Ex Parte Stern et al

Patent Trial and Appeal Board

Sep 18, 2018

12278378 (P.T.A.B. Sep. 18, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
12/278,378 12/29/2008
28765 7590 09/20/2018
Winston & Strawn LLP
1700 K Street NW, 2nd Floor
Patent Department
Washington, DC 20006
FIRST NAMED INVENTOR
Naftali Stern
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.
85189-13800 1012
EXAMINER
PROUTY, REBECCA E
ART UNIT PAPER NUMBER
1652
NOTIFICATION DATE DELIVERY MODE
09/20/2018 ELECTRONIC
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.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
patentdocket@winston.com
sfanelli @wins ton. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte NAFTALI STERN, RUTH NA VON,
ANTHONY FUTERMAN, ARI ZIMRAN, and ETTY OSHER
Appeal2017-001055
Application 12/278,378
Technology Center 1600
Before FRANCISCO C. PRATS, JEFFREY N. FRED MAN, and
DAVID COTTA, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1,2 under 35 U.S.C. § 134 involving claims to a
chimeric protein for the delivery of a therapeutic enzyme across the blood
brain barrier. The Examiner rejected the claims as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We reverse.
1 Appellants identify the Real Parties in Interest as The Medical Research
and Infrastructure Fund of the Tel-Aviv Sourasky Medical Center, Ramot at
Tel-Aviv University, Ltd., and Yeda Research Development Company Ltd.
(see App. Br. 1 ).
2 We have considered and herein refer to the Specification of Aug. 5, 2008
("Spec."); Final Office Action of Aug. 26, 2015 ("Final Action"); Appeal
Brief of Feb. 19, 2016 ("App. Br."); Examiner's Answer of Aug. 22, 2016
("Answer"); and Reply Brief of Oct. 24, 2016 ("Reply Br.").
Appeal2017-001055
Application 12/278,378
Statement of the Case
Background
"Lysosomal Storage diseases (LSD) are inherited genetic defects,
resulting in an enzyme deficiency. This deficiency prevents the lysosome
from metabolizing cellular waste, and results in their accumulation in the
cell" (Spec. 1: 14--16). "For an effective treatment of LSDs, a therapeutic
agent, such as the deficient enzyme, must be taken up by the affected cells
and routed to the lysosome where it is able to act upon the harmful material
residing therein" (Spec. 2:11-13).
The Claims
Claims 47-50, 56-59, 63, and 64 are on appeal. 3 Claim 47 is
representative and reads as follows:
4 7. A chimeric protein for the delivery of a therapeutic
enzyme across the blood brain barrier, the chimeric protein
comprising a protein hormone which is granulocyte colony
stimulating factor (G-CSF) or a precursor or an active fragment
thereof having the amino acid sequence as set forth in any one of
SEQ ID NOs: 5---6 and 9-10, covalently linked to a therapeutic
enzyme which is ~-hexosaminidase A (HEXA) or a precursor or
active fragment thereof, having the amino acid sequence as set
forth in any one of SEQ ID NOs: 13-16, wherein the G-CSF is
able to cross the blood brain barrier; and wherein ~-
hexosaminidase A is an enzyme whose deficiency is linked to
GM2-gangliosidosis type I/TaySachs disease.
3 Claims 60---62 and 65-67 were withdrawn from consideration (see App. Br.
2).
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Application 12/278,378
The Rejection
The Examiner has rejected claims 47-50, 56-59, 63, and 64 under
35 U.S.C. § 103(a) as obvious over Starr, 4 Pan, 5 Schaebitz, 6 and Mahuran 7
(Final Act. 3-10).
The Examiner finds Starr teaches a chimeric fusion protein of~-
hexosaminidase A for treatment of lysosomal storage diseases (see Final
Act. 3--4) but finds Starr does not teach "the use of G-CSF as the portion of
the chimeric protein which provides for the transport of the enzyme whose
deficiency is linked to the lysosomal storage disease across the blood brain
barrier" (Final Act. 4).
The Examiner finds Pan teaches "methods of transport of a desired
polypeptide across the blood-brain barrier include fusion to a polypeptide
which crosses the blood-brain barrier" and "that polypeptides which cross
the blood-brain barrier include cytokines including G-CSF" (Final Act. 4).
The Examiner finds Schaebitz teaches a G-CSF of SEQ ID NO: 5 that
"crosses the blood brain barrier" and "chimeric proteins in which full-length
G-CSF is fused to another sequence" (Final Act. 4--5). The Examiner finds
Mahuran teaches "the amino acid sequence of the wild type human ~-
hexosaminidase A protein is that of SEQ ID NO: 13" (Final Act. 5).
4 Starr et al., WO 03/057179 A2, published July 17, 2003.
5 Pan et al., Polypeptide Delivery Across The Blood-Brain Barrier, 3
CURRENT DRUG TARGETS-CNS & NEUROLOGICAL DISORDERS 131-36
(2004).
