Ex Parte 6583123 et al

Board of Patent Appeals and Interferences

May 29, 2009

90007916 (B.P.A.I. May. 29, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________________

Ex parte NUTRAMAX LABORATORIES, INC.,
Appellant
____________________

Appeal 2008-006219
Reexamination Control 90/007,916
Patent 6,583,123 B21
Technology Center 3900
____________________

Decided:2 May 29, 2009
____________________

Before CAROL A. SPIEGEL, DONALD E. ADAMS, and
ROMULO H. DELMENDO, Administrative Patent Judges.

SPIEGEL, Administrative Patent Judge.

DECISION ON APPEAL

1 Patent 6,583,123 B2 ("the 123 patent"), Aminosugar, Glycosaminoglycan and S-
Adenosylmethionine Composition for the Treatment and Repair of Connective
Tissue, issued 24 June 2003, to Henderson et al., based on application 09/834,726
("the 726 application), filed 16 April 2001. The 726 application is a continuation
of application 08/797,294, filed 7 February 1997, now Patent 6,271,213, which is a
continuation in part of application 08/779,996, filed 23 December 1996, now
Patent 6,492,349. The real party in interest is NUTRAMAX LABORATORIES,
INC., Patent Owner (Appeal Brief filed 26 December 2006 ("App. Br.") at 5).
2 The two month time period for filing an appeal or commencing a civil action, as
recited in 37 C.F.R. § 1.304, begins to run from the decided date shown on this
page of the decision. The time period does not run from the Mail Date.
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I. Statement of the Case
Appellant appeals under 35 U.S.C. §§ 134 and 306 from an Examiner's final
rejection of claims 9-11 (Reply Br.3 2; Communication4 1). The Examiner has
confirmed the patentability of claims 1-7, the only other pending claims (App. Br.
7; Ans.5 2). We have jurisdiction under 35 U.S.C. §§ 134 and 306. We AFFIRM.
The subject matter on appeal relates to compositions for treating, repairing,
and reducing inflammation of connective tissue in humans and animals comprising
S-adenosylmethione ("SAMe") and a glucosamine and/or a salt thereof. Claims 9-
11 read as follows (Amendment 3-4):
9. A composition for treatment and repair and for
reducing the inflammation of connective tissue in
humans and animals comprising: an aminosugar selected
from the group consisting of glucosamine, glucosamine
salts and mixtures thereof, in combination with S-
adenosylmethionine, wherein a dose of the aminosugar
ranges from about 50 mg to about 40,000 mg, and
wherein a dose of the S-Adenosylmethione ranges from
about 2 mg to about 20,000 mg.

10. A composition for treatment and repair and for
reducing the inflammation of connective tissue in
humans and animals comprising: an aminosugar selected
from the group consisting of glucosamine, glucosamine
salts and mixtures thereof, in combination with S-
adenosylmethionine, wherein a dose of the aminosugar
ranges for humans and small animals ranges from about
50 mg to about 5,000 mg, and wherein a dose of the S-

3 Reply Brief Under 37 C.F.R. § 41.41 filed 21 December 2007 ("Reply Br.").
4 Communication from the Examiner mailed 1 February 2008, entering an
Amendment filed 10 January 2008 ("Amendment") which cancelled claims 8 and
12-13 and rewrote claims 9-11 in independent form.
5 Examiner's Answer mailed 28 September 2007 ("Ans.").
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Adenosylmethionine for humans and small animals
ranges from about 5 mg to about 5,000 mg.

11. A composition for treatment and repair and for
reducing the inflammation of connective tissue in
humans and animals comprising: an aminosugar selected
from the group consisting of glucosamine, glucosamine
salts and mixtures thereof, in combination with S-
adenosylmethionine, wherein a dose of the aminosugar
for large animals ranges from about 250 mg to about
40,000 mg, and wherein a dose of the S-
Adenosylmethionine for large animals ranges from about
2 mg to about 20,000 mg.

The Examiner relies on the following references of record as evidence of
unpatentability:
Henderson 5,364,845 C1 Nov. 15, 1994

G. Douglas Andersen, "Cutting Edge Compounds -- SAM, Where are you?"
Dynamic Chiropractic, February 27, 1995, Vol. 13, No. 5, downloaded December
16, 2005 from http://www.chiroweb.com/archives/12/05/08.html ("Andersen").

Luke R. Bucci, "Nutritional Influences on Musculoskeletal Healing," presented at
the Pennsylvania Chiropractic Association Meeting, March 21-22, 1992, pp. 1-22
("Bucci I").

Benno König, "A Long-Term (Two Years) Clinical Trial with S-
Adenosylmethionine for the Treatment of Osteoarthritis," The American Journal of
Medicine, Vol. 83, No. Suppl. 5A, November 20, 1987, pp. 89-94 ("Konig").

Pujalte et al., "Double-blind clinical evaluation of oral glucosamine sulphate in the
basic treatment of osteoarthritis," Current Medical Research and Opinion, Vol. 7,
No. 2, 1980, pp. 110-114 ("Pujalte").

In addition to Andersen and the 123 patent under reexamination, Appellant
relies on the following references of record, as evidence of patentability:
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Luke R. Bucci, "Chondroprotective Agents Glucosamine Salts and Chondroitin
Sulfates," Townsend Letters for Doctors," January 1994, pp. 52-54 ("Bucci II").

Lippello et al., "Advantageous Use of Glucosamine Combined with S-
Adenosylmethionine in Veterinary Medicine: Preservation of Articular Cartilage in
Joint Disorders," Intern J Appl Res Vet Med, Vol. 3, No 1, 2005, pp. 6-12 ("the
Lippello article").

