Patrick Joseph Gerardus Hendrikus. Kamphuis et al.

Patent Trials and Appeals Board

Sep 27, 2019

12666611 - (D) (P.T.A.B. Sep. 27, 2019)

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.
12/666,611 05/11/2010 Patrick Joseph Gerardus Hendrikus Kamphuis 069818-1550 1637
22428 7590 09/27/2019
FOLEY & LARDNER LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
EXAMINER
HAYES, ROBERT CLINTON
ART UNIT PAPER NUMBER
1649
NOTIFICATION DATE DELIVERY MODE
09/27/2019 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):
ipdocketing@foley.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte PATRICK JOSEPH GERARDUS HENDRIKUS KAMPHUIS,
MARTINE GROENENDIJK, and ANKE BONGERS1
____________

Appeal 2018-007214
Application 12/666,611
Technology Center 1600
____________

Before DEBORAH KATZ, JOHN G. NEW, and JOHN E. SCHNEIDER,
Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the real party-in-interest as N.V.
Nurtricia. App. Br. 3.

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SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 18, 20, 26, 27, and 31–35.
Specifically, the claims stand rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Wurtman et al. (WO
2006/127620 A2, November 30, 2006) (“Wurtman”), P. Quadri et al.,
Homocysteine, Folate, and Vitamin B-12 in Mild Cognitive Impairment,
Alzheimer Disease, and Vascular Dementia, 80 AM. J. CLIN. NUTR. 114–22
(2004) (“Quadri”), and M.F. Folstein et al., “Mini-Mental State” A Practical
Method for Grading the Cognitive State of Patients for the Clinician, 12 J.
PSYCHIATR. RES., 189–98 (1975) (“Folstein”).
Claims 18, 20, 26, 27, and 31–35 also stand rejected as unpatentable
under 35 U.S.C. § 103(a) as being obvious over the combination of
Wurtman, Folstein, and J.A. Luchsinger et al., Dietary Factors and
Alzheimer’s Disease, 3 THE LANCET NEUROL. 579–87 (2004)
(“Luchsinger”).
Claims 18 and 33 stand rejected as unpatentable under the
nonstatutory doctrine of obviousness-type double patenting over claims 1, 4,
6 & 11 of US 8,361,989 (the “’989 patent”).2
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

2 Appellant requests that the Examiner’s rejection on this ground be held in
abeyance pending determination that the claims are otherwise allowable.
We consequently summarily affirm the Examiner’s rejection upon this
ground. See 37 C.F.R. § 41.37(c)(iv) (“[A]ny arguments or authorities not
included in the appeal brief will be refused consideration by the Board for
purposes of the present appeal”).
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NATURE OF THE CLAIMED INVENTION
Appellant’s invention is directed to the use of a composition
comprising: (a) uridine or uridine phosphate; and (b) docosahexaenoic acid
and/or eicosapentaenoic acid, for improving memory and/or the treatment or
prevention of impaired memory function, in a subject with a mini-mental
state examination of 24–26, wherein said composition is enterally
administered to the subject. Abstr.

REPRESENTATIVE CLAIM
Claim 18 is representative of the claims on appeal and recites:
18. A method for improving delayed recall and/or memory
function of a human subject with a mini-mental state
examination of 24–26, comprising enterally administering to the
subject a composition comprising:

a. 0.1–2 g uridine or uridine phosphate, calculated as
uridine monophosphate, per daily dosage unit;

b. 400–5000 mg of the sum of docosahexaenoic acid
and eicosapentaenoic acid per daily dosage unit; and

c. vitamin E, vitamin C, vitamin B 12, vitamin B6 and
folic acid, wherein 1.5–5 μg vitamin B12 and 150–750 μg folic
acid is administered per day.
+
App. Br. 11.

ISSUES AND ANALYSES

We agree with, and expressly adopt, the Examiner’s findings,
reasoning, and conclusion that the claims are prima facie obvious. We
address below the arguments raised by Appellant.
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Issue 1
Appellant argues that the combined cited prior art neither teaches nor
suggests all the claimed ingredients in the amounts required. App. Br. 4.

