Ex Parte Crine et al

Patent Trial and Appeal Board

Mar 26, 2018

13899359 (P.T.A.B. Mar. 26, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/899,359 05/21/2013
145747 7590 03/28/2018
Clark+Elbing LLP/Alexion Pharmaceuticals, Inc.
101 FEDERAL STREET
BOSTON, MA 02110
FIRST NAMED INVENTOR
Philippe CRINE
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.
50694-039005 6457
EXAMINER
EMCH, GREGORY S
ART UNIT PAPER NUMBER
1649
NOTIFICATION DATE DELIVERY MODE
03/28/2018 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):
patentadministrator@clarkelbing.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PHILIPPE CRINE and FLORENT ELEFTERIOU 1
Appeal2017-005968
Application 13/899,359
Technology Center 1600
Before ERIC B. GRIMES, TA WEN CHANG, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to methods
of treating a neurocutaneous syndrome, which have been rejected for
obviousness and obviousness-type double patenting. We have jurisdiction
under 35 U.S.C. § 6(b ).
We reverse.
1 Appellants identify the real parties in interest as Alexion Pharmaceuticals,
Inc. and Vanderbilt University. Br. 4.
Appeal2017-005968
Application 13/899,359
STATEMENT OF THE CASE
The Specification states that
neurofibromatosis, a neurocutaneous syndrome resulting in
tumors in the nervous system, results in bone manifestations
that arise from accumulation of inorganic pyrophosphate (PPi).
As alkaline phosphatase-Fe fusion proteins ... can reduce PPi
accumulation, the present invention provides a polypeptide
including a soluble alkaline phosphatase (sALP) domain (i.e.,
an sALP polypeptide), as well as compositions and uses
thereof. In addition, bone manifestations in neurofibromatosis
may also arise from overactivation of the MAP-kinase pathway,
and a natriuretic peptide (NP) or NP analog could be used to
inhibit this pathway. Accordingly, the present invention
provides a polypeptide including an NP (e.g., a CNP) domain
(i.e., an NP polypeptide) and compositions and uses thereof.
Spec. 3.
Claims 1--4, 7, 25-28, 39, 71, 82, 118, 121, 131, 132, and 139 are on
appeal. Claims 1, 25, and 118 are illustrative and read as follows:
1. A method of treating a neurocutaneous syndrome
in a subject, said method comprising administering to said
subject a therapeutically effective amount of a pharmaceutical
composition comprising:
(a) a polypeptide comprising the structure A-sALP-B;
and
(b) a pharmaceutically acceptable excipient,
wherein sALP is the extracellular domain of an alkaline
phosphatase,
A is absent or is an amino acid sequence of at least one
amino acid, and
B is absent or is an amino acid sequence of at least one
amino acid,
thereby treating said syndrome in said subject.
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Application 13/899,359
25. A method of treating a neurocutaneous syndrome
in a subject, said method comprising administering to said
subject a therapeutically effective amount of a pharmaceutical
composition comprising:
(a) a polypeptide comprising the structure V-NP-W; and
(b) a pharmaceutically acceptable excipient,
wherein NP is a natriuretic peptide that is an agonist of
natriuretic peptide receptor B (NPR-B),
V is absent or is an amino acid sequence of at least one
amino acid, and
W is absent or is an amino acid sequence of at least one
amino acid,
thereby treating said syndrome in said subject.
118. A method of treating a disease or a condition in a
subject, said method comprising administering to said subject a
therapeutically effective amount of a first polypeptide and a
second polypeptide, wherein
a) said first polypeptide comprises the structure A-sALP-
B, wherein
i) sALP is the extracellular domain of an alkaline
phosphatase,
ii) A is absent or is an amino acid sequence of at
least one amino acid, and
iii) B is absent or is an amino acid sequence of at
least one amino acid; and
b) said second polypeptide comprises the structure V-NP-
W, wherein
i) NP is a natriuretic peptide that is an agonist of
natriuretic peptide receptor B (NPR-B),
ii) V is absent or is an amino acid sequence of at
least one amino acid, and
iii) W is absent or is an amino acid sequence of at
least one amino acid; and
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Application 13/899,359
said disease or condition is selected from the group consisting
of a neurocutaneous syndrome, a disorder associated with
overactivation of FGFR3, a bone or cartilage disorder, a
vascular smooth muscle disorder, and a condition for elongation
of bone,
thereby treating said disease or said condition in said
subject.
