Ex Parte 7,777,074 et al

Patent Trial and Appeal Board

Jan 29, 2016

90011394 (P.T.A.B. Jan. 29, 2016)

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.
90/011,394 12/17/2010 7,777,074 GASP-004-501 8722
54434 7590 02/01/2016
BOOTH UDALL FULLER, PLC
1255 W. Rio Salado Pkwy.
Suite 215
Tempe, AZ 85281
EXAMINER
KUNZ, GARY L
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
02/01/2016 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
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.
90/011,869 08/18/2011 7777074 GASP-004-502 7260
54434 7590 02/01/2016
BOOTH UDALL FULLER, PLC
1255 W. Rio Salado Pkwy.
Suite 215
Tempe, AZ 85281
EXAMINER
KUNZ, GARY L
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
02/01/2016 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 APPEALS BOARD
____________________

Ex parte THERMOLIFE INTERNATIONAL, LLC.
Appellant
____________________

Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2
Technology Center 3900
____________________

Before TONI M. SCHEINER, RICHARD M. LEBOVITZ, and
RAE LYNN P. GUEST, Administrative Patent Judges.

GUEST, Administrative Patent Judge.

DECISION ON APPEAL
I. STATEMENT OF CASE
ThermoLife International, LLC (hereinafter “Appellant”), the real party in
interest1 of Patent 7,777,074 B2 (hereinafter the “’074 patent”), appeals under 35
U.S.C. §§ 134(b) and 306 from the Examiner’s decision to reject claim 62 under 35

1 See Appellant’s Appeal Brief filed January 20, 2015 (hereinafter “App. Br.”) at 2.
2 Claim 6 is the only remaining rejection on appeal. Claims 1 and 2 have been
cancelled, and claims 3, 4, 5, and 7-10 have been confirmed as patentable by the
Examiner. App. Br. 2; Advisory Action mailed July 23, 2014; Ans. 1.
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

2
U.S.C. § 102(b) as anticipated by Barger.3 Final Office Action, mailed April 2,
2014, page 15; Examiner’s Answer, mailed February 27, 2015 (hereinafter
“Ans.”), page 1. We have jurisdiction under 35 U.S.C. §§ 134(b) and 306.
We AFFIRM the Examiner’s decision as a NEW GROUND OF
REJECTION as our decision relies on further evidence in support of the
Examiner’s rejection. We also enter other NEW GROUNDS OF REJECTION
based on additional prior art in accordance with 37 C.F.R. § 41.50.
This reexamination proceeding arose from two third-party requests for ex
parte reexamination, one filed by Mr. Bruce W. Kneller and Mr. Richard Gaspari
(Request for Ex Parte Reexamination, filed December 17, 2010) and one filed by
Mr. Daniel Pierce and Mr. Richard Gaspari (Request for Ex Parte Reexamination,
filed August 18, 2011). The two requests were merged into a single ex parte
reexamination on March 30, 2012, retaining both of the reexamination control
numbers for identification. An oral hearing was held on November 13, 2015. A
transcript of the hearing was entered into the record on December 11, 2015
(hereinafter “Tr.”).
The ’074 patent relates to various amino acid compounds, in particular,
nitrates or nitrites of amino acid compounds. (’074 patent, col. 1, ll. 26-28).
Claim 6 is the only claim on appeal, and reads as follows (with underlining
showing added text relative to the original patent claims):
6. A Compound having the structure of:

3 Barger, G., “Monographs on Biochemistry,” The Simpler Natural Bases, R. H. A.
157-163, Plimmer & F. G. Hopkins (eds.) Longmans, Green & Co., London (1914)
(“Barger”).
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

3

wherein Y is selected from the group consisting of a Nitrate and a Nitrite.
Claims App’x, App. Br. 16.
The ’074 patent states that creatine nitrate (represented by the above
formula) has been cost-effectively synthesized “by combining nitric acid and
Creatine, mixing with water, and leaving to crystalize.” ’074 patent, col. 9, ll. 19-
21. The ’074 patent further states that, when ingested, creatine nitrate provides
enhanced nitric oxide production while providing improved vasodilation effects for
better circulation and distribution of creatine in the body. Id., col. 17, ll. 54-57.
II. ISSUES ON APPEAL
It is undisputed that the claim on appeal is directed solely to a creatine
nitrate or a creatine nitrite compound. The Examiner finds that Barger teaches
creatine nitrate. Final Office Action 15; Ans. 1. In particular, Barger teaches
Compounds of creatine.-The nitrate, C4H9O2N3·HNO3, is less
soluble than the hydrochloride or the sulphate. The compounds
C4H9O2N3·ZnCl2 and C4H9O2N3·CdCl2·2H2O are crystalline
(Neubauer [1862, 2]). All these salts are hydrolysed by water.
Barger 160, first full ¶.
Appellant contends that this disclosure by Barger is ambiguous, despite the
molecular formula described and the reference to the “nitrate” of creatine. App.
Br. 5. Appellant further contends that Barger does not enable one skilled in the art
to make creatine nitrate. App. Br. 12.
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

4
Appellant relies on the testimony provided by the three Chamberlin
declarations4 and the testimony of Dr. Wolff.5
Accordingly, the issue before us is: based on a preponderance of the
evidence, did the Examiner err in finding that Barger teaches a creatine nitrate salt?
III. ANALYSIS
We adopt the Examiner’s findings in the Examiner’s Final Office Action and
Answer as our own and add any additional findings of fact appearing below.
Appellant contends that Barger is ambiguous for a number of reasons,
relying on the testimony of Dr. Chamberlin and Dr. Wolff in support thereof. App.
Br. 5-8. Appellant argues that Barger does not provide a method of making
“creatine nitrate.” According to Patent Owner, in 1914, when Barger was
published, chemistry was in its infancy, and Barger could not have been aware of
the possibility of multiple ionic forms of creatine. App. Br. 6 (citing 1st Chamberlin
Decl. ¶ 5-11). Thus, with the disclosure of Barger’s formula alone, and without
knowing how the material was made, Appellant argues that there is no guarantee
that what Barger refers to as a nitrate of creatine, is, in fact, creatine nitrate. Id.; see
also App Br. 8-9 (citing Wolff Decl. ¶ 23). According to Appellant, even the

4 The Declaration of Richard Chamberlin under 37 C.F.R. § 1.132, dated
November 9, 2013, and entered into the record on November 12, 2013 (hereinafter
“First Chamberlin Declaration” or “1st Chamberlin Decl.”). The Supplemental
Declaration of Richard Chamberlin, dated May 30, 2014, and entered into the
record on June 2, 2014 (hereinafter “Second Chamberlin Declaration” or “2nd
Chamberlin Decl.”) (10 pages). The Second Supplemental Declaration of Richard
Chamberlin, also dated May 30, 2014, and entered into the record on June 2, 2014
(11 pages) (hereinafter “Third Chamberlin Declaration” or “3rd Chamberlin
Decl.”).
5 The Declaration of Dr. Manfred Wolff, dated November 8, 2014, and entered into
the record on November 12, 2013 (hereinafter “Wolff Decl.”).
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

