Ex Parte 8067035 et al

Patent Trial and Appeal Board

Jun 5, 2018

95002106 (P.T.A.B. Jun. 5, 2018)

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.
95/002,106 08/29/2012 8067035 34329-705.999 1030
21971 7590 06/05/2018
WILSON, SONSINI, GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO, CA 94304-1050
EXAMINER
CAMPELL, BRUCE R
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
06/05/2018 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

NUVO RESEARCH AG,
Respondent
v.

Patent of
NEURALTUS PHARMACEUTICALS, INC.,
____________

Appeal 2018-004289
Reexamination Control 95/002,106
Patent 8,067,035 B2
Technology Center 3900
____________

Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
RAE LYNN P. GUEST, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal by the Patent Owner from the Patent
Examiner’s rejection of claims 1–18 in the above-identified inter partes
reexamination of United States Patent 8,067,035 B2. The Board’s
jurisdiction for this appeal is under 35 U.S.C. §§ 6(b), 134, and 315 (pre-
AIA). The Examiner is affirmed.

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I. STATEMENT OF THE CASE
The patent in dispute in this appeal is United States Patent 8,067,035
B2 (“the ’035 patent”) which issued on November 29, 2011. The patent
owner and real party in interest is Neuraltus. Patent Owner Appeal Brief
(“Appeal Br.”) 2, dated May 12, 2016.
A request for inter partes reexamination of the ’035 patent was filed
August 29, 2012, by a Third-Party Requester, Nuvo Research AG
(“Requester”) under 35 U.S.C. §§ 311–318 and 37 C.F.R. §§ 1.902–1.997.
The Examiner made a determination that claims 1–18 are
unpatentable under 35 U.S.C. § 103. Patent Owner appeals from the
grounds of rejection set forth by the Examiner. Appeal Br. 3.
Requester filed a Respondent Brief, but the brief was stricken from
the record. See Decision on Petition (entered Jan. 27, 2017).
Patent Owner provided two declarations under 37 C.F.R. § 1.132
during the prosecution of the ’035 patent that have been considered in this
appeal. These declarations are:
Declaration by Michael McGrath, M.D., Ph.D., dated May 27, 2011,
discussing hematologic problems associated with WF10 administration (“1st
McGrath Decl.”).
Declaration by Michael McGrath, M.D., Ph.D., dated May 27, 2011,
discussing unexpected pH stability associated with claimed pharmaceutical
(“2nd McGrath Decl.”).
Requester provided three declarations under 37 C.F.R. § 1.132 during
the proceeding before the Examiner that have been considered in this appeal.
These declarations are:
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Declaration by Rainer Martin, Ph.D., dated January 29, 2013,
discussing the McGrath pH experiments described in the 2nd McGrath
Declaration (“1st Martin Decl.”).
Declaration by Rainer Martin, Ph.D., dated February 4, 2013,
discussing the cited prior art publications (“2nd Martin Decl.”).
Declaration by Henrich Guntermann, M.D., dated February 5, 2013,
discussing the unexpected results relating to hemoglobin side effects
described in the 1st McGrath Declaration (“Guntermann Decl.”)
Patent Owner contends that the Examiner erred by allowing entry and
considering the Martin and Guntermann declarations. Appeal Br. 3–6.
Our review for the purpose of an appeal is of a rejection of a claim.
Pre-AIA 35 U.S.C. § 134(b). We do not have jurisdiction over an
Examiner’s action in deciding whether or not to admit a declaration. A
dispute with an Examiner’s action in entering a declaration may be
addressed by a timely filed petition. See, e.g., 37 C.F.R. § 1.181(a)(1). It is
not subject to review in an appeal under 35 U.S.C. § 134(b). Thus, we have
not considered the propriety of the Examiner’s action in admitting the
declarations. Because the Examiner entered the declarations into the record,
we have taken them under consideration in this Decision on Appeal.

CLAIMS
Claims 1–18 stand rejected by the Examiner. There are two
independent claims on appeal, claims 1 and 2. Claim 1 is representative and
reads as follows:
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1. A pharmaceutical composition comprising: (a) an aqueous
solution comprising sodium chlorite, wherein the weight ratio
of chlorite: chlorate is greater than 100: 1.5, and the
concentration of chlorite is at least 60 mM; (b) a phosphate
buffer; and (c) a pharmaceutically acceptable excipient;
wherein the composition is a sterile intravenous solution having
a pH between about 7 and about 9.5.

Claim 2 recites the same limitations, but is directed to a unit dosage.

REJECTIONS
The claims stand rejected by the Examiner as follows:1
1. Claims 1 and 6–18 under pre-AIA U.S.C. § 103(a) as obvious in
view of Kühne I ’9222 and Mullerat,3 as evidenced by Kühne II ’285,4

1 To the extent that the Examiner used the term “or” in reciting the list of
cited prior art publications, we have considered all the publications to define
the scope and content of the prior art (Graham v. John Deere Co., 383 U.S.
1, 17–18 (1966)) and stated the rejection in this way.
2 U.S. Pat. No. 6,086,922, issued July 11, 2000.
3 U.S. Pat. No. 6,099,855, issued Aug. 8, 2000.
4 U.S. Pat. No. 4,507,285, issued Mar. 26, 1985.
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Steffen,5 Shahangian,6 Inorganic Ventures,7 Danner,8 Tissot,9 and McGrath
II.10 RAN 4.
2. Claims 2–5 and 9–11 under pre-AIA U.S.C. § 103(a) as obvious in
view of Kühne I ’922 and Mullerat, as evidenced by Kühne II ’285, Steffen,
Shahangian, Inorganic Ventures, Danner, Tissot, Immunokine product
insert,11 and McGrath II. RAN 7.
3. Claims 1–18 under 35 U.S.C. § 103(a) under pre-AIA U.S.C. §
103(a) as obvious in view of McGrath I12 and Mullerat, as evidenced by
Shahangian, Inorganic Ventures, Tissot, the Immunokine product insert, and
McGrath II.
CLAIM INTERPRETATION
Independent claims 1 and 2 are directed to pharmaceutical
compositions that comprise sodium chlorite “wherein the weight ratio of

