Ex Parte Beljanski et al

Patent Trial and Appeal Board

Mar 15, 2017

13941980 (P.T.A.B. Mar. 15, 2017)

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.
13/941,980 07/15/2013 Sylvie BELJANSKI 034482 W 006CON1 1047
441 7590 03/17/2017
SMITH, GAMBRELL & RUSSELL, LLP
1055 Thomas Jefferson Street
Suite 400
WASHINGTON, DC 20007
EXAMINER
SHIN, DANA H
ART UNIT PAPER NUMBER
1674
NOTIFICATION DATE DELIVERY MODE
03/17/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
dcdocketing @ sgrlaw. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SYLVIE BELJANSKI and JOHN HALL
Appeal 2015-001712
Application 13/941,980
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
RYAN H. FLAX, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1,2 under 35 U.S.C. § 134 involving claims to
chemotherapy treatment methods for treating thrombocytopenia using small
bacterial RNA fragments. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
Statement of the Case
Background
“[T]he invention provides an improved chemotherapeutic regimen to
prevent or ameliorate bone marrow suppression, and specifically
thrombocytopenia, induced by anti-cancer drugs” (Spec. 1:12—14).
1 Appellants identify the Real Party in Interest as Molecular International
Research, Inc. (see App. Br. 1).
2 This appeal is related to Appeal 2013-006747, decided on Mar. 23, 2016.
Appeal 2015-001712
Application 13/941,980
The Claims
Claims 5, 8, 13, 15, 16, and 22—26 are on appeal. Claim 5 is
representative and is reproduced below:
5. In a chemotherapy treatment regimen for treating a
solid tumor in a human subject by administering at least one
anti-cancer compound, which causes bone marrow
suppression, which lowers platelet levels, wherein the
improvement comprises administering to the human subject
at least 60 mg of small bacterial RNA fragments daily or at
least every other day to restore the lowered platelet levels to
normal levels, thereby preventing or ameliorating
thrombocytopenia associated with the lowered platelet
levels, where the bacterial RNA fragments have 10 to 80
ribonucleotide units, and an overall ratio of purine bases to
pyrimidine bases [(G+A)/(C+U)] of between 1.0 and 2.5 and
the treated subject is a later stage cancer patient, who has
undergone at least one cycle of chemotherapy with an anti­
cancer compound before the administration of the small
bacterial fragments.
The Issue
The Examiner rejected claims 5, 8, 13, 15, 16, and 22—26 under 35
U.S.C. § 103(a) as obvious over Beljanski ’649,3 Beljanski (1990),4
Beljanski (1992),5 Schachter,6 Nature Health Consult,7 and Isaacs8 (Non-
Final Act. 11/26/2013 3-9).
3 Beljanski, M., US 4,190,649, issued Feb. 26, 1980 (“Beljanski ’649”).
4 Beljanski, M., Cancer Therapy: A New Approach, 22 Deutsche
Zeitschrift fur Onkologie 145-152 (1990) (“Beljanski (1990)”).
5 Beljanski, M., A New Approach to Cancer Therapy, Proceedings of the
International Seminar: Traditional Medicine: A Challenge of the
Twenty first Century, 1-15 (1992) (“Beljanski (1992)”).
2
Appeal 2015-001712
Application 13/941,980
The Examiner finds Beljanski ’649 teaches and claims:
an “oral administration” of the claimed pharmaceutical
composition comprising up to 100 mg of the active RNA
fragments used in the method of “treating a leucocyte or platelet
deficiency” (see claim 7) caused by chemotherapeutic agents
can “bring the number of leucocytes and of platelets back to
normal” and the “prolongation of the chemotherapy requires a
repetition of the administration of the RNA fragments”
(Non-Final Act. 11/26/2013 4—5; emphasis omitted). The Examiner finds
that Beljanski (1990) teaches “‘[w]hen classic anticancer drugs induce
leukopenia and thrombocytopenia in animals or patients, BLRs (RNA-
fragments) may be given in order to protect and generate these cells during
antimitotic therapy’” {Id. at 6, emphasis omitted).