Analysis
The Examiner finds that Wurtman teaches a method of improving
memory disorder or impairment (including a mini-mental state examination
of 24–26; see Appellant’s Spec. 1, 19) by enterally administering a
composition comprising uridine phosphate and the omega-3 fatty acid
docosahexaenoic acid (“DHA”) and/or the omega-6 fatty acid
eicosapentaenoic acid (“EPA”). Non-Final Act. 7, filed April 4, 2016
(citing, e.g., Wurtman 2, 9, 12–13, 29, 46) as it relates to claims 18(a) & (b).
The Examiner finds that Wurtman teaches that its compositions comprise
100–500 mg/day uridine and 400–3000 mg/day of DHA or EPA, and
choline. Id. The Examiner also finds that Wurtman teaches the use of the
mini-mental test as another embodiment of their invention to assess
improvement of cognitive function. Id. (citing Wurtman 19).
The Examiner finds that Folstein teach a “simplified, scored form of
the mental status examination, the mini-mental state (MMS),” which
requires only 5–10 minutes to administer, as a means of assessing cognition
and delayed recall function. Non-Final Act. 9 (citing Folstein 189–90, 193).
The Examiner finds Quadri teaches that folate and vitamin B12 & B6
deficiencies may precede Alzheimer’s disease/cognitive decline and,
therefore, additional dietary intake of these nutritional factors may be
beneficial to improve cognition. Non-Final Act. 9–10 (citing Quadri 114,
115, Table 2).
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The Examiner concludes that it would have been obvious to one of
ordinary skill to supplement Wurtman’s method of improving cognition and
neurological functions with uridine, DHA, EPA, and choline, with Quadri’s
folate, and vitamins B12 and B6. Non-Final Act. 9. The Examiner
concludes that a person of ordinary skill would be motivated to combine the
references, because they each teach compositions beneficial in treating
cognitive impairments in patients beginning to experience cognitive
deficiencies in diseases such as Alzheimer’s disease. Id. The Examiner
further concludes that it would have been obvious to use the method of
Folstein to assess cognitive improvement. Id. at 9–10.
Similarly, the Examiner finds that Luchsinger teaches that “high
intake of vitamins C, E, B6, and B12, and folate, unsaturated fatty acids
[e.g., EPA and DHA] and fish are related to a low risk of AD” (Alzheimer’s
disease. Non-Final Act. 12–13 (quoting Luchsinger Abstr.).
The Examiner concludes, for the same reasons cited supra, that it
would have been obvious to a person of ordinary skill in the art to combine
Wurtman’s method with Luchsinger’s vitamins E, C, B12, B6 and folate.
Non-Final Act. 13. The Examiner concludes that a person of ordinary skill
would be motivated to combine the references, because they each teach
compositions beneficial in treating cognitive impairments in patients
beginning to experience cognitive deficiencies in diseases such
as Alzheimer’s disease. Id.
Appellant disputes the Examiner’s finding that the formulations taught
by Wurtman formulation necessarily contain dietary supplements, such as
phospholipids, choline, vitamins B6, B 12, E, C, folate and selenium in their
recommended dietary allowances for humans. App. Br. 4–5 (citing Final
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Act. 14. However, Appellant argues Wurtman’s only description is of the
diet (for gerbils) is provided in Table 4, which shows that the diet contains
protein (16.7%), carbohydrate (60.9%), oil, fiber, ash (13.7%), choline
(0.1%), saturated fatty acids (7.34 g/kg), and unsaturated fatty acids, such as
C18:1n-9 oleic acid (8.96 g/kg), C18:2n-6 linoleic acid (23.12 g/kg), and
C18:3n-3 linolenic acid (1.53 g/kg). Id. at 5 (citing Wurtman 53–54).
Therefore, Appellant argues, Wurtman does not teach formulations
comprising vitamins E, C, B12 and B6, and folic acid. Id.
Appellant argues further that, although Quadri teaches that a folic acid
deficiency may precede cognitive impairment, dementia, or Alzheimer’s
disease, Quadri does not teach that actual supplementation with folic acid
can improve or reverse such conditions. App. Br. 5. Appellant contends
that the Examiner erroneously assumes that Luchsinger teaches that: “high
intake of vitamins C, E, B6, and Bl2, and folate, unsaturated fatty acids ...
are related to a low risk of AD … in studies of treating Alzheimer’s
patients.” Id. (citing Final Act. 18 (quoting Luchsinger Abstr.)).
Appellant acknowledges that Luchsinger teaches that: “[s]ome studies
suggest high intake of vitamins C, E, B6, and B12, and folate, unsaturated
fatty acids, and fish are related to a low risk of AD,” but Appellant asserts
that the Examiner cannot dismiss that Luchsinger acknowledges that the
“reports are inconsistent.” App. Br. 5 (quoting Luchsinger Abstr.).
Appellant argues that Luchsinger consistently mentions the conflicting data
with regards to dietary factors/supplements: for instance, with respect to
vitamin C, Luchsinger mentions one study in which: “4000 people age 65
years and older found that a combination of supplements of vitamins C and
E, but not supplements of individual antioxidants, was associated with a low
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risk of AD.” Id. (quoting Luchsinger 580). Similarly, argues Appellant,
Luchsinger cites another study in which: “5395 people age 55 years and
older found that dietary intake of vitamins E and C, but not supplement
intake, was associated with a low risk of AD.” Id. at 5–6. With regard to
vitamins B12, B6, and folate, Appellant notes that Luchsinger states that
“the data relating vitamins B12, B6, and folate to cognitive decline and AD
are inconsistent” and concludes by stating that “[m]ost of the data relating
diet and AD are from observational studies and are inconsistent. Thus,
recommendations of dietary interventions specifically for the prevention of
AD cannot be made at this time.” Id. (quoting Luchsinger 585, left column).
Therefore, argues Appellant, even if Luchsinger could have been
interpreted as suggesting the use of vitamins E, B6, and B12, and folic acid,
the studies summarized in Luchsinger are conflicting at best. App. Br. 6.
Furthermore, Appellant argues, the recommended doses for vitamin B12 and
folate suggested by Luchsinger (0–4 mg of vitamin B12 and 2–5 mg of
folate) are much greater than the ranges recited in the claims (1.5–5 μg
vitamin B12 and 150-750 μg folic acid). Id. Consequently, Appellant
argues, Luchsinger not only fails complement the deficiencies of Wurtman,
it also fails to provide any reasonable motivation to combine any of the
“recommended” vitamins/supplements with uridine monophosphate, DHA
and/or EPA for treatment of the populations claimed, because Luchsinger
does not provide any assurance of a reasonable expectation of success. Id.
Despite the fact that Appellant argues both of the Examiner’s
rejections together, we are persuaded by Appellant with respect to the
Examiner’s rejection over the combination of Wurtman, Quadri, and
Folstein. Quadri is directed to the relationship between elevated plasma
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homocysteine levels caused by decreased vitamin B6, B12, and folic acid,
and the onset of vascular dementia and Alzheimer’s disease. See Quadri
Abstr., 118. Quadri is silent, however, with respect to EPA, DHA, uridine,
and the antioxidant vitamins C and E. Wurtman teaches administration of
EPA and/or DHA and uridine in treating mild or early stages of dementia
(which, as the Examiner finds) could be reasonably interpreted as
corresponding to a mini-mental examination state of 24–26), but is silent
with respect to vitamins C, E, B6, B12, or folic acid. See, e.g., Wurtman 2.
The Examiner attempts to remedy this deficiency by pointing to, inter
alia, paragraph [0199] of Wurtman, which teaches:
“Pharmaceutical composition” refers, in another embodiment, to
a dietary supplement. In another embodiment, the term refers to
a nutritional supplement. In another embodiment, the term refers
to a foodstuff of any sort that has been enriched with an omega-
3 fatty acid. In another embodiment, the term refers to a foodstuff
that has been enriched with an omega-6 fatty acid. In another
embodiment, the term refers to a foodstuff that has been enriched
with a uridine. In another embodiment, the term refers to a
foodstuff that has been enriched with a choline. In another
embodiment, the term refers to a foodstuff that has been enriched
with a choline salt.

