Ex Parte Kosutic et al

Patent Trial and Appeal Board

Dec 21, 2015

10562478 (P.T.A.B. Dec. 21, 2015)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
10/562,478 11115/2006
24239 7590 12/23/2015
MOORE & VAN ALLEN PLLC
P.O. BOX 13706
3015 Carrington Mill Boulevard, Suite 400
Research Triangle Park, NC 27709
FIRST NAMED INVENTOR
Gordana Kosutic
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.
01481 l-487.114US 8427
EXAMINER
LIU, SAMUEL W
ART UNIT PAPER NUMBER
1656
NOTIFICATION DATE DELIVERY MODE
12/23/2015 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):
iplaw@mvalaw.com
usptomail@mvalaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte GORDANA KOSUTIC, NNOCHIRI N. EKWURIBE,
CHRISTOPHER H. PRICE, ASLAM M. ANDSARI, and
AMYL. ODENBAUGH 1
Appeal2013-003792
Application 10/562,478
Technology Center 1600
Before ERIC B. GRIMES, JACQUELINE T. HARLOW, and
TA WEN CHANG, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of treating pain, which have been rejected for obviousness and obviousness-
type double patenting. We have jurisdiction under 35 U.S.C. § 6(b ).
We affirm.
1 Appellants identify the Real Party in Interest as Biocon Limited. (Appeal
Br. 3.)
Appeal2013-003792
Application 10/562,478
STATEMENT OF THE CASE
"Calcitonin is a naturally occurring hormone ... [that] may be useful
in treating various bone disorders including, but not limited to, osteoporosis
and Paget's disease." (Spec. 1:6-10.) "Various references have proposed
conjugating polypeptides such as calcitonin with polydispersed mixtures of
polyethylene glycol." (Id. at 2:15-16.) The Specification discloses
"methods of treating pain (e.g., peripheral pain; central pain)" using a
substantially monodispersed mixture of calcitonin conjugates. (Id. at 5: 19 to
6:10.) "[T]he term 'substantially monodispersed' is used to describe a
mixture of compounds wherein at least about 95 percent of the compounds
in the mixture have the same molecular weight." (Id. at 11: 15-1 7.)
Claims 1-3 are on appeal and read as follows:
1. A method of treating peripheral pain in a subject in need thereof,
comprising orally administering to the subject an effective amount of a
substantially monodispersed mixture of conjugates, wherein the conjugate
comprises a first oligomer and a second oligomer, wherein each oligomer is
coupled to salmon calcitonin and wherein the first oligomer is covalently
coupled to an amine group of Lys 11 of the salmon calcitonin and the second
oligomer is covalently coupled to an amine group of Lys18 of the salmon
calcitonin, wherein the amino acid sequence of the salmon calcitonin is SEQ
ID NO. 1 and wherein the effective amount is about 20 ug/kg twice a day.
2. A method of treating peripheral pain in a subject in need thereof,
comprising orally administering to the subject an effective amount of a
substantially monodispersed mixture of conjugates, each conjugate
comprising a calcitonin drug coupled to an oligomer that comprises a
polyethylene glycol moiety, wherein the oligomer comprises a first
polyethylene glycol moiety covalently coupled to the calcitonin drug by a
non-hydrolyzable bond and a second polyethylene glycol moiety covalently
coupled to the first polyethylene glycol moiety by a hydrolyzable bond, and
wherein the effective amount is about 20 ug/kg twice a day.
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3. A method of treating peripheral pain in a subject in need thereof,
comprising orally administering to the subject an effective amount of a
substantially monodispersed mixture of conjugates each comprising salmon
calcitonin covalently coupled at Lys 11 of the salmon calcitonin to the
carboxylic acid moiety of a carboxylic acid, which is covalently coupled at
the end distal to the carboxylic acid moiety to a methyl terminated
polyethylene glycol moiety having at least 7 polyethylene glycol subunits,
and covalently coupled at Lys 18 of the salmon calcitonin to the carboxylic
acid moiety of a carboxylic acid, which is covalently coupled at the end
distal to the carboxylic acid moiety to a methyl terminated polyethylene
glycol moiety having at least 7 polyethylene glycol subunits, wherein the
amino acid sequence of the salmon calcitonin is SEQ ID NO .1, and wherein
the effective amount is about 20 ug/kg twice a day.