The Examiner finds that Beljanski (1992) teaches BLRs “can be used
during conventional cancer therapy because they do not interfere with it and
protect blood cells from its harmful side effects so that there is no need to
suspend the treatment” {Id. at 6, emphasis omitted). The Examiner finds
“Schachter reports that BLRs are useful to reduce the ‘negative effect of
chemotherapy’ such as lowered platelet count in cancer patients undergoing
6 Schachter, M., Mirko Beljanski’'s Innovative Approach to Cancer, Chronic
Viral Diseases and Autoimmune Conditions, F AIM Innovation 12—15
(2003) (“Schachter”).
7 Natural Source, www.naturalhealthconsult.com/Monographs/
ReaLBuild.html (site created Mar. 1, 1998)(Accessed Jan. 29, 2010)
(“Natural Health Consult”).
8 Isaacs et al., Randomized Placebo-Controlled Study of Recombinant
Human Interleukin-11 to Prevent Chemotherapy-Induced Thrombocytopenia
in Patients With Breast Cancer Receiving Dose-Intensive Cyclophosphamide
and Doxorubicin, 15 J. Clinical Oncology 3368-77 (1997) (“Isaacs”).
3
Appeal 2015-001712
Application 13/941,980
chemotherapy, wherein ‘RNA primers from specific strains of E. coli
bacteria’ (so-called ‘BLRs’) help ‘platelets and WBCs rebound after dipping
from chemotherapy’” (Id. at 6, emphasis omitted). The Examiner finds
Natural Health Consult teaches:
“ReaLBuild®” is an RNA extract of E. coli and comes in 20
mg units for oral consumption such that one is recommended to
“dissolve in the mouth every other day or as directed by a
health practitioner.” ... to “naturally enhance the generation of
white blood cells and platelets.”
(Id. at 7, emphasis omitted).
The Examiner finds the combination would have been obvious:
since the RNA fragment was commercially available in 20 mg
units for sublingual consumption “every other day or as
directed by a health practitioner” . . . the person of ordinary
skill in the art would have had a reasonable, if not absolute,
expectation of success in obtaining 60 mg, 80 mg, and 100 mg
as effective doses and the treatment schedule of daily or “every
other day” for treating a cancer patient suffering from grade 3/4
thrombocytopenia through routine dose optimization.
(Id. at 7—8).
The issue with respect to the rejection is: Does the evidence of record
support the Examiner’s conclusion that the prior art renders claim 5
obvious?
Findings of Fact
1. Claim 7 of Beljanski ’649 is reproduced below:
7. A method of treating a leucocyte or platelet deficiency,
comprising administering to a subject suffering from such a
deficiency an effective dose of single-stranded chain
polyribonucleotides having 20 to 80 ribonucleotide units and in
which the sequence units G-A predominate, the overall ratio of
4
Appeal 2015-001712
Application 13/941,980
purine bases to pyrimidine bases [(G+A)/(C+U)] in said
polyribonucleotides being between 1.0 and 2.5.
(Beljanski ’649 10:6-13).
2. Claim 1 of Beljanski ’649 is reproduced below:
1. A pharmaceutical composition in dosage unit form for
treating leucocyte and platelet deficiencies, comprising from 2
to 100 mg of single-stranded chain polyribonucleotides having
20 to 80 ribonucleotide units and in which the sequence units
G-A predominate, the overall ratio of purine bases to
pyrimidine bases [(G+A)/(C+U)] in said polyribonucleotides
being between 1.0 and 2.5 associated with a pharmaceutically
acceptable vehicle.
(Beljanski ’649 8:65 to 9:5).
3. Beljanski’649 teaches:
The action of various chemical and physical agents
(Endoxan, Methotrexate, Thiotepa or radiation . . . causing a
decrease in leucopoiesis or a decrease in platelets can ... be
counterbalanced by the action of the various abovementioned
RNA fragments. . . .
The prolongation of the chemotherapy requires a
repetition of the administration of the RNA fragments without
causing exhaustion of the phenomenon.
(Beljanski ’649 8:13-24).
4. Beljanski (1990) teaches that “[wjhen classic anticancer drugs
induce leukopenia and thrombocytopenia in animals or patients, BLRs
(RNA-fragments) may be given in order to protect and generate these cells
during antimitotic therapy” (Beljanski (1990) 152, col. 1).