Declaration of David Griffin, DVM, under 37 C.F.R. § 1.132, dated September 25,
2006 ("Griffin Decl."), including an Appendix ("Griffin App'x."), the Lippiello
article (as Exhibit 1) and
Exhibit 3: Stramentinoli et al., "Intestinal Absorption of S-Adenosyl-L-
Methionine," The Journal of Pharmacology and Experimental Therapeutics, Vol.
209, No. 3, 1979, pp. 323-326 ("Stramentinoli I").
Exhibit 4: Center et al., "The Effects of S-Adenosylmethionine on Clinical
Pathology and Redox Potential in the Red Blood Cell, Liver, and Bile of Clinically
Normal Cats," Journal of Vet Intern Med, Vol. 19, 2005, pp. 303-314 ("Center").
Exhibit 5: G. Stramentinoli, "Pharmacologic Aspects of S-
Adenosylmethionine," The American Journal of Medicine, Vol. 83, Supp. 5A,
November 20, 1987, pp. 35-42 ("Stramentinoli II").
Exhibit 6: Aghazadeh-Habashi et al., "Single Dose Pharmacokinetics and
Bioavailability of Glucosamine in the Rat," J Pharm Pharmaceut Sci, Vol. 5, 2002,
pp. 181-184 ("Aghazadeh-Habashi").
Exhibit 7: Adebowale et al., "The Bioavailability and Pharmacokinetics of
Glucosamine Hydrochloride and Low Molecular Weight Chondroitin Sulfate After
Single and Multiple Doses to Beagle Dogs," Biopharmaceutics & Drug
Disposition, Vol. 23, 2002, pp. 217-225 ("Adebowale").
Exhibit 8: Huang et al., "Liquid chromatography with electrospray
ionization mass spectrometry method for the assay of glucosamine sulfate in
human plasma: validation and application to a pharmacokinetic study," Biomedical
Chromatography, Vol. 20, No. 3, 2005, pp. 251-256 ("Huang").
Exhibit 9: Du et al., "The Bioavailability and Pharmacokinetics of
Glucosamine Hydrochloride and Chondroitin Sulfate after Oral and Intravenous
Single Dose Administration in the Horse," Biopharmaceutics & Drug Disposition,
Vol. 25, 2004, pp. 109-119 ("Du").
Exhibit 10: G. Gonzales, "How to Establish an Equine Blood Donor
Protocol," AAEP Proceedings, Vol. 47, 2001, pp. 262-265 ("Gonzales").
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Exhibit 11: Householder et al., "Total Blood Volume and Thoroughbred
Racing Performance," Journal of Equine Veterinary Science, Vol. 25, No. 1,
January 2005, pp. 14-15 ("Householder").
Exhibit 12: D.M. Boothe: SMALL ANIMAL CLINICAL
PHARMACOLOGY AND THERAPEUTICS, pp. 18 and 35 ("Boothe").
Exhibit 13: THE MERCK VETERINARY MANUAL, ninth edition, Merck
& Co., Inc., Whitehouse Station, N.J., 2005, pp. ("Merck")
Exhibit 14: J.A. Helgren, " Choosing a Singapura," © 1999-2006,
Intelligent Content Corp., downloaded September 21, 2006 from
http://www.petplace.com/article-printer-friendly.aspz?id=2705 ("Halgren").
Exhibit 15: V.J. Meriwether, "Breed Profile: Ragdoll," The Cat Fanciers'
Association, ©1995-2006, downloaded from an unknown cite, September 21, 2006
("Meriwether").
Exhibit 16: DePrisco and Johnson, THE MINI-ATLAS OF DOG BREEDS,
T.F.H. Publications, Inc., 1990, "Mastiff" and "Chihuahua" ("DePrisco").
Exhibit 17: National Center for Health Statistics, "Clinical Growth Charts,"
May 17, 2006, downloaded September 25, 2006 from
http://www.cdc.gov/nchs/about/major/nhanes/growthcharts/clinical_charts.htm
("NCHS").
Exhibit 18: University of Michigan Health System, "Ideal Weight Table for
Men and Women," downloaded September 13, 2006 from
http://www.med.umich.edu/1libr/primry/life15.htm ("UMich").
Exhibit 19: F. Harper, "Broodmare Selection," Horse Express, Vol. 25, No.
2, April, May, June 2006, four page article ("Harper").
Exhibit 20: "Characteristics and Origin of the Clydesdale Horse,"
downloaded September 13, 2006 from
http://www.ansi.okstate.edu/breeds/horses/clydesdale/index.htm ("Clydesdale").

Declaration of Todd Henderson, DVM, under 37 C.F.R. § 1.132, dated September
25, 2006 ("Henderson Decl."), including
Exhibit 2: Ionac et al., "Oxaceprol, an Atypical Inhibitor of Inflammation
and Joint Damage," Pharmacological Research, Vol. 33, No. 6, 1996, pp. 367-373
("Ionac").
Exhibit 3: Kalbhen et al., "Autoradiographic Investigations on the Influence
of Oxaceprol on the Metabolism of Articular Cartilage in-vitro and in-vivo,"
Zeitschrift fűr Rheumatologie, Vol. 46, 1987, pp. 136-142, Translation ("Kalben").
Exhibit 4: PubMed Abstract of Riera et al., "Effect of oxaceprol on the
synthesis and degradation in vitro of proteoglycans and proteins by calf articular
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cartilage explants," Rev. Rhum. Mal Osteopartic, Vol. 57, No. 7-8, Jul-Sep 1990,
pp. 579-583 ("Riera abstract").
Exhibit 5: Tallarida et al., "Antinociceptive Synergy, Additivity, and
Subaddivity with Combinations of Oral Glucosamine plus Nonopoid Analgesics in
Mice," The Journal of Pharmacology and Experimental Therapeutics, Vol. 307,
No. 2, 2003, 699-704 ("Tallarida").

Final Office Action in Ex Parte Reexamination, mailed August 23, 2006 ("FR").

Response to Final Action Under 37 C.F.R. § 1.116 filed September 25, 2006
("After Final Response").

Ex Parte Reexamination Advisory Action mailed October 18, 2006 ("Advisory").

Office Action mailed May 31, 2006 ("OA").

Response to May 31, 2006 Office Action, filed June 30, 2006 ("Response"),
including the Lippiello article and
Exhibit 1: Declaration of Louis Lippiello, PhD, under 37 C.F.R. § 1.132,
dated June 28, 2000, filed in parent application 08/797,294 ("Lippiello Decl. I").
Exhibit 2: Declaration of Louis Lippiello, PhD, under 37 C.F.R. § 1.132,
dated March 9, 2000, filed in application 08/845,852 ("Lippiello Decl. II").
Exhibit 3: Declaration of Louis Lippiello, PhD, under 37 C.F.R. § 1.132,
dated January 29, 1998, filed in parent application 08/797,294 ("Lippiello Decl.
III").
Exhibit 4: Declaration of Louis Lippiello, PhD, under 37 C.F.R. § 1.132,
dated September 29, 2000, filed in grandparent application 08/779,996 ("Lippiello
Decl. IV").

