-1 activity, are known
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in the art and described in the Specification (id. at 6), and the Examiner has
not shown that undue experimentation would be required to practice the
claimed method (id. at 8).
The issue with respect to this rejection is: Has Appellant shown that
the Examiner erred in concluding that the Specification does not enable
those skilled in the art to diagnose Alzheimer’s disease based on abundance
of LRP-1 protein or transcripts or LRP-1 activity?
Findings of Fact
1. The Specification discloses that LRP-1 mediates transport of Aβ
from the central nervous system, across the blood-brain barrier (BBB), to the
systemic circulation (Spec. 1: 14-17).
2. The Specification discloses that “LRP-1 and its ligands α2M and
apoE . . . promote Aβ clearance in smooth muscle cells, neurons, and
fibroblasts” (id. at 2: 31-32, reference citations omitted).
3. The Specification discloses that the “BBB removes Aβ from the
brain largely by an age-dependent, LRP-1-mediated transport mechanism
that is influenced by α2M and/or apoE. This mechanism appears to be
impaired in Alzheimer’s disease at the level of transcript or protein
abundance or receptor function” (id. at 6: 33 to 7: 3).
4. The Specification discloses that “[g]ene expression (e.g., detected
by antibody staining) and protein activity of LRP-1 (e.g., vascular clearance
of Aβ from the brain to the systemic circulation) was decreased in
individuals with Alzheimer’s disease” (id. at 7: 20-22).
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5. The Specification discloses that, when compared to vehicle-treated
controls, anti-LRP-1 antibody produced a 58% reduction in Aβ clearance
from brain in vivo in mice (id. at 18: 15-27; 24: 33 to 25: 3).
6. The Specification discloses that “there was a significant reduction
in LRP-1 positive vessels in 9-month-old mice in comparison to 2-month-
old mice” (id. at 25: 28-29).
7. The Specification discloses that “[t]hree AD patients and three
neurologically normal, age-matched controls . . . were evaluated clinically
and followed to autopsy” (id. at 21: 19-21) and tissue samples were then
evaluated (id. at 21: 23 to 22: 20).
8. The Specification discloses that “staining for LRP-1 in the frontal
cortex of control patients revealed moderate vascular staining in capillaries
and arterioles, as well as neuronal staining. There was reduced LRP-1
staining in AD tissues.” (Id. at 26: 9-11.)
9. The Examiner has not cited any evidence showing that abundance
of LRP-1 protein or transcript or LRP-1 activity is not diagnostic of
Alzheimer’s disease.
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; this includes, of course, providing sufficient
reasons for doubting any assertions in the specification as to the
scope of enablement.
In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993).
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“Section 112 does not require that a specification convince persons
skilled in the art that the assertions therein are correct.” In re Armbruster,
512 F.2d 676, 678 (CCPA 1975).
Analysis
The Examiner’s position, as we understand it, is that “it is
unpredictable whether detection of the decrease of LRP can be used to
diagnose and identify an individual with AD as claimed because the cause of
AD is complex and LRP-1 is not only involved in Aβ clearance” but in other
processes as well (Ans. 7). The Examiner’s reasoning does not persuade us
that the claimed method is not enabled by the Specification’s disclosure.
The Specification states that LRP-1 mediates transport of Aβ through
the blood-brain barrier and that such transport is “impaired in Alzheimer’s
disease at the level of transcript or protein abundance or receptor function”
(FF 3). The Specification also discloses that brain tissue of patients
diagnosed as having AD had decreased amounts of LRP-1 protein compared
to age-matched controls who were neurologically normal; i.e., decreased
LRP-1 protein correlated with the diagnosis of AD.
The Specification thus asserts that the claimed method works, and it
provides a reasonable evidentiary basis for that assertion. The Examiner has
not provided evidence or scientific reasoning that contradicts the evidence
provided in the Specification that supports the claimed method. The
Examiner therefore has not carried the initial burden of “providing sufficient
reasons for doubting any assertions in the specification as to the scope of
enablement.” Wright, 999 F.2d at 1562.
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Conclusions of Law
Appellant has shown that the Examiner erred in concluding that the
Specification does not enable those skilled in the art to diagnose Alzheimer’s
disease based on abundance of LRP-1 protein or transcripts or LRP-1
activity.
OBVIOUSNESS
Issue
The Examiner has rejected claims 1-3 and 15-22 under 35 U.S.C.
§ 103(a) as obvious in view of Van Uden, Urmoneit, and Mackic (Ans. 11).
The Examiner finds that Van Uden teaches that “the expression level of LRP
(or LRP-1) is decreased in one of AD mouse models, transgenic mice of
human presenilin-1 mutant gene (PS-1), which is the gene found in familial
AD” (id. at 12) but does not teach “detection of the decreased level of LRP
in . . . tissues from human patients with AD as recited in instant claims” (id.
at 13).
