Ex Parte Ladenson et al

Patent Trial and Appeal Board

Jan 31, 2017

13187440 (P.T.A.B. Jan. 31, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/187,440 07/20/2011 Jack LADENSON 295002007001 6269
25225 7590 02/02/2017
MORRTSON fr FOFRSTFR T T P
EXAMINER
12531 HIGH BLUFF DRIVE GUCKER, STEPHEN
SUITE 100
SAN DIEGO, CA 92130-2040 ART UNIT PAPER NUMBER
1649
NOTIFICATION DATE DELIVERY MODE
02/02/2017 ELECTRONIC
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JACK LADENSON, YVONNE LANDT,
VIJAY MODUR, and OMAR LATERZA1
Appeal 2014-010011
Application 13/187,440
Technology Center 1600
Before CHRISTOPHER G. PAULRAJ, TAWEN CHANG, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to
methods to detect or monitor brain damage caused by Alzheimer’s disease,
which have been rejected as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b).
We AFFIRM.
1 Appellants identify the Real Party in Interest as Washington University.
(Appeal Br. 1.)
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STATEMENT OF THE CASE
According to the Specification,
[i]t is generally recognized that brain damage of various types can be
indicated by the presence in fluids such as cerebrospinal fluid (CSF)
or more conveniently, in serum or plasma or urine, of proteins or other
substances that are generally characteristic of the brain. The
desirability of identifying such factors that could be used for
diagnoses so as to identify appropriate treatment or simply for
prognosis has also been recognized widely.
(Spec. 14.) Further according to the Specification, “[t]he invention provides
methods to identify markers of brain damage and methods to predict the
presence and progression of brain damage using these markers.” {Id. at |
14.) Neurogranin is one of the markers identified by the methods described
in the Specification. {Id. at 118.)
Claims 12—14 and 16—18 are on appeal. Claim 12 is illustrative and
reproduced below:
12. A method to detect brain damage caused by
Alzheimer's Disease or stroke in a test subject which method
comprises treating a sample comprising a biological fluid, or a
fraction thereof, of said subject with antibodies or fragments
thereof specifically reactive with protein kinase C substrate RC3
(neurogranin) to form a sandwich comprising a capture antibody
and a labeled antibody wherein said label comprises a radioactive
tracer, an enzyme or a fluorescent or chemiluminescent label,
detecting any sandwich formed by said antibodies or
fragments with said neurogranin,
wherein any enhanced presence of said sandwich in the
fluid, or fraction thereof, of the test subject as compared to
normal subjects indicates an increased probability of brain
damage in the test subject.
(Appeal Br. 9 (Claims App’x).)
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The Examiner rejects claims 12—14 and 16—18 under 35 U.S.C.
§ 103(a) as being unpatentable over Davidsson.2 (Final Act. 8.)
DISCUSSION
Issue
The Examiner has rejected claims 12—14 and 16—18 under 35 U.S.C.
§ 103(a) as obvious over Davidsson. The Examiner finds that Davidsson
“discloses methods of detecting neurogranin in human CSF samples using
rabbit antiserum against human neurogranin as the capture antibody and
biotinylated goat anti-rabbit IgG alkaline phosphatase-conjugated extravidin
as the labeled antibody.” (Final Act. 8.) The Examiner finds that Davidsson
“does not use his methods to detect or monitor progression of brain damage
in [Alzheimer’s disease].” (Id.) Nevertheless, the Examiner finds that
Davidsson “makes direct suggestions to do so ... , rendering the instant
methodsprima facie obvious.” (Id.)
Appellants argue that Davidsson merely discloses a “reasonable
speculation” that, in light of alterations in neurogranin levels in the brains of
Alzheimer’s or schizophrenia patients, similar alterations may be observed
in the CSF of such patients. (Appeal Br. 6.) Relying on the Crimmins
Declaration,3 Appellants argue that, in view of the art taken as a whole, a
skilled artisan “would not consider the [Davidsson] article suggestive of
using neurogranin as a marker for Alzheimer’s disease” and thus would not
“try to develop an assay for neurogranin in bodily fluid” based on
2 Pia Davidsson et al., Identification of synaptic vesicle, pre- and
postsynaptic proteins in human cerebrospinal fluid using liquid-phase
isoelectric focusing, 20 Electrophoresis 431 (1999) (“Davidsson”).