5. Beljanski (1990) teaches that “[ijntravenous administration of
these RNA fragments restores normal circulating leukocyte counts after they
5
Appeal 2015-001712
Application 13/941,980
have been depleted by high doses of cyclophosphamide (CP) in healthy
rabbits. On account of this activity, these RNA fragments were termed
‘Beljanski Leukocyte Restorers’ (BLRs)” (Beljanski (1990) 146, col. 2—3).
6. Beljanski (1990) teaches that “rabbits were injected i.v. with
1 mg/kg of BLRs in sterile physiological saline, leukocyte count increased
and reached a normal value after 48 hours” (Beljanski (1990) 147, col. 3).
7. Beljanski (1990) teaches that “[fjurther analysis of BLR
activity at the cytological level indicated that they enhance leukocyte and
platelet genesis” (Beljanski (1990) 148, col. 1).
8. Figures 2 and 3 of Beljanski (1990) are reproduced below:
6
Appeal 2015-001712
Application 13/941,980
Figure 2 (above, top) shows “[l]eukocyte formation in cyclophosphamide
treated rabbits. . . . After leukocyte count had been strongly decreased, a 3.5
kg Endoxan treated rabbit (100 mg/day) received varying doses of BLRs
ranging from 1 to 6 mg every second day as shown by the arrows” and
Figure 3 (above, bottom) shows:
[e]ffect of BLRs on platelet count in the rabbit pretreated with
high dosages of Daunorubicin. A 4 kg rabbit received i.v. 5 mg
Daunorubicin daily for 4 consecutive days. At time shown by
arrows, the rabbit received two BLR dosages (5 mg i.v. and 20
mg per os). The leukocytes count which was low in the drug-
pretreated animal, was brought back to 10,000 within 48 h.
(Beljanski (1990) 147).
9. Beljanski (1990) teaches that “[corresponding results were
obtained when BLRs were later used in man (perlingual route). Low doses
are sufficient to protect patients undergoing radiotherapy or intensive
chemotherapy: adverse haemotologic side effects are avoided and patients
can lead a normal life, without even having to interrupt their work”
(Beljanski (1990) 148, col. 1).
10. Figure 5 of Beljanski (1990) showing treatment of a human
patient undergoing chemotherapy and concurrent treatment with BLRs is
reproduced below:
7
Appeal 2015-001712
Application 13/941,980
<35
“Fig. 5: Effect of BLRs in human lymphoblastic leukemia treated by
chemotherapy. Twenty years old female patient was treated by conventional
chemotherapy. Once long term aplasia occurred [sic], BLRs have been
administered by perlingual route as indicated in the figure (1 dose =15 mg
of BLRs)” (Beljanski (1990) 148).
11. Beljanski (1992) teaches “we were able to produce these RNA
fragments in large amounts and this allowed extensive experimentation. We
found that they promote in a physiological manner the formation of
leukocytes and platelets, rapidly restoring their normal counts and, most
importantly, also restoring normal ratios of lymphocyte subsets” (Beljanski
(1992) 2).
12. Beljanski (1992) teaches:
In cancer patients, BLRs have an optimal effect when
they are given from the inception of chemotherapy or radiation
therapy, or, at least, when patients still possess a sufficient
number of intact bone marrow and spleen blood stem cells.
When damage to these cells has become too extensive
(inducing, for instance, chromosome breakage), rapid leukocyte
8
Appeal 2015-001712
Application 13/941,980
and platelet genesis cannot always be achieved, but at least cell
count collapse is generally arrested.
(Beljanski (1992) 3, citation omitted).
13. Beljanski (1992) teaches:
validity of this strategy was demonstrated many years ago and
it has proved operational and efficient as its use started to
spread at the hands of physicians who understood its interest
and were willing to take the risk of novelty; to this day, many
patients have benefited from it and survive in good condition.
(Beljanski (1992) 9).
