Ex Parte 8445466 et al

Patent Trials and Appeals Board

Mar 4, 2019

90013933 - (D) (P.T.A.B. Mar. 4, 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.
90/013,933 04/07/2017 8445466 211960-0001(573570) 7875
123223 7590 03/05/2019
Drinker Biddle & Reath LLP (WM)
222 Delaware Avenue, Ste. 1410
Wilmington, DE 19801-1621
EXAMINER
DIAMOND, ALAN D
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
03/05/2019 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
____________

Ex parte JHO INTELLECTUAL PROPERTY HOLDINGS, LLC
Patent Owner and Appellant
____________

Appeal 2019-001597
Reexamination Control 90/013,933
Patent 8,445,466 B2
Technology Center 3900
____________

Before RICHARD M. LEBOVITZ, JEFFREY B. ROBERTSON, and
JANE E. INGLESE, Administrative Patent Judges.

INGLESE, Administrative Patent Judge.

DECISION ON APPEAL
JHO Intellectual Property Holdings, LLC, the owner of the patent
under reexamination (“the 466 Patent”), appeals under 35 U.S.C. §§ 134(b)
and 3061 from a final rejection of claims 1 and 5–12.2 We have jurisdiction
under 35 U.S.C. §§ 134(b) and 306.
We AFFIRM3.

1 Appeal Brief filed August 29, 2018 (“App. Br.”).
2 Final Office Action entered February 1, 2018 (“Final Act.”).
3 We heard oral arguments from Appellant’s representative on February 12,
2019.
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STATEMENT OF THE CASE
This reexamination proceeding is based on a third-party request for ex
parte reexamination of US 8,445,466 filed by ThermoLife International,
LLC on April 7, 2017.
The 466 Patent states that the invention provides stable aqueous
compositions of amide-protected, biologically-active creatine (creatyl-
amide). Col. 3, ll. 22–24.
Claim 1, the sole independent claim on appeal, reads as follows, with
underlining included to show language added, and brackets included to show
language removed, relative to the originally issued claim:
1. An aqueous composition for administering, to a mammal,
an amide-protected, biologically active form of creatine that is
stable in an aqueous system, wherein said composition
comprises:
a) at least one creatyl-amide species, and
b) water;
wherein, [in] said creatyl-amide species[, the carboxylic
acid group of creatine is linked, via an amide bond, to an amino
group of a species selected from the group consisting of
glutamine, leucine, arginine, histidine, isoleucine, lysine,
methionine, threonine, tryptophan, tyrosine, valine, alanine,
asparagine, aspartate, cysteine, glutamate, glycine, proline,
serine, camosine, 1-methylhistidine, beta-alanyl-1-
methyihistidine sarcosine, -alanine, citrulline,
omithine, prolinamide, 5-hydroxylysine, alanyl-L-glutamine,
taurine, and geranarnine]is: creatyl-L-glutamine

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or
creatyl-L-leucine

wherein the aqueous composition has a pH of about 1.5 to
about 6.5; and
wherein the aqueous composition is stable for 90 days at 25ºC
and 4ºC.

App. Br. 17–18 (Appendix A) (emphasis added).

THE REJECTIONS
The Examiner maintains the following rejections in the Examiner’s
Answer entered October 10, 2018 (“Ans.”)4:

4 Due to Appellant’s cancellation of claim 2, the Examiner combined the
rejection set forth in the Final Action of claims 1 and 5–12 under 35 U.S.C.
§ 103(a) as unpatentable over Burov in combination with Gastner (Final Act.
6–14), and the rejection of claim 2 under 35 U.S.C. § 103(a) as unpatentable
over Burov in combination with Gastner, and alternatively, in further
combination with Nivaggioli (Final Act. 14–16), into a single rejection in the
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I. Claims 1 and 5–12 under 35 U.S.C. § 103(a) as unpatentable
over Burov5 in combination with Gastner6, and alternatively, in further
combination with Nivaggioli7; and
II. Claims 1 and 5–12 under 35 U.S.C. § 103(a) as unpatentable
over Burov in combination with Block8, and alternatively, in further
combination with Nivaggioli.

APPELLANT’S EVIDENCE
Appellant relies on certain parts of the following declarations and
report as evidence in support of patentability (App. Br. 20, Appendix B):
I. Declaration of Gregg B. Fields executed November 29, 2017
and filed August 29, 2018 (“First Fields Declaration”);
II. Declaration of Gregg B. Fields executed April 30, 2018 and
filed August 29, 2018 (“Second Fields Declaration”);
III. Declaration of Liangxi Li executed November 10, 2017 and
filed August 29, 2018 (“First Li Declaration”);

Answer (Rejection I above). Ans. 3–4. Similarly, the Examiner combined
the rejection set forth in the Final Action of claims 1 and 5–12 under
35 U.S.C. § 103(a) as unpatentable over Burov in combination with Block
(Final Act. 18–23), and the rejection of claim 2 under 35 U.S.C. § 103(a) as
unpatentable over Burov in combination with Block, and alternatively, in
further combination with Nivaggioli (Final Act. 23–25), into a single
rejection in the Answer (Rejection II above). Ans. 3–4. The Examiner
withdrew the remaining rejections set forth in the Final Action (Final Act. 3–
5, 16–18, and 25–42) in the Answer. Ans. 18–20.
5 Burov et al., RU 2354546, published May 10, 2009.
6 Gastner et al., US 8,506,989 B2, issued August 13, 2013.
7 Nivaggioli, US 2008/0003208 A1, published January 3, 2008.
8 Block, US 2,919,195, issued December 29, 1959.
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IV. Declaration of Liangxi Li executed April 30, 2018 and filed
August 29, 2018 (“Second Li Declaration”);
V. Expert Report of Gregg B. Fields executed January 30, 2017
and filed August 29, 2018 (“Fields Report”); and
VI. Declaration of Richard Chamberlin executed September 22,
2017 and filed August 29, 2018 (“Chamberlin Declaration”).
DISCUSSION
Upon consideration of the evidence relied upon in this appeal and
each of Appellant’s timely contentions9, we affirm the Examiner’s rejections
of claims 1 and 5–12 under 35 U.S.C. § 103(a) for the reasons set forth in
the Final Office Action, the Answer, and below.
Appellant argues claims 1 and 5–12 together on the basis of claim 1,
to which we accordingly limit our discussion. App. Br. 3–15; 37 C.F.R.
§ 41.37(c)(1)(iv). Because Appellant argues Rejections I and II together, we
likewise address these rejections together, keeping in mind that Rejection I
is based on Burov and Gastner alternatively with Nivaggioli, while Rejection
II is based on Burov and Block alternatively with Nivaggioli.