3 Declaration of Dan Crimmins under 37 C.F.R. § 1.132 (April 9, 2013)
(“Crimmins Declaration”).
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Davidsson’s disclosures. (Id.) In particular, Appellants argue that
Davidsson’s statement is based on postmortem measurements of
neurogranin levels in the brain of Alzheimer patients, which do not correlate
to levels in the CSF, particular in living subjects. (Id.) Finally, Appellants
argue that Davidsson’s disclosures provide “absolutely no predictability that
[neurogranin] levels would be increased” in Alzheimer patients. (Id. at 7.)
Appellants do not separately argue the claims; we thus limit our
analysis to claim 12. The issue with respect to this rejection is whether a
preponderance of the evidence supports the Examiner’s conclusion that
Davidsson teaches or suggests “[a] method to detect brain damage caused by
Alzheimer’s disease” comprising “treating a sample comprising a biological
fluid, or a fraction thereof’ and “detecting . . . neurogranin,” as recited in
claim 12.
Findings of Fact
1. Davidsson teaches that
[s]ynaptic pathology is central in the pathogenesis of several
psychiatric disorders, for example in Alzheimer’s disease (AD) and
schizophrenia. Quantification of specific synaptic proteins has proved
to be a useful method to estimate synaptic density in the brain. Using
this approach, several synaptic proteins have been demonstrated to be
altered in both AD and schizophrenia.
(Davidsson Abstract.)
2. Davidsson teaches that “[a]ltered levels of the synaptic proteins
may . . . have diagnostic and therapeutic implications for brain disorders
such as AD and schizophrenia.” (Id. at 432, left column.)
3. Davidsson teaches that, “[i]n living subjects, these synaptic
proteins may be studied through analysis of cerebrospinal fluid (CSF).
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Analysis of synaptic proteins in CSF is a potentially useful method, since
CSF is in direct contact with the extracellular fluid of the brain.” (Id.)
4. Davidsson teaches that “[a] reduction of synaptotagmin[, one of
the synaptic proteins,] was found both in brain tissue and lumbar CSF of
AD, implying that CSF reflects the composition of synaptic proteins in the
brain under normal and pathological conditions.” (Id.)
5. Davidsson teaches that
neurogranin is the dendritic counterpart of [presynaptic growth
associated protein] GAP-43 in the postsynaptic membrane and is
specifically located in dendritic spines. The functions of neurogranin
include a role in synaptic plasticity and in long-term potentiation.
(Id. at 435 (citation omitted); see also id. at 431—432, bridging paragraph.)
6. Davidsson teaches a method of detecting neurogranin in CSF,
comprising concentrating patient CSF samples by precipitation, isoelectric
focusing the resulting protein CSF samples to separate protein fractions,4
and Western blotting. (Id. at Abstract, 432.) In particular, Davidsson
teaches determining the presence of neurogranin using this method,
including by Western blotting using rabbit antiserum against human
neurogranin, followed by incubation with biotinylated goat anti-rabbit IgG,
alkaline phosphatase-conjugated extravidin, and biotinylated alkaline
phosphatase. (Id. at 432-433.) Color reaction (indicative of alkaline
phosphatase activity) is then developed with 5-bromo-4-chloro-3 indolyl
phosphate (BCIP) and nitro-blue-tetrazolium in carbonate buffer containing
MgCh. (Mat433.)
7. Davidsson concludes:
4 Isoelectric focusing separates molecules based on the pH at which the
molecule carries no net electric charge.
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All these synaptic proteins have been demonstrated to be altered in
brains of AD and schizophrenia [6-11]. Until now, synaptic function
has been limited to studies in postmortem brain tissue and then only
information about the end-stage of the disorder was obtained. To
study synaptic pathology and function in living subjects, analysis of
CSF may be a useful method, since the CSF is continuous with the
extracellular fluid of the brain. The reduction of synaptotagmin found
both in brain tissue and lumbar CSF of AD suggests that CSF reflects
the underlying pathological processes in the brain, and may be used
for diagnostic purposes. Since all the synaptic proteins (rab3a,
synaptotagmin, synaptophysin, GAP-43 and neurogranin) are altered
in brains of AD or schizophrenia, it is reasonable to speculate that
alterations in the levels of synaptic proteins may be observed in CSF.