5 Steffen and Wetzel, “Chlorate poisoning: mechanism of toxicity,”
Toxicology 84 (1993) 217–231.
6 Shahangian and Hager, “The Reaction of Chloroperoxidase with Chlorite
and Chlorine Dioxide,” J. Biol. Chem., 1981, 256(12):6034–6040.
7 Inorganic Ventures, Certificate of Analysis for I-CAL ION
CHROMATOGRAPHY SOLUTION of chlorite in water.
8 U.S. Pat. No. 5,855,922, issued Jan. 5, 1999.
9 Tissot et al., “Anti-inflammatory properties of a novel wound healing
and immunomodulating agent, tetrachlorodecaoxygen complex
(TCDO),” Agents and Actions, 1990, 31(3/4): 368–374.
10 McGrath et al., “Development of WF10, a novel macrophage-regulating
agent,” Curr. Opin. Investig. Drugs, March 2002, 3(3):365–73.
11 Data and Instructions for the Use of IMMUNOKINE WF10 (TCDO) I.v.
Solution for Intravenous Infusion.
12 McGrath, US Pat. Appl. Publication 2005/0181068 A1, publ. Aug. 18,
2005.
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chlorite: chlorate is greater than 100: 1.5.” The claims recite that “the
composition is a sterile intravenous solution having a pH between about 7
and about 9.5.” While the composition is intended to be used intravenously,
we could not find, and have not been directed to, disclosure in the ’035
patent which identifies characteristics of an intravenous solution that would
distinguish it from other compositions for pharmaceutical use.
The claimed weight ratio of chlorite to chlorate of “greater than 100:
1.5” includes compositions where the ratio is so large that only a small
amount of chlorate is present, e.g., where chlorate is at a 0.5 weight ratio to
100 parts chlorite (claim 13) or less.

FINDINGS OF FACT (“FF”)
’035 Patent
FF1.
Chlorite has also been used to treat various diseases or
conditions. For example, chlorite has been used to treat
infections and to cause regeneration of bone marrow. See, for
example, U.S. Pat. No. 4,725,437 and U.S. Pat. No. 4,851,222.
Chlorite has also been used to treat HIV, recurrent prostate
cancer, cystitis, and chronic active hepatitis C disease. See, for
example, McGrath et al., Development of WF10, a novel
macrophage-regulating agent, Curr Opin Investig Drugs,
3(3):365–73 (March 2002). [Cited as “McGrath II” in this
reexamination] These diseases or conditions have generally
been treated with intravenous injection of WF10, a
commercially available formulation of chlorite. The
approximately 12.3 pH of this formulation may be problematic
for some forms of administration to physiological systems.
’035 patent, col. 1, ll. 21–34 (“Background”).

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FF2.
The non-chlorite elements of TCDO [WF10 as described in
Kühne II ’285] in these various forms, for example the chlorate
ions, may cause undesirable effects when administered to
physiological systems. For example, ingestion of sodium
chlorate causes irritation to the gastrointestinal tract, and may
result in nausea, vomiting and diarrhea. Mallinckrodt Baker Inc.
MSDS S3314, Aug. 10, 2004. Other symptoms include
abdominal pain, hemolysis, methemoglobinemia, cyanosis,
anuria, coma, and convulsions. Id. Further, exposure to
sodium chlorate may cause liver and kidney damage, and
repeated ingestion of small amounts may cause loss of appetite
and weight loss. Id.
’035 patent, col. 1, ll. 57–67 (“Background”).

Kühne II ’285
FF3.
This invention relates to stabilized activated oxygen which is
[i]ncorporated in a matrix of chlorite ions, and pharmaceutical
compositions containing this stabilized activated oxygen.
Kühne II ’285, col. 1, ll. 7–10.

FF4.
While here, the maximum anticipated yield of ClO2- [chlorite]
has not yet been completely attained, the ClO3- [chlorate]
content is still very small. Increasing OCl- [hypochlorite]
concentrations of course do yield more ClO2, this is
accomplished at the expense of increased chlorate formation.
Kühne II ’285, col. 2, ll. 63–68.

FF5.
The presence of undesired chlorate is evidenced by a band at
937 cm-1.
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Kühne II ’285, col. 3, ll. 5–6.

FF6.
An excessively high hydrogen ion or hypochlorite
concentration would favor the formation of chlorate (oxidation
of ClO2- [chlorite] to ClO3- [chlorate]) due to the increased
oxidizing effect.
Kühne II ’285, col. 3, ll. 8–12.

FF7.
The activated oxygen stabilized according to the invention,
which is contained in a matrix of chlorite ions, can be used in
various fields, for example, in medicine and in veterinary
medicine, in cosmetics, for the sterilization of food and
drinking water, and as feed additives.
Kühne II ’285, col. 3, ll. 35–40.

FF8.
Example I describes making a chlorite solution, where the “solution
obtained had a pH value of between 13.5 and 13.8.” Kühne II ’285, col. 4,
ll. 10–11.

FF9.
Example III describe a pharmaceutical preparation:
A medicinal solution was made from the product in Example 1
by diluting it with distilled water in a ratio of 1:50; that
medication had a pH value of 11.45–11.6 and was
physiologically tolerated.
Kühne II ’285, col. 4, ll. 43–47.

