Ex Parte Karsenty et al

Patent Trial and Appeal Board

May 19, 2016

12441060 (P.T.A.B. May. 19, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
12/441,060 11/10/2009 Gerard Karsenty
26646 7590 05/23/2016
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK, NY 10004
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.
13533/50502 8805
EXAMINER
GHAFOORIAN, REZA
ART UNIT PAPER NUMBER
1636
NOTIFICATION DATE DELIVERY MODE
05/23/2016 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):
uspto@kenyon.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte GERARD KARSENTY and PA TRICIA F. DUCY
Appeal2014-006168
Application 12/441,0601
Technology Center 1600
Before JEFFREYN. FREDMAN, ULRIKE W. JENKS, and
KRISTI L. R. SA WERT Administrative Patent Judges.
SA WERT, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the rejection of claims
58, 59, 61, and 62 of U.S. Patent Application No. 12/441,060 ("the '060
application"). We have jurisdiction under 35 U.S.C. § 6(b ). We reverse.
Appellants identify THE TRUSTEES OF COLUMBIA
UNIVERSITY IN THE CITY OF NEW YORK and Sanofi as the real
parties in interest. Appeal Br. 2.
Appeal2014-006168
Application 12/441,060
STATEMENT OF THE CASE
Claims 58, 59, 61, and 62 are on appeal and stand rejected under 35
U.S.C. § 103(a) for obviousness over Ekema2 in view ofHousey,3 and
further in view of Merchiers. 4 Answer 2. We choose independent claim 58
as representative. See 37 C.F.R. § 41.37(c)(l)(iv). Claim 58 provides:
58. A method for identifying an agent that reduces
osteocalcin carboxylation comprising:
(a) determining a first level of carboxylated osteocalcin
in a first cell that expresses osteocalcin,
(b) contacting a second cell that expresses osteocalcin
with the agent and determining a second level of carboxylated
osteocalcin in the second cell, and
( c) comparing the first level of carboxylated osteocalcin
with the second level of carboxylated osteocalcin,
wherein the first cell and the second cell have been
genetically engineered to overexpress osteocalcin, and wherein
the agent is identified as an agent that reduces osteocalcin
carboxylation if the first level of carboxylated osteocalcin is
higher than the second level.
Appeal Br. 1 7.
2 George Mbella Ekema et al., Methods for Using Osteocalcin, U.S.
Patent Publication No. 2004/0082018 (Apr. 29, 2004).
3 Gerard Housey, Method of Screening for Protein Inhibitors and
Activators, U.S. Patent No. 5,877,007 (Mar. 2, 1999).
4 Pascal Gerard Merchiers et al., Methods for IdentifYing a Compound
That Inhibits the Procession of Amyloid-Beta Protein Production in a
Mammalian Cell Expressing APP and Overexpressing a G-Protein Coupled
Receptor in the Cell, U.S. Patent No. 7,429,459 (Sep. 30, 2008).
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Application 12/441,060
FINDINGS OF FACT
1. The Specification of the '060 application discloses "cell-based and
non-cell based methods of drug screening to identify agents, or assay agents,
that ... increase the level of undercarboxylated osteocalcin." Spec. if 1.
2. Osteocalcin is a protein found associated with the bone matrix that is
synthesized by osteoblasts (a type of bone cell). Mature human osteocalcin
contains 49 amino acid residues. Post-translation, the glutamic acid (GLU)
residues at amino acid positions 17, 21, and 24 may be carboxylated by the
enzyme gamma-carboxylase to form gamma-carboxyglutamic acid (GLA)
residues. Spec. iii! 135-36.
3. The term "osteocalcin" encompasses "carboxylated, uncarboxylated
and undercarboxylated forms as well as fragments and variants thereof."
Spec. if 140.
4. The term "uncarboxylated osteocalcin" means "osteocalcin in which
all three of the glutamic acid residues at positions 17, 21, and 24 are not
carboxylated." Spec. if 141.
5. The term "undercarboxylated osteocalcin" means "osteocalcin in
which one or more of the GLU residues ... are not carboxylated." The term
"undercarboxylated osteocalcin" includes uncarboxylated osteocalcin. Spec.
ir 141.
6. Undercarboxylated/uncarboxylated osteocalcin "is responsible for
regulating various aspects of energy metabolism" and "decreases weight
gain and fat mass." Spec. if 66. But, once fully carboxylated by gamma-
carboxylase, osteocalcin becomes inactive. Id.
