Ex Parte He et al

Board of Patent Appeals and Interferences

Aug 4, 2011

11295647 (B.P.A.I. Aug. 4, 2011)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte ZHIGANG HE, JING WANG,
YING CHEN, and SHIJNIRO KANEKO
__________

Appeal 2011-000187
Application 11/295,647
Technology Center 1600
__________

Before DEMETRA J. MILLS, MELANIE L. McCOLLUM, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

McCOLLUM, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to reducing
neural degeneration. The Examiner has rejected the claims for
indefiniteness and obviousness. We have jurisdiction under 35 U.S.C.
§ 6(b). We affirm.
STATEMENT OF THE CASE
Claims 7-16 are on appeal (App. Br. 1). The claims subject to each
rejection have not been argued separately and therefore stand or fall
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together. 37 C.F.R. § 41.37(c)(1)(vii). Claim 7 is representative and reads
as follows:
7. A method for reducing neural degeneration in a patient determined
to be suffering from chronic neurodegeneration, the method comprising the
step of:
administering to the patient an effective amount of 3-pyridine-
carboxamide (nicotinamide), wherein the effective amount is 2 to 20 g/day
administered orally for at least 6 months.
Claims 7-16 stand rejected under 35 U.S.C. § 112, second paragraph,
as incomplete for omitting essential steps (Ans. 4).
Claims 7-12 stand rejected under 35 U.S.C. § 103(a) as obvious over
Szabo
1
and/or Merril
2
in view of Schulz
3
and Mokudai
4
(Ans. 5-6).
Claims 7 and 12-16 stand rejected under 35 U.S.C. § 103(a) as
obvious over Szabo and/or Merril in view of Schulz, Mokudai, and Beal
5

(Ans. 9-10).
Claims 7-16 stand provisionally rejected on the grounds of
obviousness-type double patenting (Ans. 12).

