Ex Parte Aoki et al

Patent Trial and Appeal Board

Jun 17, 2016

11740809 (P.T.A.B. Jun. 17, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111740,809 04/26/2007
51957 7590 06/21/2016
ALLERGAN, INC
2525 DUPONT DRIVE, T2-7H
IRVINE, CA 92612-1599
FIRST NAMED INVENTOR
K. Roger Aoki
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.
16952-CON6 (BOT) 1837
EXAMINER
GUPTA, ANISH
ART UNIT PAPER NUMBER
IPLA
NOTIFICATION DATE DELIVERY MODE
06/21/2016 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):
patents_ip@allergan.com
pair_allergan@firsttofile.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte K. ROGER AOKI, MICHAEL W. GRAYSTON,
STEVEN R. CARLSON, and JUDITH M. LEON
Appeal2013-002213
Application 11/740,809
Technology Center 1600
Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
RYAN H. FLAX, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1'2 under 35 U.S.C. § 134 involving claims to a
method for treating a pain associated with a muscle activity or contracture
with a botulinum toxin. The Examiner rejected the claims as obvious and on
the grounds of 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 Allergan, Incorporated (see
App. Br. 1).
2 This Appeal is related to Appeals 2013-002207, 2013-002211, 2013-
002212, 2013-002214, and Ex Parte Aoki, 2011 WL 5080231 (BPAI 2011),
aff'd 562 Fed. Appx. 976 (mem.) (Fed. Cir. 2014) (Rule 36).
Appeal2013-002213
Application 11/740,809
STATEMENT OF THE CASE
Background
"Botulinum toxins, in particular Botulinum toxin type A, has been
used in the treatment of a number of neuromuscular disorders and
conditions" (Spec. 2:6-8). "[S]even immunologically distinct [Botulinum]
neurotoxins have been identified. These have been given the designations
A, B, C, D, E, F and G" (Spec. 3:14--16). "Botulinum toxin type A, the
toxin type generally utilized in treating neuromuscular conditions, is
currently available commercially from several sources" (Spec. 5:4--6).
The Claims
Claims 1-5 and 7-18 are on appeal. Independent claim 1 is
representative and reads as follows:
1. A method for treating a pain associated with a muscle
activity or contracture, wherein said method is a human medical
application and comprises the step of administering to a human
patient a therapeutically effective amount of a single or dichain
form of the neurotoxic component of a botulinum toxin to
thereby treat said pain, wherein said neurotoxic component
administered to said human patient has a molecular weight of
about 150 kilodaltons.
(App. Br. 35 (Claims Appx.)).
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The Issues
I. Claims 1-3, 5, 11, 13, and 18 were rejected under 35 U.S.C.
§ 103(a) as obvious over Media News3 and Tse4 (Final Act. 2-3).
II. Claims 1-5, 7, 11, 14, and 18 were rejected under 35 U.S.C.
§ 103(a) as obvious over Clark,5 Reichl, 6 Tse, and Greene7 (Final Act. 4---6).
III. Claims 1--4, 7, 10, 15, and 18 were rejected under 35 U.S.C.
§ 103(a) as obvious over Borodic8 and Tse (Final Act. 6-7).
IV. Claims 1-5, 7, and 16-18 were rejected under 35 U.S.C.
§ 103(a) as obvious over Pasricha9 and Tse (Final Act. 7-9).
V. Claims 1-5, 7, 10, 15, and 18 were rejected under 35 U.S.C.
§ 103(a) as obvious over Memin10 and Tse (Final Act. 9-10).
3 Botulinum Toxin May be Useful in Range of Muscular Disorders, 24 INT.
MED. NEWS 36 (1991) (hereinafter "Media News").
4 Chun K. Tse et al., Preparation and Characterisation of Homogeneous
Neurotoxin Type A from Clostridium botulinum, 122 EUR. J. BIOCHEM. 493-
500 (1982) (hereinafter "Tse").
5 Jonathan B. Clark, Cervical Dystonia Following Exposure to High-G
Forces, 61 AVIAT. SPACE & ENVIRON. MED. 935-37 (1990) (hereinafter
"Clark").
6 M. Reichl & M. J. Allen, Hyperaesthesia Associated with Hyperextension
Injuries of the Neck, 18 INmRY 234 (1987) (hereinafter "Reichl").
7 Paul E. Greene & Stanley Fahn, Use of Botulinum Toxin Type F Injections
to Treat Torticollis in Patients with Immunity to Botulinum Toxin Type A, 8
MOVEMENT DISORDERS 479-83 (1993) (hereinafter "Greene").