Our results demonstrate that several synaptic proteins can be
measured in CSF to study the synaptic function and pathology in
different brain disorders. The quantification of synaptic proteins in
individuals may prove useful to increase the diagnostic accuracy of
AD, make an early diagnosis of AD possible, and to follow the course
of the disease, especially during pharmacological treatment.
(Id. at 435, right column.)
Analysis
We agree with the Examiner that Davidsson suggests a method of
detecting brain damage caused by Alzheimer’s disease by detecting
neurogranin in a biological fluid (i.e., CSF or a fraction thereof). As
Appellants concede, Davidsson teaches that “[s]ince all the synaptic proteins
(rab3a, synaptotagmin, synaptophysin, GAP-43 and neurogranin) are altered
in brains of AD or schizophrenia, it is reasonable to speculate that alterations
in the levels of synaptic proteins may be observed in CSF.” (FF7.)
Davidsson further articulates reasons to support this statement: CSF is
continuous with the extracellular fluid of the brain, and reduction of
synaptotagmin, one of the synaptic proteins, is found both in brain tissue and
lumbar CSF of AD, suggesting that CSF reflects the underlying pathological
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processes in the brain and may be used for diagnostic purposes. (Id.)
Finally, Davidsson explicitly suggests that quantification of synaptic
proteins in CSF “may prove useful to increase the diagnostic accuracy of
AD, make an early diagnosis of AD possible, and to follow the course of the
disease, especially during pharmacological treatment.” (Id.)
Appellants argue that paragraphs 6 and 8 of the Crimmins Declaration
shows that Davidsson’s disclosures would not have led a skilled artisan to
“try to develop an assay for neurogranin in bodily fluid” with any reasonable
expectation of success. (Appeal Br. 6.) As explained below, we have
considered the Crimmins Declaration but find that Dr. Crimmins’ statements
are not adequately supported by the evidence of record. Thus, we find the
weight of the evidence supports the Examiner’s position. See In re
American Acad. Of Science Tech Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004)
(“The Board has broad discretion as to the weight to give
to declarations offered in the course of prosecution. See Velander v. Garner,
348 F.3d 1359, 1371 (Fed. Cir. 2003) (‘[A]ccord[ing] little weight to broad
conclusory statements [in expert testimony before the Board] that it
determined were unsupported by corroborating references [was] within the
discretion of the trier of fact to give each item of evidence such weight as it
feels appropriate.’). . . .”) (alterations in internal quotation original).
In particular, Dr. Crimmins opines that “[a]Iterations of levels of a
protein in the brain do not predict these levels in CSF, especially because
[the] alterations in levels [described in Davidsson] were ascertained
postmortem,” that “there is no recognized correlation between postmortem
changes in brain levels and levels in CSF,” and that “[t]he speculation of
Davidsson . . . fails to enable any prediction of the behavior of the levels of
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the same protein in CSF as a function of disease.” (Crimmins Decl. Tfl[ 6, 8.)
However, Dr. Crimmins does not cite to corroborating references, explaining
his conclusions merely by stating that “[t]he altered level in brain tissue may
simply stay in the brain tissue and not necessarily ‘leak’ into the CSF” and
that “it could not be predicted that [alteration in neurogranin level] would be
[a] detection method available in living patients,” because “alteration in
levels of neurogranin in CSF is apparent even at earlier stages of
Alzheimer’s, whereas the discrepancies in levels in brain are detected only
post-mortem.” {Id. at || 8, 11.) As the Examiner points out, however,
Davidsson explicitly teaches that the reduction of synaptotagmin, another
synaptic protein, in both brain tissue and lumbar CSF of AD “suggests that
CSF reflects the underlying pathological processes in the brain, and may be
used for diagnostic purposes.”5 (Ans. 3; FF7.) As the Appellants also
acknowledge, “the expectation of success need only be reasonable, not
absolute.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007).
We also acknowledge but are not persuaded by Appellants’ argument
that “there is absolutely no predictability that the levels [of neurogranin]
would be increased” in a patient with Alzheimer’s disease. (Appeal Br. 7.)