9 We do not consider any new argument that Appellant presents in the Reply
Brief that Appellant could have raised in the Appeal Brief, because
Appellant does not show good cause for raising any argument for the first
time in the Reply Brief. 37 C.F.R. § 41.37(c)(1)(iv); 37 C.F.R. § 41.41(b)(2)
(arguments raised for the first time in the Reply Brief that could have been
raised in the Appeal Brief will not be considered by the Board unless good
cause is shown). Nor do we consider the new evidence that Appellant
presents at page 4 of the Reply Brief because this evidence is not of record.
37 C.F.R. § 41.33(d)(2).
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The Examiner finds that Burov discloses creatine amides of the
formula:
NH=C(NH2)-N(CH3)-CH2-CONH-R*X
where R is an amino acid radical or a substituted amino acid radical, and X
is an organic acid, mineral acid, or water. Ans. 4 (citing Burov pp. 3, 10).
The Examiner finds that Burov discloses that the amino acid radical can be
formed from various aliphatic, aromatic, and heteroaromatic L-amino acids.
Ans. 4–5 (citing Burov p. 10, ll. 1–10). The Examiner finds that Burov
describes preparation of several creatyl-amino acid derivatives utilizing the
standard amino acids tyrosine and phenyalanine. Ans. 4, 22 (citing Burov,
Exs. 2, 5, 8, pp. 13–14, 16–18, 25–27).
The Examiner finds that although Burov does not explicitly disclose
creatine amides in which R of the above formula is an L-glutamine or L-
leucine radical (creatyl-L-glutamine or creatyl-L-leucine) as recited in claim
1, these amino acid radicals, like the L-phenylalanine and L-tyrosine radicals
exemplified in Burov, are radicals of standard amino acids. Ans. 5.
Burov discloses that creatine has broad application in medicine for
treating diseases of the nervous system, including Alzheimer’s disease and
Parkinson’s disease. Burov pp. 5–6. Burov discloses that creatine is poorly
absorbed from the gastrointestinal tract, necessitating administration of high
doses in order to be effective. Burov p. 6. To address this problem, as the
Examiner finds, Burov discloses that the creatine amides described in the
reference “have increased solubility and stability in aqueous solutions in
comparison with known analogs, which allows for them to be used more
extensively as a creatine source in the body.” Ans. 5 (citing Burov p. 10).
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The Examiner concludes that it would have been obvious to one of
ordinary skill in the art at the time of the invention to prepare a creatine
amide of the formula disclosed in Burov in which R is an L-glutamine or L-
leucine radical (creatyl-L-glutamine and creatyl-L-leucine), in view of
Burov’s disclosure that R can be various aliphatic, aromatic, and
heteroaromatic L-amino acids, and because L-leucine and L-glutamine
radicals, like the L-phenylalanine and L-tyrosine radicals exemplified in
Burov, are radicals of standard amino acids. Ans. 5. The Examiner finds
that the skilled artisan would have had a reasonable expectation that creatyl-
L-glutamine and creatyl-L-leucine would exhibit increased solubility and
stability in aqueous solutions in comparison with known analogs, allowing
the compounds to be used more extensively as a source of creatine in the
body, as disclosed in Burov. Id.
The Examiner alternatively relies on Nivaggioli for suggesting a
creatine amide of the formula disclosed in Burov in which R is an L-leucine
or L-glutamine radical. Ans. 5–6. Specifically, the Examiner finds that
Nivaggioli discloses a compound in which creatine is covalently bound to a
ligand, which Nivaggioli discloses can be a standard amino acid, such as
leucine, glutamine, tyrosine, or phenylalanine. Ans. 5 (citing Nivaggioli
Abstract; ¶¶ 22, 33–34). The Examiner finds that Nivaggioli discloses that
the creatine-ligand compound can be used to treat neurological disorders,
such as Huntington’s disease and Parkinson’s disease, similar to Burov’s
disclosure that the creatine amides described in the reference have a
neuroprotective effect, and can be used to prevent and treat ischemic brain
damage. Ans. 5 (citing Nivaggioli Abstract; ¶¶ 22, 42–71 and Burov p. 11).
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The Examiner concludes it would have been obvious to one of
ordinary skill in the art at the time of the invention to prepare a creatine
amide as disclosed in Burov in which R in the formula disclosed in the
reference is an L-leucine or L-glutamine radical, in view of Burov’s
disclosure that R can be various aliphatic, aromatic, and heteroaromatic L-
amino acid radicals, Nivaggioli’s disclosure of a creatine-ligand compound
in which creatine is covalently bound to a ligand that can be a standard
amino acid such as leucine, glutamine, tyrosine, or phenylalanine, and the
disclosure in both references of using the described creatine compounds to
treat neurological disorders. Ans. 6. The Examiner finds that the skilled
artisan reasonably would have expected the suggested creatyl-L-glutamine
and creatyl-L-leucine compounds to exhibit increased solubility and stability
in aqueous solutions in comparison with known analogs, allowing the