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Mullerat
FF10.
Mullerat describes orally administering a pH-buffered composition
comprising chlorite and chlorate ions to food animals. Mullerat, col. 19–20
(claim 1).

FF11.
A preferred molar ratio of chlorite ion source to chlorate
ion source that is added to the water-containing solvent is in the
range from 2:1 to 500:1, that of chlorite ions to chloride ions is
in the range from 0.1:1 to 50:1 and that of chloride ions to
chlorate ions is in the range from 0.1:1 to 500:1.
A still more preferred embodiment of the invention
employs compositions wherein the molar ratio of chlorite ion to
chlorate ion is in the range from 2:1 to 16:1; the molar ratio of
chlorite ion to chloride ion is in the range from 0.8:1 to 5:1; and
the molar ratio of chloride ion to chlorate ion is in the range
from 1.5:1 to 16:1.
Mullerat, col. 4, ll. 11–21.

FF12.
The stability of the compositions can be improved by adding a
pH-adjusting material to adjust the pH of the resulting mixture
to a final range of 7.5 to 13. It has been found that if the pH is
adjusted to about 13, the compositions are very stable and will
retain their biocidal properties over long periods of storage. The
concentration of the buffer can range from 0.001 M up to the
saturation level of the solution. The preferred buffering
ingredients contain phosphate salts.
Mullerat, col. 4, ll. 28–35.

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Steffen
FF13.
Chlorate poisoning is associated with
methaemoglobinaemia . . .
In the case described by Steffen and Seitz (1981), a very
high dose of sodium chlorate (150-200 g) was ingested.
Methaemoglobinaemia was followed by haemolysis,
disseminated intravascular coagulation and renal failure.
Steffen 218.

Tissot
FF14.
Tissot describes injecting WF10 into the pleural cavity of rats to test
its effect on inflammation. Tissot 368, 370. Tissot teaches that “WF 10 was
adjusted to physiological pH (7.4) immediately prior to use.” Id. at 369
(“Reagents”). Tissot also teaches diluting with phosphate-buffered saline
for in vitro experiments with cells. Id. (column 2).

Immunokine
FF15.
IMMUNOKINE® (WF10 Solution) MUST BE DILUTED with
a suitable dilutant prior to intravenous infusion.
. . .
IMMUNOKINE® MUST BE DILUTED in either physiological
saline solution, Ringer solution or glucose 5% solution to
prepare 250 to 500 cc ready to use solution.

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Danner
FF16.
Danner describes compositions and methods for facilitating the
healing of dermal disorders in human skin, including wound healing.
Danner, col. 5, ll. 26–31. Danner describes
a composition for therapeutic and prophylactic treatment of
human skin which comprises an aqueous solution of a metal
chlorite, such as sodium chlorite or potassium chlorite, in a
concentration of from about 0.002% (20 ppm) to about 0.5%
(5,000 ppm). The pH of the solution should be in the range of
about 6.0 to about 10.0 and any stable buffer useful in the stated
pH range may be used.
Danner, col. 6, ll. 16–23.

FF17.
Carbonate, borate, phosphate or combinations thereof may be
used as a buffer for the solution.
Danner, col. 6, ll. 32–33.

FF18.
In alternative embodiments, the compositions of the present
invention include aqueous mixtures of metal chlorites, such as
sodium or potassium chlorite, and metal chlorates, such as
sodium or potassium chlorate.
Danner, col. 6, ll. 45–48.

FF19.
The ratio of chlorite to chlorate in the solution can be from
about 100:0% up to about 60:40%, with the ideal composition
for each application dependent upon the usage and nature of
treatment being administered.
Danner, col. 6, ll. 54–57.
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McGrath II
FF20.
WF10 is a sterile, pyrogen-free, aqueous 10% (w/v) solution of
OXO-K993 with no additional inactive ingredients and is
intended for intravenous infusion. OXO-K993 has been
analytically characterized as an aqueous solution containing
chlorite ion (4.25%) as the active principle, and the inactive
ingredients chloride (1.9%), chlorate (1.5%) and sulfate (0.7%)
ions, with and sodium as the cation.
McGrath II (first page, “Introduction”).

Inorganic Ventures
FF21.
Inorganic Ventures describes a chlorite solution comprising 12 ±
μg/ml of ClO3– (chlorate), 6 ± 1 μg/ml of Cl– (chloride), and 998 ± 3 μg/ml
of chlorite.
REJECTION 1
Ratio limitation
The claims require a weight ratio of chlorite: chlorate which is greater
than 100: 1.5.

Rejection
The Examiner found that Kühne I ’922 discloses a chlorite solution
for the treatment of HIV. RAN 4. The composition and pH of the chlorite
solution is not described by Kühne I ’922, but the Examiner found that
Kühne I ’922 teaches that the same solution – WF10 – is described in Kühne
II ’285. RAN 4 (“The chlorite matrix, designated as WF10 in the following
experiments, was produced in accordance with Example 1 of U.S. Pat. No.
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4,507,285 [i.e., Kühne II ’285.”) (quoting Kühne I ’922, col. 3, ll. 30–32).
The Examiner acknowledged that neither Kühne I ’922 nor Kühne II ’285
describes the ratio of chlorite to chlorate recited in the claims. Id. at 4–5.
However, the Examiner found such ratio is encompassed by the broad
disclosure in Mullerat. Id. at 5. The Examiner also cited Inorganic Ventures
and Shahangian as evidence of the commercial availability of chlorite
solutions meeting the recited chlorite to chlorate ratio. Id. The Examiner
determined it would have been obvious to one of ordinary skill in the art to
replace the WF10 solution in Kühne I ’922 and Kühne II ’285 with a
solution containing a minimal amount of chlorate because chlorate was
known to be toxic to humans. Id. at 6. The Examiner cited Steffen as
evidence of the toxicity of chlorate. Id. The Examiner also cited the
teaching in Kühne II ’285 that the presence of chlorate in WF10 is
undesirable. Id. at 16.

