Ex Parte Borlongan et al

Patent Trial and Appeal Board

Jan 25, 2019

14489934 (P.T.A.B. Jan. 25, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/489,934 09/18/2014
63453 7590 01/25/2019
SANBIO, INC.
c/o LEVINE BAGADE HAN LLP
2400 GENG ROAD
SUITE 120
PALO ALTO, CA 94303
FIRST NAMED INVENTOR
Cesar V. Borlongan
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
SNBINZ01301 1513
EXAMINER
SCHULTZ, JAMES
ART UNIT PAPER NUMBER
1633
MAIL DATE DELIVERY MODE
01/25/2019 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 PATENT TRIAL AND APPEAL BOARD
Ex parte CESAR V. BORLONGAN and CASEY C. CASE
Appeal2017-004297
Application 14/489,934
Technology Center 1600
Before DONALD E. ADAMS, FRANCISCO C. PRATS and
ROBERT A. POLLOCK, Administrative Patent Judges.
POLLOCK, Administrative Patent Judge.
DECISION ON APPEAL
Appellants 1 appeal the Examiner's Final rejection of claims 1-5 under
35 U.S.C. § 134(a). We have jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
STATEMENT OF THE CASE
According to the Specification, "MMPs [ matrix metallo-proteases]
have been implicated in recovery in chronic brain injury, and inhibition of
MMP activity has been shown to abrogate migration of neurogenic cells
from the SVZ [ subventricular zone] into damaged tissues and to retard
neurovascular remodeling." Spec. ,r 43 (citing Zhao et al., Neurovascular
1 Appellants identify as real parties in interest, SanBio Inc. and The
University of South Florida. App. Br. 2.
Appeal2017-004297
Application 14/489,934
proteases in brain injury, hemorrhage and remodeling after stroke, Stroke
Vol. 38, 748-752 (2007); and Zhao et al., Role of matrix metalloproteinases
in delayed cortical responses after stroke, Nat Med. Vol. 12, 441--445
(2006) ). "MMPs may thus play a role in facilitating host cell migration
towards injured brain areas as part of the process by which SB623 cells
provide functional recovery from TBI." Id.
According to the Specification, "the inventors have discovered that
transplantation of SB623 cells remodeled the traumatically injured brain by
creating a biobridge between the SVZ and the peri-injured cortex. This
method of cell therapy can now be used to create similar biobridges between
neurogenic and non-neurogenic sites, to facilitate injury-specific migration
of cells across tissues that might otherwise pose barriers to cell motility." Id.
,r 44. In one experiment, "the biobridge formed by endogenous cells
migrating from the SVZ to the site of [traumatic brain injury (TBI)] was
isolated by laser capture microdissection." Id. ,r 42. "Zymographic assays
of[] laser-captured biobridges from animals subjected to TBI revealed two-
fold and nine-fold upregulation of matrix metalloproteinase 9 (MMP-9)
expression/activity in animals that received SB623 cell transplants,
compared to vehicle infused animals or sham-operated animals, at one
month and three months post-transplantation, respectively." Id.
Claim 1, the sole independent claim before us, recites:
1. A method for treating brain injury by inducing migration of
endogenous neurogenic cells to a site of brain injury, the
method comprising administering to the brain of a subject a
therapeutically effective amount of matrix metalloprotease-9
(MMP-9).
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Application 14/489,934
The Examiner rejects claims 1-5 under pre-AIA 35 U.S.C § 103(a) as
unpatentable over Lee et al., Involvement of Matrix Metalloproteinase in
Neuroblast Cell Migration from the Subventricular Zone after Stroke,
Journal ofNeuroscience, Vol. 26, No. 13, 3491-95 (2006) ("Lee").
FINDINGS OF FACT
FF 1. According to Lee, "neurogenesis after brain injury is a functionally
meaningful response." Lee, 3491 (first para.). "Under normal
conditions, the SVZ is an active area of persistent adult neurogenesis in
the rodent brain, and neuroblasts migrate along the sagittal axis of the
rostral migratory stream to populate the olfactory bulb. However, after
stroke and other forms of brain injury, neuroblasts swerve away from
their designated path and migrate toward damaged tissue instead." Id. at
3493 (last para.). Lee posits "that neuroblasts migrate toward damaged
brain by using matrix metalloproteases (MMPs)." Id. at 3491 (second
para.).