Examiner Ex Parte Reexamination Interview Summary issued July 12, 2006 ("Exr.
Interview Summary I").

Appellant Interview Summary under 37 C.F.R. § 1.560(b), filed August 4, 2006
("App. Interview Summary I").

Examiner Ex Parte Reexamination Interview Summary issued October 13, 2006
("Exr. Interview Summary II").

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Appellant Interview Summary under 37 C.F.R. § 1.560(b), filed November 13,
2006 ("App. Interview Summary II").

Benet et al., "Appendix II: Design and Optimization of Dosage Regimens;
Pharmacokinetic Data," Goodman and Gilman's THE PHARMACOLOGICAL
BASIS OF THERAPEUTICS, sixth edition, MacMillan Publishing Co., Inc., New
York, pp. 1675, 1679-1681 only ("Benet").

Chan et al., "Glucosamine and chondroitin sulfate regulate gene expression and
synthesis of nitric oxide and prostaglandin E2 in articular cartilage explants,"
OsteoArthritis and Cartilage, Vol. 13 (2005), pp. 387, 388, and 391 only ("Chan
I").

Homandberg et al., "Mixtures of glucosamine and chondroitin sulfate reverse
fibronectin fragment mediated damage to cartilage more effectively than either
agent alone," OsteoArthritis and Cartilage, Vol. 14 (2006): 793-806
("Homandberg").

Chan et al., "Effect of glucosamine and chondroitin sulfate on regulation of gene
expression of proteolytic enzymes and their inhibitors in interleukin-1-challenged
bovine articular cartilage explants," AJVR, Vol. 66, No. 11 (November 2005), pp.
1870-1872 only, ("Chan II").

Cortial et al., "Activation by IL-1 of bovine articular chondrocytes in culture
within a 3D collagen-based scaffold. An in vitro model to address the effects of
compounds with therapeutic potential in osteoarthritis," OsteoArthritis and
Cartilage, Vol. 14 (2006), p. 631 only ("Cortial").

O'Brien et al., "Human and animal hepatocytes in vitro with extrapolation in vivo,"
Chemico-Biological Interactions, Vol. 150 (2004), pp. 97-98 only ("O'Brien").

Huntjens et al., "Correlation between in vitro and in vivo concentration-effect
relationships of naproxen in rats and healthy volunteers,” British Journal of
Pharmacology, Vol. 148 (2006), p. 398 only ("Huntjens").

The Examiner has rejected claims 9-11 as unpatentable under 35 U.S.C.
§ 103(a) over Bucci I, Pujalte, Henderson, Konig, and Andersen (Ans. 3). The
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Examiner found that Bucci I, Pujalte, and Henderson each teach compositions
containing glucosamine for treatment of osteoarthritis, that Konig teaches treating
osteoarthritis with SAMe, and that Anderson not only teaches that SAMe is an
anti-inflammatory and stimulates production of proteoglycans, but also expressly
suggests SAMe in 400 mg capsules combined with glucosamine sulfate (Ans. 4-5).
The Examiner concluded that a composition containing SAMe and glucosamine in
the concentrations recited in claims 9-11 would have been obvious based on the
teachings of Bucci I, Pujalte, Henderson, Konig, and Andersen (Ans. 6).
Appellant contends that the claimed compositions are unexpectedly
synergistic at the recited concentrations as evidenced by the Lippiello article and
the Henderson and Griffin declarations (App. Br. 13-24).
At issue is whether Appellant has shown that the claimed compositions
contain an unexpectedly synergistic combination of SAMe and glucosamine and
whether that showing is commensurate in scope with the claimed invention,
thereby overcoming the Examiner's prima facie conclusion of obviousness.
II. Findings of Fact ("FF")
The following findings of fact are supported by a preponderance of the
evidence of record.
A. The prior art
[1] Bucci I teaches using 1-2 grams glucosamine salt daily to treat osteoarthritis
and cartilage abnormalities (Bucci I 15).
[2] Pujalte teaches oral administration of 250 mg glucosamine sulphate three
times per day to treat osteoarthritis (Pujalte abstract).
[3] Henderson discloses compositions comprising glucosamine and salts
thereof, manganese sulfate, and optionally, but preferably, chondroitin
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sulfate, for protecting, treating, and repairing connective tissue in mammals
(Henderson 3:51-4:2; 8:12-14).
[4] According to Henderson, the disclosed compositions (i) are preferably
provided in capsule form, (ii) contain 250 to 750 mg (for humans and small
animals) or 1,000 mg to 3,000 mg (for large animals) glucosamine, and (iii)
are adminstered in daily amounts of 1 to 6 capsules (Henderson 7:54-8:10).
[5] Henderson is assigned to Nutramax Laboratories, Inc., the Appellant
(Henderson cover sheet § (73)).
[6] Andersen teaches that (i) SAMe is an anti-inflammatory, antiphlogistic,
analgesic, and stimulates articular chondrocytes to produce proteoglycans
and is normally administered at 400 mg three times per day (Andersen 35).
[7] Andersen expressly suggests encapsulating 400 mg SAMe in combination
with glucosamine sulfate (Andersen 35).
[8] Konig discusses a two year clinic trial in which 108 patients with
osteoarthritis were treated with 600 mg SAMe daily for two weeks, followed
by 400 mg daily until the end of the trial, which showed that SAMe was
effective and well tolerated (Konig abstract).
B. The Lippiello article
[9] According to the Lippiello article, a combination of SAMe and glucosamine
hydrochloride at doses of 0.052 µg/mL-0.52 µg/mL and 5 µg/mL,
respectively, resulted in a 15%-20% greater increase in stimulation of
glycosaminolglycan ("GAG") synthetic activity compared with the additive
value of each agent tested separately in vitro (the Lippiello article abstract;
9, Table 2; 11, "Conclusion").