Patent Owner’s arguments
Patent Owner contends that there must be a reason for a person of
ordinary skill in the art to have replaced “a high-chlorate solution of Kühne I
[’922] with a low-chlorate composition as claimed.” Appeal Br. 7. Patent
Owner acknowledged “Mullerat discloses a preferred chlorite:chlorate molar
ratio for the composition of Mullerat which is between 2: 1 and 500: 1,
which would overlap slightly with the claimed range.” Id. However, Patent
Owner contends that Mullerat “teaches away from using low-chlorite
compositions because most embodiments of Mullerat, including those
characterized as the best embodiments, along with the working examples,
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use much higher chlorate levels than those recited in the independent
claims.” Id. Patent Owner also contends the Mullerat teaches chlorate is
beneficial. Id. at 7–8. Patent Owner further contends that Steffen doesn’t
supply the “missing motivation” to have used a low-chlorite solution
because Steffen’s conclusions are based on high concentrations of chlorate,
orders of magnitude higher than those which are claimed. Id. at 8–9. Patent
Owner states:
Guided by the teachings of Steffen, a skilled person would
consider the chlorate level in the WF10 composition of Kuhne I
[’922] or in the composition of Mullerat to be de minimis and
very unlikely to cause chlorate poisoning, and would see no
further need to lower it.
Appeal Br. 9.
Patent Owner also contends that Mullerat is non-analogous prior art
and not in the same field of the invention because it relates to oral
compositions to be added to animal feed. Appeal Br. 13–14. Patent Owner
contends:
. . . a skilled person seeking to prepare a sterile pharmaceutical
formulation for intravenous administration, which can be
administered to human subjects, would be very hesitant to rely
on the teaching of a reference disclosed as applicable only to
feed animals and only by oral administration.
Appeal Br. 14.

Discussion
The Examiner’s reason to have minimized the chlorate in WF10
taught in Kühne I ’922 and Kühne II ’285 is because of the toxicity of the
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chlorate ion and its undesirability. RAN 6, 16. The Examiner’s reasoning is
supported by a preponderance of the evidence.
First, while it is unchallenged by the Examiner that Steffen’s
concentrations of chlorate are higher than the amounts in WF10 that would
be administered by Kühne I ’922, the Examiner’s response is scientifically
logical and factually supported: Chlorate is not an active ingredient of
WF10 (FF20) and a skilled artisan would not “include a substance known to
cause hypoxia, hemolysis, coagulation disturbances and renal failure in a
composition intended for intravenous administration, absent some expected
benefit.” RAN 16.
Second, as found by the Examiner, Kühne II ’285 teaches that
chlorate is undesirable. FF4, FF5. Accordingly, one of ordinary skill in the
art would have sought to minimize it, making it reasonable to have utilized
the low-chlorate commercial compositions (Shahangian, Inorganic Ventures)
identified by the Examiner. RAN 5. There is no requirement in the claim
that quantities of the chlorite solution be available or cost-effective for
“large-scale commercial use” as argued by Patent Owner. Appeal Br. 10.
Patent Owner contends “[i]t is not clear from the cited references that such
amounts could be obtained on a practical scale and at a reasonable cost,” but
Patent Owner has provided no objective evidence or scientific reasoning to
support this contention. Id. at 10–11.
Patent Owner attempts to diminish the disclosure in Kühne II ’285
that chlorate is “undesired” (FF5) by arguing that the skilled worker would
have recognized the levels of chlorate present in WF10 taught by Kühne II
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’285 are acceptable and there would be no reason to lower them. Appeal Br.
10.
However, Patent Owner cited the Veerasarn publication13 as teaching
that “74% of patients treated with WF10 exhibited hemoglobinemia,
compared to 35% of control patients” and that “Veerasarn provide clear
evidence that WF10 induces hemoglobinemia as a side effect of treatment.”
Appeal Br. 21. While Veerasarn does not teach the chlorate ion is
responsible for the deleterious effect, in view of the teachings in Steffen
(FF13) and Kühne II ’285 (FF4, FF5) about its toxicity and undesirability,
one of ordinary skill in the art would have reason to minimize chlorate’s
presence.
Third, Patent Owner’s challenge to Steffen based on the pertinence of
its teaching of toxicity because its chlorate concentrations are said to be
“many orders of magnitude higher than those of the claimed compositions”
(Appeal Br. 8–9) is inconsistent with Patent Owner’s own disclosure in the
’035 patent. The ’035 Patent in its “Background” section teaches that “non-
chlorite elements of TCDO [as described in Kühne II ’285; also known as
WF10] in these various forms, for example the chlorate ions, may cause
undesirable effects when administered to physiological systems”, such as GI
irritation and that “repeated ingestion of small amounts may cause loss of
appetite and weight loss.” FF2. Thus, Patent Owner acknowledged in its