compounds to be used more extensively as a source of creatine in the body,
as disclosed in Burov. Id.
The Examiner finds that although Example 10 of Burov describes
aqueous solutions of numerous creatine amides that have a pH of 7 or 7.2,
including an aqueous solution of creatyl-tyrosine amide succinate having a
pH of 7.2 (the compound of Burov’s Example 5), Burov does not disclose an
aqueous composition having a pH of from about 1.5 to about 6.5 as recited
in claim 1. Ans. 7 (citing Burov Table 3). The Examiner relies on Gastner
to address this feature in Rejection I, and relies on Block to address this
feature in Rejection II. Ans. 7–9, 15–16.
Specifically, for Rejection I, the Examiner finds that Gastner discloses
that creatine is highly unstable in aqueous solutions, and is converted in such
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solutions to creatinine via a pH-dependent process, which proceeds rapidly
at a pH of between 3 and 4. Ans. 7 (citing Gastner col. 3, ll. 27–40). The
Examiner finds that Gastner discloses a preparation that overcomes this
stability problem and comprises a creatine component and a buffer system
consisting of at least one sodium salt of an organic acid. Ans. 7–8 (citing
Gastner col. 3, ll. 61–65). The Examiner finds that Gastner discloses that it
is essential that the preparation has a pH of 2.5 to 7.9, which overlaps the pH
range recited in claim 1. Ans. 8, 9 (citing Gastner col. 3, ll. 61–65); see also
Gastner col. 4, ll. 37–39. The Examiner finds that Gastner discloses that the
creatine component is preferably an addition compound of creatine with
methionine, among others. Ans. 7–8 (citing Gastner col. 4, ll. 8–28). The
Examiner finds that Gastner discloses that “the creatine is surprisingly well
protected from the influence of acids” and “[u]sing the described buffer
systems would thus appear to be ideal, since on the one hand the stability of
the creatine to acids is increased and thus the breakdown of creatine in the
stomach is avoided.” Ans. 28 (citing Gastner col. 4, ll. 52–55; col. 5, ll. 34–
37). The Examiner finds that Gastner discloses that the preparation
constitutes “a further development of the prior art in terms of an increase in
stability of creatine preparations and a substantial improvement in
bioavailability.” Ans. 11 (citing Gastner col. 6, ll. 50–52).
The Examiner concludes that it would have been obvious to one of
ordinary skill in the art at the time of the invention to use the creatine-L-
glutamine or creatine-L-leucine suggested by Burov, optionally in
combination with Nivaggioli, as the creatine component in Gastner’s
preparation, because Gastner discloses that the creatine component can be an
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addition compound of creatine and an amino acid (methionine), to produce a
very stable acidic aqueous composition of creatine-L-glutamine or creatine-
L-leucine. Ans. 8–9, 28.
The Examiner determines that this aqueous composition suggested by
the combined disclosures of Burov, optionally in combination with
Nivaggioli, and Gastner containing the buffer system disclosed in Gastner
and the creatine-L-glutamine or creatine-L-leucine suggested by Burov,
optionally in combination with Nivaggioli, is essentially the same as the
composition recited in claim 1, and therefore would be stable for 90 days at
25ºC and at 4ºC as recited in claim 1, because “the discovery of a previously
unappreciated property of a prior art composition, or of a scientific
explanation for the prior art’s functioning, does not render the old
composition patentably new to the discoverer.” Ans. 9–11 (citing Atlas
Powder Co. v. IREGO Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999)).
For Rejection II, the Examiner finds that Block discloses an enriched
fruit juice composition that includes creatine and has a pH of from about 3.5
to about 4.5. Ans. 15 (citing Block col. 1, ll. 15–47; col. 1, l. 69–col. 2, l. 2;
col. 2, ll. 51–65).
The Examiner concludes that it would have been obvious to one of
ordinary skill in the art at the time of the invention to use the creatine-L-
glutamine or creatine-L-leucine suggested by Burov, optionally in
combination with Nivaggioli, “in place of creatine in Block’s enriched fruit
juice” because creatine is poorly absorbed from the gastro-intestinal tract,
and Burov discloses that creatine amides have a broad spectrum of
biological action and increased solubility and stability in aqueous solutions
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in comparison with known analogs, allowing creatine amides to be used
more extensively as a creatine source in the body. Ans. 15–16.
The Examiner determines that the enriched fruit juice suggested by
the combined disclosures of Burov and Block containing the creatine-L-
glutamine or creatine-L-leucine suggested by Burov, optionally in
combination with Nivaggioli, is essentially the same as the composition
recited in claim 1, and therefore would be stable for 90 days at 25ºC and at
4ºC as recited in claim 1, because “the discovery of a previously
unappreciated property of a prior art composition, or of a scientific