(Emphasis added). The Examiner finds that this teaching, and especially the
teaching of a nutritional supplement, necessarily include the minimum daily
requirements of the missing vitamins. However, without more evidence to
expressly support this determination, we determine that this conclusory
finding by the Examiner lacks sufficient evidentiary support to show that
Wurtman teaches the inclusion of vitamins C, E, B6, B12, or folic acid as
recited in the claims.
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Consequently, because neither Wurtman, Quadri nor Folstein teach or
suggest the administration of antioxidant vitamins C or E to human patients
with a mini-mental state examination of 24–26, we reverse the Examiner’s
rejection upon that ground.
With respect to the Examiner’s rejection of the claims over Wurtman,
Folstein, and Luchsinger, Luchsinger teaches that:
Most of the data relating diet and AD are from observational
studies and are inconsistent. Thus, recommendations of dietary
interventions specifically for the prevention of AD cannot be
made at this time. However, some of the diets that may be
beneficial for AD are beneficial for other disorders, such as
cardiovascular disease, or are unlikely to be harmful, and some
recommendations can be made on the basis of these
characteristics.
….
There are conflicting data relating antioxidant intake to risk of
cardiovascular outcomes and AD. However, in light of the
relative safety of vitamin E and the results of the only trial of
vitamin E supplementation with 2000 IU a day, it may be seen as
a benign measure that is not proven in trials of primary
prevention. The intake of multivitamins may be recommended
given the potential benefits from their content of folate and B
vitamins and the proven benefits of supplementation of other
nutrients, such as calcium and vitamin D for osteoporosis.… It
may be advisable to supplement with at least 4 mg of folic acid,
2 mg of vitamin B6, and 6 μg of vitamin B 12, and increase the
doses according to homocysteine response, up to the doses
currently used in clinical trials (25 mg of vitamin B6, 0.4 mg of
vitamin B12, and 2.5 mg of folate).