The Examiner finds that Urmoneit teaches that “the cause of cerebral
amyloid angiopathy (CAA) is due to deposition of Alzheimer Aβ, . . . which
is internalized by LRP . . . [and] proposed that the pathogenesis of CAA is
due to the internalization and accumulation of Aβ/ApoE complexes in
cerebrovascular smooth muscle cells” (id.). The Examiner finds that Mackic
teaches that “cerebrovascular deposition of soluble Aβ1-40 in brain tissues
of AD is correlated with the severity of CAA” (id.)
The Examiner concludes that a skilled worker would have been
motivated to measure the amount of LRP in AD patients’ brain tissue, with a
reasonable expectation of success, “because Aβ is deposited in brain blood
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vessels of patients who died of AD and the clearance of Aβ has been shown
to be mediated by LRP-1” (id. at 14).
Appellant contends that the “Van Uden, Urmoneit, and Mackic
documents fail to disclose[ ] any correlation between a decrease in LRP-1,
its transcript, or its receptor activity and diagnosis of Alzheimer’s disease”
(Appeal Br. 14). Appellant also contends that “none of the cited documents
diagnose Alzheimer’s disease in a human patient. . . . Further, none of the
cited documents teach or suggest comparing the amount of LRP-1 to an age-
matched control. . . . Therefore, a prima facie case of obviousness was not
established by the Examiner.” (Id.)
The issue with respect to this rejection is: Has Appellant shown that
the Examiner erred in concluding that the cited references would have made
obvious a method of diagnosing Alzheimer’s disease based on a decrease in
LRP-1 expression or activity relative to a healthy age-matched control?
Additional Findings of Fact
10. Van Uden discloses that “[l]ow density lipoprotein receptor-
related protein (LRP) polymorphisms have recently been associated with an
increased susceptibility of Alzheimer’s disease (AD)” (Van Uden, abstract).
11. Van Uden discloses that “[g]enetic evidence, combined with
clinical observations of increased serum LRP ligand levels . . . , suggests that
deficient LRP expression and/or function to be central to AD pathogenesis”
(id. at 129, right col.).
12. Van Uden discloses that “the majority of familial AD cases are
accounted for by mutations in the presenilin genes, particularly PS-1” (id.).
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13. Van Uden discloses that “LRP is decreased in pyramidal and
somatostatinergic neurons in transgenic mice expressing the PS-1 M146L
and L286V mutations” (id. at 130, left col.).
14. Van Uden discloses that the “mechanisms by which abnormal
expression of presenilin dysregulates LRP are not completely understood.
However, the present study showed that downregulation of LRP expression
occurred at the protein and mRNA levels, indicating that PS-1 disrupts LRP
transcription.” (Id. at 133, right col.)
15. Urmoneit discloses that “[m]ost cases of CAA [cerebral amyloid
angiopathy] are caused by the cerebrovascular deposition of Alzheimer
amyloid β-protein (Aβ . . .) and may occur sporadically or in association
with Alzheimer’s disease or Down’s syndrome” (Urmoneit 157, left col.).
16. Urmoneit discloses that labeled “Aβ is rapidly internalized by
smooth muscle cells obtained from human and canine leptomeninges”
(tissues covering the brain and spinal cord) (id. at 157-158).
17. Urmoneit discloses that its “findings indicate that a major fraction
of Aβ is internalized via a lipoprotein receptor” (id. at 161, right col.).
18. Urmoneit discloses that “from its binding to the cell surface to its
localization into late endosomes, Aβ was colocalized with APOE and LRP”
(id. at 161-162).
19. Urmoneit “propose[s] a pathogenetic model of CAA, in which
Aβ-APOE-complexes contained in the cerebrospinal fluid or the
extracellular fluid of the brain are internalized and accumulated in
cerebrovascular smooth muscle cells” (id., abstract).
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20. Mackic discloses that “[s]enescent squirrel monkey is a valuable
model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA)”
(Mackic, abstract).
21. Mackic discloses that the “40-amino acid form of Aβ, Aβ1-40, is
the predominant form of cerebrovascular amyloid . . . , accounting for ~90%
of soluble monomeric Aβ (sAβ) produced by different cell types” (id. at 210,
right col.).
22. Mackic discloses that “the major form of blood-borne sAβ,
sAβ1-40, is readily taken up at the luminal side of the BBB in primates.
Circulating sAβ1-40 remains associated with cortical and leptomeningeal
cerebral microvessels and crosses the BBB to enter the extracellular space of
the brain.” (Id. at 213, left col.).