explanation for the prior art’s functioning, does not render the old
composition patentably new to the discoverer.” Ans. 16. (citing Atlas
Powder, 190 F.3d at 1347).
Appellant argues that Burov provides only “a generic linear structure”
for the creatyl amide compounds disclosed in the reference. App. Br. 11–12.
Appellant contends that although Burov discloses that the R group in
Burov’s formula is an amino acid radical or substituted amino acid radical
that can be various aliphatic, aromatic, and heteroaromatic L-amino acids or
derivatives thereof, Burov “does not disclose the use of L-leucine or L-
glutamine specifically.” App. Br. 11–12; Reply Br. 3–4. Appellant argues
that the mere existence of L-leucine or L-glutamine “is insufficient to
suggest their use over any other potential amino acids.” App. Br. 12; Reply
Br. 4–5.
Although Burov does provide a “generic” structure or formula for the
creatyl amide compounds described in the reference, Burov explicitly
discloses that the R group in the formula is an amino acid radical, and Burov
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exemplifies preparation of creatyl-phenylalanine chlorohydrate, which
includes a radical of the standard amino acid phenylalanine, and creatyl-
tyrosine amide succinate, which includes a radical of the standard amino
acid tyrosine. Ans. 22 (citing Burov pp. 25–27 (Example 8); Burov pp. 13–
14 and 16–18 (Examples 2 and 5)). Accordingly, Burov’s disclosure
reasonably would have suggested to one of ordinary skill in the art that the R
group of Burov’s formula includes radicals of standard amino acid. In re
Boe, 355 F.2d 961, 965 (CCPA 1966) (All of the disclosures in a prior art
reference “must be evaluated for what they fairly teach one of ordinary skill
in the art.”). Given the existence of only twenty standard amino acids, the
skilled artisan would have readily envisaged all possible radicals of standard
amino acids, including radicals of L-glutamine and L-leucine, as recited in
claim 1, rendering use of such amino acid radicals for the R group in
Burov’s formula prima facie obvious.
Furthermore, as the Examiner correctly finds, Nivaggioli discloses a
compound useful for treating neurological disorders, such as Huntington’s
disease and Parkinson’s disease, comprised of creatine covalently bound to a
ligand, which Nivaggioli discloses can be any standard amino acid. Ans. 5
(citing Nivaggioli Abstract; ¶¶ 22, 33–34, and 42–71). Implicit in this
disclosure is a teaching that each of the standard amino acids—including
leucine, glutamine, tyrosine, and phenylalanine—can be used
interchangeably as a ligand for forming the creatine-ligand compound
described in Nivaggioli. In re Preda, 401 F. 2d 825, 826 (CCPA 1968)
(“[I]t is proper to take into account not only specific teachings of the
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reference but also the inferences which one skilled in the art would
reasonably be expected to draw therefrom.”).
Contrary to Appellant’s arguments, Burov’s exemplification of
creatyl-phenylalanine and creatyl-tyrosine compounds, and disclosure that
the compounds have a neuroprotective effect and can be used to prevent and
treat ischemic brain damage, in combination with Nivaggioli’s disclosure of
compounds useful for treating neurological disorders, such as Huntington’s
disease and Parkinson’s disease, comprised of creatine covalently bound to
any of the standard amino acids, reasonably would have suggested binding
creatine to L-glutamine or L-leucine to form creatyl-L-glutamine or creatyl-
L-leucine, as recited in claim 1, to produce compounds potentially useful for
treating neurological disorders, to one of ordinary skill in the art at the time
of Appellant’s invention. In re Fout, 675 F.2d 297, 301 (CCPA 1982)
(“Express suggestion to substitute one equivalent for another need not be
present to render such substitution obvious.”).
Appellant argues that although “Dr. Fields has previously opined that
Nivaggioli discloses creatinyl-amino acid, the Office has previously
considered and found persuasive a Declaration executed by Dr. Chamberlin,
which in part states that ‘Nivaggioli does not teach creatine-ligand
compounds.’” App. Br. 13 (citing the Fields Report pp. 11–12 and the
Chamberlin Declaration). Appellant argues that Nivaggioli, like Burov,
therefore does not disclose or suggest use of L-leucine or L-glutamine. App.
Br. 13; Reply Br. 6.
Appellant appears to be referring to paragraph 24 of the Chamberlin
Declaration, which states:
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Nivaggioli misuses the term “ligand,” which in biochemistry is
defined as a small molecule that binds to a biomacromolecule
(e,g., a protein) via non-covalent intermolecular forces, such as
ionic bonds, hydrogen bonds and Van der Waals forces. While
some of the Nivaggioli preparations may be salts (notably, the
creatine ascorbate studied in the examples of the patent
application), the inferred method of preparing them suggests that
instead they are simple mixtures of finely divides solids, with no
chance for any sort of true complexation between components,
Consequently, Nivaggioli docs not teach creatine-ligand
compounds.

