UNIVERSITY OF MANITOBA et al.

Patent Trials and Appeals Board

Jan 21, 2021

2020002857 (P.T.A.B. Jan. 21, 2021)

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
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
15/106,778 06/20/2016 Paul FERNYHOUGH WIN.006NP 1081
20995 7590 01/21/2021
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE, CA 92614
EXAMINER
HAVLIN, ROBERT H
ART UNIT PAPER NUMBER
1639
NOTIFICATION DATE DELIVERY MODE
01/21/2021 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):
efiling@knobbe.com
jayna.cartee@knobbe.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte PAUL FERNYHOUGH and NIGEL A. CALCUTT
__________

Appeal 2020-002857
Application 15/106,778
Technology Center 1600
__________

Before FRANCISCO C. PRATS, TAWEN CHANG, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL

Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 11–33. Appellant presented oral
argument on January 7, 2021. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant states that the “real parties in interest are The
Regents of the University of California, and the University of Manitoba,
both of which are assignees of record. An additional real party in interest is
WinSanTor, Inc., the exclusive licensee of the patent application.” Appeal
Br. 2.
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STATEMENT OF THE CASE
“Peripheral neuropathy is a clinical problem in persons affected with
diabetes or treated with chemotherapeutic agents. Peripheral neuropathies
can be also caused by infections such as HIV and leprosy.” Spec. 1.
“Chemotherapy-induced peripheral neuropathy (CIPN) often occurs
during treatment of various cancers and other disorders with a variety of
agents . . . [and] can limit dose and duration of treatment, thereby reducing
efficacy of the chemotherapeutic regime.” Spec. 2.
“Up to 40% of cancer patients treated with chemotherapy describe
some form of CIPN” with symptoms varying “from tingling and numbness
indicative of sensory loss to aspects of painful neuropathy such as allodynia
and spontaneous shooting pains that usually start in the hands and feet
before moving proximally.” Spec. 2
Appellant’s claim 11 is representative of the subject matter on appeal,
and reads as follows:
11. A method of treating a non-diabetic peripheral
neuropathy disorder in a subject in need thereof, the method
comprising administering at least one dosage of a composition
comprising an effective amount of a muscarinic acetylcholine
receptor M1 antagonist to treat non-diabetic peripheral
neuropathy in the subject.
Appeal Br. 9.
The sole rejection before us for review is the Examiner’s rejection of
claims 11–33, under 35 U.S.C. § 103, as being unpatentable over
Fernyhough.2 Ans. 3–5.

