Ex Parte Beljanski et al

Patent Trial and Appeal BoardMar 21, 2016

11978014 (P.T.A.B. Mar. 21, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 111978,014 10/26/2007 441 7590 03/23/2016 SMITH, GAMBRELL & RUSSELL, LLP 1055 Thomas Jefferson Street Suite 400 WASHINGTON, DC 20007 FIRST NAMED INVENTOR Sylvie Beljanski 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 034482.006 3793 EXAMINER SHIN,DANAH ART UNIT PAPER NUMBER 1674 NOTIFICATION DATE DELIVERY MODE 03/23/2016 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 Appeal2013-006747 Application 11/978,014 Technology Center 1600 Before JEFFREYN. FREDMAN, ULRIKE W. JENKS, and JOHN G. NEW, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal 1 under 35 U.S.C. Â§ 134 involving claims to anticancer treatment methods of administering a combination of an anti- cancer compound with small bacterial RNA fragments. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. Â§ 6(b). We affirm. 1 Appellants identify the Real Party in Interest as Molecular International Research, Inc. (see App. Br. 1 ). Appeal2013-006747 Application 11/978,014 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, 11. 12-14). The Claims Claims 5, 7-10, and 13-16 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 lowers platelet levels during treatment, wherein the improvement comprises administering to the subject along with the anti-cancer compound at least 60 mg of small bacterial RNA fragments at least every other day and for a time sufficient to restore and maintain platelet levels to normal levels, thereby prolonging treatment time for the chemotherapy, where the 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. The Issue The Examiner rejected claims 5, 7-10, and 13-16 under 35 U.S.C. Â§ 103(a) as obvious over Beljanski (1990),2 Beljanski (1992), 3 Schacter,4 2 Beljanski, M., Cancer Therapy: A New Approach, 22 DEUTSCHE ZEITSCHRIFT FUR ONKOLOGIE 145-152 (1990). 3 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). 2 Appeal2013-006747 Application 11/978,014 Walker,5 Nature Health Consult,6 Cole,7 and Martin8 (Non-Final Act. 2/17/12 8-16). The Examiner finds that "Beljanski (1990) teaches that intravenous administration of E. coli RNA fragments (called BLRs for Beljanski Leukocyte Restorers) at 1 mg/kg restores leukocyte counts to a normal level in rabbits after 48 hours, wherein the rabbits are treated daily with high dose (23-35 mg/kg) cyclophosphamide (CP) injections" (Non-Final Act. 2/17 /12 8). The Examiner finds that "Beljanski [1990] exemplifies BLR treatments in human leukemia patient undergoing chemotherapy, wherein BLR at 12 mg was given once per day while the patient is undergoing chemotherapy, wherein the 15 mg once daily BLR treatment results in increased counts in both leukocytes and platelets" (Non-Final Act. 2/17 /12 9). The Examiner finds that Beljanski (1992) teaches that BLRs "'can be used during conventional cancer therapy because they do not interfere with it and protect 4 Schacter, M., Mirko Beljanski 's Innovative Approach to Cancer, Chronic Viral Diseases and Autoimmune Conditions, FAIM INNOVATION 12-15 (2003). 5 Walker et al., DNA Destabilization as a Major Source of Metabolic Pathology, TOWNSEND LETTER FOR DOCTORS & PATIENTS, 105-110 (2003). 6 Natural Source, www.naturalhealthconsult.com/ Monographs/ReaLBuild.html (site created Mar. 1, 1998)(Accessed Jan. 29, 2010). 7 Cole et al., Cyclophosphamide And Nandrolone Decanoate In The Treatment Of Advanced Carcinoma Of The Breast - Results Of A Comparative Controlled Trial Of The Agents Used Singly And In Combination, 27 BR. J. CANCER 396-399 (1973). 8 Martin, M., Platinum Compounds in the Treatment of Advanced Breast Cancer, 2 CLINICAL BREAST CANCER 190-208 (2001 ). 