This opinion expressed in the Chambers Declaration, however, does
not take into consideration Nivaggioli’s explicit definition of “ligand” as “an
atom or molecule which binds to creatine through covalent or electrostatic
interactions.” Nivaggioli ¶ 33. Nor does it take into consideration
Nivaggioli’s explicit definition of a “creatine-ligand compound” as “a
compound in which creatine is bound to another atom or molecule through
covalent or electrostatic interactions.” Id. As discussed above, Nivaggioli
indicates that the “ligand” defined in the reference can be an amino acid, and
explicitly defines “amino acid” as “any molecule that contains both an
amino acid and a carboxylic acid functionality and includes standard and
non-standard amino acids.” Nivaggioli ¶ 34. Nivaggioli goes on to list each
of the standard amino acids, explicitly mentioning glutamine and leucine.
Id. Accordingly, although Nivaggioli may not use the term “ligand” in strict
conformity with the term’s biochemical definition as the Chambers
Declaration asserts, in view of Nivaggioli’s disclosures as a whole, one of
ordinary skill in the art nonetheless would have understood that Nivaggioli
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discloses compounds in which creatine is covalently bound to a standard
amino acid, such as glutamine or leucine.
Appellant argues that “even if the skilled artisan were to find
suggestion to use L-leucine or L-glutamine” as the amino acid radical in
Burov’s creatyl amide formula “there is no guarantee the specific structure,
with the specific orientation, required by the claims would have been
achieved.” App. Br. 13–14. Appellant argues that Burov requires the
creatyl amide compounds disclosed in the reference to be in either hydrated
or acid form (due to the “X” component in Burov’s formula), and “[n]either
of the structures provided in the instant claims require this ‘X’ component.”
Id.
It is unclear what Appellant means by the “specific orientation” of the
“specific structure . . . required by the claims.” Claim 1 recites an aqueous
composition comprising water and at least one creatyl-amide species that is
either creatyl-L-glutamine or creatyl-L-leucine, and claim 1 provides a
structure for both species. Due to the open nature of the “comprising”
transition recited in claim 1, the claim does not exclude additional, unrecited
components from the recited composition, such as a hydrate or acid
complexed to the recited creatyl-amide species, as disclosed in Burov.
Gillette Co. v. Energizer Holdings, Inc. 405 F.3d 1367, 1371–1372 (Fed.
Cir. 2005) (“The word ‘comprising’ transitioning from the preamble to the
body signals that the entire claim is presumptively open-ended.”).
Accordingly, as the Examiner correctly finds (Ans. 36), although claim 1
does not require the recited creatyl-L-glutamine or creatyl-L-leucine species
to be in the hydrate or acid form, claim 1 does not exclude an organic acid, a
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mineral acid, or water complexed to the recited creatyl-L-glutamine and
creatyl-L-leucine species.
Appellant argues that even if substituting L-leucine or L-glutamine for
the L-phenylalanine and L-tyrosine radicals exemplified in Burov would
have been obvious because all four radicals are radicals of standard amino
acids, or due to Nivaggioli’s suggestion of such a substitution, “there is no
reason for the skilled artisan to expect that making the particular creatyl-
amides required by the claims would have resulted in long term stability at
relatively low pH at room temperature and lower for a prolonged period of
time in aqueous solution” because none of the applied prior art references
“adequately suggests this to the skilled artisan in a manner to create prima
facie obviousness.” App. Br. 6–7, and 13. Appellant further provides
numerous arguments for why each of Burov, Gastner, and Block would not
have suggested stability for 90 days at 25ºC and 4ºC as recited in claim 1, as
discussed below. App. Br. 6–11, and 14.
For Burov, Appellant argues that the reference only refers to
“stability” in the context of a time period of three hours, and only in
solutions having neutral pH. App. Br. 7. Appellant argues that Burov
makes clear that “the goal is stability at a body pH sufficient for creatine to
enter the system” and “make it to the relevant systems without degradation,”
which “has nothing to do with potential long-term storage in aqueous
solution.” App. Br. 7, 9 (citing Burov p. 5). Appellant argues that the
solutions of Burov’s Examples 9 and 10, which did not include the creatyl
amide species required by the amended claims, had neutral pH, included
buffers to ensure maintenance of the neutral pH, and “showed degradation of
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the creatyl compound of potentially 3%” during a period of three hours.”
App. Br. 7 (citing Burov p. 29).
Appellant argues that the data presented in Tables 1 and 2 of Burov
show that stability “even at a time period of three hours” varied widely
depending on the particular species tested. App. Br. 7. Appellant argues
that the species of Example 7, which was derived from substituted
phenylalanine, showed only 85% remaining at 3 hours. Id. Appellant
argues that because Burov “appears to show certain species described
therein do not hold stability for even three hours at a neutral pH, it would
stand to reason that this instability would be even greater at lower pH, such
as those required by the claimed invention.” App. Br. 9. Appellant argues
that “Dr. Fields and Dr. Li have both noted in their declarations that the
reactivity, stability, and solubility of amino acids and peptides change
substantially with a change in pH.” App. Br. 9 (citing First Fields
Declaration ¶ 8 and First Li Declaration ¶ 5).
Appellant argues that the data presented in Burov show that stability
for 90 days at 25ºC and 4ºC as recited in claim 1 is not inherent in the
disclosure of Burov. App. Br. 8. Appellant argues that “Examples are
presented” in Burov that “fail to exhibit the required stability at 3 hours at
neutral pH, let alone at 90 days at lower pH as required by the claims
presented herein,” and the stability recited in claim 1 therefore “cannot be
said to necessarily be present” in Burov. App. Br. 8–9.
We note initially that the portions of the First Fields Declaration and
the First Li Declaration cited by Appellant do not state that “the reactivity,
stability, and solubility of amino acids and peptides change substantially
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with a change in pH” as Appellant asserts, but, rather, both Declarations
state that “many creatine solutions, originally thought to provide bioactive
creatine, degrade quickly and only provide creatinine, and therefore are not
an effective means of supplying creatine to the body.” First Fields
Declaration ¶ 8 and First Li Declaration ¶ 610.
More importantly, Appellant’s numerous arguments for Burov are
improperly based on Burov alone, and do not take into consideration what
the combined disclosures of Burov, Nivaggioli, and Gastner would have
suggested to one of ordinary skill in the art at the time of the invention. In
re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (“Non-obviousness
cannot be established by attacking references individually where the
rejection is based upon the teachings of a combination of references.”); In re
Keller, 642 F.2d 413, 425 (CCPA 1981) (The test for obviousness “is what
the combined teachings of the references would have suggested to those of
ordinary skill in the art.”)
As the Examiner correctly finds and as discussed above, Gastner
discloses a solution to the known problem of creatine’s instability in aqueous
solutions in the form of a preparation comprising a creatine component and a
buffer system consisting of at least one sodium salt of an organic acid. Ans.
7–8 (citing Gastner col. 3, ll. 61–65). As the Examiner also correctly finds
and as also discussed above, Gastner discloses that the preparation has a pH
of 2.5 to 7.9—overlapping the pH range recited in claim 1—and Gastner