The claims stand rejected as follows:
Claim 1under35 U.S.C. § 103(a) based on Lee2 and Boyd3 (Ans. 4);
Claim 1under35 U.S.C. § 103(a) based on Russo, 4 Komarova, 5 and
Boyd (Ans. 6);
Claim 2 under 35 U.S.C. § 103(a) based on Russo, Komarova,
Ekwuribe, 6 and Boyd (Ans. 7);
Claim 3 under 35 U.S.C. § 103(a) based on Russo, Komarova, Boyd,
Crotts, 7 and Ekwuribe (Ans. 9); and
Claims 1-3 for obviousness-type double patenting based on U.S.
Patent 6,713,452 in view of Boyd and Lee (Ans. 24).
2 Lee et al., U.S. 6,506,730 Bl, issued Jan. 14, 2003.
3 Boyd et al., U.S. 7,151,191 B2, issued Dec. 19, 2006.
4 Russo et al., U.S. 5,976,788, issued Nov. 2, 1999.
5 Komarova et al., Regulation of Osteoclasts by Calcitonin and Amphiphilic
Calcitonin Conjugates: Role of Cytosolic Calcium, 73 CALCIF. TISSUE INT.
265-273 (2003).
6 Ekwuribe et al., U.S. 2003/0060606 Al, published Mar. 27, 2003.
7 Crotts et al., U.S. 2003/0017203 Al, published Jan. 23, 2003.
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Application 10/562,478
Issue
I
The Examiner has rejected claim 1 as obvious based on Lee and
Boyd. The Examiner finds that Lee discloses administering PEGylated
salmon calcitonin (sCT) to treat pain, among other things. (Ans. 4.) The
Examiner finds that Lee's PEGylated sCT includes "'di-PEG-sCT', i.e., di-
conjugate wherein Lys 11 and Lys 18 of sCT [are] covalently linked to a PEG
polymer." (Id.)
The Examiner finds that Boyd teaches oral administration of sCT at a
dose of about 30 µg/kg. (Id. at 5.) The Examiner concludes that it would
have been obvious to administer Lee's PEGylated sCT orally because Lee
teaches that injection causes pain (id.), and that the claimed dosage of 20
µg/kg is an obvious variant of Boyd's dosage of 30 µg/kg. (Id. at 5-6.)
Appellants contend that Lee's Example 4, which the Examiner cites as
teaching di-PEG-sCT, "does not teach a diconjugate with a PEG at both
Lys 11 and Lys18 functionality but instead Example 4 only teaches
mon[o]conjugates." (Appeal Br. 9.) Appellants also contend that Lee
teaches only nasal, not oral, administration (id. at 10), and in fact
discourages oral administration. (Id. at 12.)
Appellants contend that Boyd's invention is a delivery compound and
Boyd does not teach administering calcitonin without the delivery
compound. (Id. at 10-11.) Appellants also contend that combining Boyd's
oral administration with Lee would render Lee unsatisfactory for its intended
purpose of nasal administration. (Id. at 13.)
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The issue with respect to this rejection is whether Lee and Boyd
support a prima facie case of obviousness.
Findings of Fact
1. The Specification states that "'substantially monodispersed' is used
to describe a mixture of compounds wherein at least about 95 percent of the
compounds in the mixture have the same molecular weight." (Spec. 11: 15-
17.)
2. The Specification states that "[t]he oligomer may be various
oligomers comprising a polyethylene glycol moiety." (Id. at 15:25.)
3. Lee states that "[i]njection ... gives patients pain and has
accompanying dangers .... Thus, there remains a need to develop other
routes for peptide administration." (Lee 1 :43--47 .)
4. Lee discloses "a pharmaceutical composition for the nasal
transmucosal delivery, comprising a ... polypeptide conjugated with an
activated biocompatible polymer." (Id. at 4:2-6.)
5. Lee states that "biocompatible polymers" include polyethylene
glycol (PEG). (Id. at 5:13-16.)
6. Lee states that "the conjugation of PEG allows biologically active
peptides or proteins to be increased [in] in-vivo half life span and solubility
and to be reduced in immune reactions." (Id. at 3:16-19.)
7. "In the case of calcitonin-PEG conjugates, PEG can conjugated to
the N-terminus of calcitonin and/or Lys18 and/or Lys 11 .... At pH 5, 6 or 7 of
the reaction solution, more than 80% of PEG is conjugated to the N-terminus
of calcitonin. On the other hand, at pH 8 or higher, PEG is increasingly
conjugated to Lys11 and Lys 18." (Id. at 5:41-53.)