The claims stand rejected as follows:
Claims 1--4, 7, and 82 under 35 U.S.C. § 103(a) as obvious based on
Crine2 and Ramachandran3 (Ans. 2);
Claims 1--4, 7, 25-28, 39, 71, 82, 118, 121, 131, 132, and 139 under
35 U.S.C. § 103(a) as obvious based on Crine, Ramachandran, and Wendt4
(Ans. 5);
Claims 1--4, 7, and 82 for obviousness-type double patenting based on
claims 6-8 of U.S. Patent 7,763,712, in view of Ramachandran (Ans. 8);
Claims 1--4, 7, 25-28, 39, 71, 82, 118, 121, 131, 132, and 139 for
obviousness-type double patenting based on claims 6-8 of U.S. Patent
7,763,712, in view ofRamachandran and Wendt (Ans. 10);
Claims 1--4, 7, and 82, provisionally, for obviousness-type double
patenting based on claims 61-72 of application 13/695, 127, in view of
Ramachandran (Ans. 11 );
2 Crine et al., US 2010/0297119 Al, Nov. 25, 2010.
3 M. Ramachandran et al., Treatment of an Anabolic Bone Deficiency in
Neurofibromatosis with Bone Morphogenetic Proteins and its Potential
Application for Congenital Pseudarthrosis of the Tibia, 91-B, Supp. 137: J.
OF BONE & JOINT SURGERY BR., Abstract only (2009).
4 Wendt et al., WO 2010/135541 A2, Nov. 25, 2010.
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Application 13/899,359
Claims 1--4, 7, 25-28, 39, 71, 82, 118, 121, 131, 132, and 139,
provisionally, for obviousness-type double patenting based on claims 61-72
of application 13/695,127, in view ofRamachandran and Wendt (Ans. 14);
Claims 1--4, 7, and 82, provisionally, for obviousness-type double
patenting based on claims 24--31, 33-36, 64, and 65 of application
12/638,527, in view of Ramachandran (Ans. 15);
Claims 1--4, 7, 25-28, 39, 71, 82, 118, 121, 131, 132, and 139,
provisionally, for obviousness-type double patenting based on claims 24--31,
33-36, 64, and 65 of application 12/638,527, in view ofRamachandran and
Wendt (Ans. 17).
I
The Examiner has rejected claims 1--4, 7, and 82 as obvious based on
Crine and Ramachandran. The Examiner also rejected claims 1--4, 7, and 82
for obviousness-type double patenting based on claims 6-8 of U.S. Patent
7,763,712, in view ofRamachandran, and provisionally rejected claims 1--4,
7, and 82 for obviousness-type double patenting based on either claims 61-
72 of application 13/695, 127 or claims 24--31, 33-36, 64, and 65 of
application 12/638,527, both in view ofRamachandran. The same issue is
dispositive of all of these rejections.
The Examiner finds that "Crine teaches a method of treating a bone
defective condition" by administering a polypeptide comprising the
A-sALP-B structure of the claims on appeal and a pharmaceutically
acceptable excipient. Ans. 2. The Examiner finds that "Crine does not teach
that the bone defective condition is a neurocutaneous syndrome, but does
teach that treatment with the disclosed polypeptide can induce increased
bone growth ... and mineralization." Id. at 3.
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Application 13/899,359
The Examiner finds that "Ramachandran teaches the use of BMP-2
treatment to induce bone formation in order to treat the orthopedic
complications of neurofibromatosis type I . . . . Ramachandran does not
teach treatment with the particular polypeptide claimed." Id. The Examiner
concludes that it would have been obvious
that the method taught by Crine could be used to treat any bone
defective condition that could benefit from increased bone
mineralization or growth. Given that ALP is reduced in
neurofibromatosis, as taught by Ramachandran, and that the
method taught by Crine via administration of ALP can increase
mineralization and bone formation, it would have been obvious
to one of skill in the art to use the method of Crine to treat
neurofibromatosis type I.
