Ex Parte Grabowski et al

Patent Trial and Appeal Board

Feb 21, 2017

11653147 (P.T.A.B. Feb. 21, 2017)

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
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
11/653,147 01/12/2007 Gregory A. Grabowski 0010872.0547702 5090
26874 7590 02/23/2017
FROST RROWN TODD T T C EXAMINER
3300 Great American Tower HOLLAND, PAUL J
301 East Fourth Street
CINCINNATI, OH 45202 ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
02/23/2017 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):
patents @ fbtlaw. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte GREGORY A. GRABOWSKI and HONG DU
Appeal 2015-008166
Application 11/653,147
Technology Center 1600
Before DONALD E. ADAMS, RYAN H. FLAX, and
DEVON ZASTROW NEWMAN, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL1
This appeal under 35 U.S.C. § 134(a) involves claims 65, 69, 73, and
78 (Final Act.2 1). Examiner entered a rejection under 35 U.S.C. § 103(a).
We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.
STATEMENT OF THE CASE
Appellants claim a method for treatment of a mammal having
cholesteryl ester storage disease (App. Br. 11 (Appellants’ claim 65)).
Claim 65 is representative and reproduced below:
65. A method for treatment of a mammal having cholesteryl
ester storage disease comprising the step of administering to the
1 Appellants identify the real party in interest as “Children’s Hospital
Medical Center” (App. Br. 3).
2 Examiner’s November 11, 2014 Final Office Action.
Appeal 2015-008166
Application 11/653,147
mammal an effective amount of lysosomal acid lipase by
intravenous infusion, wherein said administration step results in
activity of said lysosomal acid lipase in the lysosomes of cells
of the small intestine, or both the lysosomes of the cells of the
small intestine and the lysosomes of the cells of the liver,
wherein said activity is present in an amount sufficient to
reduce cholesteryl ester and/or triglyceride storage in said small
intestine or in both small intestine and liver; and
wherein the lysosomal acid lipase comprises an oligosaccharide
terminated N-acetylglycosylation residue comprising a
mannose residue.
(App. Br. 11.)
The claims stand rejected as follows:
Claims 65, 69, 73, and 78 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Dul,3 Du2,4 Du3,5 Anderson,6 and
Gabowski.7
3 Hong Du et al., Targeted disruption of the mouse lysosomal acid lipase
gene: long-term survival with massive cholesteryl ester and triglyceride
storage, 7 Human Molecular Genetics 1347-54 (1998).
4 Hong Du et al., Molecular and Enzymatic Analyses of Lysosomal Acid
Lipase in Cholesteryl Ester Storage Disease, 64 Molecular Genetics and
Metabolism 126-34 (1998).
5 Hong Du, et al., Tissue and cellular specific expression of murine
lysosomal acid lipase mRNA and protein, 37 J. Lipid Res. 937-49
6 Richard A. Anderson and Gloria N. Sando, Cloning and Expression of
cDNA encoding Human Lysosoomal Acid Lipase/Cholesteryl Ester
Hydrolase, 266 J. Biol. Chem. 22479—84 (1991).
7 Gregory A. Grabowski, MD, et al., Enzyme Therapy in Type 1 Gaucher
Disease: Comparative Efficacy of Mannose-terminated Glucocerebrosidase
from Natural and Recombinant Sources, 122 Ann. Intern. Med. 23—39
(1995).
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Application 11/653,147
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Dul discloses that “[ljysosomal acid lipase (LAL) is essential for the
hydrolysis of the triglycerides and cholesteryl esters [(CE)] in lysosomes.
Its deficiency produces two phenotypes, a severe infantile-onset variant,
Wolman disease (WD), and a later onset variant, cholesteryl ester storage
disease (CESD)” (Dul, Abstract; Ans. 3; see also Du3, Abstract and 937
(“LAL contributes to the homeostatic control of plasma lipoprotein levels
and to the prevention of cellular lipid overloading in liver, spleen,
macrophages, and smooth muscle cells of the arterial walls”); Ans. 5).
FF 2. Dul discloses that “LAL ... is trafficked to the lysosome via the
mannose-6-phosphate receptor system” (Dul 1347; Ans. 3).