5
disclosure in Barger of a structural formula is ambiguous because “many other
compounds . . . have the [sic] exactly the same atom composition.” Id. at 7 (citing
2nd Chamberlin Decl. ¶ 6).
The Examiner points out that Barger describes a process for the formation of
arginine nitrate and other nitrates, e.g., an equimolar mixture of arginine with nitric
acid, and that the process is similarly implied for creatine nitrate by the one to one
ratio of the molecular formula provided, and such mere titration would have been
within the skill of the ordinary artisan. See Ans. 4-7 and 13-14. The Examiner
further relies on the statement in Barger comparing the solubility of creatine nitrate
with the hydrochloride and “sulphate” of creatine, as evidence that the “nitrate of
creatine” represents a salt. Ans. 3. The Examiner notes that nitrous acid is one of
the “mineral acids,” along with sulfuric and hydrochloric acids, also described in
Barger as forming “salts.” Id.; see Barger 158 (“The aqueous solution is neutral.
The basic properties of creatine are very feeble (dissociation constant 1.81x10-11 at
40.2°, Wood [1903]) and its salts with mineral acids are hydrolysed by water.”)
(emphasis added) and 160 (“All these salts are hydrolysed by water.”).
On this point, Appellant argues that arginine and creatine are different, and
that even Barger recognizes their difference. According to Appellant, Barger
expressly excludes creatine as a base, but acknowledges that arginine and
creatinine are bases. App. Br. 6 (citing 1st Chamberlin Decl. ¶¶ 20-24) and 8
(citing 3rd Chamberlin Decl. ¶¶ 13 and 14). Further, according to Appellant,
Barger refers to the nitrate of creatine as a “compound” and not a “salt,” which
Appellant argues is also evidence that Barger did not consider creatine a base that
would form a salt with nitric acid. Id. at 8 (citing Chamberlin Decl. ¶ 19).
Appellant further indicates that Barger does not have a citation listed for a nitrate
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

6
of creatine, even though proper citation was a goal for the monograph in which
Barger was included. App. Br. 6 (citing First Chamberlin Decl. ¶¶ 5-11) and 8
(citing Third Chamberlin Decl. ¶ 19); Reply Br. (citing Second Chamberlin Decl. ¶
8).
Because of the lack of description for making the described nitrate of
creatine and because Appellant argues that the disclosure is ambiguous, Appellant
further contends that Barger is not enabling for the skilled artisan to have made
creatine nitrate. App Br. 12.
We are not persuaded that Barger is ambiguous or not enabled.
Contrary to Patent Owner’s assertion that Barger does not consider creatine
to be a base, Barger expressly states that creatine has basic properties, albeit
“feeble.” Barger 158, last ¶; see also, Barger, Introduction and Scope, 5-6
(attached for reference) (“those [compounds] in which the basic character
predominates have been included in this monograph.”).6 It is not reasonable to
conclude that Barger did not consider creatine a base. Dr. Chamberlin confirms
that creatine has the weak basic properties identified by Barger and forms a salt
with nitric acid. Third Chamberlin Decl. ¶ 19 (“Both [creatinine and creatine] are
bases, but in practice creatine is actually a weaker base than creatinine under most
conditions because the intrinsically more basic guanidine in creatine is already

6 Barger indicates that a “base” can be defined in a variety of ways. Barger,
Introduction and Scope, 5-6. Patent Owner relies on the one definition identified
by Barger under which creatine would not be considered a base (i.e., whether it is
precipitated by phosphotungstic acid) to the exclusion of all the references in
Barger that acknowledge the predominantly basic character of creatine, including
the title of the reference itself. Id.; see also Barger, title (“The Simple Natural
Bases”). In any case, it is the chemical properties of creatine with which we are
concerned.
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

7
protonated.”); Second Chamberlin Decl. ¶ 19 (“It [the nitrate of creatine] is a salt,
of course . . . .”). Moreover, the skilled artisan at the time of the invention, i.e., in
2007, would have been aware of the weakly basic character of creatine, which is
consistent with that understood by Barger in 1913.
A reference is presumed to be enabling and therefore, once the examiner
establishes that the reference teaches each and every limitation of the claimed
invention, the burden shifts to the applicants to prove the reference is not enabling.
Chester v. Miller, 906 F.2d 1574, 1578 (Fed. Cir. 1990); In re Sasse, 629 F.2d 675,
681 (CCPA 1980). Appellant has not shown persuasively that we should not take
the teaching of Barger at face value, i.e., that the Barger reference describes what it
says it describes – a nitrate of creatine.
Appellant argues that the unrebutted opinion testimony evidence of Dr.
Chamberlin and Dr. Wolff must control. We disagree. As discussed above, Barger
explains that creatine is a weak base. Thus, Barger’s additional reference to a salt
of creatine would not have been an unreasonable or ambiguous interpretation to the
skilled artisan. Barger’s reference to the nitrate of creatine as a “compound” is not
ambiguous, but consistent with claim 6 defining a creatine nitrate salt as a
“compound.” A salt is a compound. While we credit Dr. Chamberlin’s and Dr.
Wolff’s explanation of credible possible alternative compounds that might have
been made, these possible alternatives do not persuade us that the description in
Barger on its face is erroneous, particularly in light of additional evidence at the
time that is not persuasively rebutted by Dr. Chamberlin or Dr. Wolff, discussed in
detail below.
Because parts of the Barger reference (namely the Introduction and Scope)
were cited yet not formally entered into the record (see e.g., App. Br. 8), we
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

8
performed a search for the reference on Google Books, and duly obtained a copy
thereof. However, while doing so, we also conducted a general search7 for
references to “creatine nitrate” in the 19th Century. We discussed this search and
the results in the oral hearing. Oral Hearing Tr. 21:1-10. Several books were
returned having recitations to “creatine nitrate” very similar to that of Barger,
including reciting the same formula.8 The fact that reference to “creatine nitrate”
can be found in a large number of books at the time, similarly without citation or
reference, and in books that are considered “textbooks,” indicates that Barger’s
failure to cite a reference or provide a full description of how it was made does not
necessarily mean that a method for making creatine nitrate was not enabled.
Rather, the evidence persuasively demonstrates that the skilled worker at the time
did not think such disclosure was necessary in Barger’s 1913 reference. In re
Baxter Travenol Labs, 952 F.2d 388, 390 (Fed. Cir. 1991) (“Extrinsic evidence
may be considered when it is used to explain…the meaning of a reference.”).

7 See
, as of January 15, 2016. A
copy of the first page of the search return is attached.
8 See e.g., Bloxam, et al., Chemistry, Inorganic and Organic, with Experiments,
Eighth ed., 656, J & A Churchill, London (1898) (“Creatine is neutral in reaction,
but play the part of a weak moacid base. Creatine nitrate, C4H9O2N3·HNO3,
crystallises in prisms. When the solution of its salts are heated above 30° C., they
are converted into salts of creatinine, a stronger base.”) (attached); Johannes
Wislicenus, Adolph Strecker’s Short Text-Book of Organic Chemistry, 423, Kegan
Paul, Trench & Co., London (1881) (“With the mineral acids creatine yields salts
of acid reaction corresponding to those of glycocyamine, whose solutions can only
be brought to unchanged crystallisation at ordinary temperatures, being converted
on heating into salts of creatinine. Creatine nitrate, C4H9O2N3·HNO3, crystallises in
large colourless prisms.”) (attached).
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

9
The Examiner’s finding that Barger’s description is sufficient and enabled is
further supported by two additional references identified during our search, one of
which was previously identified in an information disclosure statement submitted
by Appellant on September 2, 2014, although we cannot confirm that the reference
was considered by the Examiner. The first of these references is: M. Dessaignes,
“Scientific and Medicinal Chemistry: Examination of some Products of the
Transformation of Creatine,” 12(279) The Chemical Gazette or Journal of Practical
Chemistry, 201-204, (June 1, 1854) (hereinafter “Dessaignes”). Dessaignes states
that
Creatine . . . in combining with acids [] form beautiful
crystalline compounds with a strongly acid reaction. If a rapid current
of nitrous acid gas be passed into water containing an excess of
undissolved creatine, the latter is quickly dissolved and a large
quantity of small brilliant crystals afterwards make their appearance.
These crystals, which may readily be obtained in thick short prisms by
solution in warm water and cooling, consist of nitrate of creatine.
Their solution which has a very acid taste is abundantly precipitated
by ammonia. The precipitate, dissolved in hot water, furnishes on
cooling small prisms, which effloresce at 212° F., and the solution of
which is neutral with paper, and does not produce precipitates with
chloride of mercury, chloride of zinc or nitrate of silver. These prisms,
dried at 212° F. and analysed, furnished in 100 parts