8 Borodic, US 5,183,462, issued Feb. 2, 1993 (hereinafter "Borodic").
9 Pasricha et al., US 5,437,291, issued Aug. 1, 1995 (hereinafter "Pasricha").
10 B. Mernin et al., Traitment de la Spasticite par la Toxine Botulique, 148
REV. NEUROL. (Paris) 212-14 (1992) (hereinafter "Mernin").
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Application 11/740,809
VI. Claims 1-5, 7, 8, and 18 were rejected under 35 U.S.C.
§ 103(a) as obvious over Davis 11 and Tse (Final Act. 10-11).
VII. Claims 1-5, 7, 9, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-2 of Aoki '130 12 and Tse
(Final Act. 12-13).
VIII. Claims 1-5, 7, 12, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-10 of Aoki '176 13 and Tse
(Final Act. 13-14).
IX. Claims 1-5, 7, 12, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-8 of Aoki '70014 and Tse
(Final Act. 14--16).
X. Claims 1-5, 7, 11, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-5 of Aoki '397 15 and Tse
(Final Act. 16-17).
11 Dave Davis & Bahman Jabbari, Significant Improvement of Stiff-Person
Syndrome After Paraspinal Injection of Botulinum Toxin A, 8 MOVEMENT
DISORDERS 371-373 (1993) (hereinafter "Davis").
12 Aoki et al., US 7,501,130 B2, issued Mar. 10, 2009 (hereinafter "Aoki
'130").
13 Aoki et al., US 7,091,176 B2, issued Aug. 15, 2006 (hereinafter "Aoki
'176").
14 Aoki et al., US 7,381,700 B2, issued June 3, 2008 (hereinafter "Aoki
'700").
15 Aoki et al., US 6,872,397 B2, issued Mar. 29, 2005 (hereinafter "Aoki
'397").
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XI. Claims 1-5, 7, 13, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1--4 of Aoki '992 16 and Tse
(Final Act. 17-19).
XII. Claims 1-5, 7, 13, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-14 of Aoki '365 17 and Tse
(Final Act. 19-20).
XIII. Claims 1, 2, 4, 5, 7, 13, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-8 of Aoki '961 18 and Tse
(Final Act. 20-22).
XIV. Claims 1, 2, 4, 5, 7, 13, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-11 of Aoki '433 19 and Tse
(Final Act. 22-23).
XV. Claims 1--4, 7, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-13 of Aoki '76920, The
Merck Manual21 , and Tse (Final Act. 23-25).
16 Aoki et al., US 6,776,992 B2, issued Aug. 17, 2004 (hereinafter "Aoki
'992").
17 Aoki et al., US 6,458,365 Bl, issued Oct. 1, 2002 (hereinafter "Akoi
'365").
18 Aoki et al., US 6,290,961 Bl, issued Sept. 18, 2001 (hereinafter "Aoki
'961 ").
19 Aoki et al., US 6,632,433 B2, issued Oct. 14, 2003 (hereinafter "Aoki
'433").
20 Aoki et al., US 7,374,769 B2, issued May 20, 2008 (hereinafter "Aoki
'769").
21 The Merck Manual, Trigeminal Neuralgia: Cranial Nerve Disorders
(http://www.merck.com/mmhe/sec06/ ch096/ cho96e.html) (last accessed
Feb. 23, 2010) (hereinafter "the Merck Manual").
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XVI. Claims 1--4, 7, and 16-18 were rejected on the grounds of
obviousness-type double patenting over claims 1-7 of Aoki '61022, The
Merck Manual, and Tse (Final Act. 25-27).
XVII. Claims 1-5, 7, 9, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1--4 of Aoki '4 7 623 ,
Escobar24, and Tse (Final Act. 27-29).
XVIII. Claims 1-5 and 7-18 were rejected on the grounds of
obviousness-type double patenting over claims 1-16 of Aoki '91525 ,
Schantz26, Johnson27, and Tse (Final Act. 29-31 ).
XIX. Claims 1-5 and 7-18 were rejected on the grounds of
obviousness-type double patenting over claims 1-9 of Aoki '28928, Schantz,
Johnson, and Tse (Final Act. 31-33).
22 Aoki et al., US 6,869,610 B2, issued Mar. 22, 2005 (hereinafter "Aoki
'610").
23 Aoki et al., US 6,887,476 B2, issued May 3, 2005 (hereinafter "Aoki
'476").
24 Pedro Luis Escobar & Julian Ballesteros, Myofascial Pain Syndrome, 16
ORTHOPAEDIC REV. 16-21 (1987) (hereinafter "Escobar").
25 Aoki et al., 6,113,915, issued Sept. 5, 2000 (hereinafter "Aoki '915").
26 Edward J. Schantz and Eric A. Johnson, Properties and Use of Botulinum
Toxin and Other Microbial Neurotoxins in Medicine, 56 MICROBIOL. REV.