3 Appeal2013-006747 Application 11/978,014 blood cells from its harmful side effects ... BLRs rapidly restore normal platelet counts'" (Non-Final Act. 2/17 /12 10; emphasis omitted). The Examiner finds that the "Natural Health Consult article reports that 'ReaLBuildÂ®' is an RNA extract of E. coli and comes in 20 mg units for oral consumption. It reports that 'ReaLBuildÂ®' helps to 'naturally enhance the generation of white blood cells and platelets'" (Non-Final Act. 2/17 /12 12). The Examiner finds it obvious to "optimize the dose and dosing schedule for the 'ReaLBuildÂ®' product for clinical use in the cancer patients undergoing chemotherapy as described by Beljanski (1990), Beljanski (1992), Schachter [sic] (2003), and Walker et al. (2003)" (id.). The issue with respect to these rejection is: Does the evidence of record support the Examiner's conclusion that the prior art renders claim 5 obvious? Findings of Fact 1. Beljanski (1990) teaches that "[i]ntravenous administration of these RN A fragments restores normal circulating leukocyte counts after they 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). 2. 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). 3. Beljanski (1990) teaches that "[f]urther analysis of BLR activity at the cytological level indicated that they enhance leukocyte and 4 Appeal2013-006747 Application 11/978,014 platelet genesis" (Beljanski (1990) 148, col. 1). 4. Figure 2 of Beljanski (1990) is reproduced below: 0 10 20 .:io O.AYS Figure 2 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" (Beljanski (1990) 147). 5. Figure 5 of Beljanski (1990) showing treatment of a human patient undergoing chemotherapy and concurrent treatment with BLRs is reproduced below: "000 '150.DOc:I moo 0~4BB~-Â·~Â·---H~~=~x== St.in Days 5 Appeal2013-006747 Application 11/978,014 "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). 6. Beljanski (1990) teaches that "[ 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" (Beljanski (1990) 152, col. 1 ). Beljanski (1990) teaches that "[ c ]orresponding 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 ). 7. Beljanski (1992) teaches that 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" (Beljanski (1992) 3). 8. Natural Health Consult teaches "ReaLBuildÂ® contains in each unit, Ribonucleic extract of Escherichia coli K-12, 20 mg .... 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 ). 9. 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). 6 Appeal2013-006747 Application 11/978,014 10. Cole teaches chemotherapeutic treatment of breast cancer with "the dose being modified at later visits according to the response and side- effects" (Cole 397, col. 1 ). 11. Cole teaches the "[ d]epression of white cell count below 3000/mm3" in patients treated with cyclophosphamide for solid carcinomas of the breast (Cole 398, col. 1, Table V). 12. Martin teaches that "Sweet et al used cisplatin (90 mg/m2) and mitomycin-C (20 mg/m2) as third-line chemotherapy. Four of the 16 evaluable patients (25%) had an objective response. Eleven patients experienced grade 3/4 thrombocytopenia, and 8 required platelet transfusions" (Martin 197, col. 1 ). Principles of Law "[C]onducting 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). "[W]here 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 re Aller, 220 F.2d 454, 456 (CCPA 1955). Analysis We adopt the Examiner's findings of fact and reasoning regarding the scope and content of the prior art (Non-Final Act. 2/17 /12 8-16; FF 1-12) and agree that claim 5 is rendered obvious by Beljanski (1990), Beljanski 7 Appeal2013-006747 Application 11/978,014 (1992), Schacter, Walker, Nature Health Consult, Cole, and Martin. We address Appellants' arguments below. Appellants contend that: What is claimed is more than an investigation using a model system. It is a solid tumor treatment protocol, where treatment time is prolonged due to the invention defined in the improvement section of the claim. This improvement involves the administration of "at least 60 mg", an established threshold dosage level, and for a "time sufficient to restore and maintain platelet levels to normal levels, thereby prolonging treatment time for the chemotherapy". (App. Br. 5). We find this argument unpersuasive for the reasons explained by the Examiner (Ans. 4--13). Cole evidences the well-known fact that some cancer treatments depress white blood cell counts (FF 11) while Martin evidences the need for platelet infusions in response to chemotherapy (FF 12), the two references suggesting the need to treat reduced platelet levels in chemotherapy patients. Beljanski (1990) satisfies this need, exemplifying treatments with the same BLR RNA fragments as those required by claim 5 in both animal and human test subjects undergoing chemotherapy (FF 1-6), demonstrating "that they enhance leukocyte and platelet genesis" (FF 3). Beljanksi (1990) teaches effective treatment with 1 mg/kg of BLRs (FF 2), an amount that when scaled up to 60 kg (132 lb.) or heavier humans would result in 60 mg or more administration of BLRs to these patients (cf Non-final Act. 2/17 /12 13). 