13 Veerasarn et al., “Reduced recurrence of late hemorrhagic radiation
cystitis by WF10 therapy in cervical cancer patients A multicenter,
randomized, two-arm, open-label trial,” Radiotherapy and Oncology 73
(2004) 179–185.
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own patent that it was known that even “small amounts” of chlorate may
have deleterious effects.
Fourth, Danner describes a solution which ranges from no chlorate to
higher amounts of it, “dependent upon the usage and nature of treatment
being administered.” FF19. Danner’s solution is for application to wounds,
and, therefore, is in contact with a cellular environment, making it pertinent
to the medical application of Kühne I ’922, which also involves
administration to a cellular environment (intravenous). Danner’s disclosure
indicates the routineness of choosing a desired level of chlorite to chlorate,
depending on the composition’s specific application.
Patent Owner states that the teaching in McGrath II that chlorate is
an inactive ingredient would have been a disincentive to remove it from the
chlorite solution. Appeal Br. 10. We do not agree. Known undesirable
effects incentivize the ordinary artisan to remove inactive, unnecessary
ingredients that cause those effects. McGrath II teaches that chlorite is the
“active principle” in regulating macrophage function, while the chlorate ion
does not possess such activity and, thus, is “inactive” with respect to this
activity. McGrath II (first page) (FF20). McGrath II was not addressing
whether the chlorate ion was deleterious when administered, which Patent
Owner acknowledges it is in its own ’035 patent. FF2.
Patent Owner also attempts to distinguish the prior art by arguing that
the cited Shahangian or Inorganic Ventures publications use the chlorite
solutions disclosed therein for a different purpose. Appeal Br. 10–11.
This argument is not persuasive. The Examiner relied on these
publications to demonstrate that chlorite compositions meeting the claimed
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ratio were known and available in the prior art, and, thus, once motivated to
use a low chlorate composition due to the undesirable effects of chlorate, the
prior art enabled the skilled worker to obtain low chlorate composition,
including those that have chlorite to chlorate ratios within the range recited
in the claims. Patent Owner did not distinguish the ratio of chlorite to
chlorate in its claims from the ratio of the solution described in the
publications cited for this purpose, such as Inorganic Ventures.
With regard to the arguments that Mullerat is non-analogous prior art,
we agree that the Mullerat’s chlorite solution is being used for a different
purpose than Kühne I ’922 – as oral animal feed additive versus as an
intravenous medical treatment. However, Kühne II ’985 describes the field
broadly, stating that the chlorite solution can be used in medicine, veterinary
medicine, and as feed additives. FF7. Thus, Mullerat is still pertinent to
Kühne II ’985. Nonetheless, we have relied upon the ratio disclosed in
Mullerat for chlorite to chlorate (FF11) only to the extent that chlorite
solutions within the scope of the claim could be made and were routinely
used, as also evidenced by Inorganic Ventures (FF21).
We find that there was a fact-based reason at the time of the invention
to have utilized chlorite solutions with as low as possible chlorate to reduce
the likelihood of adverse events when administered intravenously as taught
by Kühne I ’922 and Immunokine (FF2, FF13), and because chlorate is
undesirable (FF4, FF5). Moreover, Patent Owner has not distinguished its
chlorite solution from the chlorite solution of Inorganic Ventures, nor from
Danner’s which is also for pharmaceutical use, specifically for application to
wounds on human skin (FF16).
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Dependent claim 12
Dependent claim 12 is directed to the “composition of claim 1,
wherein the concentration of chlorite is between about 1 M and about 1.5
M.”
While we recognize that the Examiner relied upon Mullerat as
teaching a composition having 1M chlorite (RAN 6), it was known in the art
to dilute a composition comprising chlorite prior to intravenous
administration as taught by Immunokine (FF9, FF15). In other words, while
a lower molarity might be desirable for administration purposes, it was
known to store a solution at a higher molarity prior to diluting it in an
appropriate diluent when preparing the chlorite solution for intravenous
administration. Consequently, absent evidence to the contrary, we discern
no criticality to the chlorite concentration. Thus, we do not find Patent
Owner’s argument based on Mullerat to be persuasive (Appeal Br. 15–16)
since the significance of a higher chlorite concentration for storage or other
purposes has not been established.

Dependent claim 13
Dependent claim 13 is directed to the “composition of claim 1,
wherein the weight ratio of chlorite:chlorate is greater than 100:0.5.”
Patent Owner contends that this claim is separately patentable because
“Mullerat further teaches away from selecting a low level of chlorate
because Mullerat teaches that chlorate is a beneficial additive.” Appeal Br.
16.
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We have already discussed that the preponderance of the evidence
supports the determination that it would have been obvious to minimize the
chlorate concentration because it described as undesirable (FF4, FF5) and is
admitted to have deleterious effects (FF2, FF13). Patent Owner has not
demonstrated the criticality of the claimed ratio.
[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…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).