14. Natural Health Consult teaches “ReaLBuild® contains in each
unit, Ribonucleic extract of Escherichia coli K-12, 20 mg. . . . [to]support the
body’s immune system to help boost the cells which naturally enhance the
generation of white blood cells and platelets” (Natural Health Consult 1).
15. Natural Health Consult teaches to “[t]ake the content of one
unit and dissolve in the mouth every other day or as directed by a health
practitioner” (Natural Health Consult 2).
16. Schachter teaches:
During experiments on the regulation of the cell, Beljanski
discovered a way to reproduce these specific RNA primers to
stimulate the multiplication of white blood cells and platelets.
He was able to extract these RNA primers from specific strains
of E.coli bacteria. He found both in animal studies and some
pilot human studies that patients receiving these RNA primers
would have their platelets and WBCs rebound after dipping
from chemotherapy and/or radiation. In the medical literature,
these products have been called RLBs or BLRs, which stands
for Restorers of Leukocytes by Beljanski or Beljanski
Leukocyte Restorers. Commercially, this product is available as
Real Build. The powder contents of a cone of Real Build are
dissolved under the tongue as a nutritional support for the bone
9
Appeal 2015-001712
Application 13/941,980
marrow one to three times per week, while chemotherapy
and/or radiation are given.
(Schachter 14, col. 2—3).
17. Isaacs teaches “rhIL-11 significantly reduced the proportion of
patients who required platelet transfusions when the analysis was adjusted
for the influence of prior chemotherapy stratification factor” (Isaacs 3372,
col. 1).
18. Isaacs teaches “dose-intensity may be an important variable in
adjuvant therapy for breast cancer” (Isaacs 3369, col. 1).
Principles of Law
“[Conducting clinical trials to test for an optimal dose for a drug ‘is
generally a routine process[’].” Eli Lilly and Co. v. Teva Pharmaceuticals
USA, Inc., 619 F.3d 1329, 1342 (Fed. Cir. 2010). “In Mayo, the application
of the natural law was merely routine optimization of drug dosage to
maximize therapeutic effect.” Ariosa Diagnostics, Inc. v. Sequenom, Inc.,
809 F.3d 1282, 1293 (Fed. Cir. 2015) (Dyk, J., concurring).
“[Wjhere the general conditions of a claim are disclosed in the prior
art, it is not inventive to discover the optimum or workable ranges by routine
experimentation.” In reAller, 220 F.2d 454, 456 (CCPA 1955).
Analysis
Beljanski ’649, Beljanski (1990), Beljanski (1992), and Schachter
teach treatment of cancer patients who have already received chemotherapy
with the small bacterial RNA fragments termed BLRs (FF 3, 5, 10, 12, 16).
Three independent obviousness rationales of overlapping ranges, routine
optimization, and obvious to try, support selection of a dosage of “at least 60
10
Appeal 2015-001712
Application 13/941,980
mg of small bacterial RNA fragments daily or at least every other day” as
required by claim 5.
Beljanski ’649 teaches treatment of cancer patients (FF 1, 3) using a
“pharmaceutical composition in dosage unit form for treating leucocyte and
platelet deficiencies, comprising from 2 to 100 mg of single-stranded chain
polyribonucleotides” (FF 2). See In re Peterson, 315 F.3d 1325, 1329 (Fed.
Cir. 2003) (“In cases involving overlapping ranges, we and our predecessor
court have consistently held that even a slight overlap in range establishes a
prima facie case of obviousness.”)
Beljanski (1990) teaches when “rabbits were injected i.v. with 1
mg/kg of BLRs . . . leukocyte count increased” (FF 6), that a
chemotherapeutically “treated rabbit (100 mg/day) received varying doses of
BLRs ranging from 1 to 6 mg” (FF 8), and Isaacs teaches “dose-intensity
may be an important variable in adjuvant therapy for breast cancer” (FF 18),
reasonably renders the claimed dose of “at least 60 mg” obvious as a results
effective variable. See In re Boesch, 617 F.2d 272, 276 (CCPA 1980) (“This
accords with the rule that discovery of an optimum value of a result effective
variable in a known process is ordinarily within the skill of the art.”)