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Table 2. Synergistic Activity of Glucosamine as S-Adenosylmethlonine on
Uptake of 35-Sulfate by Bovine Chondrocytes
Treatment Additive Response Synergistic
Response
Difference
GLN-5* µg/mL +
SAMe 0.0052 µg/mL
15% 25% + 10%
GLN-5 µg/mL + SAMe
0.052 µg/mL
21% 44% + 23%
GLN-5 µg/mL + SAMe
0.52 µg/mL
35% 50% + 15%
* indicates glucosamine; SAMe, S- adenosylmethlonine

[10] Notably, the study documented by the Lippiello article, "tested each agent at
physiologically obtainable oral doses to explore any synergism in promoting
cartilage matrix synthesis and inhibiting those catabolic processes leading to
cartilage degradation" (the Lippiello article 7, col. 1, ¶2).
C. The Henderson Declaration
[11] Todd Henderson, DVM, testified that he is Executive Vice President of
Nutramax Laboratories, Inc., the Appellant (Henderson Decl. ¶1).
[12] Dr. Henderson testified that he supervised laboratory experiments conducted
by Dr. Louis Lippiello testing the ability of various compounds to provide
chondroprotective effects on articular cartilage (Henderson Decl. ¶4).
[13] According to Dr. Henderson, Nutramax's testing showed that a combination
of SAMe and N-acetylhydroxyproline (Oxaceprol), a known therapeutic
agent for osteoarthritis, produced lower levels of chondroprotective activity
than the additive effects of the two agents administered separately
(Henderson Decl. ¶¶ 5-11).
[14] Dr. Henderson cited Tallarida for its report on combinations of glucosamine
and certain nonopioid pain relievers (Henderson Decl. ¶12).
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[15] Tallarida reported that glucosamine sulfate in doses up to 500 mg/kg p.o. (by
mouth) had no antinociceptic (reduced sensitivity to painful stimuli) effect
when administered as the sole agent but that "certain combinations of
glucosamine with nonopioid analgesics at the oral doses and ratios tested
resulted in a synergistic (ibuprofen and ketoprofen), additive (diclofenac,
indomethacin, naproxen, and piroxicam), or subadditive (aspirin and
acetaminophen) antinociceptive interaction" (Tallarida abstract).
[16] Dr. Henderson opined that, based on the data from Nutramax's own
experiments and those of Tallarida, "a person of ordinary skill in the art
would find the demonstrated synergy of the SAMe and glucosamine to be
unexpected" (Henderson Decl. ¶13).
D. The Griffin Declaration
[17] David Griffin, DVM, testified that he is Director of Product Development of
Nutramax Laboratories, Inc., the Appellant (Griffin Decl. ¶1).
[18] Dr. Griffin calculated that administering the following amounts of SAMe
and glucosamine to small animals, humans, and large animals would
produce respective plasma concentrations of SAMe and glucosamine which
the Lippiello article identified as synergistic, i.e., 0.052 µg/mL -0.52 µg/mL
SAMe and 5 µg/mL glucosamine (Griffin Decl. ¶¶4-5):
SAMe
(approximate range)
Glucosamine
(approximate range)
Small animals 0.32 mg - 4,300 mg 13 mg - 16,500 mg
Humans 9 mg - 1,240 mg 500 mg - 5,025 mg
Large animals 15 mg - 37,000 mg 1,700 mg - 125,000 mg

[19] Dr. Griffin explained how he calculated these amounts in the Appendix to
his declaration.
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[20] According to Dr. Griffin, the ratio of maximum plasma concentration to
administered dose (Cmax/D) is generally understood to be constant for SAMe
and glucosamine (Griffin Decl. ¶6; Griffin App'x. ¶1).
[21] Dr. Griffin culled several references for disclosed Cmax and D information
and selected the following (where Dexp is an orally administered dosage
described in the referenced experiment) (Griffin App'x. ¶2):
Animal SAMe Dexp (mg/kg) SAMe Cmax (ng/ml) Reference
rat 100 970 Stramentinoli I
cat 32 - 55 150 Center
human 1.85 - 2.64 77.5 - 185 Stramentinoli II

Animal Glucosamine Dexp (mg/kg) Glucosamine Cmax (µg/ml) Reference
rat 350 2.9 - 34.7 Aghazedeh-Habashi
dog 187.5 - 136 4.88 - 13.02 Adebowale
human 22.4 - 27.3 1.9 - 4.1 Huang
horse 125 3.7 - 17.5 Du

[22] Figure 1 of Stramentinoli I, which graphs the plasma levels of SAMe after
oral (A) or i.v. (B) administration is reproduced below (Stramentinoli I 324):
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{Figure 1 of Stramentinoli I graphs the SAMe concentration (µm/ml plasma)
versus time (minutes) after oral or i.v. administration.}

[23] According to Stramentinoli I, low SAMe plasma levels after oral
administration suggest a first-pass effect characterized by an extensive
uptake of SAMe by the liver where it is rapidly metabolized (Stramentioli I
abstract; 326, col. 1, ¶4).
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[24] Center administered 180 mg SAMe tablets to cats weighing 3.4-5.1 kg,
resulting in a mean daily dosage of 48±7 mg/kg (range 32-35 mg/kg) body
weight and measured the SAMe plasma concentrations graphed in Figure 2
(Center 304, col. 2, ¶1). The highest Cmax, approximately 1.50 µg/ml, i.e.,
1,500 ng/ml, was measured on day 111 approximately 3 hours after SAMe
administration (Center Figure 2). Figure 2 (best image available) is
reproduced below.