6 Schaebitz et al., WO 2004/058287 A2, published July 15, 2004.
7 Mahuran, Biochemical consequences of mutations causing the GM2
gangliosidoses, 1455 BIOCHIMICA ET BIOPHYSICA ACTA 105-38 (1999).
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Application 12/278,378
The Examiner finds it obvious
to substitute the p97 portion of the chimeric proteins of Starr et
al. with the G-CSF protein of Schaebitz et al. as a skilled artisan
would have recognized that G-CSF would be an alternative to
p97 as each of these proteins are polypeptides which cross the
blood brain barrier and to use the protein of SEQ ID NO: 13
within the chimeric protein for the treatment of patients
(Final Act. 5).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner's conclusion that Starr, Pan,
Schaebitz, and Mahuran render claim 4 7 obvious?
Findings of Fact
1. Starr teaches "treating LSDs [lysosomal storage diseases]
involving the use of p97 proteins to target delivery of therapeutic agents,
including proteins or enzymes deficient in LSDs, to the lysosomes of cells"
(Starr ,r 13).
2. Starr teaches the "conjugate comprises any one of the following
proteins as the active agent covalently linked to a p97 molecule ... ~-
hexosaminidase A" (Starr ,r 25).
3. Starr teaches: "Fusion proteins may be prepared using standard
techniques known in the art. Typically, a DNA molecule encoding p97 or a
portion thereof is linked to a DNA molecule encoding the protein
compound" (Starr ,r 56).
4. Starr teaches the "key event for the successful delivery of
therapeutic agents into brain is the transport of these large molecules across
the tight network of capillary endothelial cells that comprise the BBB [blood
brain barrier] .... Such transport of large molecules across the BBB involves
a process known as transcytosis" (Starr ,r 11 ).
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Application 12/278,378
5. Starr teaches "[t]ranscytosis is a cell-type specific process
mediated by receptors on the BBB endothelial surface. The transport of
p97-conjugates (i.e., p97 chemically linked to macromolecules) across the
BBB occurs by transcytosis" (Starr ,r 12).
6. Pan teaches, in a section titled "Strategies for delivery of
polypeptides across the BBB [blood brain barrier]," that the "appealing idea
of fusion proteins to facilitate delivery ... involves a genetically constructed
fusion protein in the blood which is cleaved at its target site in the brain so
as to release the desired polypeptide" (Pan 132, col. 2).
7. Pan teaches that BBB "[t]ransport mechanisms can be
adsorptive-, receptor-, and carrier-mediated" (Pan 132, col. 1).
8. Pan teaches that "[ s ]everal factors, in addition to transport
mechanisms, can affect the penetration of the BBB by polypeptides. These
include binding to circulating proteins, as illustrated by insulin-like growth
factor (IGF) ... and aggregation" (Pan 132, col. 1 ).
9. Pan teaches: "Granulocyte/monocyte colony stimulating factor
( GM-CSP) exerts CNS effects .... The intact glycoprotein crosses the BBB
in mouse and rats of both sexes by a saturable transport mechanism" (Pan
133, col. 2).
10. Pan teaches "IL2, although relatively stable in blood, crosses by
simple diffusion rather than a saturable system" (Pan 133, col. 2).
11. Pan teaches that "we have not detected any saturable transport
systems for the chemokines MIP-1, CINC-1, and interleukin-8" (Pan 133,
col. 2).
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Application 12/278,378
12. Schaebitz teaches "that G-CSF injected intravenously in the
blood crosses the BBB and can principally activate specific receptors on
CNS-neurons" (Schaebitz 97).
13. Mahuran teaches the sequence of ~-hexosaminidase A (see
Mahuran 116, figure 1) identified by the Examiner as that of SEQ ID NO: 13
recited in Appellants' claim 47 (see Final Act. 5).
14. Dr. Stem8 states:
Covalent linking of a carrier protein to a therapeutic agent such
as an enzyme to generate a chimeric protein is challenging as
the conformation of the carrier protein has to be preserved in
order to enable its binding to the carrier receptors and hence to
enable the chimeric protein to cross the BBB. More
importantly, the conformation of the enzyme has to be
preserved within the chimeric protein in order to maintain its
activity so as to restore enzyme activity in the target neuronal
cell.
(Stem Deel. ,r 9).
Principles of Law
0 'Farrell states that"[ o ]bviousness does not require absolute
predictability of success." In re O 'Farrell, 853 F.2d 894, 903 (Fed. Cir.
1988). However, 0 'Farrell identifies
two kinds of error. In some cases, what would have been
"obvious to try" would have been to vary all parameters or try
each of numerous possible choices until one possibly arrived at
a successful result, where the prior art gave either no indication
of which parameters were critical or no direction as to which of
many possible choices is likely to be successful. In others,
what was "obvious to try" was to explore a new technology or
general approach that seemed to be a promising field of
experimentation, where the prior art gave only general guidance
8 Declaration of Dr. Naftali Stem, dated Aug. 21, 2012.
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Application 12/278,378
as to the particular form of the claimed invention or how to
achieve it.