Id. The double patenting and provisional double patenting rejections are
based on the same rationale. See id. at 8-9, 11-12, 15-16.
Appellants argue that "sALP and BMP-2 are not interchangeable
equivalents" and "[ w ]hile both agents induce bone formation when used to
treat their respective diseases, the cited art provides no reason to expect that
sALP and BMP-2 would be mechanistic equivalents for treating other bone
diseases that arise from distinctly different pathological mechanisms." Br. 9.
Appellants argue that "[ c ]onsequently, no reason exists, a priori, to expect
that sALP and BMP-2 are functional equivalents, such that, for example,
BMP-2 could be used to treat HPP [hypophosphatasia] and, vice versa, that
sALP could be used to treat NFl." Id.
We agree with Appellants that the Examiner has not shown that the
method of claim 1 would have been obvious to a person of ordinary skill in
the art based on the cited references. Crine discloses that
[h ]ypophosphatasia (HPP) is a rare, heritable form of rickets .
. . . This "inborn error of metabolism" is caused by loss-of-
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Application 13/899,359
function mutation( s) in the gene ( ALPL) that encodes the
tissue-nonspecific isozyme of alkaline phosphatase (TN ALP;
a.k.a liver/bone/kidney type ALP) .... The biochemical
hallmark is subnormal ALP activity in serum.
Crine i-f 4. Crine discloses a "bone targeted composition ... [that]
encompasses sequences satisfying a consensus sequence derived from the
ALP extracellular domain of human ALP isozymes and of known functional
TNALPs," and fusion proteins comprising soluble ALP (sALP). Id. i-fi-121,
40.
More specifically, ... there is provided a bone targeted alkaline
phosphatase comprising a polypeptide having the structure: Z-
sALP-Y-spacer-X-Wn-V, wherein sALP is the extracellular
domain of the alkaline phosphatase; wherein V is absent or is
an amino acid sequence of at least one amino acid; X is absent
or is an amino acid sequence of at least one amino acid; Y is
absent or is an amino acid sequence of at least one amino acid;
Z is absent or is an amino acid sequence of at least one amino
acid; and Wn is a polyaspartate or a polyglutamate wherein
n=lO to 16.
Id. i-f 64.
Crine discloses that "[ t ]he fusion proteins ... are useful for therapeutic
treatment of bone defective conditions by providing an effective amount of
the fusion protein to the bone. The fusion proteins are provided in the form
of pharmaceutical compositions in any standard pharmaceutically acceptable
carrier." Id. i-f 40. Crine states that "[t]he bone targeted sALP ... may also
be used in combination with at least one other active ingredient to correct a
bone mineralization defect or another detrimental symptom of HPP." Id.
,-r 61.
Crine provides working examples that describe a fusion protein
comprising an alkaline phosphatase domain ("sTNALP-FcDlO") and
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Application 13/899,359
administration of the fusion protein to mice that had been mutated to
eliminate TNALP expression. Id. i-fi-f 123, 142, 161. Crine discloses that
tibia and femur length was greater in mice administered the fusion protein
than in mice administered vehicle alone. Id. i-f 163.
Ramachandran discloses that "[ r ]ecombinant bone morphogenic
proteins (BMPs) are potent bone anabolic agents suggested for the treatment
of orthopaedic complications associated with neurofibromatosis type 1
(NF 1)." Ramachandran, Abstract. Ramachandran states that cultured
osteoblasts from "an Nfl +/-knockout mouse model" showed reduced
alkaline phosphatase (ALP) activity and "responded to BMP-2 treatment."
Id. Ramachandran concludes that its "data indicate that BMP therapies have
potential utility in treating orthopaedic defects in children with NFL" Id.