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7. One embodiment of the invention disclosed in the '060 application
relates to a method for screening for compounds that inhibit gamma-
carboxylase activity. Spec. i-fi-1 66, 97.
8. Another embodiment disclosed in the '060 application relates to a
method for screening for compounds that are capable of decarboxylating
osteocalcin. Spec. i1 97.
9. Specifically, the Specification teaches "cell-based methods for
identifying, or assaying, for agents that reduce gamma carboxylase activity,
and thus the level of carboxylated osteocalcin, or agents that are capable of
decarboxylating osteocalcin." Spec. i197. In one embodiment of the
invention, "the level of gamma carboxylase activity or decarboxylase
activity is determined by measuring the level of osteocalcin carboxylation."
Id.
10. Ekema discloses "methods of screening for compounds that modulate
expression or activity of osteocalcin polypeptides or nucleic acids (RNA or
DNA), modulate the interaction of osteocalcin with calcium or modulate the
interaction of osteocalcin with CaR2 [calcium sensing receptor 2]
polypeptides in cells or tissues." Ekema i19.
11. Ekema states that the "invention further provides assays for
determining the activity of, or the presence or absence of osteocalcin
polypeptides or nucleic acid molecules in biological samples." Ekema i-f 12.
12. Ekema specifically discloses a method for screening for a compound
that modifies the transcription of the osteocalcin DNA into mRNA by
comparing the level of mRNA in the presence of and in the absence of the
candidate compound:
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Thus, modulators of osteocalcin gene expression can be
identified in a method wherein a cell is contacted with a
candidate compound and the expression of mRNA determined.
The level of expression of osteocalcin mRNA in the presence of
the candidate compound is compared to the level of expression
of osteocalcin mRNA in the absence of the candidate
compound. The candidate compound can then be identified as a
modulator of nucleic acid expression based on this comparison
and be used, for example, to treat a disorder characterized by
aberrant nucleic acid expression. When expression of mRNA is
statistically significantly greater in the presence of the candidate
compound than in its absence, the candidate compound is
identified as a stimulator of nucleic acid expression. When
nucleic acid expression is statistically significantly less in the
presence of the candidate compound than in its absence, the
candidate compound is identified as an inhibitor of nucleic acid
express10n.
Ekema i-f 273.
13. Ekema inconsistently labels SEQ ID NO: 1 and SEQ ID N0:2. For
example, in Figure 1, Ekema presents SEQ ID NO: l as an amino acid
sequence, and SEQ ID N0:2 as a mRNA sequence. Ekema Fig. 1. But in
the specification, Ekema describes SEQ ID N0:2 as an osteocalcin
polypeptide and SEQ ID NO: 1 as an osteocalcin nucleic acid, respectively.
Ekema i-fi-114, 15. Finally, in the Sequence Listing, Ekema labels SEQ ID
NO: 1 as a protein sequence and SEQ ID N0:2 as a DNA sequence. Ekema,
col. 29. Based on the Sequence Listing, we conclude that SEQ ID NO: 1
represents the amino acid sequence of osteocalcin, and SEQ ID N0:2
represents the DNA sequence of osteocalcin, notwithstanding the errors in
Ekema' s written description.
14. Housey discloses methods for screening for protein inhibitors and
activators using a bioassay comprising two cells: one control cell and one
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test cell. Housey teaches that the effect of a test compound on the
expression of a target protein can be determined by comparing the
expression of the target protein in the control cell to the expression of the
target protein in the test cell. Housey, col. 29, 1. 12---col. 30, 1. 11.
15. Merchiers discloses cell-based assay methods that use polypeptide
overexpression as a means for detecting protein expression.
"Overexpression has the advantage that the level of the second messenger is
higher than the activity level by endogenous expression. Accordingly,
measuring such levels using presently available techniques is easier."
Merchiers, col. 11, 11. 30-34.
DISCUSSION
We have reviewed Appellants' arguments in the Briefs, the
Examiner's final rejection, and the Examiner's answer to the Appellants'
arguments. We find that the Examiner misinterpreted representative claim
58 as well as the teachings of Ekema. For this reason, we must reverse the
rejection of the claims under 35 U.S.C. § 103 for obviousness over Ekema in
view of Housey, and further in view of Merchiers.