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8. Lee states that "[ c ]alcitonin inhibits a bone absorption by acting
directly to osteoclast and is used for cure of hypercalcemia, Paget's disease,
pain from the bone absorption and osteoporosis." (Id. at 6:25-28.)
9. Lee states that "salmon and eel calcitonin have the most effect."
(Id. at 6:29-30.)
10. Lee exemplifies PEGylation of sCT at pH 8.0. (Id. at 7:54 to
8:14.)
11. Lee states that the PEG-sCT conjugates were isolated with the aid
of a size exclusion column, and that the "tri-PEG-sCT, the di-PEG-sCT and
mono-PEG-sCT were isolated." (Id. at 8:19-37.)
12. Lee states that PEG-sCT was prepared at various pHs, molar
ratios, and reaction times (id. at 8:49 to 9:9), and "PEG-sCT conjugates ...
were separated into tri-PEG-sCT, di-PEG-sCT and mono-PEG-sCT." (Id. at
9:13-15.) The mono-PEG-sCT was then further characterized. (Id. at 9:18-
40.)
13. Lee states that the "dose of the pharmaceutical compositions
containing the peptide-polymer conjugate of the present invention can range
from about 0 .1 ug to about 10 mg/kg/ day, and can be widely altered
according to the kind of peptide and patient's condition." (Id. at 7:38--42.)
14. Boyd discloses "compounds and compositions which facilitate the
delivery of active agents." (Boyd 2:21-22.) Boyd states that its compounds
"facilitate the delivery of biologically and chemically active agents,
particularly in oral ... systems." (Id. at 8:20-25.)
15. Boyd exemplifies oral delivery of salmon calcitonin (sCT) to rats
(id. at 18:39-57) at a dose of 30 µg/kg. (Id. at 19:10-20.)
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Analysis
We agree with the Examiner that Lee and Boyd support a prima facie
case of obviousness. Lee discloses that calcitonin is used to treat pain from
bone absorption and osteoporosis (FF8), and that salmon calcitonin (sCT) is
one of the most effective calcitonins (FF9). Lee also discloses that
PEGylation allows increased in vivo half-life, increased solubility, and
reduced immune reactions (FF6). Lee discloses sCT PEGylated at pH 8.0
(FF 10) and states that "at pH 8 or higher, PEG is increasingly conjugated to
Lys 11 and Lys18" (FF7). Lee states that "tri-PEG-sCT, the di-PEG-sCT and
mono-PEG-sCT were isolated" (FFl 1 ).
Boyd discloses a compound that facilitates oral delivery (FF 14 ), and
discloses oral delivery of sCT in combination with such a compound at a
dose of 30 µg/kg (FF15). We agree with the Examiner that, based on these
disclosures, it would have been obvious to administer Lee's di-PEG-sCT
orally to treat pain.
Claim 1 requires administering a "substantially monodispersed
mixture of conjugates," and the Specification defines "substantially
monodispersed" to mean that "at least about 95 percent of the compounds in
the mixture have the same molecular weight" (FFl). Lee states that the "tri-
PEG-sCT, the di-PEG-sCT and mono-PEG-sCT were isolated" (FFl 1). Lee
does not disclose that its di-PEG-sCT consisted of at least 95% sCT
PEGylated at Lys 11 and Lys18, but claim 1 only requires a "substantially
monodispersed mixture"; that is, a mixture in which at least about 95% of
compounds have the same molecular weight (i.e., at least about 95% di-
PEGylated). Lee states that at pH 8, as exemplified (FFlO), "PEG is
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Application 10/562,478
increasingly conjugated to Lys 11 and Lys18" (FF7). Thus, it is reasonable to
conclude that the "isolated" di-PEG-sCT disclosed by Lee includes at least
95% sCT with the same molecular weight, and some of the conjugated sCT
peptides will have a PEG moiety coupled to Lys 11 and to Lys 18.
Claim 1 also requires a dosage of about 20 µg/kg twice a day. Boyd
discloses oral administration of sCT at a dosage of 30 µg/kg (FF15). We
agree with the Examiner that the claimed dosage of 20 µg/kg twice a day
would have been obvious based on the prior art dosage of 30 µg/kg,
especially in view of Lee's teaching that the dose of its peptide-polymer
conjugate can be varied between 0.1 µg and 10 mg/kg/day, depending on the
patient (FF13).