However, as Appellants point out, hypophosphatasia (HPP) and
neurofibromatosis type 1 (NF-1) "arise from distinctly different pathological
mechanisms." Br. 9. Specifically, Crine discloses that HPP "is caused by
loss-of-function mutation(s) in the gene (ALPL) that encodes the tissue-
nonspecific isozyme of alkaline phosphatase (TN ALP; a.k.a
liver/bone/kidney type ALP)." Crine i14. Appellants' Specification states
that
neurofibromatosis type I (NF 1 or Von Recklinghausen disease)
is an autosomal dominant genetic disorder. . . . NF 1 encodes
neurofibromin, a member of the GTPase Activating Protein
(GAP) family known to suppress the Ras kinase.
Neurofibromin is a specific suppressor ofp21-RAS, and
mutations in the NF 1 gene cause unsuppressed activation of
RAS that lead to abnormal cell growth and differentiation.
Spec. 1. The Examiner does not dispute that NF 1 is caused by mutations in
the neurofibromin (NFl) gene. See Ans. 19-20.
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Application 13/899,359
Thus, Crine' s disclosure that exogenously supplied alkaline
phosphatase increases bone growth in mice that have mutations in their
alkaline phosphatase gene would not have provided the skilled artisan with a
basis to reasonably expect that exogenously supplied alkaline phosphatase
would also be effective to treat NF 1, because NF 1 arises from mutation of a
different gene. Stated differently, the fact that administering alkaline
phosphatase is effective in treating a disease caused by a deficiency in
alkaline phosphatase expression would not have led the skilled artisan to a
reasonable expectation that alkaline phosphatase would also be effective in
treating bone-related symptoms of a disease caused by mutations that result
in unsuppressed activation of p21-RAS, absent some direct connection
between the two disease etiologies or mechanisms, which the Examiner has
not provided. We are not persuaded that the fact that both diseases originate
in bone is a sufficient connection. We therefore reverse the rejection of
claim 1, and dependent claims 2--4, 7, and 82 as obvious based on Crine and
Ramachandran.
For the same reason, we reverse the rejection of claims 1--4, 7, and 82
for obviousness-type double patenting based on claims 6-8 of U.S. Patent
7,763,712, in view ofRamachandran, and the provisional rejections of
claims 1--4, 7, and 82 for obviousness-type double patenting based on either
claims 61-72 of application 13/695, 127 or claims 24--31, 33-36, 64, and 65
of application 12/638,527, both in view ofRamachandran.
II
The Examiner has rejected all of the claims on appeal as obvious
based on Crine, Ramachandran, and Wendt. The Examiner also rejected all
of the claims on appeal for obviousness-type double patenting based on
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Application 13/899,359
claims 6-8 of U.S. Patent 7,763,712, in view of Ramachandran and Wendt,
and provisionally rejected the pending claims for obviousness-type double
patenting based on either claims 61-72 of application 13/695, 127 or claims
24--31, 33-36, 64, and 65 of application 12/638,527, both in view of
Ramachandran and Wendt. The same issue is dispositive of all of these
rejections.
The Examiner finds that "Crine and Ramachandran teach as set forth
above but fail to teach treatment with a natriuretic peptide (NP) compound."
Ans. 5. The Examiner finds that
Id.
Wendt teaches a method of treating bone formation disorders
including those where bone growth or formation is to be
stimulated, said method comprising administering to a subject
in need thereof a therapeutically effective amount of a
pharmaceutical composition comprising: (a) a polypeptide
comprising the structure V-NP-W as claimed ... and (b) a
pharmaceutically acceptable excipient.
The Examiner concludes that it would have been obvious to
administer a natriuretic peptide (NP), alone (as recited in claim 25) or in
combination with a soluble alkaline phosphatase (as recited in claim 118), to
treat a neurocutaneous syndrome such as NF 1 because "Wendt teaches that
the NP fusion proteins are desirable for treatment of bone formation
disorders to stimulate bone growth." Id. at 6. The double patenting and
provisional double patenting rejections are based on the same rationale. See
id. at 10-11, 14--15, 17-18.
Appellants argue that "[ t ]he comments above regarding Crine and
Ramachandran apply equally here" and
Wendt fails to remedy the deficiencies of Crine and
Ramachandran, given that Wendt similarly fails to teach or
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Application 13/899,359
suggest a NP to treat a neurocutaneous syndrome, such as NF 1.