1
Szabo et al., US 6,531,464 B1, Mar. 11, 2003.
2
Merril et al., WO 02/076437 A2, Oct. 3, 2002.
3
Schulz et al., Coenzyme Q10 and Nicotinamide and a Free Radical Spin
Trap Protect against MPTP Neurotoxicity, 132 EXPERIMENTAL NEUROLOGY
279-283 (1995).
4
Mokudai et al., Delayed Treatment with Nicotinamide (Vitamin B3)
Improves Neurological Outcome and Reduces Infarct Volume after
Transient Focal Cerebral Ischemia in Wistar Rats, 31 STROKE 1679-1685
(2000).
5
Beal, Neurochemistry and toxin models in Huntington’s disease, 7
CURRENT OPINION IN NEUROLOGY 542-547 (1994).
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INDEFINITENESS
The Examiner finds that claims 7-16 are “incomplete for omitting
essential steps, such omission amounting to a gap between the steps”
(Ans. 4). In particular, the Examiner finds that the omitted steps are those
used to determine if a patient is “suffering from chronic neurodegeneration”
(id.).
Issue
Does the evidence support the Examiner‟s conclusion that the claims
are incomplete for omitting the step of determining if a patient is suffering
from chronic neurodegeneration?
Analysis
Appellants argue that “[t]he target patient is one that has been
determined to be suffering from chronic neurodegeneration - this is a
limitation on the target patient, and is not a missing step” (App. Br. 3). We
agree and therefore reverse the rejection.
Conclusion
The evidence does not support the Examiner‟s conclusion that the
claims are incomplete for omitting the step of determining if a patient is
suffering from chronic neurodegeneration. We therefore reverse the
rejection of claims 7-16 under 35 U.S.C. §112, second paragraph.
OBVIOUSNESS
The Examiner relies on Szabo for teaching “a method of treating
neurodegenerative disorders, such as multiple sclerosis, Huntington‟s
disease and amyotrophic lateral sclerosis (ALS) with administration [of]
nicotinamide” (Ans. 6). The Examiner further cites Szabo for teaching
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“dosages in the range of 0.05 to about 1000 mg/day orally” (id.). The
Examiner relies on Merril for teaching “a method for treating a chronic
neurodegenerative disease (i.e. Alzheimer‟s disease) in a mammal (i.e.
human) by administering nicotinamide” (id.).
The Examiner relies on Schulz for teaching “the administration of
nicotinamide and Coenzyme Q10 separately and in combination for the
treatment of neurodegenerative disease such as Parkinson‟s disease” (id.).
The Examiner also points to Schulz for teaching that “significant
neuroprotective effects were obtained with treatment with nicotinamide
alone” (id. at 7). The Examiner further finds that “Schulz teaches the
administration of nicotinamide in the dosage of 200 mg/kg (in presuming
that the average subject weighs 70 kg; the dosage of nicotinamide is 1.4
grams)” (id.).
The Examiner relies on Mokudai for teaching that “nicotinamide is
already used in large doses and has few side effects” and that it “is a robust
neuroprotective agent against ischemia/reperfusion-induce[d] brain injury in
rats” (id.). In particular, the Examiner finds that Mokudai teaches
“administration of 500 mg/kg of nicotinamide” (id.).
The Examiner concludes that “[i]t would have been obvious to one of
ordinary skill[] in the art to optimize the dosage of nicotinamide
administered to a patient with neurodegenerative disease” (id.). With regard
to the treatment duration, the Examiner finds that “it would be obvious to
one of ordinary skill[] in the art that in the treatment of a chronic disease; the
administration of nicotinamide would be longer because of the treatment of a
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chronic disease would require longer treatment than that of an acute episodic
event” (id. at 9).
In rejecting claims 7 and 12-16, the Examiner also relies on Beal for
teaching “that administering nicotinamide exert[s] neuroprotective effects in
neurodegenerative diseases” (id. at 10). The Examiner also points out that
Beal teaches “obtaining magnetic resonance imaging (MRI) before and after
the treatment, in which the MRI demonstrated significant reduction in the
increased cortical lactate concentrations” (id.). The Examiner concludes that
“the treatment of a chronic neurodegenerative disease such as Multiple
sclerosis or amyotrophic later[al] sclerosis would decrease . . . the neural
degeneration as taught by Beal” (id.).
Issue
With regard to both obviousness rejections, the issue is: Does the
evidence support the Examiner‟s conclusion that it would have been obvious
to administer nicotinamide to a patient suffering from chronic
neurodegeneration in an amount of 2 to 20 g/day for at least 6 months?
Findings of Fact
1. Szabo teaches
a method of treating symptoms associated with a
neurodegenerative disorder in a subject. The method includes
administering to the subject PARS inhibitor in an amount to
alleviate symptoms of the neurodegenerative disorder in the
subject. The neurodegenerative disorder can be, e.g., multiple
sclerosis (“MS”), AIDS-related neurodegeneration and
Alzheimer‟s disease, infectious meningitis, encephalomyelitis,
Parkinson‟s disease, Huntington‟s disease, amyotrophic lateral
sclerosis and encephalitis.
(Szabo, col. 10, ll. 46-55.)
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2. Szabo also teaches: “The PARS inhibitor used to treat, or
prevent the development of symptoms associated with a neurodegenerative
disorder can be, e.g., a PARS inhibitor according to Formula I, as described
above. Alternatively, or in addition, the inhibitor can be, e.g., benzamide,
3-aminobenzamide, nicotinamide, 4-aminobenzamide, and 1,5, dihydroxy-
isoquinoline.” (Id. at col. 11, ll. 56-63.)
3. In addition, Szabo teaches that “[o]ral dosages of the present
invention, when used for the indicated effects, will range between about 0.05
to 1000 mg/day orally” (id. at col. 14, ll. 18-21).
4. Merril teaches “methods of preventing neural tissue damage
caused by ADP-ribosylation of eucaryotic elongation factor-2 (EF-2)” and
that these “methods are especially useful in the treatment of
neurodegenerative diseases, such as Alzheimer‟s disease, Parkinson‟s
disease, and other cognitive disorders” (Merril 1: 5-9).
5. In particular, Merril teaches that its treatment method
“comprises administering an agent that will interfere (i.e. block or reverse)
with ADP-ribosylation of EF-2 in a mammal suffering from a
neurodegenerative disease” and that “[s]uch agents include reversible and
irreversible inhibitors of ADP-ribosylating toxins, including nicotinamide
(or its precursor, nicotinic acid) and its analogues” (id. at 6: 12-17).
6. Schulz teaches that MPTP “is a neurotoxin which produces
clinical, biochemical, and neuropathologic changes in both human and
nonhuman primates, which are analogous to those observed in idiopathic
Parkinson‟s disease (PD)” (Schulz 279).
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7. Schulz also teaches that “agents which improve mitochondrial
energy production (coenzyme Q10 and nicotinamide) and free radical
scavengers can attenuate mild to moderate MPTP neurotoxicity” (id.). In
particular, Schulz teaches that “both coenzyme Q10 and nicotinamide can
protect against neurotoxicity and ATP depletions produced by the
mitochondrial toxin malonate in vivo” (id.).
8. In addition, Schulz teaches giving mice a dose of 200 mg/kg
nicotinamide (id. at 280).
9. Schulz also teaches that the “present results have implications
for the treatment of neurodegenerative diseases, in particular, PD,” and that
“treatment with both coenzyme Q10 in combination with nicotinamide . . .
showed neuroprotective effects,” providing “further evidence that MPTP
may produce neurotoxic effects by a mechanism involving energy depletion
and free radical generation,” which “suggest[s] that therapeutic strategies to
improve mitochondrial energy metabolism or to scavenge free radicals might
prove useful in PD” (id. at 282).
10. Mokudai teaches that nicotinamide “is a robust neuroprotective
agent against ischemia/reperfusion-induced brain injury in rats” (Mokudai
1679).
11. In particular, Mokudai teaches treating rats with 500 mg/kg of
nicotinamide and that nicotinamide “in large doses (ie, up to 6 g) in normal
humans is reported to have very mild side effects” (id. 1679 & 1683).
Principles of Law
“[W]here the general conditions of a claim are disclosed in the prior
art, it is not inventive to discover the optimum or workable ranges by routine
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experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955). “[R]anges
which overlap or lie inside ranges disclosed by the prior art may be
patentable if the applicant can show criticality in the claimed range by
evidence of unexpected results.” In re Wertheim, 541 F.2d 257, 267 (CCPA
1976). However, “it is well settled that unexpected results must be
established by factual evidence. „Mere argument or conclusory statements
in the specification does not suffice.‟” In re Geisler, 116 F.3d 1465, 1470
(Fed. Cir. 1997) (citing In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir.
1994)).
Analysis
Merril discloses treating a neurodegenerative disease, such as
Alzheimer‟s disease and Parkinson‟s disease, by administering “inhibitors of
ADP-ribosylating toxins, including nicotinamide” (Findings of Fact (FF) 4-
5). Similarly, Szabo teaches “a method of treating symptoms associated
with a neurodegenerative disorder,” including Alzheimer‟s disease and
Parkinson‟s disease, comprising administering a PARS inhibitor, such as
nicotinamide (FF 1-2). Szabo also teaches that dosages “will range between
about 0.05 to 1000 mg/day orally” (FF 3).
Schulz teaches that nicotinamide “can attenuate mild to moderate
MPTP neurotoxicity” and that the “present results have implications for the
treatment of neurodegenerative diseases, in particular, PD” (FF 7 & 9). In
Schulz‟s experiments, mice were administered 200 mg/kg nicotinamide
(FF 8). Presuming an average subject weighs 70 kg, the Examiner finds that
this amount would result in a dosage of 1.4 grams (Ans. 7). However, it is
clear that, in actuality, 200 mg/kg would result in a dosage of 14 grams for a
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70 kg subject
6
. Mokudai teaches using nicotinamide in dosages of 500
mg/kg and that nicotinamide “in large doses (ie, up to 6 g) in normal humans
is reported to have very mild side effects” (FF 11).
Applying the KSR standard of obviousness to the findings of fact, we
agree with the Examiner that it would have been obvious to administer large
nicotinamide doses of from 2 to 20 g/day, as suggested by Schulz and
Mokudai, to a patient suffering from chronic neurodegeneration. Such a
combination is merely a “predictable use of prior art elements according to
their established functions.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
417 (2007). In addition, given the chronic nature of the neurodegeneration,
we agree with the Examiner that it would have been obvious to continue the
treatment for at least 6 months (Ans. 9).
Appellants argue, however, that Szabo does not teach “treating
neurodegenerative diseases with nicotinamide at dosages of 0.05 to
1000[m]g/day” (App. Br. 4). We are not persuaded. Although Szabo does
not specifically state that nicotinamide should be used in this amount, Szabo
does generally disclose that oral dosages of their invention, which includes
the use of nicotinamide in the treatment or prevention of symptoms
associated with a neurodegenerative disorder, “will range between about
0.05 to 1000 mg/day” (FF 2-3). We agree with the Examiner that these
teachings suggest the administration of 1000 mg, that is, 1 g, per day of
nicotinamide.