10 Although Appellant cites paragraph 5 of the first Li Declaration, Appellant
appears to actually refer to paragraph 6, in light of the fact that paragraph 8
of the first Fields Declaration and paragraph 6 of the first Li Declaration,
rather than paragraph 5, both include the statement quoted above.
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discloses that the creatine component is preferably an addition compound of
creatine with the amino acid methionine, among others. Ans. 7–9 (citing
Gastner col. 3, ll. 61–65; col. 4, ll. 8–28).
In view of Gastner’s disclosure that the preparation is “a further
development of the prior art in terms of an increase in stability of creatine
preparations and a substantial improvement in bioavailability,” and due to
the similarity of the methionine creatine addition compound disclosed in
Gastner and the creatine amide compounds of Burov’s formula in which R is
an L-glutamine or L-leucine radical, suggested by the combined disclosures
of Burov and Nivaggioli, one of ordinary skill in the art reasonably would
have been led to use the buffer system disclosed in Gastner for an aqueous
composition as disclosed in Burov that includes the suggested creatyl-L-
glutamine and creatyl-L-leucine compounds, to allow the compounds to be
used “as a creatine source in the body” as desired by Burov. The pH of such
a composition suggested by the combined disclosures of Burov, Nivaggioli,
and Gastner would have a pH of 2.5 to 7.9, overlapping the pH range recited
in claim 1.
Accordingly, regardless of whether Burov as an individual reference
only refers to stability in the context of a time period of three hours in
solutions having neutral pH, and regardless of whether data presented in
Burov show 15% degradation of single creatyl compound (Example 7 in
Burov’s Table 1) out of eight tested compounds (Examples 1–8 in Burov’s
Table 1) at neutral pH during a time period of three hours, one of ordinary
skill in the art reasonably would have expected that an aqueous composition
that includes Gastner’s buffer system having a pH of 2.5 to 7.9, and a
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creatine amide compound of Burov’s formula in which R is an L-glutamine
or L-leucine radical, as suggested by the combined disclosures of Burov,
Nivaggioli, and Gastner, would be highly stable as disclosed in Gastner, and
thus would exhibit stability for 90 days at 25ºC and 4ºC, as recited in claim
1. In re Spada, 911 F.2d 705, 709 (Fed. Cir. 1990) (explaining that a
chemical composition and its properties are inseparable).
Appellant argues that like Burov, Gastner and Block would not have
suggested the “stability at sub-7 pH for three months at room temperature
and lower required by the claims.” App. Br. 9. Appellant argues that
according to the Second Fields Declaration, no conclusion can be drawn
from Gastner as to the potential stability of creatyl amide compounds, such
as those disclosed in Burov or those recited in the claims, because Gastner
discloses creatine esters rather than the two creatyl amide species recited in
claim 1. App. Br. 10 (citing Second Fields Declaration ¶ 4). Appellant
further argues that according to the Second Fields Declaration, a creatine
amide “potentially has very different stability properties than the carbon-
oxygen bond found in creatine esters” due to the differing reactions involved
during decomposition of creatine esters and creatine amides to creatinine.
App. Br. 10, Reply Br. 13 (citing Second Fields Declaration ¶ 4).
The relied-upon portion of the Second Fields Declaration does not
address Gastner’s explicit disclosure that the creatine component of the
preparation described in the reference can be an addition compound with
creatine, preferably an addition compound of creatine with methionine,
among others. Gastner col. 4, ll. 20–28. Nor does the relied-upon portion of
the Second Fields Declaration address Gastner’s explicit disclosure that the
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buffer system described in the reference increases the stability of such
creatine addition compounds to acids. Gastner col. 4, ll. 52–58; col. 5, ll.
34–37. Accordingly, although creatine esters may have different stability
properties than creatine amides, Gastner’s disclosure that the buffer system
described in the reference increases the acid stability of addition compounds
with creatine, such as an addition compound of creatine with the amino acid
methionine, nonetheless would have suggested to one of ordinary skill in the
art that Gastner’s buffer system would increase the stability of the aqueous
creatinly amide compositions suggested by the combined disclosures of
Burov and Nivaggioli (discussed above) at acidic pHs. Velander v. Garner,
348 F.3d 1359, 1371 (Fed. Cir. 2003) (“In giving more weight to prior
publications than to subsequent conclusory statements by experts, the Board
acted well within [its] discretion.”); Yorkey v. Diab, 601 F.3d 1279, 1284
(Fed. Cir. 2010) (The Board has discretion to give more weight to one item
of evidence over another “unless no reasonable trier of fact could have done
so”).
Appellant argues that Block has similar deficiencies as Gastner
because Block “does not remotely relate to potential properties of creatine
amide compounds.” App. Br. 10. Appellant argues that “[w]hile true that
Block discloses a pH range for acidic juices which overlaps the claimed
range, ‘[t]here is no data or discussion presented as to the stability of the
creatine (or any other component), and, thus, the coincidental presence of a
form of citrate (ferric citrate) would not lead one to use this prior art in the
consideration of a buffer system to stabilize creatine amides.’” App. Br. 10
(quoting Second Fields Declaration ¶ 10).
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Appellant’s arguments and the relied-upon statement in the Second
Fields Declaration do not take into consideration what the combined
disclosures of Burov, Nivaggioli, and Block would have suggested to one of
ordinary skill in the art at the time of the invention. As discussed above,
Burov discloses that the “technical problem solved by the authors was
creation of new creatine derivatives produced by the method of chemical
synthesis that have a much higher stability [than creatine] and broader
spectrum of biological action” (pp. 7–8), and Burov discloses that the
creatine amides described in the reference “have increased solubility and
stability in aqueous solutions in comparison with known analogs, which
allows for them to be used more extensively as a creatine source in the
body” (p. 10). These disclosures, in combination with Nivaggioli’s
disclosure of a creatine-ligand compound in which creatine is covalently
bound to a standard amino acid, reasonably would have led one of ordinary
skill in the art to use a creatine amide compound of Burov’s formula in
which R is an L-glutamine or L-leucine radical in place of creatine in
Block’s enriched fruit juice, to increase the stability of the creatine in the
juice, and enhance its biological action. The pH of such an enriched fruit
juice composition suggested by the combined disclosures of Burov,
Nivaggioli, and Block would be 3.5 to 4.5, overlapping the pH range recited
in claim 1.
Accordingly, although Block may not include any data or discussion
directed to the stability of creatine, and although Block as an individual
reference may not have led one of ordinary skill in the art “to use this prior
art in the consideration of a buffer system to stabilize creatine amides,” the
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combined disclosures of Burov, Nivaggioli, and Block nonetheless would
have led one of ordinary skill in the art to produce an enriched fruit juice
composition having a pH of 3.5 to 4.5 that includes a creatine amide
compound of Burov’s formula in which R is an L-glutamine or L-leucine
radical.
Appellant argues that even if the Examiner establishes that the
composition recited in claim 1 is prima facie obvious, Appellant presents
evidence “sufficient to show unexpected results sufficient to overcome any
such prima facie case of obviousness,” for the reasons discussed below.
App. Br. 15.
First, Appellant argues that the Second Fields Declaration indicates
that “creatine itself is known to be very stable at neutral pH, while not at
lower pH values” as shown by Pischel and Gastner,11 and, accordingly, “[i]t
would have been expected that creatine amides, such as those in the ‘466
patent, would have been more stable at neutral pH values (7) compared to
lower pH values.” App. Br. 9 (citing Second Fields Declaration ¶ 5 (citing
Fig. 4 of Pischel and Gastner)); see also App. Br. 14–15, Reply Br. 14–15
(citing Second Fields Declaration ¶ 9).
Second, Appellant argues that Dr. Fields indicates that data presented
in Exhibit B of the Second Fields Declaration, in addition to data provided in
the 466 patent, demonstrate that the creatine amides recited in claim 1 “show
unexpectedly that stability, in particular long-term stability, is increased at
lower pH values.” App. Br. 14 (citing Second Fields Declaration ¶ 9).