80-99 (1992) (hereinafter "Schantz").
27 Johnson et al., US 5,696,077, issued Dec. 9, 1997 (hereinafter "Johnson").
28 Aoki et al., US 6,235,289 Bl, issued May 22, 2001 (hereinafter "Aoki
'289").
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XX. Claims 1-5 and 7-18 were rejected on the grounds of
obviousness-type double patenting over claims 1-36 of Aoki '03729,
Schantz, Johnson, and Tse (Final Act. 33-35).
XXL Claims 1-5 and 7-18 were rejected on the grounds of
obviousness-type double patenting over claim 1 of Aoki '22630 and Tse
(Final Act. 35-36).
XXII. Claims 1-5 and 7-18 were rejected on the grounds of
obviousness-type double patenting over claims 1, 4, 5-9, and 12-17 of
Donovan31 and Tse (Final Act. 36-38).
XXIII. Claims 1-5, 7, 9, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-13 of Voet '74232,
Buckelew,33 Simons,34 and Tse (Final Act. 38--40).
XXIV. Claims 1-5, 7, 13, and 18 were rejected on the grounds of
obviousness-type double patenting over claims 1-20 ofVoet '43435 and Tse
(Final Act. 40--41 ).
29 Aoki et al., US 6,333,037 Bl, issued Dec. 25, 2001 (hereinafter "Aoki
'037").
30 Aoki et al., US 6,372,226 B2, issued Apr. 16, 2002 (hereinafter "Aoki
'226").
31 Donovan, US 6,500,436 B2, issued Dec. 31, 2002 (hereinafter
"Donovan").
32 Voet, US 6,623,742 B2, issued Sept. 23, 2003 (hereinafter "Voet '742").
33 Susan P. Buckelew, Fibromyalgia: A Rehabilitation Approach, 68 AM. J.
PHYS. MED. & REHABIL. 37--42 (1989) (hereinafter "Buckelew").
34 David G. Simons, Fibrositis/Fibromyalgia: A Form of Myofascial Trigger
Points?, 81 THE AM. J. OF MED. 93-98 (1986) (hereinafter "Simons").
35 Voet, US 6,838,434 B2, issued Jan. 4, 2005 (hereinafter "Voet '434").
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XXV. Claims 1-5, 7, 10, 15, and 18 were rejected on the grounds of
provisional obviousness-type double patenting over claims 1--4 and 6-19 of
copending U.S. Application 11/740,809 (Final Act. 41--42).
I-XXIV OBVIOUSNESS AND
OBVIOUSNESS-TYPE DOUBLE PATENTING
Because rejections I-XXIV tum on the same issue, we will consider
them together.
The Examiner finds that Media News, Clark, Borodic, Pasricha,
Mernin, Davis, Aoki' 130, Aoki '397, Aoki' 176, Aoki '700, Aoki '397,
Aoki '992, Aoki '365, Aoki '961, Aoki '433, Aoki '769, Aoki '610, Aoki
'476, Aoki '915, Aoki '289, Aoki '037, Aoki '226, Donovan, Voet '742, and
Voet '434 each teach treatment of a pain associated with muscle activity or
contracture with haemagglutinin-complexed botulinum toxin but do "not
teach the use of a 150Kda component of botulinum toxin and the exact
dosage claimed" (Final Act. 2-3; cf id. at 4, 6, 8-10, 12-13, 15-17, 19, 21-
23, 25, 28-31, 33, 35-38, and 40).
However, the Examiner finds that Tse teaches that the neurotoxic
component of type A botulinum "specifically and characteristically inhibited
stimulated and spontaneous release of acetylcholine at the vertebrate
neuromuscular junction" (Final Act. 5) in the same manner as the complexed
toxin, and also, "when injected into the hind leg muscle of a rat, produced
local paralysis within 24 hours" (id.).
The Examiner concludes that the ordinary artisan would have found it
obvious to "use the pure toxin of Tse to treat neck pain as taught by Clark
because Tse teaches that pure toxin has similar activity in the paralysis of
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Application 11/740,809
muscles as complexed neurotoxin" (Final Act. 5). The Examiner finds "a
reasonable expectation of success because both the pure toxin and the
complexed toxin have similar activity against spontaneous release of
acetylcholine" (id.).
ISSUE
Has the Examiner established that treating a pain associated with a
muscle activity or contracture by administering the neurotoxic component of
a botulinum toxin, rather than a complexed form of the botulinum toxin,
would have been obvious over the evidence of record?
FINDINGS OF FACT
1. Media News teaches that the "efficacy ofbotulinum toxin A
(BTXA) in treating dystonias suggests that it may be useful for any disease
characterized by abnormal muscular contraction ... BTXA reduces the
headaches that often accompany torticollis. BTXA may be equally effective
in other forms of muscle tension headaches" (Media News, abstract).