{Figure 2 of Center graphs plasma SAMe concentrations after a 180 mg dose
administered PO to 15 clinically healthy cats on days 0, 29, and 111.}

[25] Stramentinoli II Figure 4 depicts the time course of plasma SAMe
concentrations in four men and four women after receiving 2 x 200 mg of
SAMe (Stramentinoli II 37). Stramentinoli did not specify the weights of
the eight human volunteers. Figure 4 (best image available) is reproduced
below.
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{Figure 4 of Stramentinoli II graphs the time course of plasma SAMe
concentrations in men (dotted lines) and women (solid lines) after receiving 400
mg SAMe orally.}

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[26] Thus, according to Stramentinoli II Figure 4, the maximum plasma SAMe
concentrations range from about 80 to about 195 µg/ml, i.e., about 80,000
to about 195,000 ng/ml.
[27] According to Aghazadeh-Habashi, oral administration of 350 mg SAMe/kg
body weight to rats produced a Cmax between 2.9 and 34.7 µg/ml (i.e., 18.8 ±
15.9 µg/ml) (Agahazadeh-Habashi abstract; Table 1).
[28] According to Adebowale, initial oral administration of 1500 mg of
glucosamine (in combination with 1200 mg low molecular weight
chondroitin sulfate) to beagle dogs weighing approximately 9 kg (i.e., 167
mg glucosamine /kg) produced a mean (±SD) Cmax of 8.95 (4.07) µg/ml (i.e.,
4.88 - 13.00 µg/ml), whereas intraperitoneal administration produced a mean
Cmax of 228 (41.8) µg/ml (i.e., 186.2 - 269.8 µg/ml) (Adebowale 219, col. 2;
Table 1).
[29] Huang orally administered test tablets for a total dose of 1500 mg
glucosamine to eighteen men weighing 61.2 ± 5.9 kg (55.3 - 67.1 kg), i.e.,
doses ranging from 22.1 mg/kg to 27.1 mg/kg, and measured a Cmax of 3.0 ±
1.1 µg/ml, i.e., 1.9 - 4.1 µg/ml (Huang, ¶ bridging 252-253; Table 1).
[30] According to Du, oral administration of 125 mg/kg glucosamine to two
horse yielded a mean Cmax of 10.6 (6.9) µg/ml, i.e., 3.7-17.5 µg/ml (Du
abstract; Table 1; Figure 1).
[31] According to Dr. Griffin, Nutramax orally administered 225 mg SAMe to
dogs weighing 10 - 12 kgs, i.e., 18.75 -22.5 mg SAMe/kg, resulting in a
mean Cmax of 1,451 ng/ml with a range of 230 ng/ml to 3,026 ng/ml (Griffin
App'x. ¶3).
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[32] According to Dr. Griffin, the ratio of the synergistic concentration (Csyn) of
SAMe or glucosamine to the dosage required to provide that Csyn (i.e., Dsyn)
should equal its respective Cmax/D ratio (Griffin App'x. ¶ 5).
[33] Using the Cmax and dosage Dexp information set forth in FF 21 and 31 above,
Dr. Griffin calculated the experimental Cmax/Dexp ratios and solved for Dsyn
given the Csyn values disclosed in the Lippiello article (Griffin App'x. ¶¶6-7).
[34] Dr. Griffin further stated that one of ordinary skill in the art would have
expected the Dsyn of dogs and horses to be approximately the same because
dogs and horses have similar blood volumes, as evidenced by Gonzales,
Householder, and Boothe (Griffin App'x. ¶ 8).
[35] According to Gonzales, the maximum amount of blood that can be collected
from a horse weighing above 200 pounds (i.e., about 74.6 kilograms) for
transfusion purposes is 6-8 liters (Gonzales 262, col. 2, ¶ 2; 265, col. 2, ¶2).
[36] According to Householder, the total blood volume measured on 47 mature
race-retired thoroughbred horses had a normal distribution with a mean of
49.2 ± 5.0 liters (Householder abstract).
[37] According to Boothe, the dosing regimens recommended for dogs and
frequently be extrapolated to the cat (Boothe 35, col. 1, ¶4).
[38] Further according to Boothe, the blood volume of the cat is 70 ml/kg and
that of the dog is 90 ml/kg (Boothe 35, col. 2, ¶3).
[39] Thus, Dr. Griffin concluded that his calculated dog SAMe Dsyn holds true for
the horse (Griffin App'x. ¶8).
[40] In addition, Dr. Griffin extrapolates his calculated Dsyn dosages to
encompass subjects beyond those tested in the culled references and at
Nutramax by multiplying the calculated Dsyn by the typical mass of a rat
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(0.25-0.5 kg), a cat (2-9 kg), a dog (1-86 kg), a human (including a child)
(18-70 kg), and a horse (including a foal) (50-750 kg), as evidenced by
Merck, Helgren, Meriwether, DePrisco, CCHS, UMich, Harper, and
Clydesdale, to obtain species specific dosage ranges (Griffin App'x. ¶¶9-10).
[41] Thus, Dr. Griffin concludes (Griffin Decl. ¶ 5):
5. Though a straight forward calculation known to a
person of ordinary skill in the art and described in this
Declaration, I have calculated that the concentrations of
SAMe and glucosamine found by Dr. Lippiello to by
synergistic would result from doses of SAMe and
glucosamine administered to small animals (rats, dogs,
and cats), humans (including children) and large animals
(horses, including foals) as set forth in the following
table.

TABLE 1
SAMe
(approximate range)
Glucosamine
(approximate range)
Small animals 0.32 mg – 4,300 mg 13 mg – 16,500 mg
Humans 9 mg – 1,240 mg 500 mg – 5,025 mg
Large Animals 15 mg – 37,00 mg 1,700 mg -125,000 mg

E. References submitted with the Appeal Brief in support of determining
in vivo administration dosages from in vitro data

[42] With the exception of Homandberg, none of the remaining references
submitted in support of determining in vivo administration data for in vitro
data is a complete publication or book chapter.
[43] According to Benet,
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[t]he object of this appendix is to present
pharmacokinetic data in a format that allows the clinician
to make rational choices of doses of drugs. The tables
contain quantitative information about the absorption,
distribution, and elimination of drugs and the effects of
disease states on these processes, as well as information
concerning the correlation of efficacy and toxicity with
measured concentrations of drugs in plasma. In this
compilation emphasis is placed on the relationship
between pharmacokinetic parameters and physiological
variables, rather than on the use of compartmental
models to define pharmacokinetic concepts. [Benet
1657, opening ¶.]