I also determined the quantity of nitric acid in the nitrate of
creatine and found it to contain 32.36 per cent of monohydrated nitric
acid The formula C8H18N6O4, H2N2O6 [which equates to
C4H9O2N3·HNO3] requires 32.47 per cent of N4H2O6. The same
compound was produced by dissolving 1.057 gr of crystallized
creatine in nitric acid containing 0.447 gr of H2N2O6 and evaporating
at 86° F. The crystals were homogeneous and weighed 1.373 gr.
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

10
From calculation they should weigh 1.376 gr. The sulphate and
muriate [chloride] of creatine form fine prisms, which are more
soluble than the nitrate, but like this are not deliquescent.
Dessaignes 203 (attached for reference).9
The second of these reference is: Leopold Gmelin, “Creatine,” Hand-Book
of Chemistry, Vol. 10: Organic Compounds Containing Eight and Ten Atom of
Carbon, 249-255, Henry Watts, trs., Harrison and Sons for the Cavendish Society,
London (1856).10 Gmelin states that
Nitrate of Creatine. – 1. Obtained by dissolving crystallized
creatine in the requisite quantity of nitric acid, and evaporating the
solution at 30°. – 2. By passing a rapid stream of nitrous gas through
water containing an excess of creatine in suspension. The creatine
dissolves with tolerable rapidity, and a considerable quantity of small
shining crystals of the nitrate are formed, which when recrystallized
by dissolving them in lukewarm water and cooling, form thick short
prisms. This salt is less soluble in water than the sulphate or
hydrochlorate. The solution has a very sour taste, and is decomposed
by ammonia with precipitation of creatine. (Dessaignes.) Compt.
Rend. 38, 839; Ann. Pharm. 92, 409.

By dissolving 1.057 grm. of creatine in a quantity of nitric acid
containing 0.447 grm. HO,NO5 and evaporating at 30°, Dessaignes
obtained 1.373 grms. of crystallized nitrate; the formula requires
1.376.
Gmelin 254 (attached for reference).

9 We note that there was in improper submission by email that also identified this
reference. See Appellant’s Communication of January 7, 2016. However, we
note, as did Appellant, that this reference was already of record and was obtained
by us prior to the improper submission. See Oral Hearing Tr. 21:1-10.
10 Google Books identified this reference as being published in 1879. See attached
Google Books results.
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

11
In light of this additional evidence, Appellant’s arguments that the teachings
of Barger are either ambiguous or not enabled are not persuasive. Rather, based on
a preponderance of the evidence, we find that Barger’s teaching of creatine nitrate
is the recitation of a material that was so conventional to organic chemists at the
time of the invention that there was not need either for citation or for a description
of how to make the salt. Moreover, the salt described in Barger was
conventionally made by dissolving crystallized creatine in the requisite quantity of
nitric acid and allowing to crystallize by evaporation of the water, as evidenced by
Dessaignes and Gmelin, identically to that described in the ’074 patent. See ’074
patent, col. 9, ll. 19-21. An express articulation of what the skilled artisan would
have known is not required where it is evident that those of ordinary skill in the art
possessed the requisite knowledge. See Motorola, Inc. v. Interdigital Tech. Corp.,
121 F.3d 1461, 1472 (Fed. Cir. 1997).
When a claimed product appears to be substantially identical to a product
disclosed by the prior art, the burden is on the Applicants to prove that the product
of the prior art does not necessarily or inherently possess characteristics or
properties attributed to the claimed product. In re Spada, 911 F.2d 705, 708 (Fed.
Cir. 1990); In re Best, 562 F.2d 1252, 1255 (CCPA 1977). Accordingly, the
burden shifts to Appellant to demonstrate that Barger’s nitrate of creatine, as
evidenced by Dessaignes and Gmelin, is not inherently the compound recited in
claim 6.
Accordingly, we affirm the Examiner’s finding that claim 6 is anticipated
under 35 U.S.C. § 102(b) by Barger, as evidenced by Dessaignes and Gmelin.
However, because we rely upon new evidence in support of this affirmance, we
designate this rejection as a new ground in accordance with 37 C.F.R. § 41.50(b).
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

12
Alternatively, also under 37 C.F.R. § 41.50(b), we enter a new ground of rejection
of claim 6 under 35 U.S.C. § 102(b) as being anticipated by Dessaignes or Gmelin,
because both Dessaignes and Gmelin teach the compound of claim 6 and a method
for making the same consistent with that of the ’074 patent.

IV. CONCLUSION
On the record before us, we enter the following new grounds of rejection of
claim 6:
Claim 6 rejected under 35 U.S.C. § 102(b) as anticipated by Barger, as
evidenced by Dessaignes and Gmelin; and
Claim 6 rejected under 35 U.S.C. § 102(b) as anticipated by Dessaignes or
Gmelin.

V. NEW GROUND OF REJECTION
This decision contains new grounds of rejection pursuant to 37 C.F.R.
§ 41.50(b) which provides that “[a]ny decision which includes a new ground of
rejection pursuant to this paragraph shall not be considered final for judicial
review.” Correspondingly, no portion of the decision is final for purposes of
judicial review.
For further guidance on new grounds of rejection, see 37 C.F.R. § 41.50(b)–
(f). The decision may become final after upon conclusion of proceedings on
remand before the Examiner. 37 C.F.R. § 41.50(e).
37 C.F.R. § 41.50(b) also provides that the Patent Owner, WITHIN TWO
MONTH FROM THE DATE OF THE DECISION, must exercise one of the
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

13
following two options with respect to the new grounds of rejection to avoid
termination of the appeal as to the rejected claims:
(1) Reopen prosecution. The owner may file a response requesting
reopening of prosecution before the examiner. Such a response must be either an
amendment of the claims so rejected or new evidence relating to the claims so
rejected, or both.
(2) Request rehearing. The owner may request that the proceeding be
reheard under § 41.52 by the Board upon the same record. . . .

NEW GROUND OF REJECTION
ack

FOR PATENT OWNER:

BOOTH UDALL FULLER, PLC
1255 W. RIO SALADO PKWY.
TEMPE, AZ 85281

FOR THIRD-PARTY REQUESTER:

GREGORY M. KRAKAU, ESQ.
LELAND PARACHINI STEINBERG MATZGER & MELNICK LLP
199 FREMONT STREET, 21ST FLOOR
SAN FRANCISCO, CA 94105

Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

14
Attachment 1
Barger, Introduction and Scope

1 r
"B
THE
SIMPLER NATURAL BASES
GEORGE BARGER, M.A., D.Sc.
FORMERLY FELLOW OF KING'S COLLEGE, CAMBRIDGE
PROFESSOR OF CHEMISTRY IN THE ROYAL HOLLOWAY COLLEGE, UNIVERSITY OF LONDON
LONGMANS, GREEN AND CO.
39 PATERNOSTER ROW, LONDON
NEW YORK, BOMBAY AND CALCUTTA
1914
INTRODUCTION AND SCOPE 5
of purity, and here we are likely to learn more from colloidal than
from organic chemistry. Recent work on anaphylaxis seems to indicate
that this phenomenon is primarily concerned with a basic part of the
protein molecule which is resolved by hydrolysis into diamino-acids.
We are almost as ignorant of the more interesting toxic products
of putrefaction as we are of pathogenic toxins. Very little is known
about the poisonous substances in food, popularly called ptomaines.
Many cases of so-called ptomaine poisoning are in reality bacterial
infections, but others are purely chemical intoxications. Perhaps the
best known of these is due to Bacillus botulinus which, without obvious
signs of putrefaction, produces in meat or even in vegetable nitrogenous
substances (beans) an excessively poisonous toxin, readily destroyed
at 80 and capable of yielding an antitoxin (Van Ermengem [1907,
1912; Ch. I]; Ornstein [1913; Ch. I]). The poisonous properties
occasionally exhibited by boiled mussels are on the other hand due to
a thermostable base [Brieger, 1886, I, p. 65 ; Ch. I]. The physi-
ological actions of the most active amines described in Chapter I do
not account satisfactorily for such intoxications ; other substances must
be present, and one of these is sepsine, a base of simple constitution
obtained by Faust from putrid yeast. The experimental difficulties
of the subject are illustrated by the fact that 100 kilos, of yeast did not
yield enough of the pure substance for quite satisfactory analysis.
Against this difficulty, that many of the bases described in the follow-
ing chapters are only obtainable in minute quantity from natural
sources, we may, however, set the advantage of a simple constitution,
so that when the latter has once been fully established, a synthesis on
a large scale may be possible, which in some cases has greatly increased
our knowledge of the chemical and physiological properties of the base.
Without an exact knowledge of the properties, the identification is
often very difficult and for this reason detailed descriptions have as far
as possible been given in the appendix. Many bases which have been
insufficiently characterised have not been mentioned, except where it
was possible to suggest identity with better known ones.
In conclusion we may discuss the meaning of the following terms.
Base. Many substances of physiological importance are at the
same time acids and bases
;
those in which the basic character predomin-
ates have been included in this monograph ; others, like the a-amino-
acids of protein are not generally regarded as bases, although glycine, for
instance, yields a hydrochloride. The predominance of the basic char-
acter may be deduced from a comparison of the (basic and acidic) affinity
constants (see the beginning of Chapter II). For our purposes a better
6 THE SIMPLER NATURAL BASES
practical definition is to describe a base as a substance which is pre-
cipitated by phosphotungstic acid. Adopting this criterion we consider
creatinine to be a base but creatine not.
Alkaloid. ^Some writers have used this term to include all natural
bases, but the objections to this are evident from what has been said
above, and the word is best restricted to complex vegetable heterocyclic
bases derived from pyridine, quinoline, etc.
1 There is no doubt as to
what is generally meant by an alkaloid, but nevertheless a rigid definition
is almost impossible. On the one hand narceine, for instance, is a
typical alkaloid from opium, but the nitrogen atom does not form part
of a ring ; narceine is an amine. On the other hand histidine and its
derivatives are not classed as alkaloids, although they contain the
heterocyclic glyoxaline ring, which is also present in pilocarpine. The
latter substance is an undoubted alkaloid. In a few cases the inclusion
of bases in this monograph is arbitrary ; thus hordenine, which is usually
called an alkaloid, has been included on account of its relationship to
tyrosine ; ephedrine, which is isomeric with hordenine, has been ex-
cluded. All betaines have been included, for no typical alkaloid shows
a betaine structure. One further point should be noted. The typical
alkaloids are generally found only in one or a few closely related
species, but the simpler natural bases, in accordance with their close
connection with proteins and phosphatides, have generally a much
wider distribution.
Ptomaine was originally applied by Selmi to bases from corpses
and afterwards became identical with putrefaction base (Brieger).
Some writers have restricted the term to poisonous bases. Lately it
has fallen into disuse.
Leucomaine was a term used by Gautier for animal bases such as
creatinine, which are not formed by putrefaction ; this term is now
quite obsolete.
Toxins are poisonous bacterial products which when injected cause
the production of anti-bodies, neutralising their poisonous properties ;
an example is diphtheria toxin. Gautier has applied the word, in a
different sense, to simple poisonous putrefaction bases.
1 Winterstein and Trier define plant alkaloids as nitrogenous substances which can no
longer be utilised for building up protein. Thus they would call betaine an alkaloid.
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

15
Attachment 2
Dessainges

THE
CHEMICAL GAZETTE,
on,
JOURNAL OF PRACTICAL CHEMISTRY,
IN ALL ITS APPLICATIONS TO
PHARMACY, ARTS AND MANUFACTURES.
CONDUCTED BY
WILLIAM FRANC IS, Pn.D., F.L.S,, F.R.A.S., F.C.S.
UUk\U
: ~ J) H
1| 4.) J ' J0 Ga 1, ., ‘o"' 5 J 0 ¢u , J: 4 ’J"v Iv cu )~) .,
0 -. _, "' ’ "J 5 J "‘,‘,'J: 9' ,0‘ 9'1 J) 1,‘ Q‘,
u u o v u Q v J ,U 0 "- J J‘; " J J J J J‘. 1.’. " J
Duo "U. ‘J uau ) ‘ 5
" w u) 3 " 950‘ ,"’ "’ ‘'0 ‘.
J 0
J J] ‘WU ~15 §9 3
.:J ' J J J )1 J
O o;'\,‘ t , 3 C. J q‘ I'\
~ J-”1;,0.1~ 01~~-~
)) -I .,J J J I. \
Joli ' ' ' '
PUBLISHED BY TAYLOR AND FRANCIS,
RED LION COURT, FLEET STREET

THE CHEMICAL GAZETTE.
No. CCLXXIX.--June 1, 1854.