(Id. ( citations omitted)).
Analysis
Appellants contend "[ n Jone of Pan, Schaebitz and Mahuran discloses
or suggests that G-CSF can be actively transported from the blood into the
brain to be used as a transport protein" (App. Br. 4). Appellants contend
"[ s ]killed artisans would know that not all proteins that are capable of
crossing the blood brain barrier ('BBB') are suitable for use as BBB
transporter proteins" and that "the conformation of the enzyme has to be
preserved within the chimeric protein in order to maintain its activity so as to
restore enzyme activity in the target neuronal cell" (App. Br. 8-9).
The Examiner responds:
The production of fusion proteins in which the fusion protein
maintains the activities of both fusion partners is not
unexpected in the art. In both applications the hurdle to be
overcome is transport of the enzyme to the lysosome of the
brain cells not of producing a fusion with activity. If the fusion
protein was successfully transported to the lysosomes of brain
cells the skilled artisan would have every expectation that the
enzymatic activity was present in the lysosomes of brain cells.
(Ans. 11).
We think the instant fact pattern falls into O 'Farrell's first type of
error, since the ordinary artisan, armed with the teachings of Starr, Pan, and
Schaebitz would have had to vary a large number of possible choices with
no indication of which choices were likely to be successful.
Starr and Pan may render it "obvious to try" fusion proteins for
delivery of desired enzyme activities past the blood brain barrier (FF 1---6),
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Application 12/278,378
but Starr, Pan, and Schaebitz provide no indication of which parameters
were critical and no direction as to which of many possible choices is likely
to be successful. That is, the Examiner provides no specific reason to select
G-CSF from the long list of proteins known to cross the BBB as the
targeting fusion partner. Instead, the Examiner relies upon an obvious
equivalence rationale where "a skilled artisan would have recognized that G-
CSF would be an alternative to p97" (Final Act. 5).
The Examiner does not establish that G-CSF is transported across the
BBB using the transcytosis mechanism that Starr teaches is key for
successful delivery of large molecules such as p97 fusion proteins through
the BBB (FF 4--5).
Instead, Pan evidences that proteins cross the BBB through multiple
transport mechanisms including adsorptive-, receptor-, and carrier-mediated
(FF 7) and various factors impact the ability of a protein to penetrate the
BBB (FF 8). Pan teaches that some cytokines, including GM-CSP, use a
"saturable transport mechanism" (FF 9) suggesting a receptor mediated
approach while other cytokines, including IL2, MIP-1, and IL-8, cross by
simple diffusion (FF 10-11). Neither Pan nor Schaebitz provides any detail
regarding the mechanism of transport of G-CSF (FF 7-12).
Our conclusion is further bolstered by Dr. Stem's evidence that there
is additional unpredictability in ensuring that the targeting portion of the
fusion protein retains the ability to bind to the receptor for transcytosis and
in ensuring that the enzymatic portion, here ~-hexosaminidase A, retains
sufficient activity to "restore enzyme activity in the target neuronal cell" (FF
14).
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Application 12/278,378
The Examiner disagrees with this evidence and contends that the
ordinary artisan would have expected a fusion protein to retain activity (see
Ans. 11 ), but the Examiner provides no evidence showing that any prior art
fusion protein successfully crossed the BBB while retaining enzymatic
activity in the target cells. The Examiner does not identify any examples of
fusion transport in Pan and we note that Starr's treatment examples,
including Examples 3 and 5, were written in the present tense, suggesting
that the examples were prophetic and not performed prior to filing (see Spec.
,r,r 140-141, 147-148). See Atlas Powder Co. v. E.I. du Pont De Nemours &
Co., 750 F.2d 1569, 1578 (Fed. Cir. 1984) ("the examples were written in
the present tense to conform with the PTO requirements on prophetic
examples").
Consequently, without any evidence in the prior art that G-CSF
crosses the BBB by a mechanism suitable for transport of large fusion
proteins, and the resulting need for the ordinary artisan to test a large
number of different proteins with no direction as to which of many possible
choices is likely to be successful, we find that there would not have been a
reasonable expectation of success and the claims are not rendered obvious
by the cited prior art.
Conclusion of Law
A preponderance of the evidence of record does not support the
Examiner's conclusion that Starr, Pan, Schaebitz, and Mahuran render claim
47 obvious.
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Application 12/278,378
SUMMARY
In summary, we reverse the rejection of claims 47-50, 56-59, 63, and
64 under 35 U.S.C. § 103(a) as obvious over Starr, Pan, Schaebitz, and
Mahuran.
REVERSED
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