2 WO 2012/055018 A1 (published May 3, 2012).
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DISCUSSION
The Examiner’s Prima Facie Case
The Examiner found that Fernyhough describes methods of treating
diabetic peripheral neuropathy by administering to patients a muscarinic
acetylcholine receptor M1 antagonist, such as pirenzepine. Ans. 3–4.
The Examiner found that Fernyhough’s treatment methods differ from
the methods of Appellant’s claims only in that “Fernyhough does not
specifically teach the treatment of ‘non-diabetic’ peripheral neuropathy as in
the instant claims.” Ans. 4.
The Examiner reasoned, however, that a skilled artisan would have
known “from the teaching of Fernyhough that the mechanism of action of
MIR antagonists, including pirenzepine, accelerate axonal outgrowth in
peripheral neurons and would therefore be useful in treating peripheral
neuropathy generally.” Ans. 4–5.
The Examiner found that the usefulness of muscarinic acetylcholine
receptor M1 antagonists for treating non-diabetic peripheral neuropathy, as
recited in Appellant’s claims, “is further supported by Fernyhough’s
experiments in ‘neurites from excised neurons from a normal rat’ where the
administration of pirenzepine tripled the neurite outgrowth rate (page 33,
Example 2) and a number of mouse models of neuropathy including
prophylactic and reversal effects from administering pirenzepine (Example
7, 9-18).” Ans. 5.
The Examiner reasoned that the results disclosed in Fernyhough’s
examples would have suggested to a skilled artisan that “antagonists such as
pirenzepine would have utility in treating peripheral neuropathy even in non-
diabetic cases” and that a skilled artisan “would have [had] a reasonable
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expectation of success because of the successful demonstration of increased
neurite growth which is related to the underlying condition of peripheral
neuropathy, even with non-diabetic causes.” Ans. 5.
The Examiner found that skilled artisans would have considered it
“routine and well within their technical grasp the process of utilizing a
therapeutic agent shown to have positive effects in a related experimental
demonstration.” Ans. 5. In addition, the Examiner found, “those of ordinary
skill in the art routinely screen agents for therapeutic use in treating a
condition shown to share a pathway related to the condition.” Id.
Accordingly, the Examiner concluded, a skilled artisan would have
considered it obvious “to apply the teachings of Fernyhough and administer
pirenzepine to subjects with peripheral neuropathies including nondiabetic”
neuropathies as recited in Appellant’s claims. Ans. 5.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
In the present case, Appellant does not persuade us that the
preponderance of the evidence fails to support the Examiner’s conclusion
that the therapeutic treatment method recited in Appellant’s representative
claim 11 would have been obvious in view of Fernyhough.
We acknowledge, as Appellant argues (Appeal Br. 6), that
Fernyhough’s central focus is using muscarinic acetylcholine receptor M1
antagonists to treat diabetic neuropathy, rather than non-diabetic neuropathy,
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as recited in Appellant’s representative claim 11. See Fernyhough, abstract
(disclosing “[c]ompositions for therapy of a diabetic symmetrical
polyneuropathy a subject in need thereof, the compositions comprising: an
effective amount of a muscarinic acetylcholine receptor antagonist
exemplified by pirenzepine, telenzepine, atropine, or derivatives thereof”).
Fernyhough explains that, among other properties, the capacity of M1
receptor antagonists to stimulate neurite outgrowth in cultured nerve cells
from diabetic rats in vitro is indicative of the compounds’ efficacy against
diabetic neuropathy:
We have surprisingly found that culturing excised adult
and juvenile neurons from diabetic rats, in culture media
comprising pirenzepine stimulates neurite outgrowth from the
excised neurons. Additionally, we found that all of topical
applications, subcutaneous injections, injections of pirenzepine