There is some evidence to suggest that intake of macronutrients,
such as saturated fats, is related to AD, and that caloric restriction
may prevent AD and other ageing related disorders…. A diet low
in saturated and trans fatty acids and high in monounsaturated,
polyunsaturated, and fish-related fats seems to prevent
cardiovascular disease. These observations may be extrapolated
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to the prevention of cognitive problems awaiting the results of
randomised trials specific to cognition.

Luchsinger 585 (internal references omitted).
Luchsinger, a review article, thus teaches that, although the results of
different studies have provided some inconsistent results and, in the case of
polyunsaturated fatty acids, awaits further testing, there are generally
positive results and further testing is encouraged. We do not agree with
Appellant that the teachings of Luchsinger are such that the expectation of
success by a person of ordinary skill in the art in combining the references as
claimed would be prima facie unreasonable. This is particularly true in view
of the teachings of Wurtman that EPA and/or DHA and uridine are effective
in treating early or mild stages of dementia. See In re Longi, 795 F.2d 887,
897 (Fed. Cir. 1985) (holding that “[o]nly a reasonable expectation of
success, not absolute predictability, is necessary for a conclusion of
obviousness.”).
Finally, with respect to dosages, Luchsinger teaches administration of
folate at dosages of 2.5–4 mg and B12 at 6–400 μg. Luchsinger 585. Claim
18 recites daily dosages of 150–750 μg folate and 1.5-5 μg. We
acknowledge that there is some distance between the prescribed dosages of
Luchsinger and the claims, however:
The law is replete with cases in which the difference between the
claimed invention and the prior art is some range or other
variable within the claims. These cases have consistently held
that in such a situation, the applicant must show that the
particular range is critical, generally by showing that the claimed
range achieves unexpected results relative to the prior art range.