FF2. Lee teaches that MMPs are rapidly upregulated after brain injury due
to trauma, ischemia, and hemorrhage. Id. at 3494 (first full para.). With
respect to the effects of this upregulation, Lee states that "the
overwhelming evidence points to a detrimental effect in the acute phase
after brain injury." Id. at 3494. In contrast, during the delayed stages
after brain injury, Lee posits that "MMPs may play beneficial roles by
mediating the neurogenic response in the SVZ. By allowing neuroblasts
to expand and migrate, MMPs should facilitate the endogenous recovery
response in a damaged brain." Id. Noting that earlier studies had shown
that of the proteases in the MPP family, "MMP-9 was the most
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Application 14/489,934
responsive to acute brain injury" (id. at 3493 (first full para.) (citations
omitted)), Lee states that "immunohistochemistry data suggest that
MMP-9 plays a role in this phenomenon." Id.
FF3. Lee demonstrates that, in a mouse model of ischemic brain injury,
MMP-9 localizes with the neurogenic cells migrating in response to the
injury. According to Lee, "bromodeoxyuridine-labeled and doublecortin-
positive cells from the SVZ colocalize with the extracellular protease
matrix metalloproteinase-9 (MMP-9) during the 2 week recovery period
after transient focal cerebal ischemia in mice." Id., Abstract. More
particularly,
MMP-9 levels within the SVZ were higher in the ischemic
hemisphere compared with the contralateral side (fig 2a, b ). Z-
stack confocal analysis of double-stained
immunohistochemistry demonstrated that MMP-9 was
colocalized in cells that incorporated BrdU (Fig. 2c-e) and
streams of DCZ-positive structures that extended from the SVZ
into damaged striatal tissue in the ischemic hemisphere (Fig. 2/-
i).
Id. at 3493 (first full para.).
FF4. Lee notes that "[a]lthough colocalization of MMP-9 with these
markers of neuroblast migration after stroke supports our central idea, it
does not prove causality. To further test our hypothesis, we next
examined mice subjected to 60 min focal cerebral ischemia ... with ...
the broad spectrum MMP inhibitor GM600I." Id. at 3493 (third para.).
"MMP inhibition clearly suppressed the neurogenic migratory response
induced by stroke." Id. at 3493 (fourth para.), Abstract ("Treatment with
the broad spectrum MMP inhibitor GM6001 significantly decreases the
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Application 14/489,934
migration of doublecortin-positive cells that extend from the SVZ into
the striatum. ")
FF5. According to Lee, "[ o ]ur data here show for the first time that
extracellular proteolysis via MMP is required for neuroblast migration as
the brain attempts to heal itself." Id. at 3494 (last para.). Lee further
teaches that its "immunohistochemistry data suggests that MMP-9 plays
a role in this phenomenon," however:
A caveat here is that our MMP inhibitor GM6001 broadly
targets the entire MMP family. What other proteases may be
involved? A more careful delineation of how the full spectrum
of MMP family members and other proteases interact to
modulate matrix and subserve neurogenesis is warranted. A
second caveat involves the precise mechanisms and
consequences of neuroblast migration, it remains possible that
the neuroblast migration toward damaged tissue reflects an
endogenous response to inflammation .... [S]uppression of
neuroblast profiles in our MMP inhibited brains may simply be
attributable to reductions in inflammation and may be unrelated
to matrix modulations and migration per se.
Id. at 3494 (second full para.).
ANALYSIS
Lee teaches that, cells of the SVZ migrate toward damaged areas of
the brain in response to ischemic brain injury. FFI. Lee posits that the
activity of MMP-9 plays a role in this phenomenon as part of the healing
process. FF5. Lee basis this hypothesis on several lines of evidence: (1)
that MMPs, and MMP-9 in particular, are upregulated in response to acute
brain injury (FF2); (2) that MMP-9 colocalizes with migrating neurogenic
cells in a mouse model of ischemic brain injury (FF3-5); and (3) that a
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Application 14/489,934
broad spectrum MMP inhibitor, GM6001, suppresses that neurogenic
migratory response (FF4). See e.g., Ans. 7-8. 2
We further adopt the Examiner's findings of fact and reasoning
regarding the scope and content of the prior art. See Final Act. 3-8; Ans. 4--
17. As set forth in the Examiner's Answer, it would have been obvious to
provide MMP-9 to a patient suffering from brain injury because "Lee
strongly suggest[s] and encourage[s] treating brain injury with MMP-9," and
"[ s ]ince delivery to the brain was well known at the time of filing, one of
ordinary skill in the art would have had a reasonable expectation of success
as well." Ans. 5.
Appellants raise two arguments pertaining to all claims on appeal.