SCIENTIFIC AND MEDICINAL CHEMISTRY.
Examination of some Products of the Trans/'orfliati0n of Creatine.
By M. Dsssmouns.
OXIDE of mercury, when heated with an aqueous solution of crea
tine or of creatinine, acts upon both these bodies. The fluid evolves
an odour which is peculiar to the products of the dry distillation of
creatine, and which has been compared by M. Chevreul to that of
phosphorus. Carbonic acid is disengaged without any trace of am
monia, and the oxide of mercury is partially reduced. The principal
product of the reaction consists in a crystalline body, which I de
clared, some time since, to be a new alkaloid, on account of its alka
line reaction. I have resumed the investigation of this subject; the
crystals obtained with creatinine are not homogeneous. By the em
ployment of alcohol and repeated crystallizations, I at last obtained,-—
lst, crystals which were sparingly soluble in water, and still more
sparingly in alcohol, neutral to test-papers, efliorescent at 212° F.,
and recognizable as creatine by all their characters; 2nd, a larger
quantity of flattened prisms, attached to one another by their sides
and imbricated. Creatine, when the oxide of mercury was present
in suflicient excess, produced only these latter crystals.
This substance is very soluble in water; it has a disagreeable
taste, and becomes opake at 212° F., losing water. When heated on
platinum foil, it emits the same odour as creatine; it imparts a
slight blue colour to reddened litmus-paper. Brought into con
tact with potash in the cold, it evolves no ammoniacal odour; it
precipitates the chlorides of barium and calcium, nitrate of silver
and acetate of lead. This last precipitate, when washed and decom
posed by srrlphuretted hydrogen, furnished oxalic acid. That which
Itook for an alkaloid is consequently the oxalate of a strong base.
This base was isolated by heating its oxalate with a very small ‘ex
cess of pure milk of lime and filtering. By evaporating in vacuo, I
obtained a colourless body, with a crystalline surface, which is per
haps to be attributed to the absorption of carbonic acid by this
alkali, as it attracts it strongly. It is also deliquesceut; it has a very
caustic and somewhat ammoniacal taste. When heated on platinum
foil, it is almost entirely volatilized, with a strong odour of burnt
creatine; it expels ammonia from its salts in the cold, and produces
copious precipitates with chlorides of barium and calcium. The pre
Chem. Gaz. 1854. M
202 Scientific and Zlledicinal Chemistry.
cipitates are soluble in a large quantity of water, and also in weak
acetic acid, without eifervescence. It precipitates sulphate of alu
mina and chloride of iron, the precipitates dissolving in an excess of
the precipitant. It produces a white precipitate with a yellowish
tinge with nitrate of silver; it dissolves oxide and chloride of silver.
It also precipitates the salts of mercury, lead and copper.
With the oxalate of this alkali and chloride of calcium, or nitrate
and sulphate of lime, crystallized salts may be readily prepared;
they have a weak alkaline reaction. With its hydrochlorate and
chloride of platinum in concentrated solutions, superb orange rhom
bohedral crystals are obtained after some time; these consist of a
double salt, which, when redissolved and crystallized by cooling,
often takes the form of flat prisms, attached side by side; the
coloured mother-liquors, obtained in the preparation of the oxa
late, have a strongly alkaline reaction upon-paper. When deprived
of oxalic acid by chloride of calcium, they furnish with chloride of
platinum a considerable quantity of the double salt which has just
been mentioned.
The oxalate prepared from creatine lost l3'25 per cent. of Water
at 212° F.; the same salt furnished a quantity of oxalate of lime,
which, when dried at 212° F., represented 38'4~l per cent. of C‘2 H2 0‘.
By combustion with oxide of copper and oxygen, and with soda
lime for the nitrogen, I found that the same salt, dried at 212° F.,
contained-
Found. Calculated.
Carbon . . . . . . . . . . . . 30'9O 4 30'5O
Hydrogen . . . . . . . . . . 6'93 ~14 6'77
Nitrogen. . . . . . . . . . . . 3505 6 35'59
The oxalate produced from creatinine lost l3'34 per cent. of water
at 212° F. Dried at this temperature, it contained in 100 parts
Carbon. . . . . . . . . . . . . . . . . . . . 30'98
Hydrogen . . . . . . . . . . . . . . . . 7'27
Nitrogen . . . . . . . . . . 3543
The hydrated oxalate, according to the formula C4 H14 N6, C9 H‘2 O‘,
H4 09, ought to lose 13-23 per cent. of water at 212° F., and con
tains 3811* per cent. of monohydrated oxalic acid.
I also analysed the platino-chloride dried in vacuo :—
' Found. Calculated.
Carbon . . . . . . . . . . . . 8'77 4‘ 8'60
Hydrogen . . . . . . . . . . 3'03 l6 2'87
Nitrogen . . . . . . . . . . . . 14'85 6 15'O5
Chlorine . . . . ¢ . . . . . . . 38'7l 6 88'18
Platinum. . . . . . . . . . . . 35'] 9 1 3530
The composition of this remarkable base is therefore represented
by the formula C4 HH 06. What is its constitution? Just as crea
tine may be represented as urea and sarcosine conjoined, with
elimination of water, this new base appears to be a conjugate com
pound of urea and methylamine with elimination of water. Thus
C4 H14 N6+H4 09:02 He N4 Oe+Cs Hm N2,
Scientific and Medicinal Chemistry. 208
This base, which may be called methyluramine, when heated with
a solution of baryta, is decomposed, ammonia being evolved accom
panied by a fishy odour. The platino-chloride, when heated, emits
an odour of trimethylamine. Sarcosine may be represented as gly
collate of methylamine minus water, and it no doubt bears the same
relation to glycollic methylamine that sugar of gelatine does to
glycollamide. It is the elements of glycollic acid in the creatine
which are oxidized by the oxide of mercury so as to produce oxalic
acid, carbonic acid and water, as expressed in the equation
C8 Hla N6 O4+O5=C* HH N6, Cez H9 O‘ +C9 O*+H‘Z O.
I have also attempted to throw some light upon the constitution
of creatine, by submitting it to the action of nitrous acid, and this
inquiry has enabled me to recognize a character of this interesting
body which had escaped M. Liebig. Creatine difi'ers, it is true, from
sugar of gelatine, and other analogous bodies, by its refusing to
combine with metallic oxides; but it resembles them in combining
with acids to form beautiful crystalline compounds with a strongly
acid reaction. If a rapid current of nitrous acid gas be passed into
water containing an excess of undissolved creatine, the latter is
quickly dissolved, and a large quantity of small brilliant crystals
afterwards make their appearance. These crystals, which may
readily be obtained in thick short prisms by solution in warm water
and cooling, consist of nitrate of creatine. Their solution, which
has a very acid taste, is abundantly precipitated by ammonia. The
precipitate, dissolved in hot water, furnishes on cooling small prisms,
which eflloresce at 212° F., and the solution of which is neutral with
paper, and does not produce precipitates with chloride of mercury,
chloride of zinc or nitrate of silver. These prisms, dried at 212° F.
and analysed, furnished in 100 parts
Calculated
Found. (anhydrous creatine).
Carbon . . . . . . . . 3677 3664
Hydrogen . . . . . . 7'13 6'87
Nitrogen . . . . . . . . 3218 32°06
I also determined the quantity of nitric acid in the nitrate of crea
tine, and found it to contain 32°86 per cent. of monohydrated nitric
acid. The formula C8 H18 N6 0‘, N5‘ H2 06 requires 3247 per cent.
of Ni2 HQ 06. The same compound was produced by dissolving
l'O57 gr. of crystallized creatine in nitric acid containing 0'44-7 gr.
of N“ Hg 06, and evaporating at 86° F. The crystals were homo
geneous, and weighed 1-373 gr. From calculation _they should
weigh 1'876 gr. The sulphate and muriate of creatme form fine
prisms, which are more soluble than the nitrate, but like this are not
deliquescent ; they may be obtained by direct combination with the
acids, and evaporating at 86° F. or in vacuo. From these I have
separated the creatine free from all traces of creatinine; I have also
determined their proportions by synthesis, and their formulae are
C‘ H18 N6 O‘, SHEl O4 and C4 H‘8 N6 0‘, CP H’. The solution of
nitrate of creatine, traversed by a current of nitrous vapour; d1sen
M
204- Scientific and Medicinal Chemistry.
gages much gas; but the reaction, however long it might be con
tinued, did not give rise to an acid free from nitrogen. By neu
tralizing the product with potash, separating the greater part of the
nitrate of potash by crystallization, and then adding nitrate of silver,
crystals soluble in hot water are obtained, which after several cry
stallizations acquire the form of long white needles, which become
slightly yellow when exposed to the light. This salt is a compound
of nitrate of silver and of a new alkaloid. When calcined, it evolves
a fishy odour; it contains in 100 parts
Carbon. . . . . . . . . . . . . . . . . . . . 16"29
Hydrogen . . . . . . . . . . . . . . . . 2'37
Silver..........., . . . . . . .. 4797
which may be represented by he formula C6 H'° N9, N‘-‘ AgO6.
This salt, decomposed by the exact quantity of muriatic acid, fur
nished the chloride of the alkaloid which it contains. This chloride
crystallizes in a fibrous mass or in little prisms; it is very acid to
the taste. With bichloride of mercury it produces long needles of a
double salt, from which the organic base may be isolated ; but before
I can pursue the investigation of this base, I must prepare a fresh
supplyof creatino._ Comptes Rendus, May 8, 1854, p. 839.
On Glucinum and its Compounds. By H. Dnnaav.
M. Wiihler obtained the metal of glucina by means of the redu
cing action of potassium upon the chloride of glucinum; he assigns
to it the following properties :
“Glucinum forms a dark gray powder, having exactly the a -
pearance of a metal precipitated in a very divided form. Under t e
. burnisher it acquires a dull metallic lustre. As it is not agglome
rated by the violent heat at which it is reduced, it may be imagined
that it is very difficult of fusion. It does not oxidize in the air at
ordinary temperatures, nor in water even when boiling. Heated on
platinum foil in contact with the air, it takes fire, and burns with
a brilliant flame, becoming converted into white glucina.
“It dissolves readily in sulphuric, muriatic and nitric acids; in
the two former with disengagement of hydrogen, in the latter of
nitrous acid gas.”
The recent researches upon aluminium have induced me to take
up the study of glucinum; assisted by the advice of M. Sainte
Claire Deville, and by availing myself of his methods, I have been
enabled to obtain some new results, which I think worthy of the
notice of the Academy. '
Glucinum is the lightest of all the known metals which do not
decompose water at ordinary temperatures or at the boiling-point;
its density is 2'1. It is therefore lighter than aluminium. From its
appearance it might be confounded with zinc; but its less degree of
fusibility, which places it between the latter metal and aluminium,
its fixity in the fire, and its low specific gravity are so many phy
sical properties which would suifice to distinguish it from zinc.
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