6
We take judicial notice of the fact that a 200 mg/kg dosage multiplied by a
70 kg patient would result in 14 grams (0.2 g/kg x 70 kg = 14) and that the
Examiner‟s calculation was mathematically incorrect.
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Appellants also argue that “there is no rational basis for extrapolating
from a dosage used to reduce dopamine depletion caused by acute poisoning
of a mouse [in Schulz] to treating intractable neurodegenerative disease in
people” (App. Br. 5-6). Appellants make the same argument with respect to
Mokudai: there is “no rational basis for anthropomorphizing this data, and
extrapolating from rat to human” (id. at 6). We find these arguments
unconvincing.
Schulz and Mokudai are merely relied on to demonstrate that it would
have been obvious to use amounts higher than the 1 g/day disclosed in
Szabo. We recognize that Schulz does not specifically disclose human
dosages. However, Schulz does relate to a neurodegenerative disease,
specifically Parkinson‟s disease (FF 6-9). Thus, in the absence of evidence
to the contrary, we conclude that the Examiner was reasonable in
extrapolating the amount per kilogram disclosed in Schulz to determine
amounts that would be appropriate for humans with a neurodegenerative
disease. Moreover, Mokudai discloses that nicotinamide “in large doses (ie,
up to 6 g) in normal humans is reported to have very mild side effects”
(FF 11), providing further evidence that it would have been obvious to use
nicotinamide in amounts of from 2 to 20 g.
In addition, Appellants argue that their claims are “narrowly” drawn
to “unexpectedly-required large dosages and long treatments” using
nicotinamide (App. Br. 6). In support of this position, Appellants rely on a
Declaration by Zhigang He,
7
one of the present inventors, as well as
evidence discussed therein. However, Appellants have not provided