In re Woodruff, 919 F. 2d 1575, 1578 (Fed. Cir. 1990). We address
Appellant’s argument concerning unexpected results infra. However,
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Appellant does not argue that the range of folic acid and vitamin B 12
recited in the claim is critical to its function or, more importantly, that higher
dosages, though still within the usual range (as taught by Luchsinger 585),
would not achieve the same or similar results. We are therefore not
persuaded by Appellant’s arguments with respect to this rejection.

Issue 2
Appellant argues that the Examiner erred because cone of the cited
prior art references teach treatment of “a human subject with a mini-mental
state examination of 24–26.” App. Br. 6.

Analysis
Appellant argues that Wurtman does not teach improving delayed
recall and/or memory function in a human subject with a mini-mental state
examination of 24–26. App. Br. 6. Appellant contends that the Examiner
appears to have interpreted the reference to mini-mental state examination as
the use of the mini-mental state examination (MMSE) for “assessing
improvement of cognitive function.” Id. (citing Final Act. 15). However,
argues Appellant, claim 18’s recitation of “a human subject with a mini-
mental state examination of 24–26” is not in reference to a method of
“assessing improvement of cognitive function,” but rather a characterization
of a specific human subject population that is to be administered the
compositions recited. Id.
Appellant contends that, although Wurtman teaches administering its
compositions to subjects with Alzheimer’s disease, the disease may be in the
early, mild, or late stage, and the stage of Alzheimer’s can be assessed using
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the Functional Assessing Staging (“FAST”) scale. App. Br. 7. Appellant
contends that the inventors of the claims on appeal have discovered that,
“within the group of 20–26, the memory impairment in the sub-group of 24–
26 may even be reversible, as the pathological pathways have just started to
develop.” Id. (quoting Spec. 1–2). Appellant asserts that the inventors then
learned that compositions comprising uridine or uridine phosphate, DHA
and/or EPA, vitamins E, C, B12 and B6, and folic acid would be particularly
beneficial in subjects having a MMSE score of 24–26, which is nowhere
suggested by Wurtman. Id.
Appellant therefore contends that, because of the unpredictable and
conflicting state of the art, a person of ordinary skill in that art would not
have a reasonable expectation of success of improving delayed recall and/or
memory function in a human subject with a MMSE score of 24–26 by
administering a composition comprising uridine or uridine phosphate, DHA
and/or EPA, and vitamins E, C, B12 and B6, and folic acid. App. Br. 7.
We are not persuaded by Appellant’s argument. Wurtman expressly
teaches that:
This invention provides methods of increasing or enhancing the
synthesis and levels of phospholipids, synapses, synaptic
proteins, and synaptic membranes by a neural cell or brain cell,
methods of treating a subject with a memory disorder, memory
impairment, neurological disorder, or brain disease or disorder,
comprising administering to the subject a composition
comprising an omega-3 fatty acid, an omega-6 fatty acid, uridine,
a metabolic precursor thereof, or a combination thereof.

Wurtman ¶ 1. Furthermore, Wurtman teaches that: “In another embodiment,
the Alzheimer’s disease is at an early stage. In another embodiment, the
Alzheimer’s disease is at a mild stage.” Id. at ¶ 79; see also claim 14.
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Appellant’s Specification discloses that:
In the MMSE test, any score of 27 or higher (out of 30) is
effectively normal. In the patients with dementia, 20–26
indicates mild dementia, 10–19 moderate dementia, and below
10 severe dementia.
….

The subgroup of subjects with a MMSE score of 24 to 26
comprises two populations. Firstly, it comprises those subjects
who do not receive medication for memory impairment, i.e. the
drug naive subjects. The treatment of this subgroup is
particularly preferred as in these subjects the balance between
side effects and benefits of pharmaceutical intervention is still
negative.….

Secondly, the subgroup of subjects with a MMSE score of 24 to
26 comprises a population of subjects with a very mild form of
Alzheimer’s Disease. Memory improvement through nutritional
therapy is particularly desired in subjects with a very mild form
of Alzheimer’s Disease. If improvement of memory function
could be achieved pharmaceutical intervention could be reduced
or even postponed if significant improvements are observed.