2. Clark teaches that a "36-year-old designated naval aviator was
in good health until October 1987, when he developed left sided neck pain
... he underwent local botulinum A toxin injections (100 units) into the
affected neck muscles .... He had dramatic improvement with near
complete symptomatic relief for several weeks" (Clark 935, col. 2).
3. Borodic teaches that "diseases involving muscle spasticity in
general can be treated" (Borodic, col. 4, 11. 22-26) and that "[i]n situations
where spasticity is involved with pain ... use of the toxin may be indicated"
(Borodic, col. 10, 11. 54--57).
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4 Borodic teaches that the "invention may be practiced on any
substance capable upon injection of interrupting nerve impulse transmission
across the neuromuscular junction ... and the most preferred is
pharmaceutical grade botulinum toxin Type A" (Borodic, col. 4, 11. 50-56).
5. Borodic teaches that "it is contemplated that other materials,
protein subunits, recombinantly produced materials, and other various novel
types of pharmaceutical preparations can be used in the practice of the
invention" (Borodic, col. 4, 11. 65---68).
6. Pasricha teaches that "mammals are treated by direct (local)
injection of a neurotoxin into a smooth muscle which exhibits elevated tone
or spasms ... In some cases alleviation of a symptom of the muscle
disorder, such as pain, is the goal" (Pasricha, col. 5, 11. 5-15).
7. Pasricha teaches that "[t]he preferred toxin according to the
present invention is botulinum toxin type A" (Pasricha, col. 5, 11. 24--25).
8. Mernin teaches that "[i]n this pilot and open study we use
botulinum toxin in spasticity ... There were no side effects. Spasticity was
improved in all patients. Five patients reported significant pain relief'
(Mernin, abstract).
9. Davis teaches that "[ w ]e now report a patient with clinical,
EMG, and autoimmune features of stiff-person syndrome in whom injection
of botulinum toxin type A in the lumbar paraspinal musculature resulted in
remarkable relief from pain and stiffness and significant improvement of
ambulation" (Davis 371, col. 2).
10. Aoki' 130 claims: "A method for treating myofascial pain in a
patient in need thereof, the method comprising the step of intramuscularly
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administering to the patient an effective amount of a botulinum toxin type
A" (Aoki '130, claim 1; cf Aoki '176, claim 1 "relieving pain associated
with contractions in arthritis"; Aoki '700, claim 1 "relieving pain associated
with arthritis"; Aoki '992, claim 1 "treating tension headache pain"; Aoki
'365, claim 1 "relieving pain of a headache"; Aoki '961, claim 8 "treating
cervical dystonia ... thereby reducing a neck pain symptom"; Aoki '433,
claim 9 "treating cervical dystonia ... thereby reducing a neck pain
symptom"; Aoki '4 7 6, claim 1 "treating pain associated with a muscle
disorder").
11. Aoki '397 claim 3 recites: "A method of treating cervical
dystonia ... comprising intramuscular or subcutaneous administration ... of
a botulinum toxin type A" with dependent claim 5 reciting "wherein treating
the cervical dystonia reduces a neck pain" (Aoki '397, claims 3, 5).
12. Aoki '769 claim 1 recites: "A method for treating trigeminal
neuralgia pain, the method comprising the step of peripheral administration
of a therapeutically effective amount of a botulinum toxin" (Aoki '769,
claim 1; cf Aoki '610, claim 1).
13. Aoki '915 claim 1 recites: "A method for treating pain, the
method comprising the step of intraspinal administration of an effective
amount of a botulinum toxin" (Aoki '915, claim 1; cf Aoki '289, claim 1;
Aoki '037, claim 1; Aoki '226, claim 1).
14. Donovan claim 1 recites: "A method for treating pain in a
patient, comprising subcutaneous, intramuscular or intrathecal
administration of a therapeutically effective amount of an agent to the
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patient, wherein the agent comprises a botulinum toxin component"
(Donovan, claim 1 ).
15. Voet '742 claim 10 recites: "A method for treating fibromyalgia
pain, the method comprising the step of administering subcutaneously or
intramuscularly a therapeutically effective amount of a botulinum toxin"
(Voet '742, claim 10).
16. Voet '434 claim 1 recites: "A method for treating a sinus
headache, the method comprising a step of local administration of a
botulin um toxin" (Voet '434, claim 1 ).
17. Tse describes removal of the immunogenic haemagglutinin
component of the type A haemagglutinin-neurotoxin complex, and
characterization of the isolated, purified 150 kD neurotoxic component (Tse
493, col. 2; 494, cols. 1-2; 496, col. 2; 499, col. 2).