The claims do not require a prediction that the levels of neurogranin will be
5 Appellants argue that “[t]he correlation between CSF and brain levels of
synaptotagmin [referred to in Davidsson] reflects studies only on
postmortem subjects,” which “offers no information regarding correlation of
CSF and brain levels of any proteins in living subjects.” (Reply 2—3.) As an
initial matter, “[attorneys’ argument is no substitute for evidence.”
Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989). Neither
Appellants nor the Crimmins Declaration provide a sufficiently persuasive
reason why correlations seen in postmortem tissues and fluids would not be
suggestive of correlations in living tissues and fluids, despite Davidsson’s
suggestion to the contrary.
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increased. Moreover, to the extent Appellants’ argument is directed towards
the limitation “wherein any enhanced presence of said sandwich in the fluid,
or fraction thereof, of the test subject as compared to normal subjects
indicate an increased probability of brain damage in the test subject,” we
find that phrase merely states the inherent results of the claimed step
rendered obvious by Davidsson. Cf. Texas Instruments Inc. v. U.S. Intern.
Trade Comm., 988 F.2d 1165, 1172 (Fed. Cir. 1993) (noting that a
“whereby” clause that merely states the result of a claim limitation does not
further limit the claim).
Finally, Appellants raise two arguments for the first time in their
Reply Brief. First, Appellants argue that, aside from whether level of
neurogranin would or would not be a useful marker for Alzheimer’s disease,
Davidsson “does not suggest that a straightforward sandwich assay
performed on the biological fluid would be successful in detecting
neurogranin.” (Reply Br. 3—4.) Second, Appellants allege that, despite
Davidsson’s publication in 1999, it was not until 2010 that Thorsell, which
did not cite Davidsson and also disclosed a “much more complex assay [than
claimed],” described elevated levels of neurogranin in CSF of patients with
Alzheimer’s disease. Id. at 4.
Appellants have not explained why these arguments could not have
been raised in the Appeal Brief. Hence, they have been waived. See Ex
parte Nakashima, 93 USPQ2d 1834 (BPA1 2010) (informative) (arguments
and evidence not timely presented in the Principal Brief will not be
considered when filed in a Reply Brief, absent a showing of good cause
explaining why the argument could not have been presented in the Principal
Brief); Ex parte Borden, 93 USPQ2d 1473, 1477 (BPA1 2010) (informative)
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(explaining that “the Rules do not require the Board to take up a belated
argument that has not been addressed by the Examiner, absent a showing of
good cause”).
In any event, we are not persuaded by these arguments. Appellants
fail to explain how the claims are limited to “a straightforward sandwich
assay performed on the biological fluid” — or, for that matter, what
constitutes a “straightforward” sandwich assay.6 We note that claim 12
claims a method that “comprises treating a sample comprising a biological
fluid, or a fraction thereof.” Given the use of the open transitional phrase
“comprises,” the claim encompasses methods that include steps not
explicitly recited in the claim. Furthermore, the broadest reasonable
interpretation of “a sample comprising a biological fluid, or a fraction
thereof,” encompasses a sample containing part of a biological fluid, such as
the protein CSF samples used in Davidsson, in addition to other
components. (FF6.)
We are similarly unconvinced by Appellants’ argument that the
claims are non-obvious because (1) of the eight documents Appellants found
to have cited to Davidsson, only one was published prior to the application
date and did not mention neurogranin and (2) another reference that
disclosed elevated neurogranin levels in CSF of patients with Alzheimer’s
disease was published five years after the application date and did not cite
Davidsson. (Reply Br. 4—5.) Assuming Appellants’ assertions regarding the
art to be true, the fact that Davidsson was infrequently cited prior to the
6 For similar reasons, we are not persuaded by Appellants’ argument in the
Reply that their invention is distinguishable from the prior art because it is
“a practical assay.” (Reply Br. 4—5.)
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application date is not sufficient to show that Davidsson would not have
suggested the claimed method to a skilled artisan. Cf. In re Wright, 569 F.2d
1124, 1127 (CCPA 1977) (“The mere age of the references is not persuasive
of the unobviousness of the combination of their teachings, absent evidence
that, notwithstanding knowledge of the references, the art tried and failed to
solve the problem.”)
SUMMARY
For the reasons above, we affirm the Examiner’s decision rejecting
claims 12—14 and 16—18 under 35 U.S.C. § 103(a) as obvious over
Davidsson.
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
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