16
Attachment 3
Gmelin

HAND-BOOK
or
CHEMISTRY.
BT
LEOPOLD GMELIN
VOL. X.
ORGANIC CHEMISTRY,
VOL. IV.
ORGANIC COMPOUNDS CONTAINING EIGHT AND TEN ATOMS OF CARBON.
TRANSLATED BY
HENRY WATTS, B.A., F.C.S.
6 LONDON :
PRINTED FOR THE CAVENDISH SOCIETY.
MDCCCLVI.
CREATINE. 249
cent. (Biltz); it dissolves in 1000 pts. of cold and 290 pts. of boiling
alcohol of 80 per cent; and in 500 pts. of cold and 40 pts. of boiling
alcohol of 60 per cent. (Biltz.)
It does not dissolve in ether, or, even with the aid of heat, in oils either
fixed or volatile. (Plisson & Henry.)
Oxalate of Asparagine. — An aqueous solution of 150 pts. (1 At.)
crystallized asparagine and 126 pts. (1 At.) hydrated oxalic acid, yields
by evaporation, a homogeneous mass consisting of very small crystals,
which, after drying in vacuo, amount to 222 pts. and give off nothing at
100°. Consequently, G At. of water have escaped, and there remains the
compound C"N2He06, C4H209. — An aqueous solution of 2 At. asparagine
and 1 At. oxalic acid in water, yields by evaporation a crystalline
mixture of the same compound and pure asparagine. (Dessaignes &
Chautard.)
*f. Malamide. C8NJH9Oc. — Isomeric, if not identical with asparagine. —
Obtained by the action of ammonia on malamic ether. When malamic
ether is dissolved in alcohol and ammoniacal gas passed through the solu
tion, pure malamide separates out in roundish nodules. — Or tho same
result may be more easily attained by mixing malic ether with strong
alcohol, passing dry ammoniacal gas through the liquid and then leaving
it at rest. Malamide appears to resemble asparagine in most, if not in
all, its properties. Crystallizes from its aqueous solution by slow evapo
ration in vacuo, in right rectangular prisms with dihedral summits, whoso
faces meet at an angle of 92° 50'. (Demondesir, Compt. rend. 33, 227 ;
Pasteur, X. Ann. C/dm. Phys. 38, 437; Jahresber. 1853, 411.) %
c. Nitrogen-nuclei,
a. Nitrogai-nucleus. CN'AdH7.
Creatine.
C»N'H»0«= CeN*AdH',04.
Chevrecl. J. Pharm. 21, 234; also J. pr. Chem. 6, 120.
Max Pettenkofer. Ann. Pharm. 52, 97.
Ltebig. Ann. Pltarm. 62, 28'2.
Heintz. Pogg. 62, 602; 70, 460; 73, 696; 74, 125. — Compt. rend.
24, 500.
Gregory. Cliem. Soc. Qu. J. 1, 25; also Ann. Pharm. 64, 100.
Krealin, Creatine. — Discovered in 1835 by Chevrcul in the juice of
flesh; more minutely examined by Licbig in 1847.
Source*. In the muscular flesh of mammalia, birds, amphibia, and
fishes. Lean horse-flesh contains 0 070, and the flesh of poultry 0-35 per
cent. That of the marten yields less than that of poultry, but more than
that of other mammalia; after horse-flesh follow in decreasing series the
flesh of tho fox, roc-buck, stag, bare, ox, sheep, pig, calf, and pike;
bullock's heart contains a large quantity of creatine. Fat animals yield
250 PRIMARY NUCLEUS C-H" : NITROGEN-NUCLEUS C"N*AdH*.
much less creatine tlian lean ones; e. g. a fox fattened on meat for 100
days, yields only -J^ as much as ono that has heen killed in the chase.
(L'ichig.) — Bullock's heart yields 0-142; the flesh of poultry 0-321; that
of the pigeon 0 083, that of Gadus morrhua 0-170; and that of the Raja
0 061 per cent. (Gregory.) Human flesh yields 0 067 p. c, and that of
the alligator likewise contains creatine (Sclilossberger, Ann. Pharm. 66,
80; 49, 344.) — The flesh of the Rorqual whale (BalcenopUra musculus)
likewise yields a small quantity of creatine. (D. Price, them. Soc. Qu. J.
3, 229.) — Pettenkofer admits the existence of creatine in human urine;
Liehig, that of creatine and cratinino together; but from Heintz's expe
riments, it appears probable that human urine contains only cratinine,
and that the precipitate obtained by treating the alcoholic extract of
urine with chloride of zinc, is only a cratinine-compound, in the decom
position of which, however, part of the cratinine is converted into creatine.
This however does not explain why the zinc-prccipitato obtained by
Liehig from fresh human urine yields creatine by decomposition as well as
cratinine, whereas that which is obtained from putrid urine yields only the
latter. — Heintz supposes further that creatine is a product of muscular
movement, and is discharged as an excrcmentitious matter in the urine
in the form of cratinine, and therefore cannot well be regarded as an
essential nutritive constituent of meat. — Creatine is likewise found,
together with cratinine and seroliue in blood. (Verdeil & Marcet, N. J.
P/iarm. 20, 89.)
Formation. From cratinine (.. 23-42 . ... 2511
CNWO4 .... 131 .... 100-00 100-00 .... 100-00 . ... 100-00
a was obtained from meat; b and c from the chloride of zinc and cratinine prepared
from human urine.
Decompositions. 1. Hydrated creatine when heated, first gives off
its water of crystallization with decrepitation; then melts without
becoming coloured; afterwards emits an odour of ammonia, hydrocy
anic acid and phosphorus; and, lastly, gives off yellow fumes, which
condense partly to an oil, partly to needle-shaped crystals, and leaves
a small quantity of charcoal. (Chevreul.) The charcoal is difficult to
burn. (Schlossberger.) — 2. The solution of creatine in aqueous hyper-
manganate of potash is decolorized by continued digestion, without evo
lution of gas, the creatine being decomposed and carbonate of potash
formed. (Liebig.) The aqueous solution of creatine is not decomposed
by boiling with peroxide of lead. (Liebig.) It is not coloured by boiling
with mercuric nitrate. (Chevreul.) — 3. Creatine dissolved in strong
nitric, sulphuric, phosphoric, or hydrochloric acid, is converted into cra
tinine by abstraction of 2HO, the cratinine then combining with tho
acid. (Liebig.) — But if these acids are dilute, the creatine remains
unaltered, even after loug boiling, and the solution in cold hydrochloric
acid leaves, by spontaneous evaporation, crystals of puro creatine.
CREATINE. 253
(Liebig.) — If dry hydrochloric acid gas be passed over 149 pts. (1 At.)
of hydrated creatine heated to 100° in Liebig's drying apparatus, the
weight first increases by absorption of hydrochloric acid; but if dry air
be then passed through the apparatus for some time, water is continu
ously given off, and the compound diminishes in weight, till it amounts
to only 154-16 pts. and contains 38'05 pts. (a little more than 1 At.)
hydrochloric acid. Hence 36 pts. (2 At.) of water of crystallization, and
2 At. more produced from the creatine), have been given off, and on
the other hand, 38-05 pts. (1 At.) hydrochloric acid have entered into
combination with the hydrated creatine :
C»N3H»0« + HCl = OWIlW.HCl + 4110.
131 pts. (1 At.) of dry creatine similarly treated with hj'drocbloric
acid gas take up about 18-04 pts., because, in this case, only 18 pts.
(2 At.) water are given off for every 36'4 pts. (1 At.) hydrochloric acid
taken up. (Liebig.) — The colourless solution of creatine in nitric acid
of sp. gr. 1-34 gives off nitrous fumes when heated in the water-bath,
and leaves on evaporation a colourless residue [of nitrate of cratininc ?],
which dissolves in water, separates out therefrom in small granules, and
does not precipitate bichloride of platinum. (Chevreul.) — 4. By boiling
with a small quantity of baryta dissolved in water, creatine is resolved
into sarcosine (ix. 432), and urea, which is then quickly resolved by the
baryta into carbonic acid and ammonia. (Liebig) :
CaN3H»04 + 2HO = CNH'Cr1 + C2N2H402.
An aqueous solution of creatine saturated at a boiling heat, and mixed
with crystals of baryta amounting to 10 times the weight of the creatine,
remains clear at first, but, if the boiling be continued, gives off abun