18. Tse teaches that the "purified neurotoxin ... is homogeneous
by all criteria tested including dodecyl sulphate gel electrophoresis under
non-reducing conditions, isoelectric focussing [sic] and immunodiffusion"
(Tse 499, col. 2).
19. Tse teaches that "[w]hen this neurotoxin (5 mouse LDso units;
60 pg protein) was injected into rat hind-leg muscle, it produced local
paralysis within 24 h" (Tse 498, col. 1 ).
20. Tse teaches that "[a]s clearly demonstrated with impure
neurotoxin complexes ... , pure neurotoxin specifically and
characteristically inhibited stimulated and spontaneous release of
acetylcholine at the vertebrate neuromuscular junction" (Tse 499, col. 2
(internal citations omitted)).
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21. Schantz, cited by Appellants, discusses the properties of
botulinum toxins, including the purified neurotoxic component. According
to Schantz:
The nontoxic proteins bound to the neurotoxin apparently play
an important role in maintaining the toxic shape of the
neurotoxin. Careful handling of purified toxin is therefore
important for maintenance of stability. Botulinum toxin type A
is readily denatured by heat at temperatures above 40°C,
particularly at alkaline pH. Solutions of the toxin lose toxicity
when bubbles form at the air/liquid interface causing stretching
and pulling of the neurotoxin out of its toxic shape (173). This
denaturation also takes place in an atmosphere of nitrogen or
carbon dioxide. Dilution to extremely low concentrations
(nanograms per milliliter) also tends to decrease the stability of
the neurotoxin, but this can be prevented by diluting with a
buffered solution (at pH 6.8 or below) containing another protein
such as gelatin and certain albumins such as bovine or human
serum albumin. When the pH is raised above 7.3, the neurotoxin
is liberated, which is very labile. Because of its lability the
neurotoxin is not practical for medical applications.
(Schantz 82, col. 2, internal citations omitted).
22. Schantz teaches that:
Most recent information concerning the structure and
pharmacology of botulinum toxin has been obtained with
purified neurotoxins, but it is unlikely that these will be used in
a clinical setting. The toxin complexes are much more stable than
neurotoxins and can be diluted and formulated with retention of
toxicity. Pure neurotoxins can be kept for several weeks to
months in solution in the cold but are inactivated on dilution,
formulation, and drying.
(Schantz 89, col. 2).
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23. Schantz teaches that:
we recommend that fresher batches of toxin periodically be
prepared to avoid detrimental changes that may occur on aging.
. . . Diluting a solution of botulinum toxin type A from a
concentration of 1 or 2 mg/ml to nanogram concentrations causes
detoxification unless another protein is added for protection"
(Schantz 83, col. 2).
24. DasGupta36 teaches that the "pure NT is stable for months at pH
7.9 and 4°C," and teaches that the neurotoxin:
isolated from the complex by ion-exchange chromatography,
first reported in 1966 (16) and now routinely prepared in various
laboratories (73, 48), has stable activity; Williams et al. (81) have
found that the homogenous preparation of type A NT, stored at
4°C in 0.15 M TRIS/HCl buffer, pH 7.9, is stable for several
months. The pure preparations NT types A and E at very low
concentrations (such as 1 x 10-10 Mand lower) in physiological
buffers, with and without added gelatin or serum albumin, are
highly active (25, 48, 59, 73, 86) ....
REFERENCES
16. DasGupta BR, Boroff DA, Rothstein E. Chromatographic
fractionation of crystalline toxin of Clostridium botulinum
type A, Biochem Biophys Res Commun 1966;22:750-
756.
48. Tse CK, Dolly JO, Hambleton P, Wray D, Melling J.
Preparation and characterization of homogenous
36 Bibhuti R. DasGupta, Structures of Botulinum Neurotoxin, Its Functional
Domains, and Perspectives on the Crystalline Type A Toxin, in Therapy with
Botulinum Toxin 15-39 (J. Jankovic ed. 1994).
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neurotoxin type A from Clostridium botulinum. Its
inhibitory action on neuronal release of acetylcholine in
the absence and presence of ~-bungaro toxin. Eur J
Biochem 1982; 122:493-500.
59. Lomneth R, Suszkiw JB, DasGupta BR. Response of the
chick ciliary ganglion-iris neuromuscular preparation to
botulinum neurotoxin. Neurosci Lett 1990;113:211-216.
73. Sugii S, Sakaguchii G. Molecular construction of
Clostridium botulinum type A toxins. Infect Immun
1975; 12: 1262-1270.
81. Williams RS, Tse CK, Dolly JO, Hambleton P, Melling J.
Radioiodination of Botulinum Neurotoxin Type A with
Retention of Biological Activity and Its Binding to Brain
Synaptosomes. Eur. J. Biochem. 1983; 131 :437--445.