Appellants argue that Lee's Example 4 "does not teach a diconjugate
with a PEG at both Lys 11 and Lys18 functionality but instead Example 4 only
teaches mon[o]conjugates." (Appeal Br. 9.)
This argument is unpersuasive, because Lee expressly states that the
"tri-PEG-sCT, the di-PEG-sCT and mono-PEG-sCT were isolated" (FFl 1).
Even though Lee's Example 4 only further characterizes the mono-PEG-
sCT, the reference nonetheless discloses isolation of di-PEG-sCT as well.
Appellants also argue that Lee discloses only nasal administration
(Appeal Br. 10) and "discourages the use of oral route." (Id. at 12.)
Appellants argue that "ifthe teachings of Boyd (oral delivery) were
combined with Lee (nasal delivery), then the end product of Lee could be
rendered unsatisfactory for its intended use." (Id. at 13.)
These arguments are also unpersuasive, because they fail to address
the teachings of the cited references when considered together. Although
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Application 10/562,478
Lee discloses that nasal administration has the advantage, compared to oral
administration, of avoiding first-pass metabolism in the liver (Lee 1 :62-67),
Boyd states that "[ o ]ral delivery of many biologically or chemically active
agents would be the route of choice for administration to animals if not for
biological, chemical, and physical barriers." (Boyd 1 :44--47 .) Boyd
discloses that its compositions facilitate oral delivery of active agents
(FF14), including sCT (FF15), and thus oral administration of Lee's di-PEG-
sCT would have been obvious based on the combined disclosures of Lee and
Boyd.
Appellants also argue that Boyd teaches only delivery of calcitonin in
combination with a delivery agent, and "there is no discussion that the
calcitonin can be delivered without the delivery agent." (Appeal Br. 11.)
This argument is unpersuasive because claim 1 does not exclude
administering sCT in combination with other compounds, such as the
delivery agent taught by Boyd.
Conclusion of Law
Lee and Boyd support a prima facie case of obviousness. The
rejection of claim 1 under 35 U.S.C. § 103(a) based on Lee and Boyd is
affirmed.
II
Issue
The Examiner has rejected claim 1 as obvious based on Russo,
Komarova, and Boyd. The Examiner finds that Russo teaches treating pain
using calcitonin. (Ans. 6.) The Examiner finds that Komarova teaches "an
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Application 10/562,478
orally bioavailable form of calcitonin ... which is PEGylated Salmon
calcitonin (sCT) peptide (Fig. 1 ), wherein PEG polymers are conjugated to
Lys 11 and Lys18 residues" (id.), and oral administration of sCT to treat pain.
(Id.) The Examiner relies on Boyd for the teachings previously discussed.
(Id.) The Examiner concludes that it would have been obvious to use
Komarova's di-PEGylated sCT to treat pain and to administer it orally. (Id.
at 6-7.) The Examiner also concludes that the claimed dosage of 20 µg/kg
twice a day would have been an obvious variation of Boyd's 30 µg/kg
dosage. (Id. at 7.)
Appellants contend that Russo and Boyd do not teach di-PEGylated
calcitonin (Appeal Br. 14--16) and Komarova does not "mention[] treating
peripheral pain or the amount necessary to have such an effect." (Id. at 15.)
Appellants also contend that the Specification's Example 53 provides
evidence of unexpected results. (Id. at 16-17.)
The issues with respect to this rejection are (1) whether Russo,
Komarova, and Boyd support a prima facie case of obviousness, and (2)
whether Appellants' evidence of unexpected results, when weighed with the
evidence favoring obviousness, shows that the claimed method would not
have been obvious.
Findings of Fact
16. Russo teaches that "the application of calcitonin will relieve pain
in [a] subject." (Russo 9:19--21.)
1 7. Komarova discloses salmon calcitonin having polyethylene
glycol (PEG) oligomers covalently attached at Lys 11 and Lys 18. (Komarova
266, Fig. 1.)
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Application 10/562,478
18. Komarova states that "calcitonin is used in the treatment of
metabolic bone diseases characterized by excessive bone resorption, such as
osteoporosis and Paget's disease." (Id. at 265, right col.)