dance of ammonia; deposits carbonate of baryta at the same time; and, if
fresh baryta be added from time to time, is ultimately found to contain
scarcely any thing but sarcosine and carbonato of baryta; and, if the
operation be interrupted during the strongest evolution of ammonia,
likewise a little urea. A small quantity of another substance, probably
urethane (ix. 274), is however produced at the same time; for if the
alcohol from which the sulphate of sarcosine has crystallized out (ix, 433)
be mixed with water, neutralized with carbonate of baryta, filtered and
evaporated to a thin syrup, colourless needles and laniimo are obtained,
which redden litmus very slightly, fuse and volatilize when heated, without
leaving baryta, dissolvo in water, in alcohol, and in 30 pts. of ether, and
whose aqueous solution does not precipitate the salts of baryta lime or silver,
or neutral acetate of lead, or corrosive sublimate. (Liebig.) — 5. The
aqueous solution becomes turbid by long standing (if, according to
Liebig, it contains a trace of foreign organic matter), and evolves a
sickening ammoniacal odour. (Chevreul.) — IT. G. When nitrous gas i.s
passed into a solution of creatine in nitric acid, an alkali is formed,
having the' composition C*NH*. (Dessaignes, Compt. rend. 38, 839; see
also ix. 378.) — 7. When an aqueous solution of creatine is heated with
mercuric oxide, carbonic acid is evolved, and methyluramino (C*N3H7)
obtained in the form of an oxalate. (Dessaignes, ix. 357) :
2CSN3H»04 + 10O = 2C,N3H?,C'HJ08 + 4C02 + 2IIO.
Combinations, a. With Water. — a. Hydrated Creatine, Crystals of
Creatine. — Creatine crystallizes from its aqueous solution in trans
254 PRIMARY NUCLEUS C»H">: NITROGEN-NUCLEUS C»N=AdH*
parent, colourless, highly lustrous, oblique rhombic prisms and needles,
resembling in form those of neutral acetate of lead (Liebig). {Fig- 91,
together with the <-face; i : f=108° 55'; u : w = 46° 58': Heintz). In
nacreous rectangular prisms (Chevreul); in cubes (Schlossberger). —
Their specific gravity lies between 135 and l-84. (Chevreul.) When
covered with a uon-exhausted bell-jar, they effloresce on the surface, and
become covered with a mealy powder, giviug off 2-84 p. c. water
(Heintz); at 100° thev become quite opaque, and give off 12-17 p. c.
(Liebig); 13 08 p. c. (Heintz.)
Crystals. Liebig. Or :
8 C 48 .... 32-22 32-70
3 N 42 .... 28-19 28-32 CWH'O4.... 131 .... 87'92
11 H 11 .... 7'38 7-3G
6 O 48 .... 32-21 31-62 2HO 18 .... 12-08
CNWO* 149 .... 100 00 100 00 149 .... 100-00
y3. Aqueous Creatine. — Creatine dissolves in 83 pts. of water at 18°
(Chevreul), in 74-4 pts. (Liebig); it dissolves abundantly in hot water,
so that a solution saturated at the boiling heat solidifies on cooling in a
mass of delicate needles.
b. With Acids. Creatine dissolves slowly in oil of vitriol and without
colour in strong hydrochloric acid. (Chevreul ) It does not neutralize
the weakest acid, even when added in very largo quantity. (Liebig.)
T. Sulphate of Creatine. CBN3H°04,HO,S03, and the Hydrochlorate
CN'H'O'jHCI, are obtained in fine prisms by dissolving creatine in the
proper quantity of acid, and evaporating the solution at 30° or in vacuo;
they are soluble in water but not deliquescent. (Dessaignes.)
Nitrate of Creatine. — 1. Obtained by dissolving crystallized creatine
in the requisite quantity of nitric acid, and evaporating the solution at 30°.
— 2. By passing a rapid stream of nitrons gas through water containing
an excess of creatine in suspension. The creatine dissolves with tolerable
rapidity, and a considerable quantity of small shining crystals of the
nitrate are formed, which, when recrystallized by dissolving them in
lukewarm water and cooling, form thick short prisms. This salt is less
soluble in water than the sulphate or hydrochlorate. The solution has
a very sour taste, and is decomposed by ammonia with precipitation of
creatine. (Dessaignes.) Com.pt. rend. 38, 839; Ann. Pliarm. 92, 409.
Crystals. Dessaignes.
CsVH!'Oj 131 .... C7-53
HO.NO* 54 .... 32-47 32-36
C8N3H»04,HO,NOs .... 185 .... 100-00
By dissolving 1-057 grm. of creatine in a quantity of nitric acid containing 0-447
grm. HO,NO5, and evaporating at 30°, Dessaignes obtained 1-373 grms. of crystallized
nitrate; tlie formula requires 1*376. %.
From a solution in warm baryta-water creatine crystallizes on cooling
without taking up any baryta. (Liebig.)
The aqueous solution of creatine does not precipitate: Chloride of
barium, subacetate of lead, ferric sulphate, cupric sulphate, nitrate of
silver, or bichloride of platinum. (Chevreul.) — It does not precipitate
chloride of zinc, unless it contains cratinine. (Heintz.) — The warm non
CRATIMNE. 255
boiling, aqueous solution, added to chloride of zinc, docs not throw-
down any crystalline compound, but yields the creatine in the separate
state on cooling. (Liebig.) On boiling the mixture, the zinc-precipitate is
formed (Heintz), probably from conversion of the creatine with cratinine.
Creatine dissolves in 2000 pts. of alcohol of sp. gr. 0 810 at 15°
(Chevreul); it dissolves in 9410 pts. of cold absolute alcohol, more readily
in hydrated alcohol. (Liebig.)
It is nearly or quite insoluble in ether. (Heintz.)
p. Nitrogen-nucleus. C'N'H'O2.
Cratinine.
C»N»H'0»=C»N,H»0,,H«.
Liebio. Ann. Pharm. 62, 298 and 324.
Heintz. Pogg, 62, 602; 73, 595; 74, 125.
Kratinin, Kreatinin, Criatinine. On account of the too great similarity between
the words creatine and creatinine, which might lead to confusion, I propose to drop
the e in the first syllable of the latter. (Gm.) — Heintz and Pettenkofer in 1 844,
and nearly at the same time, discovered in human urine a nitrogenous
substance which formed a crystalline precipitate with chloride of zinc.
The crystalline substance separated from this precipitate was regarded
by Pettenkofer as a peculiar compound =C8N3H803 [plainly a mixture of
creatine and cratinine], by Heintz, at first as an acid, and afterwards as
creatine, — till Liebig, in 1847, showed that it was a mixture of creatine
and cratinine together, — which cratinine he had just before discovered
and investigated, having obtained it by decomposing creatine with con
centrated acids.
Sources. — ]. In human urine to the amount of 0 5 per cent. (Petten
kofer), and, according to Heintz, likewise in the urine of horses and other
mammalia. Socoloff has likewise found it in the urine of horses and of
calves. — 2. In muscular flesh. As it occurs in the mother-liquor of the
creatine prepared from flesh, and as dilute acids do not convert creatine
into cratinine, we cannot suppose that this cratinine of muscular flesh is
formed by heating the decoction of the flesh. (Liebig.) — 3. In blood.
(Verdeil & Marcet; see p. 250.)
Formation. From creatine, by the action of the stronger mineral
acids.
Preparation — 1. From hitman urine. — a. Fresh human urine is
neutralized with carbonate of soda, and evaporated below 100° to a
syrup (till the salts crystallize out, according to Liebig); this syrup
exhausted with alcohol; the filtrate mixed with a concentrated solution,
— (alcoholic, according to Heintz), of chloride of zinc, which at first
throws down a brown amorphous precipitate containing zinc (phosphate
of zinc, according to Heintz), then after several hours, crystalline grains;
the whole of the precipitate, after standing for some time collected
on a filter, (Heintz washes it with weak alcohol;) boiled with water,
which leaves the amorphous precipitate undissolved; and the filtrate
Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