(DasGupta 31-32, 35-39).
25. Lamanna37 1988 discloses "a purified sample of type A toxin
free of hemagglutinin ... dissolved in a sterilized phosphate-0.2% gelatin
buffer (pH 6.2----6.7) for storage and i.v. injection" into mice, rats, and dogs
(Lamanna 1988 70).
26. Lamanna 1988 teaches that "[h]emagglutinin-free toxin had the
same qualitative effects on the heart" as hemagglutinin-containing (i.e.,
complexed) toxin, but was more potent than the hemagglutinin-containing
toxin on a weight to weight basis (Lamanna 1988 72).
27. The Specification's only disclosure regarding the neurotoxic
component is reproduced below:
37 C. Lamanna et al., Cardiac Effects of Botulinal Toxin, 293 ARCH. INT.
PHARMACODYN. THER. 69-83 (1988) (hereinafter "Lamanna 1988").
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The neurotoxic component of Botulinum toxin has a
molecular weight of about 150 kilodaltons and is thought to
comprise a short polypeptide chain of about 50 kD which is
considered to be responsible for the toxic properties of the toxin,
i.e., by interfering with the exocytosis of acetylcholine, by
decreasing the frequency of acetylcholine release, and a larger
polypeptide chain of about 100 kD which is believed to be
necessary to enable the toxin to bind to the presynaptic
membrane.
(Spec. 3, 1. 27 to 4, 1. 2.).
PRINCIPLES OF LAW
[O]bviousness must be determined in light of all the facts, and
there is no rule that a single reference that teaches away will
mandate a finding of nonobviousness. Likewise, a given course
of action often has simultaneous advantages and disadvantages,
and this does not necessarily obviate motivation to combine. See
[Winner Int'! Royalty Corp. v. Wang, 202 F.3d 1340, 1349 n.8
(Fed. Cir. 2000)] ("The fact that the motivating benefit comes at
the expense of another benefit, however, should not nullify its
use as a basis to modify the disclosure of one reference with the
teachings of another. Instead, the benefits, both lost and gained,
should be weighed against one another."). Where the prior art
contains "apparently conflicting" teachings (i.e., where some
references teach the combination and others teach away from it)
each reference must be considered "for its power to suggest
solutions to an artisan of ordinary skill .... consider[ing] the
degree to which one reference might accurately discredit
another." In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991).
Medichem, S.A. v. Rolabo, S.L.,437 F.3d 1157, 1165 (Fed. Cir. 2006).
DISCUSSION
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art (Final Act. 2--41; FF 1-27) and agree that
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the claims are obvious over the cited prior art. We address Appellants'
arguments below.
Appellants contend that "the Schantz et al. reference clearly
discourages use of the neurotoxic component for human therapeutic
purposes" (App. Br. 10-11) and that the Board "ignores the plain, express
language of the Schantz et al. reference" (App. Br. 12). Specifically,
Appellants argue that the following statements in Schantz teach away from
the claimed method:
Because of its lability the neurotoxin is not practical for medical
applications.
(Schantz 82, col. 2; App. Br. 12 (emphasis Appellants')).
Most recent information concerning the structure and
pharmacology of botulinum toxin has been obtained with
purified neurotoxins, but it is unlikely that these will be used in
clinical settings. The toxin complexes are much more stable than
neurotoxin and can be diluted and formulated \'l1ith retention of
toxicity. Pure neurotoxins can be kept for several weeks to
months in solution in the cold but are inactivated on dilution,
formulation, and drying.
(Schantz 89, col. 2; App. Br. 12 (emphasis Appellants')).
Appellants' argument is alleged to be supported by Declarant Dr.
Leonard A. Smith, whose work "has involved production, formulation, and
characterization of native botulinum toxin and recombinant neurotoxin
component fragments" (Deel. 138, i-f 9). Dr. Smith concludes that "a person
having ordinary skill in the art reading Schantz 1992 and considering the Tse
38 Declaration of Leonard A. Smith, PhD. (dated Nov. 20, 2007) (hereinafter
"Deel. I").
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et al. reference ... with or without consideration of the Lamanna [1988 and
1993] references clearly would have been discouraged from using the
neurotoxic component for human therapeutic purposes" based, at least in
part, on the statements quoted above (Deel. III39, ,-r 4).
There are, however, substantive and irreconcilable inconsistencies
between Deel. I and Deel. III. Deel. I states that "[t]here is no doubt in my
mind and it is my opinion that the statements in Schantz 1992 that the
neurotoxic component is 'not practical for medical applications' and that the
neurotoxic component 'is unlikely .. (to ) .. be used in a clinical setting' are
clearly wrong" (Deel. I, i-f 15), while Deel. III states that
[ w ]hen considering all the facts presented in paragraph 15 of my
First Declaration with the exception of those from the DasGupta
reference and the Goodnough thesis, I conclude that a person
having ordinary skill in the art would not have considered the
statements within Schantz 1992 to be clearly wrong.