Finally, the Examiner finds:
since the RNA fragment was commercially available in 20 mg
units for sublingual consumption ‘every other day or as directed
by a health practitioner’ . . . the person of ordinary skill in the
art would have had a reasonable, if not absolute, expectation of
success in obtaining 60 mg, 80 mg, and 100 mg as effective
doses...
(Non-Final Act 11/26/2013 7; cf. FF 1^N15).
11
Appeal 2015-001712
Application 13/941,980
We, therefore, adopt the Examiner’s findings of fact and reasoning
regarding the scope and content of the prior art (Non-Final Act. 11/26/2013
3—9; FF 1—18) and agree that claim 5 is rendered obvious by Beljanski ’649,
Beljanski (1990), Beljanski (1992), Schachter, Nature Health Consult, and
Isaacs.
We address Appellants’ arguments below.
Appellants contend “Table 3 [of the Specification] shows the
criticality for both the dosage and frequency. The other claimed
‘improvement’ is the patient population treated, i.e. a later stage cancer
patient” (App. Br. 4). Appellants further contend that
[e]vidence is of record which establishes that the successful
treatment outcome: the results reported in the specification and
also those reported in more detail in the Fevin et al article
(BMC Cancer 2010, 10:565). This ‘safe and effective’
outcome of the clinical trial is not foreseeable with reasonable
certainty from the art of record . . .
(App. Br. 5). Appellants contend the “teachings of the references are
incomplete, as viewed by one of skill in the art to which they are addressed,
to establish a prima facie case of obviousness for a safe and effective
treatment regimen” (App. Br. 6).
We do not find these arguments persuasive in view of the extensive
evidence in the prior art demonstrating efficacy of BFRs in treating
leucocyte and platelet deficiencies, including experiments in animals (FF 8)
and humans (FF 10). Countering Fevin,9 Beljanski (1992) teaches the
9 Fevin et al., Dose escalation study of an antithrombocytopenic
agent in patients with chemotherapy induced thrombocytopenia, 10
BMC Cancer 1-8 (2010).
12
Appeal 2015-001712
Application 13/941,980
“validity of this strategy was demonstrated many years ago and it has proved
operational and efficient” (FF 13), reasonably suggesting that the artisan
would have expected a safe and effective treatment regimen (cf. FF 9, 11,
14).
In addition, the Levin postfiling date reference simply evidences an
effort to optimize the dose of BLRs, teaching that the “first goal is to
evaluate the effect of increasing dose of RNA fragments on platelet nadir
following chemotherapy and on platelet recovery time” (Levin 3, col. 2).
Levin does not report dosing in terms of mg/kg of patient weight, nor does
Levin show an untreated control, to demonstrate the efficacy of the 20 mg
dose. At best, Levin demonstrates that in some patients, there was a
“significant relationship between recovery platelet levels and increasing
doses of E. coli RNA fragments at the baseline or initial dose escalation”
(Levin 5, col. 2). However, this represents the expected result of
optimization, that after testing several dose levels, certain doses would yield
better results than others. Indeed, Levin teaches “[a]t all doses, patients
receiving E. coli RNA fragments showed a recovery in platelet numbers to
80000/ml by eight days following chemotherapy induced nadir” (Levin 7,
col. 1), though the higher doses were stated to limit the need for transfusion
in some patients (see Levin 7, col. 12).
Appellants cite three declarations by Dr. James Grutsch (see App. Br.
6), stating the “declarations were also an attempt to illustrate that the
discovery of an activity in preclinical research does not insure a successful
outcome in the clinical phases- most drug candidates fail” (App. Br. 6).
13
Appeal 2015-001712
Application 13/941,980
Appellants specifically cite the Gratsch Decl. I,10 contending that
“conclusions based on patient sample size of one relevant subject (paragraph
No. 8) would not be given weight by a practicing scientist in this area. He is
clearly familiar with M. Beljanski’s early work and how much more was
needed to arrive at the regimen described by the claims” (App. Br. 7).
Appellants contend Gratsch Decl. Ill* 11 “indicates that patient population size
is critical as to the use of experimental results. He relates his practical
experience as when positive preclinical results evaporate when the more
formal study is undertaken with a larger population size” (App. Br. 8).