Spec. 1–2 (emphasis added). Appellant’s Specification thus teaches that
“human subject[s] with a mini-mental state examination of 24-26” include
those suffering from a very mild form of Alzheimer’s disease, which
corresponds to Wurtman’s teaching that its compositions can be
administered to individuals with an early or mild stage of Alzheimer’s
disease. Wurtman ¶ 79; see also claim 14. We acknowledge that Wurtman
does not teach administration of folic acid, vitamins C, E, B6, or B12, but
the Examiner relies upon the teachings of Luchsinger as teaching those, as
well as polyunsaturated fatty acids such as DHA or EPA. See Luchsinger
582–83. We therefore do not find Appellant’s arguments persuasive with
respect to this issue.
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Issue 3
Appellant argues that their unexpected results are sufficient to
overcome the Examiner’s prima facie conclusion of obviousness. App. Br.
7.

Analysis
Appellant argues that the inventors discovered an effect of B-
vitamins (i.e., vitamins B6 and Bl2 and folic acid) in the presence of
antioxidants (i.e., vitamins C and E), polyunsaturated acids (“PUFA,” i.e.,
EPA and DHA), and uridine monophosphate (“UMP”) on improving
delayed recall and/or memory function of a human subject with a mini-
mental state examination of 24–26. App. Br. 7. However, Appellants assert
that they have also discovered an unexpected synergistic effect. Id.
In support of this contention, Appellant presents data showing that a
combination of PUFAs, UMP, and antioxidants increases cholinergic M1
receptor activity in PC12 cells by approximately 25% over baseline levels.
App. Br. 8.3 However, Appellant explains, if B-vitamins are added to the
combination, the activity rises to 45% over baseline, well above the
additional 5% contribution expected of B-vitamins alone. Id. In support of
this argument, Appellant points to the Declaration of Dr. Laus Broersen,

3 Appellant states that this data was presented at the 12th Congress of the
EFNS (25 August 2008, Madrid, Spain) (of record), and that a similar
study was subsequently published as PJ. Savelkoul et al., A Specific Multi-
Nutrient Formulation Enhances M1 Muscarinic Acetylcholine Receptor
Responses in vitro, 120 J. NEUROCHEM. 631–40 (2012).

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filed July 6, 2017 (the “Broersen Declaration”). In his Declaration, Dr.
Broersen presents the data depicted below:

The data depicted in the Broersen Declaration demonstrates the
effect on M1 receptor response of incubation of PC12 cells with
various nutrient solutions