(Deel. III, i-f 4; cf Deel. II40 , i-f 4). Deel. III excludes the DasGupta reference
from the analysis, apparently because DasGupta itself is not prior art (see
Deel. III, i-f 3) but DasGupta was a review article that relied upon Williams,
which is a prior art reference, as evidence of the stability of the purified
neurotoxic component (FF 24; cf Ans. 53), as well as a number of additional
references that teach neurotoxin isolation (FF 24).
Because the statements in Deel. II and III are inconsistent with Deel.
I, and Deel. II and III fail to consider the prior art teachings of Williams
39 Declaration of Leonard A. Smith, PhD. (dated Dec. 16, 2011) (hereinafter
"Deel. III").
40 Declaration of Leonard A. Smith, PhD. (dated May 25, 2011) (hereinafter
"Deel. II").
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relied upon by DasGupta, we determine that those statements are reduced in
credibility and we afford them less weight. See Scripps Clinic & Res.
Found. v. Genentech, Inc., 927 F.2d 1565, 1578 (Fed. Cir. 1991) (overruled
on other grounds) ("[A ]pparent inconsistencies among the three [expert]
declarations raise questions of credibility and weight").
We have, however, carefully considered Dr. Smith's Declarations.
However, we do not agree that Schantz teaches away from substituting the
neurotoxic component of botulinum toxin for the haemagglutinin-complexed
form of the toxin used by Media News, Clark, Borodic, Pasricha, Mernin,
Davis, Donovan, and the Aoki and Voet patents. That is, we do not agree
that anything in Schantz would have led one of ordinary skill in the art to
expect that the purified neurotoxin would be ineffective in treating spasticity
disorders, as there is ample evidence of record that the complexed toxin and
the purified neurotoxic component both produce the desired effect - local
paralysis (FF 1-16, 19), and both operate by the same mechanism (FF 20).
While we agree that one of ordinary skill in the art would have concluded
from the Schantz reference that the purified toxin is less practical in
comparison with the complexed toxin, Schantz also teaches that the purified
neurotoxin can be stored for weeks in the cold, and can be successfully
diluted with careful buffering and handling (FF 22-23) - which is not
unusual for therapeutic agents.
Appellants contend that "the Board and the Examiner appear to
somehow base their various obviousness rejections for this family of
applications on the teachings of the Lamanna publications. As the record
indicates, the Lamanna references, however, are not cited in the current
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obviousness rejections" (App. Br. 10), but Appellants also note that "[ w ]hen
assessing obviousness, the prior art as a whole including any evidence of
teaching away must be considered. Medichem v. Rolabo, 437 F.3d 1157,
1166 (Fed. Cir. 2005)" (App. Br. 16 (emphasis Appellants')).
We agree with Appellants that the prior art must be assessed as a
whole, in combination with the entirety of the evidence of record including
the Smith Declarations and the teachings of the Specification in order to
assess the overall power to suggest solutions to an artisan of ordinary skill.
We also agree with Appellants that no special weight is given references
relied upon by the Examiner (see App. Br. 16)41 .
"When prior art contains apparently conflicting references, the Board
must weigh each reference for its power to suggest solutions to an artisan of
ordinary skill." In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991). Moreover,
Although a reference that teaches away is a significant factor to
be considered in determining unobviousness, the nature of the
teaching is highly relevant, and must be weighed in substance.
A known or obvious composition does not become patentable
simply because it has been described as somewhat inferior to
some other product for the same use.
In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
Lamanna 1988 is part of the record and prior art as a whole. Indeed,
the Examiner cites Appellants' own Reply Brief filed on February 24, 2009
in U.S. Application 10/933,723 that the "Lamanna and DasGupta
41 With regard to Appellants' citation of an unrelated, nonprecedential PT AB
decision (see App. Br. 13-15), we note that "[e]ach case must be decided on
its own merits." In re Gyurik, 596 F.2d 1012, 1016 (CCPA 1979).
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publication provide evidence that at the time the '996 parent application was
filed, purified neurotoxic component had been isolated, formulated, and
stored in stable form. Moreover, these publications provide evidence that
the neurotoxic component is sufficiently stable and active to be
administered intravenously" (Ans. 53; emphasis in original). Lamanna
1988, a prior art reference, supports this position, evidencing the storage and
use of the purified neurotoxin component for treatment of animals (FF 25).