[44] Further according to Benet, "[d]osage describes both the route and the rate
of administration of drugs, and knowledge of pharmacokinetic principles is
important in making such decisions" (Benet 1679, col. 1, ¶2).
[45] Benet also discloses a "target level strategy" for choosing a desired steady
state concentration of a drug, i.e.,
… for some drugs it is rational to use the measured
concentration of the drug in plasma as an indirect or
intermediate therapeutic endpoint. Intermediate end
points are observable events that tell the clinician
something about the consequences of his therapeutic
decisions and help improve future decisions through
feedback. … When ultimate endpoints are difficult to
measure, delayed, or dangerous, when a drug has a low
therapeutic index, where the steady-state concentration of
the drug in plasma is known to correlate directly with
pharmacological and clinical effects, and when no better
intermediate end point (such as blood pressure) is readily
available, it is rational to use the measured concentration
of drug itself as an indirect therapeutic end point for
planning and regulating therapy. [Benet, ¶ bridging
1680-81, original emphasis.]
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[46] According to Chan I and II, most in vitro research has been performed with
concentrations of glucosamine and chondroitin sulfate that exceed those
likely to be obtained by oral administration, but the Chan I and II studies are
based on concentrations reported in blood after oral or intravenous
administration (Chan I 388, col. 1, ¶3; 391, col. 1, ¶1; Chan II 1872, col. 2,
last ¶).
[47] According to Homandberg, the object of their study was to test the
effectiveness of glucosamine and/or chondroitin sulfate in protecting
cartilage exposed to fibronectin fragments, an exposure known to enhance
catabolic cytokinetics and matrix metalloproteinases (Homandberg 793
Summary).
[48] According to Cortial,
[i]n order to investigate the potential anti-arthritic and/or
anti-osteoarthritic effects of drugs and to obtain
information on their mechanisms of action, it is important
to culture chondrocytes within microenvironments as
close as possible to in vivo conditions and without major
changes in their cartilage phenotype (Cortial 631,
sentence bridging cols. 1-2).
[49] The first sentence of the O'Brien abstract reads, "Human and animal
hepatocytes are now being used as an in vitro technique to aid drug
discovery by predicting the in vivo metabolic pathways of drugs or new
chemical entities (NCEs), identifying drug-metabolizing enzymes and
predicting their in vivo induction."
[50] The last bullet point of the Huntjens abstract reads, "The results confirm the
value of exposure-effect relationships determined in vitro as a means to
predict the pharmacological activity in vivo. This analysis also highlights
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the need to parameterize concentration effect relationships in early drug
development, as indicated by the estimates of IC50 for PGE2 and TXB2
inhibition."
F. The Lippiello Declarations
[51] Louis Lippiello, Ph.D., testified that he is the Director of Research at
Nutramax Laboratories, Inc., the Appellant (Lippiello Decl. I ¶ 1; Lippiello
Decl. II ¶1; Lippiello Decl. III ¶1; Lippiello Decl. IV ¶1).
[52] Dr. Lippiello testified that SAMe, glucosamine, and chondroitin sulfate help
regulate cartilage metabolism by three different mechanisms. The first is the
polyamine pathway mediated by SAMe as well as by a mechanism of
acetylating and sulfating glucosamine; the second is the anabolic activity of
glucosamine; and the third is the inherent anticatabolic activity of
chondroitin sulfate. [Lippiello Decl. I ¶7; Lippiello Decl. II ¶ 9.]
[53] Dr. Lippiello testified that
[a]dditive effects are seen when two agents work through
the same mechanism which has limitations in its ability
to respond to the addition of the agents. Cellular
metabolism has defined rate-limiting mechanisms. If two
agents act through different mechanisms, a possibility
exists that the rate limiting component (commonly,
receptor binding) will be side-stepped allowing for a rate
greater than that reached by two agents acting through a
single mechanism. [Lippiello Decl. II ¶14.]
III. Discussion
The Examiner has rejected claims 9-11 as unpatentable under 35 U.S.C.
§ 103(a) over Bucci I, Pujalte, Henderson, Konig, and Andersen (Ans. 3).
A. The positions of the Examiner and the Appellant
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The Examiner found that Bucci I, Pujalte, and Henderson each teach
compositions containing glucosamine for treatment of osteoarthritis, that Konig
teaches treating osteoarthritis with SAMe, and that Anderson not only teaches that
SAMe is an anti-inflammatory and stimulates production of proteoglycans, but also
expressly suggests SAMe in 400 mg capsules combined with glucosamine sulfate
(Ans. 4-5). The Examiner concluded that a composition containing SAMe and
glucosamine in the concentrations recited in claims 9-11 would have been obvious
based on the teachings of Bucci I, Pujalte, Henderson, Konig, and Andersen (Ans.
6).
Appellant does not dispute that the applied prior art references establish a
prima facie case of obviousness. Arguments not raised in the principal brief on
appeal are waived. 37 C.F.R. ♀ 41.37(c)(1)(vii). Rather, Appellant contends that
the claimed compositions are unexpectedly synergistic at the recited concentrations
as evidenced by the Lippiello article and the Henderson and Griffin declarations
(App. Br. 13-26). Moreover, Appellant argues that the Lippiello article "confirms
that synergy does occur, and can be expected to occur, over a substantially greater
range of concentrations of at least SAMe than those concentrations used by Dr.
Griffin to show that evidence of synergy is commensurate in scope with the
claims" (App. Br. 22 n.8). Appellant further contends that determining in vivo
administration dosage from an in vitro concentration is common practice for those
of ordinary skill in the art (App. Br. 24, especially n.9 citing to the Information
Disclosure Statement and references (Benet, Chan I and II, Homandberg, Cortial,
O'Brien, and Huntjens) accompanying the principal Brief). Appellant reiterates
these contentions and arguments in the Reply Brief filed December 21, 2007
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("Reply Br."), which provides expanded comments on the Benet, Chan I, Chan II,
Homandberg, Cortial, O'Brien, and Huntjens references (Reply Br. 20-24).
The Examiner responds that Tallarida and the Hendersen Declaration show
that not every combination of two chondroprotective agents is synergistic (Ans. 7).
According to the Examiner, the Lippiello article only shows a synergistic response
for 0.052 and 0.52 µg/ml of SAMe in combination with 5 µg/ml glucosamine and
this 100-10:1 ratio is critical for synergy to occur (Ans. 8, 11). Further according
to the Examiner, "a skilled artisan would not expect a universal synergy of any
combination of drugs over a broad range of dosages" (Ans. 14) and, here, "a
sufficient number of tests both inside and outside the claimed range have not been
performed to establish unexpected results over a claimed range" (Ans. 15). Thus,
the Examiner finds that, insofar as the calculated data in the Griffin Declaration
encompasses ratios of SAMe:glucosamine outside of a 100-10:1 ratio, the Griffin
Declaration is insufficient to establish the synergistic results of the Lippiello article
as commensurate in scope with the claimed invention (Ans. 9-10, 20-22, 24-25).
The Examiner also notes that no underlying reference has been cited to
support the relationships relied on in the Griffin Declaration, particularly that
Cmax/D is generally a constant and that Dsyn=Csyn*D/Cmax (Ans. 12-13). The
Examiner acknowledges Appellant's submission of the Benet, Chan I,
Homandberg, Chan II, Cortial, O'Brien, and Huntjens references, but notes that
"Appellant does not discuss how and where in the cited references are the
arguments being supported" (Ans. 18). The Examiner expressly finds that there is
no teaching in these references regarding the extrapolation from in vitro data to an
in vivo situation as asserted by Appellant and that Cortial, Huntjens, and O'Brien
use different in vitro models than the Lippiello model (Ans. 18-20). The Examiner
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further finds that the Cmax values used in Dr. Griffin's calculations were obtained
under different conditions, e.g., using different formulations and routes of
administration, than used in the Lippiello article (Ans. 16-17).
Appellant replies that
[t]he Examiner's efforts to undercut Dr. Griffin's careful
and thorough analysis cannot withstand scrutiny. At
base, for all of her assertions and contentions, the
Examiner still does not contend that a person of ordinary
skill would use a different procedure than Dr. Griffin
used, or would determine different dosage ranges than
Dr. Griffin determined from the Veterinary Medicine
[i.e., the Lippiello] articles. [Reply Br. 13.]
Morever, Appellant argues that there is no absolute requirement that Appellant
conduct multiple tests inside and outside the claimed dosage ranges, so long as a
skilled artisan "could reasonably ascertain a trend in the exemplified data that
would allow him to reasonably extend the probative value thereof" (Reply Br. 17,
citing In re Clemens, 622 F.2d 1929, 1036 (CCPA 1980). Nor is there any
requirement that Appellant's specification explicitly disclose which dosages are
synergistic or in what proportions (Reply Br. 17 n.28).
Appellant further replies that the synergistic dosages identified in the Griffin
Declaration were derived using the target level strategy outlined in Benet where
the synergistic dose Dsyn correlates to Benet's maintenance dosage (Reply Br. 20-
21). Appellant emphasizes that Homandberg, Chan I and II, Cortial, O'Brien, and
Huntjens all used in vitro experiments to derive clinical conclusions (Reply Br. 21-
24) and that the Lippiello article experiment concluded that synergy occurs at
physiological levels of SAMe and glucosamine (id. 24-25).