We have considered the Gratsch Declarations, including Gratsch
Decl. II,12 but find these arguments unpersuasive for the reasons given by
the Examiner (see Ans. 9—10). In particular, we note that Beljanski (1990)
provides specific dosing information for a human patient, a dose of 15 mg
per day was administered to a human female undergoing chemotherapy for
leukemia (FF 10). While Dr. Gratsch contends that “no scientist would
assume that a relationship found between any experimental agents in one
laboratory species would extrapolate to be found to be true in humans”
(Gratsch Dec. 11 8; cf. Gratsch Decl. Ill 14), the point of animal research is
to apply the information to human treatments. See, e.g., In re Brana, 51
F.3d 1560, 1568 (Fed. Cir. 1995). Even if we credited the position that
10 Declaration of Dr. James Gratsch, dated May 30, 2012 (“Gratsch Decl.
I”).
11 Declaration of Dr. James Gratsch, dated Mar. 10, 2014 (“Gratsch Decl.
III”).
12 Declaration of Dr. James Gratsch, dated Oct. 30, 2013 (“Gratsch Decl.
II”).
14
Appeal 2015-001712
Application 13/941,980
animal studies were insufficient, Beljanski (1990) took the next step,
applying the treatment found effective in rabbits to a human patient with
successful results (FF 10) and with this evidence in hand “there was little left
to do but to confirm that the strategy suggested by the various prior art
references would work. Substantial evidence therefore supports the Board’s
finding that a person of ordinary skill would have had a reasonable
expectation of success based on the combinations of references.” Genzyme
Therapeutic Products Limited Partnership v. Biomarin Pharmaceutical Inc.,
825 F.3d 1360, 1373 (Fed. Cir. 2016).
And while we recognize the difference between anecdotal reports and
clinical trials, positive preclinical reports that demonstrate efficacy of BLRs
in a human patient provide a reasonable expectation of success. In
O ’Farrell, the court found that
The admonition that “obvious to try” is not the standard under
§ 103 has been directed mainly at two kinds of error. In some
cases, what would have been “obvious to try” would have been
to vary all parameters or try each of numerous possible choices
until one possibly arrived at a successful result, where the prior
art gave either no indication of which parameters were critical
or no direction as to which of many possible choices is likely to
be successful. ... In others, what was “obvious to try” was to
explore a new technology or general approach that seemed to be
a promising field of experimentation, where the prior art gave
only general guidance as to the particular form of the claimed
invention or how to achieve it.
In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). The instant case does
not fall into either kind of error. The prior art directly focuses on treatment
of cancer patients undergoing chemotherapy with BLRs and specifically
teaches an example of such a treatment in a human patient (FF 1—18).
15
Appeal 2015-001712
Application 13/941,980
Moreover, the prior art gave direction and indication of the critical
parameters, with Beljanski (1990) showing actual successful treatment of
animals and humans with the BLRs in multiple cycles with 15 mg doses in
humans and 1 mg/kg dose in animals (FF 4—10). In combination with the
other cited art, the ordinary artisan would have reasonably found it obvious
to optimize the BLR dose in humans for treatment of the chemotherapeutic
side of effect of reduced platelets in cancers including solid tumors (FF 12—
15, 18; cf. Ans. 14).
Moreover, to the extent that the Grutsch Decl. I states that Schachter
is a “puff piece[] directed at an audience that does not include scientists or
physicians” (Grutsch Decl. 17; cf. App. Br. 7), the paper by Dr. Michael
Schachter reviewing Dr. Beljanski’s work represents the opinion of a
medical expert who was “impressed with the both the science presented in
the lectures and the apparent benefits obtained by patients using the
products” (Schachter 12, col. 2). Dr. Schachter’s expert views provides
further evidence supporting the Examiner’s position that the Beljanski prior
art references have a reasonable expectation of success.
Appellants contend that the “points of novelty are clearly indicated:
the threshold dosage of 60mg, the frequency of administration of the
threshold dose and the treated patient population, which includes late stage
cancer patients” (App. Br. 9).