Lamanna 1988 also found that the purified neurotoxin component was more
potent than the hemagglutinin-containing toxin on a weight to weight basis
(FF 26). These teachings support the Examiner's position that the ordinary
artisan, weighing the teachings of the different references, would have had
reason to use the purified neurotoxin component as more potent, and would
have had a reasonable expectation of success in storing and using the
purified neurotoxin (FF 25-26).
When we consider the Schantz reference as a whole, together with the
Media News, Clark, Borodic, Pasricha, Mernin, Davis, Aoki patents,
Donovan, Voet patents, Tse, and Lamanna 1988 references, we are not
persuaded that one of ordinary skill in the art would have been dissuaded
from substituting the neurotoxic component of botulinum toxin for the
larger, more immunogenic haemagglutinin-complexed form of the toxin in
the prior art methods of treating neuromuscular disorders.
The Court of Customs and Patent Appeals has concluded that "[when
an] advantage is not disclosed in appellant's application" he is "not in a
favorable position to urge it as a basis for the allowance of claims." In re
Herr, 304 F.2d 906, 909 (1962) (internal citation and quotations omitted).
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The Herr reasoning, though addressing unexpected results and not
obviousness per se, is apt here, where the Specification has a single, limited
disclosure relating to the existence of a neurotoxic component of botulinum
toxin (FF 16), but provides no disclosure whatsoever on methods of
purifying the neurotoxic component, methods of stably storing a purified
neurotoxic component, or any clinical method for using the purified
neurotoxic component. In sum, the Specification provides no guidance on
how to make or use "a therapeutically effective amount of a single or dichain
form of the neurotoxic component" as required by claim 142, relying fully
upon the prior art to enable and disclose this teaching.
Thus, to the extent that Appellants rely upon the purified neurotoxic
component as a distinguishing limitation, their own Specification is solely
enabled for patient administration of a purified neurotoxic component by the
prior art or general knowledge in the field, not by any teachings disclosed by
Appellants.
Appellants contend that "DasGupta specifically corroborates
Appellant[s'] position that Schantz would have discouraged one of ordinary
42 We note, but do not rely upon, the absence of any requirement in claim 1
for purification of the neurotoxic component. This would have provided the
Examiner a reasonable basis to interpret claim 1 broadly to encompass
botulinum toxin including both the neurotoxic component and
haemagglutinin component, consistent with the Specification's reliance
solely on commercially available botulinum toxin that includes both
components and the absence of any disclosure in the Specification teaching
purifying the neurotoxic component. Under this claim interpretation, which
we do not rely upon, the primary references would have anticipated claim 1
(see Spec. 8, 11. 22-25).
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skill from clinical use of the neurotoxic component" citing DasGupta' s
teaching that "this prevailing view needs rectification" (Reply Br. 5, citing
DasGupta 31 (emphasis Appellants')). Appellants contend that
[i]f a person having ordinary skill in the art as of December
1993 already knew that Dr. Schantz's statements were incorrect
as the Examiner repeatedly insists is the case, then the statements
within the DasGupta reference are nonsensical as there would
have been no prevailing view needing rectification as of 1994.
(Reply Br. 5.)
We do not find this argument persuasive because DasGupta is not
relying upon newly disclosed, post-filing-date evidence from 1994, but
rather expressly relies upon prior art references to establish the functionality
of the purified neurotoxin, specifically stating that
Williams et al. (81) have found that the homogeneous
preparation of type A NT, stored at 4°C in 0.15 M TRIS-HCl
buffer, pH 7.9, is stable for several months. The pure
preparations of NT types A and E at very low concentrations
(such as 1x10-10 Mand lower) in physiological buffers, with and
without added gelatin or serum albumin, are highly active
(25,48,59,73,86).
(DasGupta 32.) As already noted, Williams was published in 1983 (FF 24).
The other references cited by DasGupta were published from 1966 to 1990
(FF 25; cf Ans. 53) and reasonably establish that DasGupta was relying on
knowledge in prior art regarding storage and use of the purified neurotoxin,
not post-filing date information.
CONCLUSION OF LAW
The Examiner has established that treating a pain associated with a
muscle activity or contracture by administering the neurotoxic component of
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a botulinum toxin, rather than a complexed form of the botulinum toxin,
would have been obvious over the evidence of record.
XXV- PROVISIONAL OBVIOUSNESS-TYPE DOUBLE PA TENTING
We agree with Appellants that the "Examiner has mistakenly cited the
instant application (11/740,809) as a copending application in this
nonstatutory obviousness-type double patenting rejection" (App. Br. 32).
We therefore reverse this rejection.
SUMMARY
In summary, we affirm the obviousness rejection and obviousness-
type double patenting rejections.
We reverse the provisional obviousness-type double patenting
rejection over U.S. Application 11/740,809.
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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