FF 3. Dul discloses “[a] mouse model with a LAL null mutation,” wherein
the “[hjomozygote knockout mice (lallal) produce no LAL mRNA, protein
or enzyme activity” (Dul, Abstract; see also id. at 1348 (describing the
“Generation of LAL-deficient mice”; Ans. 3).
FF 4. Dul discloses that “for 6-week-old mice [] [tjotal CEs in lal lal'
livers were estimated at ~32-fold greater than those in lal+lal+ livers,”
wherein “[t]he levels of CEs in lal+lal~ mouse liver were similar to those in
lal+lal+ mice” (Dul 1349; Ans. 3).
FF 5. Dul discloses that “[t]he CEs also accumulated in spleen and small
intestine [],” wherein “[t]he CE levels in spleen and small intestine were
~10- and ~2-fold higher in the affected mice” (Dul 1349; Ans. 3).
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Application 11/653,147
FF 6. Dul discloses that while there are species differences in lipid
metabolism between mouse and humans, Dul’s “lal~lal~ model has several
advantages for exploring[, inter alia,] the physiological role of acid lipase
and its deficiency states,” “the opportunity to explore the pathogenesis of
this disease in utero[,]to initiate investigations into the early pathology of
therapy of this disease . . . and there is potential for dissecting the basis of
the differential phenotypes of WD and CESD” (Dul 1352; Ans. 3 4).
FF 7. Examiner finds that Dul fails to disclose a method comprising, inter
alia, “administering to the mammal an effective amount of lysosomal acid
lipase by intravenous infusion, lysosomal acid lipase in the small intestine,
[or] lysosomal acid lipase [that] comprises [an] oligosaccharide[]
terminated-acetylglycosylation residue comprising a mannose residue”
(Final Act. 5).
FF 8. Examiner finds that Du2 discloses “protein expression of human
LAL, both wild type and various polymorphic variants] present in [] CESD
patients, in insect cells and the analysis of the enzymatic activities of these
various forms of human LAL polypeptides;” and “the correlation of in vitro
catalytic activity toward substrates and the pathophysiology of distinctive
phenotypes of CESD require further investigation” (Ans. 4—5, citing Du2
129: Table 3 and 132: right column).
FF 9. Du3 discloses that “LAL mRNA [is] expressed at low levels in most
tissues,” wherein “[h]igh level expression was found in hepatocytes and
splenic and thymic cells,” and “[v]ery high level expression was observed in
cells of the small intestinal villi, the zona fasciculate and reticularis of the
adrenal cortex, pancreatic acini, and renal tubular epithelium” (Du3,
Abstract; see also id. at 944: Table 1; Ans. 5).
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FF 10. Anderson discloses the “[mjolecular cloning of a full-length cDNA
for human lysosomal acid lipase/cholesteryl ester hydrolase” (Anderson,
Abstract; see also id. at 22482: Fig. 4; Ans. 5).
FF 11. Examiner finds that Anderson discloses “that there are six . . .
potential N-glycosylation sites disclosed in [the sequence illustrated in
Anderson’s] Fig. 4” (Ans. 5; see Anderson 22482: Fig. 4 and Fig. 4, Legend
(“ Underlined tripeptides in brackets, [_], represent potential N-glycosylation
sites”) (emphasis and alteration original)).
FF 12. Anderson discloses that “[w]hen [their] purified lipase was applied
to HLAL-deficient WD or CESD fibroblasts in culture, it was taken up via
the mannose 6-phosphate recognition system and packaged into lysosomes
where it functioned to correct the abnormal cholesteryl ester accumulation in
the diseased cells” (Anderson 22479: col. 2, first full paragraph; Ans. 5—6).
FF 13. Grabowski discloses that “Gaucher disease, an inborn error of
glycosphingolipid metabolism, is the most frequent lysosomal storage
disease[,]” wherein “[n]on-neuronopathic or type 1 disease is the most
comment variant” (Grabowski 33: col. 2, first full paragraph (endnote
omitted); see generally Ans. 6).
FF 14. Grabowski discloses that “[u]ntil recently, enzyme or protein
therapies have been limited to agents that are retained in the plasma space []
or have actions at the plasma membrane [],” Grabowski, nevertheless,
“demonstrat[ed] that intravenous [administration of a mannose-terminated]
glucocerebrosidase could reverse disease symptoms and signs in patients
with Gaucher disease indications [and] that functional enzymes can be
delivered to intracellular sites” (Grabowski 37; see id. at 33, Abstract; Ans.