11 Ivo Pischel and Thomas Gastner, Creatine—Its Chemical Synthesis,
Chemistry, and Legal Status, in Creatine and Creatine Kinase in Health and
Disease 291, 296–297 (G.X. Salomons and M. Wyss eds., 2007).
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Appellant argues that the 466 patent shows that creatyl-L-glutamine “is
significantly more stable at an acidic pH of 3.3 than it is at a neutral pH
between 7 and 8, in particular at room temperature.” App. Br. 15 (citing 466
patent col. 26).
Third, Appellant argues that additional testing set forth in the Second
Li Declaration “supports that both creatyl-L-glutamine and creatyl-L-
leucine, the two species of amended claim 1, demonstrate significantly
improved long-term stability even at low pH values, when compared to the
testing in the specification al a pH of 7–8.” App. Br. 15. Appellant argues
that because “results are demonstrated for both creatyl-L-leucine and
creatyl-L-leucine, and at all claimed pH values and temperatures, these
results are commensurate in scope with claim l as amended in this
reexamination.” App. Br. 15. Appellant argues that “[a]s they go against
the understood properties of creatine-based compositions for the reasons set
forth by Dr. Fields, they are unexpected.” Id.
The burden of analyzing and explaining Specification disclosures and
other data to establish unexpected results rests with the Appellant. In re
Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (“the burden of showing
unexpected results rests on he who asserts them”). “[W]hen unexpected
results are used as evidence of nonobviousness, the results must be shown to
be unexpected compared with the closest prior art.” In re Baxter Travenol
Labs., 952 F.2d 388, 392 (Fed. Cir. 1991).
For reasons that follow, Appellant’s arguments and the relied-upon
portions of the Specification, the Second Fields Declaration, and the Second
Li Declaration do not establish that the stability recited in claim 1 would
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have been unexpected by one of ordinary skill in the art at the time of
Appellant’s invention in view of the closest prior art, Burov.
First, we point out that the pH range recited in claim 1 is “about 1.5 to
about 6.5.” To establish unexpected results, Appellant must therefore
demonstrate an unexpected difference in stability between aqueous solutions
having a pH outside this range as compared to solutions having a pH within
this range, such as an unexpected difference in stability between aqueous
solutions having a pH of 6.5 and a pH of 7.0. In re Hill, 284 F.2d 955, 958–
59 (CCPA 1960).
Second, although the Second Fields Declaration states that one of
ordinary skill in the art would have expected creatine amides, such as those
disclosed in the 466 patent, to be more stable at neutral pH than at lower pH
because creatine was “known to be very stable at neutral pH, while not at
lower pH values” as shown by Pischel and Gastner, this statement does not
take into consideration Burov’s disclosure of creatine amides that exhibit
“increased solubility and stability in aqueous solutions in comparison with
known analogs, which allows them to be used more extensively as a creatine
source in the body.” Burov, p. 10. Nor do Appellant and Dr. Fields explain
why the stability of creatyl-L-glutamine or creatyl-L-leucine at a pH of
“about 6.5” recited in claim 1 would have been unexpected to one of
ordinary skill in the art at the time of the invention in view of Burov’s
disclosure of increased stability of creatine amides in aqueous compositions
having a pH of 7.0 or 7.2
The relied-upon portion of the Second Fields Declaration also does
not take into consideration Gastner’s disclosure of a preparation having a pH
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of 2.5 to 7.9 that includes an addition compound of creatine with methionine
and a buffer system that protects the creatine addition compound from the
influence of acid, and constitutes “a further development of the prior art in
terms of an increase in stability of creatine preparations and a substantial
improvement in bioavailability.” The Second Fields Declaration only
addresses the expected relative stability of creatine amides, such as those
disclosed in the 466 patent, and creatine itself, and does not address the
expected relative stability of the creatyl-amide species recited in claim 1 and
the creatine preparation disclosed in Gastner. Neither Appellant nor Dr.
Fields explains why one of ordinary skill in the art would not have expected
creatine amides, such as those disclosed in the 466 patent, to be more stable
at neutral pH values than lower pH values when included in a composition
containing Gastner’s buffer system, having a pH of 2.5 to 7.9, which
overlaps the pH range recited in claim 1, and solves the problem of the
instability of creatine in aqueous solutions and protects creatine from the
influence of acid.
Hence, neither Appellant nor Dr. Fields explains why the stability
recited in claim 1 would have been unexpected in view of the disclosures of
each of Burov and Gastner.
Third, as the Examiner points out, Exhibit A of the Second Li
Declaration presents data showing that aqueous compositions of creatyl-L-
glutamine and creatyl-L-leucine exhibited very high stability at pH values
ranging from 2.5 to 7.0 at both 25ºC and 4ºC for time periods spanning 1
day to 2 months. Ans. 32; Second Li Declaration ¶¶ 3–7, Exhibit A. The
difference in stability exhibited by the compounds at pH values of between
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2.5 and 7.0 at both 25ºC and 4ºC was very small, and the data show only a
very slight difference in the stability of both compounds at a pH of 6.5 (the
upper limit of the range recited in claim 1) and at a pH of 7.0 (the pH
disclosed in Burov) after two months at 25ºC and 4ºC. Although Appellant
asserts that the data in Exhibit A of the Second Li Declaration demonstrate
“the unexpected nature of the property being claimed herein” because one of
ordinary skill in the art would have expected stability to be negatively
affected by a reduction in pH below neutral levels (Reply Br. 15–16), neither
Appellant nor the Declarant explain why the slight difference in stability
exhibited by creatyl-L-glutamine and creatyl-L-leucine at pH 6.5 and pH 7.0
at both 25ºC and 4ºC represents a significant stability difference that would
have been unexpected.
Thus, due to any evidence to the contrary on this appeal record, as the