to and into various skin targets in diabetic mice: (i) prevented
deficits in motor nerve conduction velocity, (ii) prevented and
reversed loss of intraepidermal nerve fibers, (iii) prevented loss
of sub-epidermal nerve plexi, (iv) prevented tactile allodynia,
and (v) prevented and reversed the development of thermal
hypoalgesia. Furthermore, we have found that oral delivery of
pirenzepine reversed sensory neuropathy.
Fernyhough 10 (emphasis added).
The fact that Fernyhough might not expressly describe treating non-
diabetic peripheral neuropathy does not demonstrate Examiner error because
the rejection at issue in this appeal is for obviousness, not anticipation. As
the Supreme Court has explained, the obviousness analysis “need not seek
out precise teachings directed to the specific subject matter of the challenged
claim, for a court can take account of the inferences and creative steps that a
person of ordinary skill in the art would employ.” KSR Int’l Co. v. Teleflex
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Inc., 550 U.S. 398, 418 (2007); see also id. at 421 (“A person of ordinary
skill is . . . a person of ordinary creativity, not an automaton.”).
In the present case, as the Examiner found, despite its central focus on
treating diabetic neuropathy, Fernyhough teaches that at least three M1
receptor antagonist compounds stimulate neurite outgrowth in cells from a
normal rat, i.e., in a “non-diabetic model”:
[T]he lowest pirenzepine dosage of 0.01 µM more than tripled
neurite outgrowth from the excised neurons from a non-diabetic
model, and . . . increasing pirenzepine dosages of 0.1, 1.0, and
10.0 µM did not further increase neurite outgrowth rates. . . .
[T]he lowest telenzepine dosage of 0.01 mM more than
doubled neurite outgrowth from the excised neurons from a
non-diabetic model, and . . . the 0.1 µM and the 10.0 µM
dosages tripled the neurite outgrowth rates. . . . [T]he lowest
atropine dosage of 0.01 µM more than tripled neurite
outgrowth from the excised neurons from a non-diabetic model,
and that the 0.1 µM and the 10.0 µM dosages did not further
increase neurite outgrowth rates.
Fernyhough 35 (Example 2; emphasis added).
Given Fernyhough’s teaching that stimulating neurite outgrowth in
cultured nerve cells is predictive of a compound’s efficacy against diabetic
peripheral neuropathy (Fernyhough 10), and further given Fernyhough’s
teaching that three M1 receptor antagonists had significant neurite outgrowth
stimulating activity in cultured nerve cells expressly described as “a non-
diabetic model” (id. at 35), we agree with the Examiner that a skilled artisan
had a good reason for, and a reasonable expectation of success in,
administering an M1 receptor antagonist to treat non-diabetic neuropathy.
We therefore also agree with the Examiner that the process recited in
Appellant’s representative claim 11 would have been prima facie obvious to
a skilled artisan.
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Appellant contends that, despite Fernyhough’s teaching that M1
receptor antagonist compounds significantly stimulate neurite outgrowth in
an in vitro non-diabetic model, it was not predictable that the compounds
would be active in an in vivo treatment, because “it was known that other
compounds which increase neurite outgrowth and treat diabetic peripheral
neuropathy did not work for treating non-diabetic peripheral neuropathies.”
Appeal Br. 5 (citing Saleh,3 Calcutt,4 Mizisin5); see also id. at 7 (“[S]uch in
vitro data cannot render the subject matter obvious under § 103 because a
person having skill in the art would not expect, with a reasonable likelihood
of success, that the compounds disclosed by Fernyhough for treating diabetic
peripheral neuropathy would be useful for treating non-diabetic peripheral
neuropathy.”). We are not persuaded.
We acknowledge, as Appellant contends, that Saleh discloses that
ciliary neurotrophic factor (CNTF) stimulates neurite outgrowth in vitro in
cells from normal rats as well as diabetic rats. Saleh 67 (“CNTF
significantly elevated neurite outgrowth in a dose-dependent manner. . . .
CNTF significantly enhanced neurite outgrowth in cultures from control and