8 Appeal2013-006747 Application 11/978,014 Moreover, Natural Health Consult demonstrates that 20 mg units of BLRs "enhance the generation of white blood cells and platelets" in human patients (FF 8) and may be administered every other day (FF 9). This teaching, in combination with the dosage suggestions in Beljanski (1990) (FF 2) and Cole's evidencing the well-known fact that drug dosages are optimized to patient response and side effects (FF 10), reasonably renders the claimed does of "at least 60 mg" obvious as a result 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.") Appellants cite the Grutsch Declaration,9 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. 6). Appellants contend that the Beljanski prior art "involv[ es] model systems and animal models. As evident from the articles, none reports a dosage amount suitable for humans or a dosage regimen like that claimed. This detail should be contrasted with that provided in the specification and in the Levin et al article" (App. Br. 6). 9 Declaration of Dr. James Grutsch, dated May 30, 2012. 9 Appeal2013-006747 Application 11/978,014 We have considered the Grutsch Declaration and Levin10 article, but find these arguments unpersuasive for the reasons given by the Examiner (see Ans. 13-16). In particular, we note that Beljanski (1990) does provide 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 5). While Dr. Grutsch 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" (Grutsch Deel. i-f 8), the point of animal research is to apply the information to human treatments. See, e.g., In re Brana, 51F.3d1560, 1568 (Fed. Cir. 1995). Beljanski (1990) takes this next step, applying the treatment found effective in rabbits to a human patient with successful results (FF 5). With regard to Levin, this postfiling date art 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 result represents the expected result of 10 Levin et al., Dose escalation study of an antithrombocytopenic agent in patients with chemotherapy induced thrombocytopenia, 10 BMC CANCER 1-8 (2010). 10 Appeal2013-006747 Application 11/978,014 optimization, that after testing several dose levels, certain doses would yield better results than others. Appellants contend that knowledge of a result dependent variable is needed before optimization using routine trial and error experimentation is possible. The teaching of 'early' administration in the M. Beljanski et al article would not have led one to a series of cyclic treatments, multiple dosages, or dosages of at least 60 mg at intervals of every other day at later treatment stages (App. Br. 8-9). We are not persuaded. Beljanski (1990) teaches that the dose of BLRs is optimizable, showing cyclic treatment of rabbits with doses of 1 to 6 mg "every second day" (FF 4) as well as 1 mg/kg (FF 2) while Cole further evidences that dose optimization is routine in the art (FF 10). Moreover, Natural Health Consult demonstrates every other day treatment of 20 mg for humans (FF 9). This is precisely a situation where the prior art suggests routine dosage optimization in 20 mg increments as argued by the Examiner (see Ans. 16). We recognize, but find unpersuasive, Appellants contention that the "possibility of achieving the disclosed outcomes- the avoidance of the need for transfusions during treatment, prolonged treatment, multiple cycle use, treatment for solid tumors, even at later stages- is clear from Appellants specification but not from the art relied upon in the rejection" (App. Br. 9). In Kubin the court found that "this court [in 0 'Farrell] stated: ' [ o ]bviousness does not require absolute predictability of success . . . all that is required is a reasonable expectation of success."' In re Kubin, 561 11 Appeal2013-006747 Application 11/978,014 F.3d 1351, 1360 (Fed. Cir. 2009) (citing In re O'Farrell, 853 F.2d 894, 903- 904 (Fed. Cir. 1988)). Beljanski (1990) provides more than sufficient evidence to support a finding of reasonable expectation of success in teaching 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 1---6). 