6).
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FF 15. Grabowski discloses that their “findings show that an intracellular
protein produced by recombinant methods can be delivered to a subcellular
compartment (the lysosomes) and affect clinical reversal of the signs and
symptoms of a human-inherited metabolic disease” (Grabowski 37; Ans. 6).
FF 16. Grabowski discloses that:
Overall, our results show the general similarity of patient
response to natural and recombinant glucocerebrosidase, for
enzyme therapy in Gaucher disease. . . . We show that that first
generation of recombinant enzymes for delivery to intracellular
and subcellular compartments can result in efficacious
treatment of an inherited inborn metabolism error. Clearly,
these approaches are directly applicable to other lysosomal
storage diseases and disorders requiring intracellular
replacement of proteins.
(Grabowski 38—39, bridging paragraph; Ans. 6.)
FF 17. Grabowski declares:
That, it is my opinion that one of ordinary skill in the art would
not have expected that LAL could be administered to a mammal
to successfully treat CESD for at least the reason that, at the
time of filing the instant application, the highest levels of
expression of LAL were found in the zona reticularis and
fasciculate of the adrenal cortex and small intestinal villi. At
the time of filing, these had not been considered potential
targets for enzyme therapy. Thus, this understanding would
dissuade one o[f] ordinary skill in the art from administering
LAL for the treatment of CESD as claimed. Our subsequent
studies showed (preliminary data presented in the original
filing) that the intestine was very responsive to the therapy
whereas the adrenal was unresponsive.
(2011 Grabowski Decl.817; see also 2014 Grabowski Deck91 8 (“unlike
CESD/WD, the intestine is not a major/significant site of pathology in
8 Declaration of Gregory Grabowski, signed Feb. 25, 2011.
9 Declaration of Gregory Grabowski, signed June 14, 2014.
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Gaucher disease. . . . The success of LAL delivery in CESD and WD was
completely unexpected as no one had contemplated the intestinal
involvement of such diseases, and this was and is a totally novel finding”);
2014 Grabowski Decl. 17.)
FF 18. Grabowski declares that “Gaucher disease is and was not known to
involve the hepatocytes or the intestinal villi. [] As a result, the Grabowski []
reference did not teach or suggest delivery of enzyme to these cell/organ
types” (2014 Grabowski Decl. 17 (footnote omitted)).
FF 19. Grabowski declares:
That, [] in the Grabowski [] [reference, Gaucher disease was
treated with recombinant glucocerebrosidase that was mannose
terminated specifically for targeting to the major sites of
pathology: the macrophages of the reticulaoendothelial system.
This includes the Kupffer cells of the liver, but not the
parenchymal cells of the liver, the hepatocytes, which do not
have mannose receptors. ... In contrast, WD and CESD have
major pathological involvement of the Kupffer cells AND
parenchymal liver cells, hepatocytes, [] and both types of cells
would have needed to be treated to address the disease states.
(2014 Grabowski Decl. 6—7 (footnote omitted); see Grabowski 33 (In
Gaucher disease “accumulation of glucocerebroside (glucosylceramide) in
cells of monocyte-macrophage lineage leads to the visceral manifestations of
anemia, thrombocytopenia, hepatosplenomegaly, skeletal disease, and less
frequently, primary lung involvement”).)
FF 20. Grabowski declares that “there are major differences between FAF
deficiencies (such as Wolman’s disease (WD) and cholesterol ester storage
disease (CESD)) and Gaucher Disease, as well as the enzymes that underlie
these diseases,” therefore, “given the unique properties of FAF as compared
to other enzymes and the differences in disease states (for example,
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CESD/WD vs Gaucher Disease), there would not have been an expectation
of success that IV administration of LAL could be used to successfully treat
CESD or Wolman’s disease (WD)” (2014 Grabowski Decl.104—5 and 7).