3 Ali Saleh et al., Ciliary neurotrophic factor activates NF-κB to enhance
mitochondrial bioenergetics and prevent neuropathy in sensory neurons of
streptozotocin-induced diabetic rodents, 65 NEUROPHARMACOLOGY 65–73
(2013).
4 N. A. Calcutt et al., Prevention of sensory disorders in diabetic Sprague-
Dawley rats by aldose reductase inhibition or treatment with ciliary
neurotrophic factor, 47 DIABETOLOGIA 718–724 (2004).
5 Andrew P. Mizisin et al., Ciliary Neurotrophic Factor Improves Nerve
Conduction and Ameliorates Regeneration Deficits in Diabetic Rats, 53
DIABETES 1807–1812 (2004).
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diabetic rats, although levels of growth in control cultures were significantly
higher under all conditions (Fig, 1D).”).
We also acknowledge, as Appellant contends, that Calcutt discloses
that CNTF is active in vivo against peripheral neuropathy in diabetic rats.
Calcutt 718 (“Thermal hypoalgesia was present after 8 weeks of diabetes
and was prevented by insulin treatment, which maintained normoglycaemia,
by the aldose reductase inhibitor Statil or by ciliary neurotrophic factor.
Brain-derived neurotrophic factor did not have an effect.”) (emphasis
added).
We further acknowledge, as Appellant contends, that despite CNTF’s
in vitro neurite outgrowth stimulating activity in cultured nerve cells from
both diabetic and non-diabetic rats (Saleh), and despite CNTF’s activity in
vivo in diabetic rats shown in Calcutta, Mizisin discloses that CNTF is not
active in vivo in rats with non-diabetic neuropathy:
Four weeks of CNTF treatment significantly improved nerve
conduction compared with untreated diabetic rats and also
normalized the recovery of toe s1mead after sciatic nerve crush.
One week of CNTF treatment significantly improved the
distance of sensory nerve regeneration achieved after nerve
crush injury compared with untreated diabetic rats. CNTF was
without effects on any parameter in nondiabetic rats.
Mizisin 1807 (emphasis added).
It is well settled, however, that “[o]bviousness does not require
absolute predictability of success. . . . For obviousness under § 103, all that
is required is a reasonable expectation of success.” In re Kubin, 561 F.3d
1351, 1360 (Fed. Cir. 2009) (quoting In re O’Farrell, 853 F.2d 894, 903–04
(Fed. Cir. 1988) (emphasis removed).
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In the present case, as noted above, Fernyhough teaches that
stimulating neurite outgrowth in cultured nerve cells is predictive of a
compound’s efficacy against diabetic peripheral neuropathy (Fernyhough
10), and Fernyhough also teaches that three M1 receptor antagonists had
significant neurite outgrowth stimulating activity in cultured nerve cells
expressly described as “a non-diabetic model” (id. at 35). The fact that one
compound, ciliary neurotrophic factor (CNTF), lacked in vivo activity
despite having in vitro neurite outgrowth stimulating activity shows, at best,
that it was not absolutely predictable based on Fernyhough’s teachings
whether M1 receptor antagonists would be effective in an in vivo treatment.
As discussed above, however, bsolute predictability is not required to show
obviousness. See Kubin, 561 F.3d at 1360.
Moreover, that one compound was known to lack in vivo activity
despite having in vitro neurite outgrowth stimulating activity does not
persuade us that the general state of the art was such that, despite
Fernyhough’s disclosure of in vitro neurite outgrowth stimulating activity in
cultured nerve cells expressly described as a non-diabetic model, a skilled
artisan nonetheless lacked a reasonable expectation of success in treating
non-diabetic neuropathy. Indeed, Appellant identifies no teaching of record
suggesting that CNTF is either an M1 receptor antagonist, or has any other
similarities with the active compounds in Fernyhough, that might suggest
that CNTF’s lack of in vivo activity would be predictive of whether
Fernyhough’s M1 receptor antagonists would be an ineffective non-diabetic
peripheral neuropathy treatment.
In addition, Mizisin suggests that CNTF was active in diabetic rats,
but not non-diabetic rats, because diabetes involves a CNTF deficiency. See
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Mizisin 1810 (“A diabetes-induced CNTF expression deficit coupled with
possible age-dependent expression differences in nondiabetic rats may
explain why CNTF was effective only in the diabetic and not the mature,
treated-control rats studied here.”) (citation omitted); id. at 1810–1811 (“The
lack of an effect of CNTF in treated nondiabetic animals suggests that there
is sufficient CNTF available to promote recovery in adult normal rats and
that this cannot be enhanced further, at least with the dose and treatment
regimen used here.”).
Mizisin thus teaches that CNTF’s lack of in vivo activity against non-
diabetic rats as compared to diabetic rats was likely because CNTF corrected
a deficiency in the diabetic rats, whereas no such deficiency was present in
the non-diabetic rats. We are not persuaded, therefore, that the lack of in
vivo activity of CNTF in non-diabetic rats described in Mizisin is sufficient
to show a lack of a reasonable expectation of success in using other
compounds, such as the M1 receptor antagonists described in Fernyhough,
to treat non-diabetic peripheral neuropathy, when those compounds were
shown to have significant neurite outgrowth stimulating activity in cultured