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B. Legal principles
The factual inquiry to determine whether an invention is obvious under 35
U.S.C. § 103 requires consideration of (1) the scope and content of the prior art, (2)
the differences between the claimed subject matter and the prior art, (3) the level of
ordinary skill in the art, and (4) secondary considerations, e.g., unexpected results.
Graham v. John Deere Co., 383 U.S. 1, 17 (1966). "Section 103 forbids issuance of
a patent when 'the differences between the subject matter sought to be patented and
the prior art are such that the subject matter as a whole would have been obvious at
the time the invention was made to a person having ordinary skill in the art to
which said subject matter pertains.'" KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398,
405 (2007).
It is well settled that the Examiner "bears the initial burden of presenting a
prima facie case of unpatentability. . . . However, when a prima facie case is made,
the burden shifts to the applicant to come forward with evidence and/or argument
supporting patentability." In re Glaug, 283 F.3d 1335, 1338 (Fed. Cir. 2002).
Rebuttal evidence is "merely a showing of facts supporting the opposite
conclusion." In re Piasecki, 745 F.2d 1468, 1472 (Fed. Cir. 1984). Evidence
rebutting a prima facie case of obviousness can include evidence of secondary
considerations, such as synergy. Richardson-Vicks Inc. v. The Upjohn Co., 122
F.3d 1476, 1483 (Fed. Circ. 1997). "If . . . a patent applicant presents evidence
relating to these secondary considerations, the board must always consider such
evidence in connection with the determination of obviousness." In re Sernaker,
702 F.2d 989, 996 (Fed. Cir. 1983). However, objective evidence of
nonobviousness must be commensurate in scope with the claimed invention. In re
Tiffin, 448 F.2d 791, 792 (CCPA 1971). Furthermore, synergism, in and of itself,
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is not conclusive evidence of non-obviousness because synergism might be
expected. In re Huellmantel, 324 F.2d 998, 1003 (CCPA 1963).
C. Analysis
The claimed subject matter is directed to a composition comprising two
agents, SAMe and glucosamine, in defined concentrations. The claimed
composition broadly encompasses solids, liquids, and gases which can be
administered by any known route, such as tablets for oral administration, liquids
for intravenous administration, and aerosols for inhalation administration. The
concentrations of SAMe and glucosamine contained in the compositions of claims
10 and 11 overlap, i.e., 5-5,000 mg SAMe in claim 10 versus 2-20,000 mg SAMe
in claim 11, and 50-5,000 mg glucosamine in claim 10 versus 250-40,000 mg
glucosamine in claim 11. Moreover, since none of claims 9-11 are directed to a
method of use, administration of multiple compositions according to claim 10 may
be equivalent to administration of a single composition according to claim 11. In
other words, none of claims 9-11 define or require a dosage of x mg SAMe and y
mg glucosamine/kg body weight/day, for example.
That being said, we agree with the Examiner that the subject matter of
claims 9-11 is prima facie obvious over the combined teachings of Bucci I, Pujalte,
Henderson, Kronig, and Andersen (see FF 1-4, 6-8), particularly in view of
Andersen's express teaching to encapsulate 400 mg SAMe in combination with
glucosamine (FF 7) for substantially the same purpose(s), e.g., treatment of
cartilage abnormalities and sequelae thereof, including osteoarthritis and its
accompanying pain and inflammation. Indeed, Appellant does not contend that the
Examiner failed to make out a prima facie case of obviousness.
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Instead, Appellant urges that its evidence of unexpected synergism of the
claimed compositions, as shown by the Lippiello article and the Henderson and
Griffin declarations, is sufficient to rebut the Examiner's prima facie conclusion of
obviousness. We do not agree.
First, Dr. Lippiello has testified that SAMe and glucosamine regulate
cartilage metabolism by different mechanisms (FF 52). Dr. Lippiello also testified
that agents having different mechanisms for the same action would, in
combination, often require lower doses than when administered individually for
that action (FF 53). Thus, it is not necessarily unexpected that the Lippiello article
reported results produced by the combination of SAMe and glucosamine which
were greater than the additive value of SAMe and glucosamine tested separately
(FF 9). Dr. Henderson's testimony (FF 16) does not persuade us otherwise because
simply observing that synergistic, additive, or less than additive effects were
produced by combinations of glucosamine and oxaceprol or a nonopioid pain
reliever does not explain why synergy would or would not have been expected
with the claimed compositions and on what basis. Rohm and Haas Co. v. Brotech
Corp., 127 F.3d 1089, 1092 (Fed. Cir. 1997) (nothing in the rules or in
jurisprudence requires the fact finder to credit unsupported or conclusory
assertions); In re Schulze, 346 F.2d 600, 602 (CCPA 1965) (argument in the brief
does not take the place of evidence of record).
Second, Appellant has not explained the data presented in Table 2 of the