ANALYSIS
The evidence relied upon by Examiner, in combination, discloses that:
(1) LAL expression in different tissues was known in the art at the time of
Appellants’ claimed invention (see FF 9; see also FF 17); (2) The full-
length cDNA for human LAL was known in the art at the time of
Appellants’ claimed invention (FF 10); (3) At the time of Appellants’
claimed invention it was known that the expression product of human LAL
cDNA “was taken up [in culture] via the mannose 6-phosphate recognition
system and packaged into lysosomes where it functioned to correct the
abnormal cholesteryl ester accumulation in [] diseased cells” (FF 12); and
(4) It was known at the time of Appellants’ claimed invention that “an
intracellular protein produced by recombinant methods [could] be delivered
[through intravenous administration] to [a] subcellular compartment (the
lysosomes) [resulting in the] clinical reversal of the signs and symptoms of a
human-inherited metabolic disease,” specifically Gaucher disease, and that
the approach taken to clinically treat Gaucher disease was “[c]learly,. . .
directly applicable to other lysosomal storage diseases and disorders
requiring intracellular replacement of proteins” (FF 14—16). Thus, absent
evidence to the contrary, we find that the evidence relied upon by Examiner
supports a conclusion that a person of ordinary skill in this art would have
reasonably expected success in performing a method, wherein, the
intravenous administration of an effective amount of LAL that comprises an
10 Declaration of Gregory Grabowski, signed June 14, 2014.
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oligosaccharide-terminated N-acetylglycosylation residue comprising a
mannose residue, will result in activity of LAL in the lysosomes of cells of
the small intestine, or both the lysosomes of the cells of the small intestine
and the lysosomes of the cells of the liver, wherein the activity is present in
an amount sufficient to reduce cholesteryl ester and/or triglyceride storage in
the small intestine or in both small intestine and liver, as required by
Appellants’ claim 65.
Based on the combination of Dul, Du2, Du3, Anderson, and
Gabowski, Examiner concludes that, at the time Appellants’ invention was
made, it would have been prima facie obvious to treat a mammal having
cholesteryl ester storage disease comprising the step of administering to the
mammal an effective amount of lysosomal acid lipase, which comprises an
oligosaccharide-terminated N-acetylglycosylation residue comprising a
mannose residue, by intravenous infusion, wherein the administration step
results in activity of the lysosomal acid lipase in the lysosomes of cells of:
(1) the small intestine or (2) both the small intestine and liver to be present
in an amount sufficient to reduce cholesteryl ester and/or triglyceride storage
in the: (1) small intestine or (2) both the small intestine and liver (see Ans.
6-7).
Appellants contend that “Examiner failed to give due consideration
and deference to the Declaration evidence of record,” which, Appellants
contend,
provided substantial evidence by an expert in the field that the
results of the claimed combination were unexpected, that one of
ordinary skill in the art would not have had a reasonable
expectation of success,. . . [or] have been motivated to combine
the art, that there was not a reasonable level of predictability in
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arriving at the claimed invention, and that unexpected results
were obtained.
(App. Br. 8.) We are not persuaded {see generally Final Act.11 8—10; Ans.
7-12).
Grabowski declares that “WD and CESD have major pathological
involvement of the Kupffer cells [of the liver] AND parenchymal liver cells,
hepatocytes,[] and both types of cells would have need to be treated to
address the diseases states” (FF 19 (emphasis added)). Thus, the 2014
Grabowski Declaration is not commensurate in scope with Appellants’
claimed invention which requires only that the
activity of [] lysosomal acid lipase in the lysosomes of cells of
the small intestine or both the lysosomes of the cells of the
small intestine and the lysosomes of the cells of the liver ... is
present in an amount sufficient to reduce cholesteryl ester
and/or triglyceride storage in [the] small intestine or in both
small intestine and liver.
(App. Br. 11 (Appellants’ claim 65) (emphasis added).) “The evidence
presented to rebut a prima facie case of obviousness must be commensurate
in scope with the claims to which it pertains.” In re Dill, 604 F.2d 1356,
1361 (CCPA 1979).