Appellant disputes the Examiner’s findings that synergism should be
based on the raw percentages of M1 receptor activity and that the data
therefore fail to demonstrate synergy. App. Br. 8. However, Appellant
contends, the Examiner’s method for calculating synergism fails to discount
the baseline activity. Id. And, Appellant argues, because all of the
combinations contain antioxidants (“AOX,” i.e., vitamins C and E), the most
appropriate baseline for determining the effect of the additional components
would be the AOX baseline value, as indicated by the dashed line. Id.
Therefore, contends Appellant, in determining the effect of the addition of
B-vitamins (bar# 5 = AOX + B vitamins = 105%), the baseline for AOX
(100%) must be subtracted (105%-100% = 5%). Id. at 9. Accordingly, as
shown in the table below, the various combinations of B-vitamins, PUFA
(i.e., EPA and DHA), and Nucl (i.e., UMP) to AOX (i.e., vitamins C and E)
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are synergistic (i.e., the effect of the combination is greater than the sum of
each effect taken separately).
Appellant also disputes the Examiner’s finding that the data from this
study on PC12 cells has “no reasonable merit in regards to ‘improving
delayed recall and/or memory.’” App. Br. 9 (quoting Final Act. 6).
Appellant argues that the Examiner fails to recognize that the purpose for
providing the PC12 cell line data is to merely provide a mechanistic basis for
the improvement in delayed recall and/or memory, showing that a
composition comprising the combination of UMP, DHA and/or EPA,
vitamins B6, B12, C, and E and folic acid has a synergistic effect on Ml
receptor activity. Appellant points to the Broersen Declaration and
Examples 1 and 2 of Wurtman, PC 12 are an art-recognized model system
for studying brain function. Id. (citing Broersen Decl. ¶¶ 13–19).
Appellant argues further that the Specification demonstrates that the
compositions recited in the claims are effective in achieving the claimed
method. App. Br. 9. Appellant points to Example 2 of the Specification,
which summarizes a study in which groups with a MMSE of 24–26 were
administered a drink with or without EPA, DHA, phospholipids, choline,
UMP, vitamin E, vitamin C, selenium, vitamin B12, vitamin B6 and folic
acid. Id. Appellant states that the outcome measured was a (delayed) verbal
memory task (derived from Wechsler Memory Scale-revised, “WMS-r”).
Id. Appellant asserts that, as shown in Example 2 and Table 1, there was a
significant difference between the two groups, with the control group
showing an average decline of -0.165 point and the treatment group showing
an average improvement of 0.983 points. Id. Appellant argues that the
ability of such compositions to improve delayed recall and/or memory in
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subjects with MMSE of 24–26 is completely absent from the teachings of
Wurtman, Folstein, Quadri, and Luchsinger. Id. at 9–10.
We are not persuaded by Appellant’s arguments. Even if we assume,
arguendo, that the data presented in the Figure presented in the Broersen
Declaration is probative of synergy in the amplitude of M1 receptor
potentials generated in vitro in PC12 cells exposed to the constituents of
Appellant’s composition, we are not persuaded that the nexus between the
synergy observed in the PC12 cell receptor potentials in vitro and the
claimed “improve[ed] delayed recall and/or memory function” has been
sufficiently established by Appellant. Synergism, in and of itself, is not
conclusive evidence of non-obviousness in all instances. See In re Kollman,
595 F.2d 48, 55 n.6 (CCPA 1979). We acknowledge the Broersen
Declaration’s opinion that: “many experts in the field of neuron study
routinely rely on PC 12 cells as a model for neurobiological and
neurochemical studies linked to memory loss and for drawing the same
conclusions made by the present inventors.” See Broersen Decl. ¶ 14 et seq.
Nevertheless, although the PC12 cell in vitro system may serve as a
useful model of neuronal function that may play a role in progressive
dementia, it is a long way, in terms of explaining mechanisms and causality,
from PC12 cells in vitro to the loss of memory and cognitive function in an
intact and functioning human brain. We do not find Appellant’s argument
that the allegedly unexpected in vitro results are probative of a direct causal
link between in vitro and in vivo, despite their usefulness as a model. See In
re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (holding that unexpected
results must also be “commensurate in scope with the degree of protection
sought by the claimed subject matter”).
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Moreover, neither Appellant’s Specification nor the Broersen
Declaration demonstrate that the recited composition has an actual
synergistic effect on “a human subject with a mini-mental state examination
of 24–26,” as required by the claims. We agree with Appellant that the
composition does demonstrate a statistically significant effect on such
patients when compared to control, but we are not persuaded that such
results are unexpected or surprising in view of the teachings of the combined
cited prior art. See Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d
1317, 1322 (Fed. Cir. 2004) (Unexpected results that are probative of
nonobviousness are those that are “different in kind and not merely in degree
from the results of the prior art”) (citation omitted). We are consequently
not persuaded that Appellant’s evidence of unexpected results are sufficient
to overcome the Examiner’s prima facie conclusion of obviousness. See
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007) (“Although
secondary considerations must be taken into account, they do not necessarily
control the obviousness conclusion”).
NEW GROUND OF REJECTION
We enter the following new ground of rejection for claims 18, 20, 26,
27, and 31–35 under the provisions of 37 CFR § 41.50(b).
Claims 18, 20, 26, 27, and 31–35 are rejected under 35 U.S.C. §
103(a) as being obvious over the combination of Wurtman, Folstein, and
Luchsinger, and Quadri. As we have explained supra, Quadri does not teach
administration of antioxidant vitamins C or E, however Luchsinger teaches a
review of studies using of those antioxidants in individuals with dementia.
See Luchsinger 580–81.
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19