Lippiello article, e.g., whether one of ordinary skill in the art would have
considered the differences to be statistically significant, or what would have been
the expected standard deviation of the experimental measurement
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Third, assuming arguendo that Dr. Griffin's mathematical equations are
correct (see FF 20 and 32), his ultimate calculation of what concentration ranges of
SAMe and glucosamine administered to small animals, humans, and large animals
would have yielded the plasma concentrations which the Lippiello article identified
as synergistic is based upon a cascade of calculations. Errors in earlier calculations
are multiplied in later calculations thereby diminishing the persuasiveness of the
finally calculated ranges of SAMe and glucosamine. For example, the human
SAMe Cmax range reported in Stramentinoli II Figure 4 ranges from about 80 to
about 195 µg/ml, which converts to about 80,000 to about 195,000 ng/ml (FF 26),
while Dr. Griffin used a human SAMe Cmax range of only 77.5-185 ng/ml based on
Stramentinoli II (FF 21). Similarly, the highest SAMe Cmax disclosed by Center is
approximately 1.50 µg/ml, i.e., 1,500 ng/ml (FF 24), whereas Dr. Griffin used a cat
SAMe Cmax of 150 ng/ml his calculations (FF 21). In other words, Dr. Griffin is
using a human SAMe Cmax range in his calculations that is approximately one
thousand times less than Stramentinoli II discloses. Dr. Griffin is also using a cat
SAMe Cmax value in his calculations that is ten times less than Center discloses.
Therefore, at least the amounts of SAMe that must be administered to small
animals and humans to produce plasma concentrations of SAMe which the
Lippiello article identified as synergistic is in error and that error is compounded in
further calculations based on these erroneous amounts of administered SAMe. In
addition, Stramentinoli II did not specify the weights of the human volunteers in
the study (FF 25) and, therefore, it is unclear how Stramentinoli II can reasonably
provide a mg/kg body weight basis for subsequently calculating Dsyn dosages for
humans, including children, based on the body weight ranges disclosed in CCHS
and UMich.
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Fourth, Dr. Griffin testified that the Cmax/D ratio for SAMe and glucosamine
is generally understood to be constant (FF 20). However, Stramentinoli II Figure 4
suggests otherwise (FF 25).
Fifth, Dr. Griffin testified that dogs and horses have similar blood volumes
based on the teachings of Gonzales, Householder, and Boothe (FF 34). However,
Gonzales describes a horse weighing above 200 pounds and Householder is
specific to a mature race-retired thoroughbred horse (FF 35-36). Not all horses are
mature race-retired thoroughbred horses, just as not all dogs are greyhounds. Dr.
Griffin has not explained why one of ordinary skill in the art would have
considered the mean weight of a horse to be about 200 pounds and the mean blood
volume of a horse to be that of a mature race-retired thoroughbred.
Sixth, the data in the Lippiello article is based on physiologically obtainable
oral doses (FF 10) and Dr. Griffin culled data based on oral administration (FF 21-
23, 25, 27-31). However, as noted above, the compositions of claims 9-11 are not
limited to oral administration forms. Indeed, as seen in Figure 1 of Stramentinoli I
and Table 1 of Adebowale, the Cmax range of intravenously administered SAMe
and intraperitoneally administered glucosamine, respectively, varied markedly
from the Cmax range of these agents when the same amount of agent is orally
administered (FF 22, 28).
Finally, while we agree with Appellant that in vitro experiments are used to
derive valuable clinical conclusions, that fact alone is insufficient to support the
relationships relied on in the Griffin Declaration, particularly that Cmax/D is
generally a constant and Dsyn=Csyn*D/Cmax for SAMe and glucosamine for all
embodiments within the scope of claims 9-11.
D. Conclusion
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Therefore, based on the foregoing, we find that Appellant has not shown that
the claimed compositions contain an unexpectedly synergistic combination of
SAMe and glucosamine and the proffered showing is not commensurate in scope
with the claimed invention. Since Appellant has failed to meet its burden of
persuasion to rebut the Examiner's prima facie conclusion of obviousness, we will
sustain the rejection of claims 9-11 under § 103 over Bucci I, Pujalte, Henderson,
Konig, and Andersen.
IV. Order
Upon consideration of the record, and for the reasons given, it is
ORDERED that the decision of the Examiner to reject claims 9-11 as
unpatentable under 35 U.S.C. § 103(a) over the combined teachings of Bucci I,
Pujalte, Henderson, Konig, and Andersen is AFFIRMED; and,
FURTHER ORDERED that requests for extending time for taking any
subsequent action in connection with this appeal are governed by 37 C.F.R.
§ 1.550(c). See 37 C.F.R. § 41.50(f).
AFFIRMED

ack

For Patent Owner:
COVINGTON & BURLING, LLP
Attn: Patent Docketing
1201 Pennsylvania Avenue, N.W.
Washington, DC 20004-2401

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cc:
Third Party Requester
Kristen E. Bianchard
NUTRAMAX LABORATORIES, LTD.
2208 Lakeside Boulevard
Edgewood, MD 21040