Examiner correctly finds, the slight difference in the degree of stability
exhibited by creatyl-L-glutamine and creatyl-L-leucine at pH 6.5 (the upper
limit of the range recited in claim 1) and at pH 7.0 (the pH disclosed in
Burov) at both 25ºC and 4ºC represents a mere difference in degree, rather
than a difference in kind necessary to demonstrate unexpected results. Ans.
32; In re Aller, 220 F.2d 454, 456 (CCPA 1955) (explaining that
modification of a parameter may be patentable if it “produce[s] a new and
unexpected result which is different in kind and not merely in degree from
the results of the prior art.”).
Fourth, the relied-upon data in the Specification of the 466 patent
show that a creatyl-L-glutamine formulation having a pH of 7.0 was stable
for three months at 4ºC, but was unstable at room temperature after only a
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week, while a creatyl-L-glutamine formulation having a pH of 3.3 was stable
for three months at both 4ºC and room temperature. 466 patent col. 26, ll.
15–46. Although these data do show that creatyl-L-glutamine is more stable
at room temperature at pH 3.3 than it is at pH 7.0, the data do not provide a
comparison between the stability of creatyl-L-glutamine at a pH of about
6.5—the upper limit recited in claim 1—and at a pH of 7.0 or 7.2 as
disclosed in Burov. Hill, 284 F.2d at 958–59.
Furthermore, the relied-upon data in the Specification include only a
single data point within the range recited in claim 1 (pH 3.3), while the
recited range spans a pH of about 1.5 to about 6.5. Consequently, the single
data point does not demonstrate stability across the full scope of the pH
range recited in claim 1. 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). When unexpected
results are proffered by an appellant to rebut a prima facie case of
obviousness, the appellant must “provide[] an adequate basis to support the
conclusion that other embodiments falling within the claim will behave in
the same manner” in order to “establish that the evidence is commensurate
with [the] scope of the claims.” In re Kao, 639 F.3d 1057, 1068 (Fed. Cir.
2011). One data point is insufficient to “to ascertain a trend in the
exemplified data which would allow [one having ordinary skill in the art] to
reasonably extend the probative value thereof.” In re Kollman, 595 F.2d 48,
56 (CCPA 1979).
Accordingly, the relied-upon data in the Specification do not establish
that stability across the full scope of the pH range recited in claim 1 would
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have been unexpected by one of ordinary skill in the art at the time of the
invention relative to Burov, the closest prior art. In re Baxter Travenol
Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are
used as evidence of nonobviousness, the results must be shown to be
unexpected compared with the closest prior art.”).
Furthermore, the data discussed above in the Specification of the 466
patent appear to be contradicted by data presented in Exhibit A of the
Second Li Declaration. Specifically, Exhibit A of the Second Li Declaration
shows that creatyl-L-glutamine and creatyl-L-leucine were both stable at
25ºC at pH 7.0 for two months, with 94.3% and 96.6%, respectively, of each
compound remaining, whereas the 466 patent indicates that virtually no
creatyl-L-glutamine at pH of 7.0 was present after two months at 25ºC. Col.
26, ll. 15–29. Appellant does not provide any explanation for this apparently
contradictory data, calling into question its accuracy.
Fifth, we note that Exhibit B of the Fields Declaration is the same as
Exhibit C of the Second Li Declaration; consequently, we will address only
Exhibit C of the Second Li Declaration, but in so doing, we also address
Exhibit B of the Fields Direction.
Exhibit B of the Second Li Declaration presents data showing that
creatyl-L-glutamine having a pH of 3.3 was stable at both 4ºC and 25ºC for
6 months, while creatyl-L-glutamine having a pH of 8.0 was unstable at
25ºC after only two weeks, but was stable at 4ºC for up to 5 months. Exhibit
C of the Second Li Declaration presents data showing that creatyl-L-leucine
having a pH of 3.1 was stable at both 4ºC and 25ºC for 6 months, while
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creatyl-L-leucine having a pH of 6.0 was stable at 4ºC for 6 months (99.48%
remaining), but was less stable at 25ºC after 6 months (84.36% remaining).
Similar to the data presented in the Specification of the 466 patent
discussed above, as the Examiner correctly finds (Ans. 33), Exhibits B and C
of the Second Li Declaration do not provide a comparison between the
stability of creatyl-L-glutamine and creatyl-L-leucine at a pH of about 6.5—
the upper limit recited in claim 1—and at a pH of 7.0 or 7.2 as disclosed in
Burov, the closest prior art. Thus, it is unclear from Exhibits B and C of the
Second Li Declaration whether aqueous compositions of creatyl-L-
glutamine and creatyl-L-leucine having pH values of 6.5 and 7.0 would
exhibit any difference in stability over three months at temperatures of both
4ºC and 25ºC. Nor do the limited data in Exhibits B and C of the Second Li
Declaration demonstrate stability across the full scope of the pH range
recited in claim 1. Accordingly, the data do not establish that stability across
the full scope of the pH range recited in claim 1 would have been
unexpected by one of ordinary skill in the art at the time of the invention
relative to Burov, the closest prior art. Baxter, 952 F.2d at 392; Kollman,
595 F.2d at 56.
Therefore, Appellant’s arguments and the relied-upon portions of the
Second Fields Declaration and the Second Li Declaration do not provide
sufficient evidence to establish that stability for 90 days at 25ºC and 4ºC of
an aqueous composition of creatyl-L-glutamine or creatyl-L-leucine at a pH
of about 1.5 to about 6.5 would have been unexpected to one of ordinary
skill in the art at the time of the invention relative to the closest prior art
reference, Burov.
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Considering the totality of the evidence relied-upon in this appeal, a
preponderance of the evidence weighs in favor of the Examiner’s conclusion
of obviousness. We accordingly sustain the Examiner’s rejections of claims
1 and 5–12 under 35 U.S.C. § 103(a).

DECISION
We affirm the Examiner’s rejections of claims 1 and 5–12 under
35 U.S.C. § 103(a).
Requests for extensions of time in this ex parte reexamination
proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f).
AFFIRMED