Quadri is directed to examining the associations of plasma total
homocysteine, serum folate, and vitamin B-12 concentrations with mild
cognitive impairment, Alzheimer’s disease, and vascular dementia,
independently of other vascular and nonvascular risk factors. Quadri 115.
Quadri’s subjects are selected, inter alia, from control patients group
(showing new signs of dementia) and patients defined clinically at a level of
0.5 on the Clinical Dementia Rating (“CDR”). Patients in the latter group
correspond generally with the 24–26 range of the mini-mental state
examination. See Quadri Table 1.
Quadri teaches that “[I]n this mildly cognitively impaired group [i.e.,
the CDR 0.5 group], the homocysteine concentration appeared to be
significantly correlated with global cognitive performance, despite the
narrower range of MMSE scores considered.” Quadri 119. Quadri further
teaches that:
It is possible, however, to modify these putative environmental
determinants of cognitive deterioration by nutrition: dietary folic
acid alone or in combination with vitamin B-12 is in fact a safe,
simple, and economic therapeutic strategy to effectively reduce
plasma homocysteine concentrations. The adjunct of vitamin B-
6 does not seem to have a significant additional effect, although
each of the B vitamins might have an effect on cognition
independent of their potential influence on plasma homocysteine
concentrations. A homocysteine-lowering effect in AD patients
has also been shown in an open-label trial of folic acid, Vitamin
B-12, and vitamin B-6 regimen.

Id. at 121. Quadri thus expressly suggests that administration of vitamins
B12, B6, and folate can be beneficial to patients by reducing the levels of
serum homocysteine that is correlated with cognitive performance in this
group.
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We conclude that a person of ordinary skill in the art would have
found it obvious to combine the teachings of Quadri with those of the other
cited prior art references to arrive at the claimed invention. We further
conclude that a person of ordinary skill in the art would have been
motivated, and with a reasonable expectation of success, to combine the
teachings of Quadri with those of Wurtman, Luchsinger, and Folstein
(descried supra), to reduce the levels of serum homocysteine that is
positively associated with impaired global cognitive performance of a
human subject with a mini-mental state examination of 24–26.

DECISION
The Examiner’s rejection of claims 18, 20, 26, 27, and 31–35 under
35 U.S.C. § 103(a) is affirmed.
We have also entered a new ground of rejection under 37 C.F.R.
§ 41.50(b) for claims 18, 20, 26, 27, and 31–35.
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b). 37 C.F.R. § 41.50(b) provides that “[a] new ground of
rejection … shall not be considered final for judicial review.”
37 C.F.R. § 41.50(b) also provides that the Appellants, WITHIN
TWO MONTHS FROM THE DATE OF THE DECISION, must exercise
one of the following two options with respect to the new ground of rejection
to avoid termination of the appeal as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate amendment of
the claims so rejected or new evidence relating to the claims so
rejected, or both, and have the matter reconsidered by the
examiner, in which event the proceeding will be remanded to the
examiner.…

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(2) Request rehearing. Request that the proceeding be reheard
under § 41.52 by the Board upon the same record.…

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

AFFIRMED
37 C.F.R. § 41.50(b)

Claims Rejected Basis Affirmed Reversed New Ground
18, 20, 26, 27, and
31–35
§ 103(a) over
Wurtman, Quadri,
Folstein
18, 20, 26, 27,
and 31–35

18, 20, 26, 27, and
31–35
§ 103(a) over
Wurtman, Folstein,
Luchsinger
18, 20, 26, 27,
and 31–35

18, 33 Obviousness-type
double patenting
18, 33
18, 20, 26, 27, and
31–35
§ 103(a) over
Wurtman, Folstein,
Luchsinger, Quadri
18, 20, 26, 27,
and 31–35
Overall Outcome 18, 20, 26, 27,
and 31–35
18, 20, 26, 27,
and 31–35