The presence of a reasonable expectation of success is measured from
the perspective of a person of ordinary skill in the art at the time the
invention was made. Life Techs., Inc. v. Clontech Labs., Inc., 224 F.3d
1320, 1326 (Fed. Cir. 2000). On this record, Grabowski discloses, at the
time of Appellants’ claimed invention, that the approach and results obtained
in their clinical treatment of a human-inherited metabolic disease,
specifically Gaucher disease, was “[c]learly,. . . applicable to other
11 Examiner’s November 7, 2014 Final Office Action.
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lysosomal storage diseases and disorders requiring intracellular replacement
of proteins,” i.e. CESD and/or WD (FF 16; see generally FF 1-15). Thus, at
the time of Appellants’ claimed invention, Grabowski provides a person of
ordinary skill in this art with the motivation to treat lysosomal storage
diseases and disorders, such as CESD and/or WD as set forth by Examiner
and a reasonable expectation of success in successfully treating lysosomal
storage diseases and disorders, such as CESD and/or WD. Therefore, we are
not persuaded by Appellants’ reliance on the 2014 Grabowski Declarations’
assertion that the evidence relied upon by Examiner fails to establish a
reasonable “expectation of success that IV administration of LAL could be
used to successfully treat CESD or Wolman’s disease (WD),” that “there
was no expectation that either CESD or WD could be treated by enzyme
replacement therapy with LAL,” or that “[t]he success of LAL delivery in
CESD and WD was completely unexpected” (App. Br. 8 (emphasis
removed); see Reply Br. 6—8; FF 17 and 20; cf. FF 16). See In re O’Farrell,
853 F.2d 894, 903 (Fed. Cir. 1988) (“Obviousness does not require absolute
predictability of success ... all that is required is a reasonable expectation of
success.”).
For the foregoing reasons we are not persuaded by Appellants’
contention that Grabowski’s disclosure is limited “to Gaucher’s disease”
(Reply Br. 6; cf. FF 16).
For the foregoing reasons, we are not persuaded by Appellants’
contention that Examiner “improperly ignored [Appellants’ declaratory
evidence]” and did not “give[] due weight” or “identify] . . . deficiencies in
the Declaration^] that would render such [declaratory] evidence ineffective”
(App. Br. 9). To the contrary, for the reasons set forth above, we find that
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Application 11/653,147
Examiner properly considered Appellants’ Declarations and contentions,
but, when viewed together with the evidence relied upon by Examiner,
found Appellants’ contentions and Declarations insufficient to overcome
Examiner’s prima facie case of obviousness {see generally Final Act. 8—10;
Ans. 7—12).
We recognize, but are not persuaded by, Appellants’ contentions that
Du3’s disclosure of the tissue specific expression levels of LAL, which
includes very high expression levels in the small intestine (i.e., small
intestinal villi) “is irrelevant to exogenous administration of LAL in [the]
treatment of CESD as claimed” and “that the small intestine was not
considered a potential target at the time of filing despite expression of LAL
in this tissue” (Reply Br. 5—6; cf. FF 9). To the contrary, Grabowski makes
clear that their intravenous approach to treating inherited metabolic diseases
is applicable to “other lysosomal storage diseases and disorders requiring
intracellular replacement of proteins” (FF 16). Simply stated, the evidence
relied upon by Examiner establishes that the intravenous administration of
the appropriate protein, such as LAL, that comprises an oligosaccharide
terminated N-acetylglycosylation residue comprising a mannose residue,
will necessarily result in the protein’s up-take by receptors on the
appropriate cells, which include cells of the small intestine, and
incorporation into the lysosomes of the appropriate cells. Thus, Appellants
failed to provide persuasive evidence or argument to support a contrary
conclusion.
For the foregoing reasons we are not persuaded by Appellants’
contention that Examiner’s reliance on Du3 to establish that tissue specific
expression levels of LAL “contradicts] the evidence of record and [is] not
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factually correct” (Reply Br. 6; see Ans. 11; FF 9). Appellants’ fail to
provide persuasive evidence or argument to support a conclusion that Du3’s
disclosure of the tissue specific expression of LAL is factually incorrect. In
this regard, notwithstanding Appellants’ contention to the contrary,
Examiner did not rely exclusively upon Du3 to suggest the delivery of LAL
that comprises an oligosaccharide terminated N-acetylglycosylation residue
comprising a mannose residue to the small intestine (see Reply Br. 6; cf FF
1-16 ; see Ans. 7—12 (wherein Examiner relies on the combination of Dul,
Du2, Du3, Anderson, and Gabowski to make obvious Appellants’ claimed
subject matter)).
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness. The rejection of claim 65 under 35 U.S.C.
§ 103(a) as unpatentable over the combination of Dul, Du2, Du3, Anderson,
and Gabowski is affirmed. Claims 69, 73, and 78 are not separately argued
and fall with claim 65.
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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