We are not persuaded. Beljanski (1990) teaches cyclic treatment of
rabbits with doses of 1 to 6 mg “every second day” (FF 8) as well as
1 mg/kg (FF 6) and Natural Health Consult teaches administration “every
other day or as directed” (FF 15), reasonably teaching an identical frequency
16
Appeal 2015-001712
Application 13/941,980
of administration to that required by claim 5. Beljanski (1990) exemplifies
treatment of a cancer patient after receiving chemotherapy (FF 10) and
Beljanski (1992) suggests efficacy of treatment on patients who have already
undergone chemotherapy (FF 12).
Moreover, these results do not demonstrate that the specific 60 mg
dose provides unexpected results relative to the disclosed 1 mg/kg treatment
dose of Beljanski (1990) (FF 6). That is, Appellants do not report, in either
their Specification or in Levin, doses administered per kg of patient body
weight. In addition, we agree with the Examiner that based on Beljanski
(1990) and the other Beljanski related references, “one of ordinary skill in
the art would have reasonably expected that ReaLBuild® administration
after at least four cycles of chemotherapy can successfully restore platelet
numbers to a normal level” (Ans. 17). See In re Skoner, 517 F.2d 947, 950
(CCPA 1975) (“Expected beneficial results are evidence of obviousness of a
claimed invention.”)
We also note that the results offered by Appellants as evidence are not
commensurate in scope with claim 5, because the results are limited to 60 or
80 mg treatment doses, but the claim is drawn to “at least 60 mg,” thereby
encompassing doses within the range taught by Beljanski ’649 of 2 to 100
mg (FF 2) and any dose greater than 100 mg for which no data has been
provided. See In re Tiffin, 448 F.2d 791, 792 (CCPA 1971). “[Ojbjective
evidence of non-obviousness must be commensurate in scope with the
claims which the evidence is offered to support”).
Appellants contend the “Examiner commits error in considering the
prima facie case of obviousness without apparently considering the
17
Appeal 2015-001712
Application 13/941,980
showings provided in the specification” and Hall Declarations (App. Br. 9).
Appellants contend:
Considering] the present specification, the Levin article, the
Declaration under 37 CFR § 1.132 dated 6 July 2010 by Dr.
John Hall, especially paragraphs 8 (patient population), 10
(dosage amount criticality), 11 (no super inducement of white
blood cells), 12 (RNAase degradation of anti-CIT agent), 13
(discussion of unexpected results and why) and 15 (the
reluctance of clinicians to employ a dietary supplement as a
medicament in a clinical trial), and the Declaration under 37
CFR $ 1.132 dated 16 November 2009 by Dr. John Hall,
especially paragraphs 9, 10 (failure of 20 and 40 mg dosage to
provide adequate support of platelet levels; no need for platelet
transfusions at dosages of 60 and 80mg) and 11 (no
overproduction of platelets; amelioration of thrombocytopenia
in wide range of solid tumor types and in the use of a wide
range of drug types, which lower platelet levels).
(App. Br. 10).
The Examiner notes the Hall Declarations13,14 were not properly
submitted, but were nevertheless fully addressed in prior responses (see Ans.
11). We have considered the Specification and Hall Declarations, but are
likewise not persuaded of any unexpected results. Table 3 of the
Specification shows efficacy at doses as low as 20 mg (see Spec. 18) and
Table 4 evidences improved platelet counts in three patients with 20 mg
doses of RealBuild (see Spec. 20) and the Specification states that
“[administration of the ReaLBuild® product restored normal levels of
platelets in both of these patients” (Spec. 19:15—16). This evidences that the
13 Declaration of John Hall, dated Nov. 16, 2009 (“Hall Decl. I”).
14 Declaration of John Hall, dated July 6, 2010 (“Hall Decl. II”).
18
Appeal 2015-001712
Application 13/941,980
use of BLRs achieves the expected result from the Beljanski references of
improved platelet levels; it does not evidence an unexpected result.
The Hall Decl. I states that:
successful results from the clinical trial were unexpected. The
beneficial effects of the Real Build® product were specific in
its stimulation of white blood cells .... To my knowledge,
clinicians in the field were surprised to find that RNA
fragments, given at the indicated dosing regimen, ameliorated
thrombocytopenia in patients with various solid tumors taking
drugs
(Hall Decl. 1111; cf. Hall Decl. II114).