17
Attachment 4
Bloxam

Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

18
Attachment 5
Wislicenus

Appeal 2015-006203
Merged Reexamination Control 90/011,394 and 90/011,869
Patent 7,777,074 B2

19
Attachment 6
Google Books Search

1/15/2016 creatine nitrate ­ Google Search
https://www.google.com/search?tbm=bks&q=creatine+nitrate#q=creatine+nitrate&tbm=bks&tbs=cdr:1,cd_min:1800,cd_max:1899 1/2
36% Off Creatine Capsules​
Ad www.lifeextension.com/Creatine​
Now only $6.94 ­ Save 36% Buy Now While Supplies Last
Creapure® Creatine Powder​
Ad www.swansonvitamins.com/Creatine​
1000g Size, $21.49 "Best Creatine". Swanson® Premium Creatine Products!
APS Creatine Nitrate​
Ad www.amazon.com/health​
Huge Selection at Great Low Prices Vitamins, Personal Care and More
Chemistry, Inorganic and Organic, with Experiments ­ Page 656
https://books.google.com/books?id=T4U­AAAAYAAJ
Charles Loudon Bloxam, ​John Millar Thomson, ​Arthur George Bloxam ­ 1895 ­
​Read ­ ​More editions
Creatine forms prismatic crystals easily soluble in hot water, but very
sparingly in alcohol and ether. The crystals are C^HjNjOj.Aq. Creatine is
neutral in reaction, but plays the part of a weak monacid base. Creatine
nitrate, C4H>NJ0,.HNO, ...
Short Text Book of Organic Chemistry ­ Page 423
https://books.google.com/books?id=d3hJAAAAYAAJ
1881 ­ ​Read ­ ​More editions
Creatine is obtained synthetically by the union of methyl glycocine or
sarcosine (§ 722) with cyanamide. Creatine crystallises in large, ... Creatine
nitrate, C4H9N 302,11X03, crystallises in large colourless prisms. On boiling
with solution of ...
Adolph Strecker's Short Text­book of Organic Chemistry ­ Pa…
https://books.google.com/books?id=ErlDAQAAMAAJ
Adolph Strecker, ​Johannes Wislicenus, ​Alfred John Greenaway ­ 1882 ­ ​Read
Creatine is obtained synthetically by the union of methyl glycocine or
sarcosine (§ 722) with cyanamide. Creatine crystallises in large, ... Creatine
nitrate, C,H9N302,HN03, crystallises in large colourless )I'ISIXIS. 1 On
boiling with solution of ...
Adolph Strecker's Short text­book of organic chemistry, by ... ­…
https://books.google.com/books?id=32gDAAAAQAAJ
Adolph Friedrich L. Strecker, ​Johannes Wislicenus ­ 1881 ­ ​Read
Creatine is obtained synthetically by the union of methyl glycocine
orsarcosine (§ 722) with cyanamide. Creatine crystallises in large, ... Creatine
nitrate, C4II9N30:;,HN03, crystallises in large colourless prisms. On boiling
with solution of baric ...
The Chemical Gazette, Or, Journal of Practical Chemistry, ...
https://books.google.com/books?id=sH4MAQAAIAAJ
1854 ­ ​Read ­ ​More editions
These crystals, which may readily be obtained in thick short prisms by
solution in warm water and cooling, consist of nitrate of creatine. Their
solution, which has a very acid taste, is abundantly precipitated by ammonia.
The precipitate ...
The Chemical Gazette ­ Volume 12 ­ Page 203
https://books.google.com/books?id=JwcAAAAAMAAJ
1854 ­ ​Read ­ ​More editions
These crystals, which may readily be obtained in thick short prisms by
solution in warm water and cooling, consist of nitrate of creatine. Their
solution, which has a very acid taste, is abundantly precipitated by ammonia.
Any books Any document 19th century Sorted by relevance Clear
All Shopping Videos News Books Search toolsMore
creatine nitrate Rae Lynn
1/15/2016 creatine nitrate ­ Google Search
https://www.google.com/search?tbm=bks&q=creatine+nitrate#q=creatine+nitrate&tbm=bks&tbs=cdr:1,cd_min:1800,cd_max:1899 2/2
1 2 3 4 5 6 7 8 9 10 Next
The precipitate ...
The Chemical Gazette: Or, Journal of Practical Chemistry, ...
https://books.google.com/books?id=9kgzAQAAMAAJ
William Francis, ​Henry Croft ­ 1854 ­ ​Read ­ ​More editions
These crystals, which may readily be obtained in thick short prisms by
solution in warm water and cooling, consist of nitrate of creatine. Their
solution, which has a very acid taste, is abundantly precipitated by ammonia.
The precipitate ...
Hand­book of chemistry ­ Volume 10 ­ Page 254
https://books.google.com/books?id=5nMMAAAAYAAJ
Leopold Gmelin ­ 1856 ­ ​Read ­ ​More editions
Nitrate of Creatine. — 1. Obtained by dissolving crystallized creatine in the
requisite quantity of nitric acid, and evaporating the solution at 30°. — 2. By
passing a rapid stream of nitrons gas through water containing an excess of
creatine in ...
A dictionary of chemistry and the allied branches of other ... ­ …
https://books.google.com/books?id=XIYPAQAAIAAJ
Henry Watts ­ 1879 ­ ​Read ­ ​More editions
found the amount of creatine in 100 pts. of the flesh of various animals to be
as follows : Ox Pig Calf Sheep 1 2 8 "\ T 1 P ... Creatine forms similar
compounds with cupria chloride and mercuric nitrate (Neubauer, Ann. Ch.
Pharm. cxxxvii. 298).
Year Book of Pharmacy ­ Page 23
https://books.google.com/books?id=iO43AAAAMAAJ
1875 ­ ​Read ­ ​More editions
Creatine. M. Engel. (Journ. de Pharm. et de Chim., 4th series, xx., 103.) It is
well known that nitrate of silver and ammonio­nitrate of silver produce no
effect on a solution of creatine. But if a saturated solution of creatine is
mixed with a solution ...
Creatine Supplements​
Ad www.puritan.com/​
Buy 1 Get 1 Free at Puritan. Plus, Free Shipping on All Orders!
Help  Send feedback  Privacy  Terms