23. Mackic concludes that “multiple age-related systemic effects, i.e.,
reduced body elimination and systemic clearance of sAβ1-40, and reduced
peripheral metabolism, may act in concert with BBB mechanisms, i.e.,
increased transendothelial transport and microvascular accumulation of
blood-borne sAβ1-40, and reduced brain metabolism to enhance the
development of CAA” (id., abstract).
Principles of Law
An invention “composed of several elements is not proved obvious
merely by demonstrating that each of its elements was, independently,
known in the prior art. . . . [I]t can be important to identify a reason that
would have prompted a person of ordinary skill in the relevant field to
combine the elements in the way the claimed new invention does.” KSR
Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). That is, conclusion of
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obviousness under 35 U.S.C. § 103 requires showing that “there was an
apparent reason to combine the known elements in the fashion claimed by
the patent at issue.” Id.
Analysis
Van Uden teaches that certain mutations in the presenilin gene PS-1,
which is associated with familial Alzheimer’s disease, cause downregulation
of LRP-1 expression. Van Uden does not, however, teach that
downregulation of LRP-1 expression is diagnostic of Alzheimer’s disease
itself.
Urmoneit teaches that Aβ peptide is internalized by smooth muscle
cells via LRP. Urmoneit proposes that the pathogenesis of CAA is caused
by internalization and accumulation of Aβ in cerebrovascular smooth muscle
cells. Mackic teaches that Aβ crosses the blood-brain barrier (BBB), from
the blood to the brain. Mackic concludes that the movement of Aβ across
the BBB, combined with reduced body elimination and systemic clearance,
and reduced brain metabolism, enhances the development of CAA.
The Examiner concluded that it would have been obvious to combine
the cited references and detect the abundance of LRP in brain tissue of
patients with AD with an expectation of success “because Aβ is deposited in
brain blood vessels of patients who died of AD and the clearance of Aβ has
been shown to be mediated by LRP-1. The reduced level of LRP in blood
vessels of AD would result in a decrease of LRP-1 mediated removal of Aβ
from brain to blood in AD patients.” (Ans. 14.)
We agree with Appellant that the Examiner has not adequately
explained how his conclusion follows from the disclosures of Van Uden,
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Urmoneit, and Mackic. The Examiner does not identify where the cited
references teach that the clearance of Aβ is mediated by LRP-1 or that
decreased LRP-1 would be expected to result in decreased removal of Aβ
from brain to blood.
We are unable to identify any such disclosures in the cited references.
Van Uden teaches that LRP-1 is downregulated by certain mutations in PS-
1, but does not disclose that LRP-1 mediates clearance of Aβ or that
decreased LRP-1 would be expected to produce decreased brain-to-blood
transport of Aβ or an increased amount of Aβ in brain. Urmoneit teaches
that LRP causes uptake of Aβ by brain smooth muscle cells, not transport of
Aβ from brain to blood. Urmoneit also concludes that the LRP-mediated
uptake and accumulation of Aβ causes pathogenesis in CAA, suggesting that
a decrease in LRP level or activity would be less – not more – likely to cause
CAA, which in any case is a different disorder than AD (see FF 15). Mackic
does not mention LRP-1 or LRP.
Conclusion of Law
Appellant has shown that the Examiner erred in concluding that the
cited references would have made obvious a method of diagnosing
Alzheimer’s disease based on a decrease in LRP-1 expression or activity
relative to a healthy age-matched control.
OBVIOUSNESS-TYPE DOUBLE PATENTING
The Examiner has provisionally rejected claims 1-3 and 15-20 for
obviousness-type double patenting based on the claims 1-3, 6, and 27-40 of
Application 10/516,729 and claims 1, 2, 4-24, 26, and 30-37 of Application
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10/451,917 (Ans. 10). The Examiner concludes that the rejected claims and
the claims of the co-pending applications are directed to methods that are not
patentably distinct (id. at 10-11).
Appellant does not dispute the Examiner’s conclusion that the rejected
claims are not patentably distinct from the claims in the ‘729 and ‘917
applications, but argues that the present application was filed first, and
therefore the rejection should be withdrawn and the double patenting issue
addressed in the later-filed applications (Appeal Br. 10). Appellant states
that he “intends either to cancel conflicting claims or to distinguish claims in
them as patentable over the pending claims” (id.)
Since Appellant has presented no basis on which to conclude that the
Examiner’s rejection is erroneous, we will affirm it. On return of this
application, the Examiner will determine the best way, consistent with the
MPEP, to address the conflicting claims presented in this application and in
the ‘729 and ‘917 applications.
SUMMARY
We affirm the provisional rejection for obviousness-type double
patenting but reverse the rejections for indefiniteness, nonenablement, and
obviousness.
TIME PERIOD FOR RESPONSE
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-IN-PART
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901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON VA 22203