The Hall Decl. I does not explain why clinicians were surprised by the
result, given the extensive prior art animal and human data in Beljanski
(1990) that BLRs functioned to ameliorate thrombocytopenia in patients
taking chemotherapeutic drugs (FF 6—10), and the other cited Beljanski
references. That some clinicians were unaware of the prior art does not
render the result unexpected. Nor is the finding that the BLRs specifically
performed as taught by Beljanski (1990) in stimulating white blood cells
represent an unexpected result (FF 6—10).
The Hall Decl. II states that “prior to the invention described in the
‘014 application, those skilled in the art could not have reasonably predicted
whether a dose of 20 mg daily or every other day would be effective, or a
higher dose would be required, for stimulating production of platelets” (Hall
Decl. HI 11).
We are not persuaded. Beljanski (1990) teaches that 15 mg BLR
doses administered every other day stimulated production of platelets in a
19
Appeal 2015-001712
Application 13/941,980
human patient undergoing chemotherapy, and Natural Health Consult
teaches administration of 20 mg BLR doses every other day (FF 10, 14, 15).
The Hall Decl. II contends that “[tjhose skilled in the art could not
have predicted whether administration of small RNA fragments would be
effective in stimulating the production of platelets and treating
thrombocytopenia when given to a cancer patient undergoing chemotherapy
that includes mitomycin” (Hall Decl. II113).
We find this argument unpersuasive because none of the claims are
limited to mitomycin nor does the Hall Decl. II provide specific evidence
that BLRs would not have been expected to function with mitomycin. See
In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005) (Unexpected results must
also be “commensurate in scope with the degree of protection sought by the
claimed subject matter.”)
Finally, even if we agreed that the efficacy shown by treatment with
60 or 80 mg of BLR was “unexpected,” the showing here is insufficient to
overcome the very strong showing of obviousness in this case where
Beljanski ’649 teaches an overlapping range (FF 1—3), and the prior art
demonstrates efficacy using 15 mg treatments with BLRs in a human cancer
patient (FF 10) and using 1 mg/kg of body weight of BLRs in an animal
model of cancer (FF 8). See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372
(Fed. Cir. 2007) (“[W]e hold that even if Pfizer showed . . . unexpectedly
superior results, this secondary consideration does not overcome the strong
showing of obviousness in this case. Although secondary considerations
must be taken into account, they do not necessarily control the obviousness
conclusion.”).
20
Appeal 2015-001712
Application 13/941,980
Claims 24—26
Appellants contend:
the Examiner commits error in maintaining the rejection
especially as to these claims. The results described in the
specification and in more detail in the Levin et al. article are
even more unexpected when one considers the later stage
cancer patient population treated. A preclinical discovered
activity does not provide reasonable assurance of success in a
clinical setting for the claimed late state cancer patient
population.
(App. Br. 13).
We remain unpersuaded by this argument because, as the Examiner
points out, animal studies showed “BLRs administered after 4 cycles of
chemotherapy that significantly reduced the number of platelets were shown
to be effective in increasing platelet counts. See Figure 3 of Beljanski
(1990)” (Ans. 18; cf. FF 8). Moreover, Schachter teaches in “pilot human
studies that patients receiving these RNA primers would have their platelets
and WBCs rebound after dipping from chemotherapy and/or radiation” (FF
16). Thus, for these reasons and those already discussed, we agree with the
Examiner that “one of ordinary skill in the relevant art would have had a
reasonable expectation of success in treating grade 3 or 4 thrombocytopenia
in a later stage cancer patient who has undergone at least two or four
chemotherapy cycles” (Ans. 18).
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that the
prior art renders claims 5 and 24—26 obvious.
21
Appeal 2015-001712
Application 13/941,980
SUMMARY
In summary, we affirm the rejection of claims 5 and 24—26 under 35
U.S.C. § 103(a) as obvious over Beljanski ’649, Beljanski (1990), Beljanski
(1992), Schachter, Nature Health Consult, and Isaacs. Claims 8, 13, 15, 16,
22, and 23 fall with claims 5 and 24—26.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
22