nerve cells expressly described as “a non-diabetic model.” Fernyhough 35.
Appellant contends that the unpredictability in the art is further shown
by the fact that, although CNTF and brain-derived neurotrophic factor
(BDNF) had the “same effect on neurite outgrowth of DRG [dorsal root
ganglia] sensory neurons, they did not have the same effect in diabetic
neuropathy induced in rats. Calcutt, et al. discovered that only CNTF but
not BDNF prevented diabetic sensory neuropathy in type 1 diabetic rats
(Fig. 1) (Calcutt, et al.).” Appeal Br. 6; see also Lindsay 2394 (“[B]oth
NGF [nerve growth factor] and brain-derived neurotrophic factor (BDNF)
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were found to stimulate the regeneration of axons from adult DRG
neurons.”); Calcutt 718 (“Thermal hypoalgesia [in diabetic rats] was present
after 8 weeks of diabetes and was prevented by . . . ciliary neurotrophic
factor. Brain-derived neurotrophic factor did not have an effect.”).
We are not persuaded. As noted above, “[o]bviousness does not
require absolute predictability of success. . . . [A]ll that is required is a
reasonable expectation of success.” In re Kubin, 561 F.3d at 1360.
In the present case, at least one compound known to have in vitro
neurite outgrowth stimulating activity in cultured nerve cells (CNTF) also
had in vivo activity against diabetic peripheral neuropathy in rats. See
Calcutt 718. The in vivo activity of CNTF against diabetic neuropathy
supports the Examiner’s finding (and Fernyhough’s teaching) that in vitro
neurite outgrowth stimulating activity is reasonably predictive of in vivo
activity.
The fact that another compound (BDNF) having in vitro neurite
outgrowth stimulating activity in cultured nerve cells did not have in vivo
activity against diabetic peripheral neuropathy in rats shows, at best, that in
vitro neurite outgrowth stimulating activity is not absolutely predictive of in
vivo efficacy. Again, however, absolute predictability is not required to
show obviousness. Kubin, 561 F.3d at 1360.
We note, moreover, that Appellant’s representative claim 11 is
directed to treating non-diabetic peripheral neuropathy, rather than the
diabetic neuropathy treated in Calcutt. We are not persuaded that Appellant
has explained sufficiently why a skilled artisan would have considered
Calcutt’s teachings regarding a disorder expressly excluded from claim 11 to
be predictive of whether Fernyhough provided a reasonable expectation of
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success in performing the process recited in claim 11. Indeed, Appellant’s
argument, that a skilled artisan would have correlated the efficacy (or lack
thereof) of diabetic neuropathy treatments taught in Calcutt with the efficacy
of non-diabetic neuropathy treatments, is not consistent with Appellant’s
argument above, that a skilled artisan would not have correlated
Fernyhough’s teachings regarding the efficacy of M1 receptor antagonists
against diabetic neuropathy with the efficacy of non-diabetic neuropathy
treatments.
Lastly, we are not persuaded that, by disagreeing with Appellant about
the significance of the cited teachings in Saleh, Calcutt, Mizisin, and
Lindsay in relation to the obviousness of claim 11 over Fernyhough, the
Examiner relied on improper hindsight in concluding that the process recited
in claim 11 would have been obvious to a skilled artisan. See Appeal Br. 7
(citing In re Piasecki, 745 F.2d 1468, 1474 (Fed. Cir. 1984)).
As noted above, in concluding that the process recited in Appellant’s
representative claim 11 would have been obvious, and in answering
Appellant’s arguments in relation to Saleh, Calcutt, Mizisin, and Lindsay,
the Examiner relied on Fernyhough’s teachings that stimulating neurite
outgrowth in cultured nerve cells is predictive of a compound’s efficacy
against diabetic peripheral neuropathy, as well as Fernyhough’s teachings
that three M1 receptor antagonists had significant neurite outgrowth
stimulating activity in cultured nerve cells expressly described as a non-
diabetic model. See Ans. 3–7. Because the Examiner’s conclusion of
obviousness relied only on teachings available to a skilled artisan at the time
of Appellant’s invention, we are not persuaded that the Examiner used
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improper hindsight in concluding that claim 11’s process would have been
obvious:
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level
of ordinary skill at the time the claimed invention was made
and does not include knowledge gleaned only from applicant’s
disclosure, such a reconstruction is proper.
In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
In sum, for the reasons discussed, Appellant does not persuade us that
the preponderance of the evidence fails to support the Examiner’s
conclusion that the therapeutic treatment method recited in Appellant’s
representative claim 11 would have been obvious in view of Fernyhough.
We therefore affirm the Examiner’s rejection of claim 11 over Fernyhough.
The remaining claims were not argued separately and therefore fall with
claim 11. 37 C.F.R. § 41.37(c)(1)(iv).

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
11–33 103 Fernyhough 11–33

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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). See 37 C.F.R.
§ 1.136(a)(1)(iv).

AFFIRMED