During examination, claim terms are given their "broadest reasonable
interpretation" consistent with the specification as it would be understood by
one of ordinary skill in the art. In re Am. Acad. of Sci. Tech Ctr., 367 F.3d
1359, 1364 (Fed. Cir. 2004). "While the Board must give the terms their
broadest reasonable construction, the construction cannot be divorced from
the specification and the record evidence." In re NTP, Inc., 654 F.3d 1279,
1288 (Fed. Cir. 2011).
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The claim construction analysis begins with the claim language.
Phillips v. AWH Corp., 415 F.3d 1303, 1312 (Fed. Cir. 2005) (en bane).
Representative claim 58 recites a method for identifying an agent that
"reduces osteocalcin carboxylation." Appeal Br. 17. The method utilizes
two cells that overexpress osteocalcin: a first (control) cell and a second
(test) cell that contains the test agent. Id. The level of carboxylated
osteocalcin in the first cell is compared with the level of carboxylated
osteocalcin in the second cell. Id. If the level of carboxylated osteocalcin is
reduced in the second (test) cell as compared to the first (control) cell, then
the agent is identified as a compound that "reduces osteocalcin
carboxylation." Id. Based on the claim language, we find that a person of
ordinary skill in the art would understand that the method of claim 58 is
directed to measuring levels of a specific form of the osteocalcin protein,
namely "carboxylated osteocalcin."
Next, we tum to the Specification to help determine the meaning of
"carboxylated osteocalcin," recited in the method steps of claim 58. As
noted above, the Specification defines "osteocalcin" as encompassing all
three forms of the osteocalcin protein: fully carboxylated,
undercarboxylated, and uncarboxylated. Spec. i-f 140. And the Specification
defines "undercarboxylated osteocalcin" as "osteocalcin in which one or
more of the GLU residues ... are not carboxylated" including
"uncarboxylated osteocalcin." Id. Considering these two definitions
together, we find that the term "carboxylated osteocalcin" requires full
carboxylation. Put differently, "carboxylated osteocalcin" encompasses
osteocalcin in which all three GL U residues at amino acid positions 1 7, 21,
and 24 of the osteocalcin polypeptide are carboxylated, but does not
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encompass osteocalcin in which none or only one or two of those GLU
residues are carboxylated (i.e., "uncarboxylated osteocalcin" or
"undercarboxylated osteocalcin").
We next consider the meaning of "osteocalcin carboxylation" found in
the preamble and the "wherein" clause of claim 58. The Specification
teaches that a test agent may bring about lower-than-normal levels of
"osteocalcin carboxylation" in two ways: (1) the agent may "reduce gamma
carboxylase activity," or (2) the agent may be "capable of decarboxylating
osteocalcin." Spec. i-f 97. In either case, the result is "reduce[d] osteocalcin
carboxylation" as recited in the preamble and "wherein" clause of claim 58.
Appeal Br. 17 (emphasis added).
Based on the claim language and the specification, we find that a
person of ordinary skill in the art would recognize claim 58 as encompassing
a method for identifying an agent that "reduces osteocalcin carboxylation"
by measuring the levels of "carboxylated osteocalcin,'' i.e., fully-
carboxylated osteocalcin. The reduced levels of carboxylated osteocalcin
may result from direct action, i.e., the agent has the ability to directly
decarboxylate osteocalcin, Spec. i-f 99, or the reduced levels of carboxylated
osteocalcin may result from indirect action, i.e., the agent has the ability to
inhibit gamma-carboxylase, which in tum is not available to carboxylate
osteocalcin, id. at i-f 97. Again, either pathway would "reduce osteocalcin
carboxylation."
On the other hand, we find that a person of ordinary skill in the art
would not recognize claim 58 as encompassing a method for identifying an
agent that reduces the levels of the "osteocalcin" protein itself. Again,
"osteocalcin" encompasses all carboxylation states of osteocalcin
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(uncarboxylated, undercarboxylated, and fully carboxylated). Thus,
although an agent that prevents, for example, expression of osteocalcin DNA
into mRNA would necessarily reduce the level of "osteocalcin" present in a
cell, that agent would not necessarily "reduce osteocalcin carboxylation."
See Appeal Br. 14. In other words, that agent would decrease the levels of
all forms of osteocalcin, instead of just the levels of "carboxylated
osteocalcin."