Dependent claims 14–16
Dependent claims 14 and 15 are directed to particular weight ratios of
chlorite to sulfate, i.e., “greater than 100: 16.4” and “greater than 100: 1.6,”
respectively. Claim 16 is to no more than 1 part sulfate in 1000 per weight
of solvent. Thus, claims 14–16 read on as little as de minimus amounts.
The Examiner relied upon Shahangian and Inorganic Ventures for
their teaching of chlorite solutions within the scope of claim 1. RAN 5, 9,
15 (“The rejection states that it would have been obvious to modify the
chlorite containing solution of Kühne I by replacing WF10 with a solution of
sodium chlorite containing a minimal amount of chlorate, adjusted to
physiological pH with phosphate buffer.”). There is no evidence that these
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solutions comprise sulfate. The Examiner also found that Mullerat describes
a chlorite solution lacking sulfate. RAN 6.
Patent Owner contends that all Mullerat’s examples comprise sulfate.
Appeal Br. 16.
However, Mullerat does not require sulfate to be present in any
particular amount or the presence of sulfate at all. Rather, Mullerat states
that “sulfates can also be utilized to retard the formation of chlorine dioxide”
(Mullerat, col. 4, ll. 38–44), indicating that sulfates may be included when it
is desired to control the level of chlorine dioxide. While the working
examples of Mullerat may all contain sulfate, there is no teaching that the
amount present is the only workable amount or that the sulfate is even
necessary. To the extent this disclosure could be interpreted as a preference
for sulfate, a non-preferred embodiment, i.e., chlorite without sulfate, is not
any less a prior art disclosure than a preferred embodiment, but rather simply
reflects the inventor’s choice of one suitable alternative for another.
Moreover, Patent Owner has distinguished Mullerat’s compositions as
being feed additives, not pharmaceutical preparations for intravenous use.
Appeal Br. 13–14. Consequently, the need for a retardant in the quantities
described by Mullerat might be different when the chlorite is used as an
additive to water for oral ingestion by animal as taught by Mullerat (FF10),
rather than when used as a pharmaceutical composition for intravenous use
as taught by Kühne I ’922 or Immunokine. Patent Owner did not direct us to
evidence that sulfate is must be present in any particular amount or is
necessary in a composition intended for intravenous administration.
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Nonetheless, even if sulfate is present as a retardant in an intravenous
compositoin, it would have been obvious to determine an effective amount
when used in a pharmaceutical composition because it is a result-effective
parameter that would require only routine optimization to determine such
effective amount. We have not been directed to evidence to the contrary.
In addition to this, McGrath II, which discloses a composition for
intravenous solution, expressly teaches that the sulfate present in WF10 is an
“inactive ingredient[ ].” FF20. Accordingly, one of ordinary skill in the art
would have regarded the sulfate as dispensable and non-critical and that de
minimus amounts of sulfate are suitable for use.

Claim 17
Dependent 17 is directed to the “composition of claim 1, wherein the
weight ratio of chlorite:chloride is greater than 100:10.”
Patent Owner contends that the recited ratio is non-obvious because:
In view of the teachings of Mullerat, a skilled person would
have been taught away from selecting a chlorite:chloride range
greater than 100:10 because Mullerat discloses that “sodium
chloride and potassium chloride are especially useful because of
their cost and solubility” (col. 3, lines 61-62).
Appeal Br. 16.
We have not been directed to evidence that the presence of chloride
ion in a chlorite composition for intravenous use is necessary. Thus, while
Mullerat may teach its presence when the composition is used for oral
administration to animals, this teaching does not lead to a determination that
it necessary for a pharmaceutical composition for intravenous use or in any
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particular amount. McGrath II, which discloses a composition for
intravenous use, expressly teaches that the chloride present in WF10 is an
“inactive ingredient[ ].” FF19. Accordingly, one of ordinary skill in the art
would have regarded the chloride ion as dispensable and non-critical. In
regards to the amounts which are claimed, Inorganic Ventures, for example,
contains only a small amount of chloride (6± 1 μg/ml) as compared to
chlorite (998 ± 3 μg/ml).

Buffer and pH limitation
Rejection
Claim 1 recites that the composition comprises “(b) a phosphate
buffer; and (c) a pharmaceutically acceptable excipient; wherein the
composition is a sterile intravenous solution having a pH between about 7
and about 9.5.”
The Examiner cited Mullerat for its teaching of a phosphate buffered
chlorite solution. RAN 5. The Examiner also cited Tissot for adjusting the
pH to 7.4 of a chlorite solution with phosphate buffered saline prior to
administration, and Danner for a metal chlorite solution for medical
applications. Id.
The Examiner found that “it was known in the art that solutions of
pharmaceuticals in general, and sodium chlorite in particular, should be
adjusted to physiological pH prior to injection, as shown by Tissot.” Id. at 6.

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Patent Owner’s argument
Patent Owner contends that Mullerat teaches that the pH is adjusted to
13 to provide stability over long periods of storage, and, thus, teaches away
from the claimed range. Appeal Br. 12. Patent Owner also contends that the
lower ranges described in Tissot are not pertinent since Tissot is not a
solution for intravenous use. Id.
Patent Owner further argues that Kühne II ’285 also teaches a chlorite
solution having a high pH and that lower pH can result in toxic chlorine gas.
Id. at 12–13.
Patent Owner states that “None of the references cited by the
Examiner even attempt to teach the skilled person how the pH could be
safely lowered.” Id. at 13.