Instead, Wendt teaches the treatment of a list of skeletal
dysplasias, in particular achondroplasia, and vascular smooth
muscle disorders by administering a NP.
Br. 11-12.
We agree with Appellants that the Examiner has not shown that the
method of claims 25 and 118 would have been obvious to a person of
ordinary skill in the art based on the cited references. The relevant
disclosures of Crine and Ramachandran are discussed above. Wendt
discloses "methods of using CNP [ ( C-type natriuretic peptide)] variants to
treat disorders responsive to CNP, including but not limited to bone-related
disorders such as skeletal dysplasias (e.g., achondroplasia) and vascular
smooth muscle disorders." Wendt 1:9-11.
Wendt states that
CNP binds to and activates natriuretic peptide receptor B (NPR-
B), also termed guanylyl cyclase B (GC-B), resulting in higher
intracellular cyclic guanosine monophosphate ( cGMP) levels.
Downstream signaling mediated by cGMP generation
influences a diverse array of biological processes that include
endochondral ossification. Accordingly, elevated or depressed
levels of any of the components in this pathway may lead to
aberrant bone growth.
Id. at 2:27-32.
Wendt also states that
[a ]chondroplasia is a result of an autosomal dominant mutation
in the gene for fibroblast growth factor receptor 3 (FGFR-3),
which causes an abnormality of cartilage formation. FGFR-3
normally has a negative regulatory effect on chondrocyte
growth, and hence bone growth. In achondroplasia, the
mutated form of FGFR-3 is constitutively active, which leads to
severely shortened bones. . . . CNP is an agonist for NPR-B, a
positive regulator of chondrocyte and bone growth.
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Downstream signaling of CNP/NPR-B inhibits the FGFR-3
pathway.
Id. at 3:6-23.
However, as Appellants point out, Wendt "fails to teach or suggest a
NP to treat a neurocutaneous syndrome, such as NF 1. Instead, Wendt
teaches the treatment of a list of skeletal dysplasias, in particular
achondroplasia, and vascular smooth muscle disorders by administering a
NP." Br. 11-12. Crine discloses treating hypophosphatasia (HPP) by
administering a soluble alkaline phosphatase (sALP), Ramachandran
discloses treating NF-1 by administering BMP-2, and Wendt discloses
treating achondroplasia by administering CNP.
However, the evidence of record shows that the specific disorders
being treated have different genetic causes: HPP is caused by "loss-of-
function mutation(s) in the gene (ALPL) that encodes the tissue-nonspecific
isozyme of alkaline phosphatase" ( Crine i-f 4 ), NF-1 is caused by "mutations
in the NFl gene [that] cause unsuppressed activation of RAS" (Spec. 1), and
"[a]chondroplasia is a result of an autosomal dominant mutation in the gene
for fibroblast growth factor receptor 3 (FGFR-3)" (Wendt 3:6-7).
Thus, Wendt's disclosure that exogenously supplied CNP can be used
to treat achondroplasia would not have provided the skilled artisan with a
basis to reasonably expect that exogenously supplied CNP would be
effective to treat NF 1, because NF 1 arises from mutation of a different gene.
Stated differently, the fact that administering CNP is effective in treating a
disease caused by a mutation in FGFR-3 gene would not have led to a
reasonable expectation that CNP would also be effective in treating bone-
related symptoms of a disease (i.e., NF-1) caused by mutations that result in
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unsuppressed activation ofp21-RAS. We therefore reverse the rejection
under 35 U.S.C. § 103(a) based on Crine, Ramachandran, and Wendt.
For the same reason, we reverse the rejection of the claims for
obviousness-type double patenting based on claims 6-8 of U.S. Patent
7,763,712, in view ofRamachandran and Wendt, and the provisional
rejections of the claims for obviousness-type double patenting based on
either claims 61-72 of application 13/695,127 or claims 24--31, 33-36, 64,
and 65 of application 12/638,527, both in view of Ramachandran and
Wendt.
SUMMARY
We reverse all of the rejections on appeal.
REVERSED
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