The Examiner appears to have interpreted the method steps of claim
58 as determining "a first level" and "a second level" of all forms of
osteocalcin, rather than "carboxylated osteocalcin." See Ans. 6 (stating that
"carboxylated osteocalcin" "include[ s] both uncarboxylated and fully
carboxylated osteocalcin"). As we found above, however, "carboxylated
osteocalcin" must mean fully-carboxylated osteocalcin. The Examiner also
appears to have interpreted Ekema as disclosing a method of determining the
levels of "carboxylated osteocalcin.'' Ans. 6. We disagree. Although
Ekema provides methods for determining "the presence or absence of
osteocalcin polypeptides," Ekema i-f 12, Ekema does not teach or disclose a
method for determining the levels of "carboxylated osteocalcin" or
"osteocalcin carboxylation." A person of ordinary skill in the art would
understand that a method that measures total osteocalcin (in all three
carboxylation states) as Ekema teaches would not necessarily identify an
agent that reduces "osteocalcin carboxylation." Instead, that method could
only identify an agent that reduces "osteocalcin."
Nevertheless, the Examiner relies on paragraph 29 to find that
Ekema's methods measure "carboxylated osteocalcin." Ans. 6. This
paragraph does not support the Examiner's position. Paragraph 29 only
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describes the characteristics of the osteocalcin protein that were already
known in the art. See Ekema i-f 29 (detailing the length, mass, origin, and
carboxylation sites of the osteocalcin protein). Thus, paragraph 29 does not
purport to describe Ekema' s methods for using osteocalcin.
The Examiner also states that Ekema "discloses using expression of
SEQ ID N0:2 in the method of identifying compounds," and refers to SEQ
ID N0:2 as "carboxylated osteocalcin." Final Act. 6. But, as found above,
SEQ ID N0:2 is a DNA sequence that, by definition, cannot be carboxylated
because carboxylation occurs post-translation to proteins. Spec. i-fi-1 135-36;
see also Ekema i-f 29. But even if we understood Ekema as referring to an
amino acid sequence, that sequence is not necessarily a "carboxylated
osteocalcin" as properly interpreted because it is not inherently fully
carboxylated as discussed above. See MEHL/Biophile Int 'l Corp. v.
Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999) ("Inherency ... may not be
established by probabilities or possibilities. The mere fact that a certain thing
may result from a given set of circumstances is not sufficient.") (quotation
omitted).
The Examiner also points to the specification as admitting that the
present invention cannot distinguish between carboxylated osteocalcin and
undercarboxylated osteocalcin. Ans. 6-7 (quoting Spec. i-f 399). The
Specification explains that osteocalcin levels may be determined by IRMA
(immunoradiometic assay). Spec. i-f 399. The technique measures "total
osteocalcin, but cannot specifically recognize undercarboxylated
osteocalcin." Id. Thus, the inventors used hydroxyapatite (HA) resin-
which only binds to carboxylated osteocalcin-to separate the "two forms."
Id. We interpret those two forms to be "carboxylated osteocalcin" and
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"undercarboxylated osteocalcin" (which, as the specification explains,
includes uncarboxylated osteocalcin). Id. In this way, the claim method can
identify an agent that reduces osteocalcin carboxylation. A cell contacted
with that agent would have lower-than-normal levels of carboxylated
osteocalcin.
Finally, we note that the Examiner rejected Appellants' arguments as
to the distinctions between the claimed method and the prior art because "the
preamble of claim 58 is in conflict with the steps and the result of the
claim." Ans. 5---6. The Examiner appears to have read out of claim 58 the
preamble and "wherein" clause, and thus broadened the scope of the claim to
encompass the prior art. Enzo Biochem Inc. v. Applera Corp., 780 F.3d
1149, 1154 (Fed. Cir. 2015). But "[a] claim construction that gives meaning
to all the terms of the claim is preferred over one that does not do so."
Merck & Co. v. Teva Pharms. USA, Inc., 395 F.3d 1364, 1372 (Fed. Cir.
2005). We find that giving proper weight to both the preamble and
"wherein" clause of claim 58 excludes the methods of Ekema.
The Examiner has not found that any of the other references of record
teach a method for identifying an agent that reduces osteocalcin
carboxylation. Thus, we cannot sustain the Examiner's obviousness
rejection.
SUMMARY
We reverse the rejection of claims 58, 59, 61, and 62 under 35 U.S.C.
§ 103(a).
REVERSED
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