19. Komarova states that, "[i]n patients with Paget's disease, only
parenteral injections are effective in relieving bone pain .... Therefore,
preparations suitable for oral administration of calcitonin are highly
desirable." (Id.)
20. Komarova states that"[ o ]rally bioavailable forms of calcitonin
have recently been developed, in which amphiphilic poly( ethylene glycol)
(PEG)-alkyl oligomers are covalently linked to calcitonin (Fig. 1)." (Id.)
Analysis
Russo teaches using calcitonin to treat pain in a subject (FF16).
Komarova discloses orally bioavailable forms of PEGylated calcitonin
(FF20). Komarova discloses that oral administration of calcitonin is
desirable in relieving the pain related to Paget's disease (FFl 9). Komarova
also discloses di-PEGylated sCT having PEG oligomers attached at Lys 11
and Lys18 (FFl 7). Boyd has been discussed previously.
We agree with the Examiner that, based on these disclosures, it would
have been obvious to administer Komarova's di-PEGylated sCT to a subject
in pain, from for example Paget's disease, using Boyd's oral dosage form.
As previously discussed, the claimed dosage of 20 µg/kg twice a day would
have been obvious based on Boyd's teaching of a 30 µg/kg dosage of
calcitonin.
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Application 10/562,478
Appellants argue that Russo does not teach di-PEGylated calcitonin
(Appeal Br. 14--15), that Komarova does not teach treating pain (id. at 15),
and that Boyd also does not teach di-PEGylated calcitonin. (Id. at 16.)
These arguments are unpersuasive because they fail to address the
teachings of the references when considered together. See In re Merck &
Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) ("Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references. . . . [A reference] must
be read, not in isolation, but for what it fairly teaches in combination with
the prior art as a whole.").
Appellants also argue that they have presented evidence of
unexpected results. (Appeal Br. 16.) Specifically, Appellants argue that the
Specification's Example 53 shows that, after two weeks of treatment, mice
administered compound CT-025 showed a statistically significant difference
from mice administered the drug vehicle alone in a test for pain. (Id. at 16-
17.)
This argument is also unpersuasive. Appellants do not point to
evidence showing that compound CT-025 is the same as the di-PEGylated
sCT recited in claim 1 but, even assuming that it is, Appellants' evidence
does not show that the claimed method would have been nonobvious. The
Specification's Example 53 shows a comparison of compound CT-025 to the
vehicle used for drug delivery, for treatment of pain. (Spec. 102: 12-15.)
The results show that, after two weeks of twice-daily treatment, mice treated
with CT-025 showed statistically significant improvement over those treated
with the vehicle alone. (Id. at 102:13, 104:10-15.)
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Unexpected results, however, must be shown compared to the closest
prior art. Here, the prior art taught that calcitonin was known for treating
pain; thus, the fact that compound CT-025 was more effective than the drug
vehicle alone would not have been unexpected. Russo and Komarova,
among other references, teach treating pain using calcitonin, and Appellants
have not provided evidence that the pain relief shown in the Specification's
Example 53 is any greater than would have been expected based on the prior
art.
Conclusion of Law
Russo, Komarova, and Boyd support a prima facie case of
obviousness. Appellants' evidence of unexpected results, when weighed
with the evidence favoring obviousness, does not show that the claimed
method would not have been obvious.
III
Issue
The Examiner has rejected claim 2 as obvious based on Russo,
Komarova, Ekwuribe, and Boyd. The Examiner finds that Ekwuribe
discloses diPEG-sCT in which one PEG oligomer is attached by a non-
hydrolyzable bond and the other PEG oligomer is attached by a hydrolyzable
bond. (Ans. 8.) The Examiner concludes that "it would have been obvious
to apply the non-hydrolysable and hydrolysable coupling (bond) to the
PEGylation of sCT for treating pain" because Ekwuribe teaches the
advantages of doing so: the hydrolyzable bond allows a controlled release
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of sCT and the non-hydrolyzable bond allows extended circulation in the
blood. (Id. at 8-9.)
Appellants contend that "the Examiner has previously stated
numerous time[ s] that Ekwuribe does not describe the use of diconjugate
calcitonin for peripheral pain." (Appeal Br. 18.) Thus, according to
Appellants, "the Ekwuribe reference is not even competent prior art because
the Examiner has dismissed it and stated that it provide no guidance,
teaching or suggestion for treating peripheral pain with a mixture of
conjugates of the presently claimed invention." (Id. at 19.)