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 8-12; cf Ans. 18-19). Appellants contend that the results establish the criticality of the threshold dose and the mode of administration. The art relied upon does not recognize this amount as being critical, especially in the context of the treatment of a solid tumor. ... The declaration reports the results and the uniqueness of the 60 and 80 mg doses relative to the lower dosage amounts (App. Br. 10). We are not persuaded. To the extent that Appellants are contending that they have unexpected results, 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 2). 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, "the instantly claimed results ('restore and maintain platelet levels to normal levels, thereby prolonging treatment time for the chemotherapy') were 12 Appeal2013-006747 Application 11/978,014 indeed expected at the time of the invention" (Ans. 17). See In re Skoner, 517 F .2d 94 7, 9 50 ( CCP A 197 5) ("Expected beneficial results are evidence of obviousness of a claimed invention.") We have also considered the Hall Declarations, 11 ,12 but are not persuaded of any unexpected results. The Hall Declaration (2009) states that the successful results from the clinical trial were unexpected. The beneficial effects of the Real BuildÂ® 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 Deel. (2009) ii 11; cf Hall Deel. (2010) ii 14). The Hall Declaration (2009) 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 1-6), 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 BL Rs specifically performed as taught by Beljanski (1990) in stimulating white blood cells represent an unexpected result (FF 1, 3, 5, 6). The Hall Declaration (2010) states that "prior to the invention described in the 'O 14 application, those skilled in the art could not have 11 Declaration of John Hall, dated Nov. 16, 2009. 12 Declaration of John Hall, dated July 6, 2010. 13 Appeal2013-006747 Application 11/978,014 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 Deel. (2010) i-f 11 ). The Hall Declaration (2010) states that "the efficacy of the preparation of small RNA fragments across different types of cancers were also unexpected ... see Maor" (Hall Deel. (2010) ,-r 12). We are not persuaded. Beljanski (1990) teaches that 15 mg BLR doses administered every other day stimulated production of platelets in a human patient undergoing chemotherapy, and Natural Health Consult teaches administration of 20 mg BLR doses every other day (FF 5, 8, 9). We recognize, but find unpersuasive, the citation to Maor. 13 Table 6 of Maor shows that the highest ribonuclease activity against poly U is found in leukemia, which also has among the highest levels against poly C, but Beljanski (1990) teaches the efficacy of the BLRs in a leukemic patient (FF 5). Thus, the ordinary artisan, aware of efficacy in a leukemic patient in the highest ribonuclease cancer group in Maor, would have reasonably expected efficacy of the BLRs in the other cancer groups with lower ribonuclease activity levels. The Hall Declaration (2010) contends that "[t]hose 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 13 We believe the correct citation to be Maor et al., Alteration of Human Serum Ribonuclease Activity in Malignancy, IO CRC CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES 89-111 (1979). 14 Appeal2013-006747 Application 11/978,014 thrombocytopenia when given to a cancer patient undergoing chemotherapy that includes mitomycin" (Hall Deel. (2010) i-f 13). We find this argument unpersuasive because none of the claims are limited to mitomycin nor does the Hall Declaration (2010) 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.") Conclusion of Law The evidence of record supports the Examiner's conclusion that the prior art renders claim 5 obvious. SUMMARY In summary, we affirm the rejection of claim 5 under 35 U.S.C. Â§ 103(a) as obvious over Beljanski (1990), Beljanski (1992), Schacter, Walker, Nature Health Consult, Cole, and Martin. Claims 7-10, and 13-16 fall with claim 5. 37 C.F.R. Â§41.37(c)(l)(iv). No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. Â§ 1.136(a). AFFIRMED 15