Appellants first argue that "Lee's disclosure does not direct the skilled
artisan specifically and predictably to MMP-9 as a mediator of neurogenic
cell migration." App. Br. 3-7 (emphasis omitted); Reply Br. 2-9. In sum,
Appellants argue that Lee: (1) merely demonstrated a correlation between
the presence of MMP-9 and cell migration; (2) acknowledges that GM6001
inhibits MMPs other than MMP-9; (3) failed to show that the levels of
GM6001 used were sufficient to inhibit MMP-9 in the mouse model; and (4)
admits that the disclosed data may reflect the involvement of MMPs in
inflammation rather than neuroblast migration. We do not find Appellants
arguments persuasive for the reasons set forth by the Examiner's Answer.
With respect to (1) and (2 ), we agree with the Examiner's summation
that it is not necessary for any single line of evidence be dispositive on its
2 Although we decline to address the Examiner's invitation to address
enablement (see Ans. 11-12), we do note that the Appellants' evidence for
enablement (see Reply Br. 11-12) is no greater than that disclosed in Lee.
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own. Ans. 8-9. "Rather, it is the accumulated weight of evidence, data and
reasoning that tends to lead to scientific consensus." Id. at 9. "That Lee
hypothesizes a causative role of MMP-9 in the process of stroke-induced
neuroblast migration and then proceeds to provide t[ w Jo independent lines
of evidence supporting this hypothesis is considered to provide sufficient
suggestion of same." Id.; see also id. at 10 ("[The GM6001 data] is not
considered dispositive on its own, but when taken with the strong correlation
data specific for MMP-9 discussed above, along with the fact that scientists
behind the Lee publication hypothesized a role for MMP-9 in the process of
stroke-induced neuroblast migration, the fact that MMP inhibition clearly
suppressed the neurogenic migratory response induced by stroke provides
strong evidence that MMP-9 plays a causative role in this process.").
With respect to (3), we agree with the Examiner that there is no
evidence "to suggest that Lee used GM6001 improperly, or otherwise failed
to achieve GM6001-mediated inhibition." Ans. 10-11. Appellants'
arguments to the contrary are speculative and unsupported attorney
argument. See Reply Br. 5---6.
With respect to (4), Appellants point to Lee's acknowledgment that
additional proteases may be involved in mediating cell migration and that "it
remains possible that the neuroblast migration toward damaged tissue
reflects an endogenous response to inflammation." App. Br. 6 ( quoting Lee,
3494 (second full para.)). We find supported, however, the Examiner's
response that Lee presents such caveats "as part of a legitimate and
necessary scientific discussion ... [ regarding] possible alternative
explanations for their results" but, nevertheless, "provide[ s] ample
suggestion to use MMP-9 in an effort to provide treatment to a subject
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suffering from a brain injury with a reasonable expectation of success." Ans.
12-13. Under the proper inquiry, "obviousness cannot be avoided by a
showing of some degree of unpredictability in the art so long as there was a
reasonable probability of success." Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1364 (Fed. Cir. 2007).
With respect to "teaching away," Appellants rely on four prior art
references in support of the argument that the art as a whole taught that
MMP-9 is involved in the pathology of brain injury as opposed to the
healing process. See App. Br. 7-8, Reply Br. 7-10. But in discussing this
art, Lee posits that although
the overwhelming evidence points to a detrimental effect [ of
MPP expression] in the acute phase after brain injury .... what
happens during the delayed stages after brain injury may be
quite different. Our present study suggest[ s] that, in fact,
MMPs may play beneficial roles by mediating the neurogenic
response in the SVZ. By allowing neuroblasts to expand and
migrate, MMPs should facilitate the endogenous recovery
response in a damaged brain.
Lee, 3494, (second and third paras.). Accordingly, and for the reasons set
forth at pages 13-14 of the Examiner Answer, we find supported the
Examiner's determination that Lee does not teach away from the use of
MMP-9 for the treatment of brain injury.
Appellants further argue that claim 4 is separately patentable for
reciting treatment of traumatic brain injury because Lee presents evidence
based on a model of ischemic stroke; and that claim 5 is separately
patentable for reciting treatment of brain injury in a human because Lee
presents evidence derived from a mouse model. App. Br. 8; Reply Br. 10-
11. Appellants present no evidence that one of ordinary skill in the art
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would consider Lee so limited and we do not find Appellants' arguments
persuasive for the reasons set forth at pages 14--15 of the Examiner's
Answer.
SUMMARY
For the reasons above, we affirm the Examiner's decision rejecting
claims 1-5.
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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