The issue with respect to this rejection is whether the cited references,
considered as a whole, would have made obvious the method of claim 2.
Findings of Fact
21. Ekwuribe discloses a substantially monodispersed mixture of
conjugates in which each conjugate include salmon calcitonin with a methyl-
terminated PEG moiety having at least 7 PEG subunits coupled at each of
Lys 11 and Lys18. (Ekwuribe 1-2 i-f 13.)
22. Ekwuribe discloses that "a hydrolyzable coupling may provide
for a time-release or controlled-release effect, administering the calcitonin
drug over a given time period as one or more oligomers are cleaved from
their respective calcitonin drug-oligomer conjugates to provide the active
drug." (Id. at 6 ,-r 93.)
23. Ekwuribe discloses that "[u]se of a non-hydrolyzable bond may
be preferable when it is desirable to allow the calcitonin drug-oligomer
conjugate to circulate in the bloodstream for an extended period of time."
(Id.)
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24. Ekwuribe discloses that "[ w ]hen a plurality of oligomers are
coupled to the calcitonin drug, it may be preferable to couple one or more of
the oligomers to the calcitonin drug with hydrolyzable bonds and couple one
or more of the oligomers to the calcitonin drug with non-hydrolyzable
bonds." (Id. at 6 i-f 95.)
Analysis
The disclosures of Russo, Komarova, and Boyd have been discussed
previously. Ekwuribe discloses di-PEG sCT (FF21) and suggests attaching
one oligomer with a hydrolyzable bond and one with a non-hydrolyzable
bond (FF24). Ekwuribe discloses that a hydrolyzable bond can provide a
controlled-release effect (FF22) and a non-hydrolyzable bond allows the
PEGylated sCT to remain in the bloodstream longer (FF23). We agree with
the Examiner that, in view of these teachings, it would have been obvious to
modify the di-PEG sCT used in the method of treating pain that is made
obvious by Russo, Komarova, and Boyd to include one PEG moiety that is
coupled to sCT by a hydrolyzable bond and one PEG moiety that is coupled
to sCT by a non-hydrolyzable bond.
Appellants argue that the Examiner has stated that Ekwuribe does not
teach using di-PEG sCT to treat peripheral pain and, because the Examiner
has stated that Ekwuribe does not teach or suggest treating peripheral pain as
presently claimed, it "is not even competent prior art." (Id. at 18-19.)
This argument is not persuasive because the Examiner is not relying
on Ekwuribe to disclose every limitation of claim 2. Rather, the Examiner
concludes that the claimed method would have been obvious based on the
combined teachings of Russo, Komarova, Ekwuribe, and Boyd. Appellants'
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arguments merely address the references individually, rather than what their
combined teachings would have made obvious to a person of ordinary skill
in the art. See In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991) ("The test for
obviousness is what the combined teachings of the references would have
suggested to one of ordinary skill in the art.").
Conclusion of Law
The cited references, considered as a whole, would have made
obvious the method of claim 2.
IV
The Examiner has rejected claim 3 as obvious based on Russo,
Komarova, Boyd, Crotts, and Ekwuribe. Claim 3 includes the limitation that
the sCT includes methyl-terminated PEG moieties having at least 7 PEG
subunits covalently coupled to sCT at Lys 11 and Lys18. This limitation is
taught by Ekwuribe (FF21 ). Therefore, the method of claim 3 would have
been obvious based on the cited references for the same reasons discussed
above with respect to claim 2.
Appellants argue that "[t]he Examiner has cited five different
references . . . . Appellants submit that if the Examiner had a soundly based
position on the issue of obviousness, it would not be necessary to rely on so
many references." (Appeal Br. 21.) "Appellants insist that the use by the
Examiner of a multiplicity of references in an effort to show obviousness is
in itself persuasive of the futility of attempting to establish a prima facie
case of obviousness." (Id.)