Discussion
WF10, a commercially available chlorite solution which has been
used intravenously, has been described as having a pH of 12.3 (FF1) or
diluted to a medicinal solution of a pH of 11.45–11.6 (FF9). The issue is
whether it would have been obvious to one of ordinary skill in the art to have
adjusted the pH of the chlorite solution of the claims to a pH of “about 7 and
about 9.5” in a phosphate buffer.
While the intravenous chlorite solutions of WF10 described in the
prior art have a higher pH than the claimed range, the Examiner provided
evidence of chlorite solutions used physiologically that are within the
claimed pH range and which are buffered with phosphate.
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Specifically, Tissot describes a chlorite solution adjusted to pH 7.4
and diluted with a phosphate buffered saline. FF14. While Tissot’s solution
is not used intravenously, it is introduced into a cellular environment of the
pleural cavity of rats or in contact with cells. FF14.
Danner also describes a chlorite solution with a pH range overlapping
with the claimed range. FF16. Danner teaches that the chlorite solution can
be buffered with phosphate. FF17. While Danner’s chlorite composition is
applied to the skin, it is used for wound healing and, thus, would be in
contact with cells, as would be an intravenous solution.
Consequently, contrary to Patent Owner’s contentions, we conclude
that both Tissot and Danner provide relevant guidance on how to make a
chlorite solution which is placed in contact with cells for medical uses.
Additional evidence is provided by Immunokine. Immunokine is
package insert for the intravenous use of WF10. While Immunokine does
not specifically disclose a pH nor phosphate buffer, it indicates that the
chlorite solution is diluted in a suitable diluent. FF15. Each of Tissot and
Danner teach that a phosphate buffer is suitable as a diluent for in vivo use,
and such a buffer is used for solutions of target pH of about 7.0 (1st Martin
Decl. ¶ 13). Thus, a pH of about 7 would have been obvious when a
phosphate buffer is utilized as a diluent.
While Mullerat describes a pH of 13 for storage, Mullerat also
describes a suitable pH range beginning at 7.5. FF12. Thus, we do not see
how a pH of 13 can be a teaching away from the claim range of 7.5 to 9,
when Mullerat expressly teaches a pH as low as 7.5 as suitable for a chlorite
solution. Moreover, as discussed above, the teachings in Tissot and Danner
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are even more pertinent because their compositions are placed in contact
with cells – as is an intravenous solution. Indeed, the claims are not
restricted to a composition for intravenous use, but would read on the
pharmaceutical compositions of Tissot and Danner.
With regard to the claimed pH of about 7 and above, as acknowledged
by Patent Owner, an acid pH (below 7) is known to be undesirable. Appeal
Br. 12–13; FF6. Consequently, the skilled worker would have reason to
have utilized a chlorite composition with a pH of about 7 or above.
In sum, it would have been obvious to have made a chlorite solution
with a phosphate buffer having a pH of about 7 or above because these
conditions are suitable and conventional for medical applications of chlorite
solutions (FF6, FF14, FF16–FF18). Moreover, Immunokine discloses
diluting a chlorite solution with a “suitable” diluent prior to use
intravenously (FF15), and Tissot and Danner disclosure a phosphate buffer
as suitable for in vivo medical applications.

Unexpected results
A showing of “unexpected results” can be used to demonstrate the
non-obviousness of the claimed invention. In re Soni, 54 F.3d 746, 750 (Fed
Cir. 1995) (“One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of ‘unexpected results,’ i.e., to show that
the claimed invention exhibits some superior property or advantage that a
person of ordinary skill in the relevant art would have found surprising or
unexpected.”). Patent Owner provided evidence said to establish unexpected
results for the rejected claims.
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Hemoglobin toxicity
The first McGrath declaration was provided during the prosecution of
the patent to show that “sodium chlorite formulated according to claims 21
or 27 has reduced hemoglobin toxicity compared to WF10 when
administered to human patients.” 1st McGrath Decl. ¶ 3. Claims 21 and 27
correspond to claims 1 and 2 of the issued patent.
Dr. McGrath stated in his declaration that “[h]ematologic problems
including red blood cell loss (‘hemoglobinemia’) have been reported for
WF10 by Veerasarn et al. (Radiotherapy and Oncology, 73 (2004) 179–
185).” 1st McGrath Decl. ¶ 4. Dr. McGrath explains that hemoglobinemia
is a potentially dangerous condition. Id. at ¶ 5. Dr. McGrath states that
Veerasarn’s study showed “74% of patients receiving WF10 were found to
have hemoglobinemia compared to 35% of control patients.” Id. at ¶¶ 7, 9,
11. In contrast, Dr. McGrath describes a clinical study performed using
“[s]odium chlorite formulated according to claims 21 or 27” which “shows
no evidence of causing hemoglobinemia.” Id. at ¶ 13.
Requester provided a declaration by Henrich Guntermann, M.D., to
rebut the McGrath Declaration. While Dr. Guntermann challenges Dr.
McGrath’s statements about the hematologic problems observed in
Veerasarn (Guntermann Decl. 7–9, 13), Veerasarn explicitly states that
“transient hemoglobinaemia” was “occasionally observed in patients treated
with WF10.” Veerasarn 183 (Section 3.4). Dr. Guntermann did not provide
adequate evidence to doubt the credibility of this statement in Veerasarn.
Dr. McGrath stated:
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In the attached Figure 2, 12 ALS patients were selected at
random to receive 0, 1, or 2 mg/kg sodium chlorite formulation.
The results of the Phase 2 trial have not yet been unblinded, so
the actual dose of sodium chlorite cannot yet be assigned to
individual patients. However, as seen in Figure 2, no significant
differences were observed between levels of hemoglobin before
and after treatment, regardless of sodium chlorite formulation
dose.
1st McGrath Decl. ¶ 14.
Dr. Guntermann testified in response that, across all the treatment
protocols, “hemoglobin levels at the second post-treatment time point
(labeled "HGB post 2" in Figure 2) are always below the pretreatment
hemoglobin levels (labeled "HGB pre" in Figure 2), with the possible
exception of patient 4 where pre and post treatment levels appear very
comparable.” Guntermann Decl. ¶ 23. Because of the lack of discussion by
Dr. McGrath of this apparent decline in hemoglobin levels, Dr. Guntermann
found the “the scientific validity of the assertions made in the McGrath
Declaration” to be undermined. Id.
While it is true that Dr. McGrath did not explain the apparent decline
in hemoglobin levels, Dr. Guntermann did not provide adequate reason to
doubt Dr. McGrath’s conclusion that that there was no significant change in
hemoglobin level during the clinical study. At least one of these dosages
was 2 mg, which is about the amount administered in the Veerasarn study.
Thus, while the clinical study described by Dr. McGrath might not be
completely comparable to Veerasarn as discussed by Dr. Guntermann
(¶¶ 16, 17, 19), the study does have some pertinence in showing that the
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administered formulation did not produce hemoglobaemia as observed by
Veerasarn (1st McGrath Decl. ¶¶ 13, 16).
Nonetheless, the data is not persuasive for at least two independent
reasons.
First, as stated by Dr. Guntermann, Dr. McGrath did not disclose the
formulation which was administered to the patients. He stated that the
sodium chlorite was formulated according to claims 21 and 27 (the claim
numbers during the prosecution which led to the ’035 patent), but these
claims – now claims 1 and 2 in the issued patent – cover a range of weight
ratios of chlorite to chlorate, a range of pH values, and a range of chlorite
concentrations. Dr. McGrath did not disclose the chlorite:chlorate ratio, the
concentration of chlorite, nor the pH of the formulation administered.
Unexpected results must be “commensurate in scope with the degree of
protection sought by the claimed subject matter.” In re Harris, 409 F.3d
1339, 1344 (Fed. Cir. 2005). Dr. McGrath did not explain how the results
for an apparently single composition, which is not even identified, establish
unexpected results for the full scope of the claim.
Second, as acknowledged by Patent Owner, it was known that sodium
chlorate may cause undesirable effects when administered. FF2, FF13.
Consistently, Veerasarn describes hemoglobinanemia in patients when
WF10 was administered (Veerasarn 183), which was known to comprise
chlorate ion. Thus, Dr. Guntermann’s statement that “such results would not
have been surprising or unexpected, given the known toxicity of chlorate
and its association with hemoglobinemia” is supported by a preponderance
of the evidence. Guntermann Decl. ¶ 26.
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pH stability
Dr. McGrath stated in his declaration that he “observed unexpected
results for the pH stability of sodium chlorite in formulations neutralized
with phosphate buffer according to the claims compared to other buffers.”
2nd McGrath Decl. ¶ 5. Dr. McGrath stated that the sodium chlorate was
“pH’d to 7 in the presence of water, citrate (cit), carbonate (car), borate
(bor), and phosphate (phos) buffers.” Id. at ¶ 7. Dr. McGrath further stated
that “As shown in Figure 1, phosphate buffer gives the greatest pH
stability.” Id. at 8.
This data is not persuasive. As explained in detail in the declaration
by Rainer Martin, “a skilled person working in the field in December of
2005 or December of 2006 would have expected an aqueous sodium chlorite
solution to exhibit stability when buffered to a pH of 7 with a phosphate
buffer.” 1st Martin Decl. ¶ 6. Dr. Martin provided a detailed scientific
explanation as to why it would have been expected that a phosphate would
be an effective buffer at pH 7 (id. at ¶ 13), and more effective than the other
buffers tested by Dr. McGrath (id. at ¶¶ 14–17). Patent Owner did not
identify a defect in Dr. Martin’s scientific reasoning. Appeal Br. 24.
Patent Owner also states “Martin's argument fails because Martin
ignores the fact that the claim recites a range between about pH 7 and about
pH 9.5, and because it is not obvious to one of skill in the art which buffer
system would be optimal over this range.” Id. However, despite Patent
Owner’s contention, the only pH studied in Dr. McGrath’s declaration was a
pH of 7. 2nd McGrath Decl. ¶ 7. Patent Owner did not explain how this
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result obtained at a pH 7 established that the buffering was optimal over the
entire range of about 7 to 9.5.
Summary
For the foregoing reasons, the obviousness Rejection 1 of claims 1
and 12–17 is affirmed. Claims 6–11 and 18 were not argued separately and
fall with claim 1.