7
Declaration of Zhigang He, submitted August 4, 2009.
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sufficient factual evidence indicating that the claimed amount for the
claimed duration provides an unexpectedly superior result as compared to
the closest prior art.
Nor do we agree that this Declaration provides sufficient evidence of
copying or long felt need. In particular, Appellants‟ Declaration states that
“[o]ur disclosed treatment of degenerative diseases with extraordinarily
large (multigram/day) nicotinamide dosages over extraordinarily long (at
least 6 month[s]) was . . . quickly adopted in an ongoing human clinical
trial” (He Dec. ¶ 9). However, given the relevance of the applied prior art,
there is insufficient evidence indicating that this clinical trial copied
Appellants‟ work. In addition, given that the clinical trial was ongoing at the
time of the Declaration, the evidence clearly does not indicate whether it
meets a long felt need. Thus, we are not convinced by Appellants‟ evidence.
Conclusion
The evidence supports the Examiner‟s conclusion that it would have
been obvious to administer nicotinamide to a patient suffering from chronic
neurodegeneration in an amount of 2 to 20 g/day for at least 6 months. We
therefore affirm the obviousness rejections of claim 7. Claims 8-16 fall with
claim 7.
DOUBLE PATENTING
With regard to the provisional obviousness-type double patenting
rejection, Appellants “acknowledge” the rejection and indicate that they
“will file terminal disclaimer(s) upon an indication of allowability of the
related claims” (App. Br. 12). In view of Appellants failure to traverse the
rejection, we summarily affirm it.
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SUMMARY
We affirm the obviousness rejections and the provisional obviousness-
type double patenting rejection of claims 7-16. However, we reverse the
rejection of claims 7-16 under 35 U.S.C. § 112, second paragraph.

TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

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