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This argument lacks merit. As discussed above, Crotts is not
necessary to support a prima facie case of obviousness for claim 3. And
even if it was, "[ t ]he criterion ... is not the number of references, but what
they would have meant to a person of ordinary skill in the field of the
invention." In re Gorman, 933 F.2d 982, 986 (Fed. Cir. 1991). In Gorman,
"[t]he claims were rejected in view of thirteen references," id. at 985, but the
court held that "[t]he large number of cited references does not negate the
obviousness of the combination, for the prior art uses the various elements
for the same purposes as they are used by appellants, making the claimed
invention as a whole obvious in terms of 35 U.S.C. § 103." Id. at 987. The
same is true of the references relied on here.
v
Issue
The Examiner has rejected claims 1-3 for obviousness-type double
patenting based on various claims of U.S. Patent 6,713,452 in view of Boyd
and Lee. The Examiner finds that claims 70-72 and 76-84 of the '452
patent define a method of using sCT PEGylated at Lys 11 and Lys18 in "a
method of treating a bone disorder in a subject wherein the bone disorder is
Paget's disease ... which is associated with pain from the bone absorption,"
as evidenced by Lee. (Ans. 25.) The Examiner concludes that an oral
dosage of 20 µg/kg twice a day, as recited in the instant claims, would have
been an obvious variant of the patented method in view of Boyd's disclosure
of oral delivery of sCT at 30 µg/kg. (Id.)
"Appellants contend that it is patentably distinct to recite a method of
treatment for peripheral pain with a calcitonin hav[ing] two oligomers
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attached to specific amino acids and in an amount of about 20 ug/kg twice a
day." (Reply Br. 19.)
The issue with respect to this rejection is whether the claims on appeal
are patentably distinct from the claims of the '452 patent.
Findings of Fact
25. Claim 1 of the '452 patent reads as follows:
1. A substantially monodispersed mixture of conjugates,
wherein the conjugate comprises a first oligomer and a second
oligomer, wherein each oligomer comprises a polyethylene
glycol moiety and is coupled to salmon calcitonin and wherein
the first oligomer is covalently coupled to an amine function of
Lys11 of the salmon calcitonin and the second oligomer is
covalently coupled to an amine function of Lys18 of the salmon
calcitonin.
('452 patent 67:21-28.)
26. Claim 70 of the '452 patent reads as follows:
70. A method of treating a bone disorder in a subject in need of
such treatment, said method comprising:
administering an effective amount of a pharmaceutical
composition comprising a mixture according to claim 1, to the
subject to treat the bone disorder.
(Id. at 72:50-54.)
27. Claim 72 of the '452 patent reads as follows:
72. The method according to claim 70, wherein the bone
disorder is osteoporosis, Paget's disease, or hypercalcemia.
(Id. at 72:58-59.)
Analysis
Claim 72 of the '452 patent is directed to a method of treating Paget's
disease, among others, by administering a pharmaceutical composition
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comprising a mixture of conjugates comprising sCT having a first PEG
moiety coupled to Lys 11 and a second PEG moiety coupled to Lys18 (FF25-
FF27). Lee teaches that Paget's disease is associated with pain from the
bone absorption (FF8). Boyd teaches oral delivery of sCT at a dose of
30 µg/kg (FF15). In view of Lee and Boyd, we agree with the Examiner that
the instant claims are an obvious variant of the claims of the '452 patent.
Appellants argue that Lee teaches away from an oral dose and that
combining Boyd with Lee would change Lee's principle of operation (i.e.,
nasal delivery). (Reply Br. 20.) These arguments have been addressed
above.
Appellants also argue that Boyd uses 30 µg/kg and "the end result was
less than stellar." (Id. at 20-21.) Appellants present calculations that, they
assert, show that Boyd's method resulted in low levels of calcitonin in the
rats' serum. (Id. at 21.) Appellants ask"[ w ]ith so little amount of calcitonin
found in the rat serum, why would anyone skilled in the art look to the Boyd
reference and consider reducing the amount of calcitonin to about 20 ug/kg
as recited in the presently claimed invention." (Id.)
This argument is also unpersuasive. First, Appellants point to no
evidence of record to show the accuracy of the calculations in the Reply
Brief, and "[a]ttomey's argument in a brief cannot take the place of
evidence." In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). Second, Lee
states that the dose of PEGylated sCT "can range from about 0.1 ug to about
10 mg/kg/day, and can be widely altered according to the kind of peptide
and patient's condition" (FF13). In short, Appellants have not shown that
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Application 10/562,478
the dosage of 20 µg/kg twice a day recited in the instant claims makes them
patentably distinct from the claims of the '452 patent.
We therefore affirm the rejection of claims 1-3 for obviousness-type
double patenting based on the claims of the '452 patent.
SUMMARY
We affirm all of the rejections on appeal.
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
cdc
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