REJECTIONS 2 AND 3
With respect to Rejections 2 and 3, Patent Owner referred to the same
arguments present for Rejection 1. Appeal Br. 18, 19. We have reviewed
these arguments and do not find Patent Owner in their discussion of the
rejections have further distinguished the claims over the additionally cited
prior art. Rejections 2 and 3 are affirmed for the same reasons as for
Rejection 1.

For the purposes of any appeal pursuant to under 35 U.S.C. §§ 141-
144 and 315 and 37 C.F.R. § 1.983, this Decision relies on each publication
cited in all each of the rejections as defining the scope and content of the
prior art. To the extent that any publication is not discussed in this Decision,
we rely on the Examiner’s findings of fact. In addition, as noted above, the
discussion focused on Rejection 1 because Patent Owner’s arguments
centered on this rejection. However, we consider these arguments
applicable to all rejections.

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TIME PERIOD FOR RESPONSE
In accordance with 37 C.F.R. § 41.79(a)(1), the “[p]arties to the
appeal may file a request for rehearing of the decision within one month of
the date of: . . . [t]he original decision of the Board under § 41.77(a).” A
request for rehearing must be in compliance with 37 C.F.R. § 41.79(b).
Comments in opposition to the request and additional requests for rehearing
must be in accordance with 37 C.F.R. § 41.79(c) & (d), respectively. Under
37 C.F.R. § 41.79(e), the times for requesting rehearing under paragraph (a)
of this section, for requesting further rehearing under paragraph (d) of this
section, and for submitting comments under paragraph (c) of this section
may not be extended.
An appeal to the United States Court of Appeals for the Federal
Circuit under 35 U.S.C. §§ 141–144 and 315 and 37 C.F.R. § 1.983 for an
inter partes reexamination proceeding “commenced” on or after November
2, 2002 may not be taken “until all parties’ rights to request rehearing have
been exhausted, at which time the decision of the Board is final and
appealable by any party to the appeal to the Board.” 37 C.F.R. § 41.81. See
also MPEP § 2682 (8th ed., Rev. 7, July 2008).
In the event neither party files a request for rehearing within the time
provided in 37 C.F.R. § 41.79, and this Decision becomes final and
appealable under 37 C.F.R. § 41.81, a party seeking judicial review must
timely serve notice on the Director of the United States Patent and
Trademark Office. See 37 C.F.R. §§ 90.1 and 1.983.

AFFIRMED