Ex Parte Beljanski et al

Patent Trial and Appeal BoardFeb 13, 2019

14693779 (P.T.A.B. Feb. 13, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/693,779 04/22/2015 441 7590 02/15/2019 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 W 006CON2 9128 EXAMINER SHIN,DANAH ART UNIT PAPER NUMBER 1635 NOTIFICATION DATE DELIVERY MODE 02/15/2019 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): docketing@sgrlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte SYLVIE BELJANSKI Appeal2017-007033 Application 14/693,779 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 appeal 1,2,3 under 35 U.S.C. Â§ 134 involving claims to methods for treating thrombocytopenia using 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 Appellant identifies the Real Party in Interest as Molecular International Research, Inc. (see App. Br. 2). 2 This appeal is related to Appeal 2013-006747, decided on Mar. 23, 2016 and Appeal 2015-001712, decided on Mar. 17, 2017. 3 We have considered and herein refer to the Specification of Apr. 22, 2015 ("Spec."); Non-Final Office Action of Aug. 18, 2015 ("Non-Final Act."); Final Office Action of Nov. 23, 2015 ("Final Act."); Appeal Brief of Apr. 26, 2016 ("App. Br."); Examiner's Answer ofNov. 9, 2016 ("Ans."); and Reply Brief of Jan. 5, 2017 ("Reply Br."). Appeal2017-007033 Application 14/693,779 Statement of the Case Background "The critical drop in platelet levels induced by chemotherapy, a condition called thrombocytopenia, is frequently the main factor in the demise of the patient" (Spec. 1 :30 to 2:2). "Thrombocytopenia is also a significant problem for individuals suffering from defects in platelet production and processing associated with a disease known as Immune Thrombocytopenic Purpura (ITP)" (id. at 3:16-18). The "pathology and the clinical symptoms of ITP and drug-induced thrombocytopenia are consistent and the present invention describes an agent that effectively stimulates platelet production and thus successfully treats thrombocytopenia in both patient populations" (id. at 4: 1--4). The Claims Claims 1 and 22-31 are on appeal. 4 Claim 1 is the sole independent claim, is representative, and is reproduced below: 1. A method for treating thrombocytopenia in a subject, comprising administering as a medicament a platelet restoring amount of a preparation of small RNA fragments to said subject, wherein the subject is suffering from immune thrombocytopenia (ITP), wherein the preparation is derived from E. coli RNA and composed of single chain polyribonucleotides having 10 to 80 ribonucleotide units, and having an overall ratio of purine bases to pyrimidine bases [(G+A)/(C+U)] of between 1.0 and 4.0, and wherein the subject is not taking any other medications that influence white blood cell populations. 4 Appellant states that claim 32 is not currently on appeal (see App. Br. 16). 2 Appeal2017-007033 Application 14/693,779 The Issue The Examiner rejected claims 1 and 22-31 under 35 U.S.C. Â§ 103(a) as obvious over Beljanski '649, 5 Beljanski (1990), 6 Levi,7 and Nature Health Consult8 (Non-Final Act. 5-7). The Examiner finds Beljanski '649 teaches and claims "a method of treating platelet deficiency comprising administering the instantly claimed preparation" (Non-Final Act. 5). The Examiner finds that Beljanski (1990) teaches "that administration of E. coli RNA fragments results in an increase in platelet counts at least by 6-fold in a human patient having severe thrombocytopenia with platelet counts below 50,000" (id.). The Examiner finds Levi teaches that the same pharmaceutical composition (fibrinogen-coated albumin microcapsules) can effectively treat both immune thrombocytopenia and chemotherapy-induced thrombocytopenia by showing that rabbits that received anti- rabbit platelet antibodies (thus model of ITP) showed about 30 xl09 per liter platelet counts prior to treatment and CIT rabbits showed about 15 x 109 per liter platelet counts prior to treatment, wherein bleeding time was significantly decreased for both thrombocytopenia models after treatment. (id. at 6). The Examiner finds Natural Health Consult teaches "ReaLBuildÂ® is administered sublingually and helps to 'support the body's immune 5 Beljanski, US 4,190,649, issued Feb. 26, 1980 ("Beljanski '649"). 6 M. Beljanski, Cancer Therapy: A New Approach, 22 DEUTSCHE ZEITSCHRIFT FUR ONKOLOGIE 145-52 (1990) ("Beljanski (1990)"). 7 M. Levi et al., Fibrinogen-coated albumin microcapsules reduce bleeding in severely thrombocytopenic rabbits, 5 NATURE MED. 107-11 (1999) ("Levi"). 8 Natural Source, www.naturalhealthconsult.com/Monographs/ ReaLBuild.html (site created Mar. 1, 1998) ("Natural Health Consult"). 3 Appeal2017-007033 Application 14/693,779 system to help boost the cells which naturally enhance the generation of white blood cells and platelets"' and that "20 mg ReaLBuildÂ® is taken "as directed by a health practitioner"' (id. at 6). The Examiner finds the combination would have been obvious: to use Beljanski's patented method of treating 'platelet deficiency' (thus encompassing ITP) so as to treat an ITP patient, with a reasonable expectation of success, because a successful increase in platelet counts using Beljanski's patented method in a human subject having severe thrombocytopenia induced by chemotherapy was already demonstrated in the art as evidenced by Beljanski's Figure 5, and because it was demonstrated in the art that the same pharmaceutical composition can be used to treat both ITP and CIP subjects as taught by Levi. (Non-Final Act. at 6-7)(see also Final Action 2-7 (maintaining the obviousness rejection as final). The issue with respect to the rejection is: Does the evidence of record support the Examiner's conclusion that the prior art renders claims 1, 23, and 24 obvious? Findings of Fact 1. Claim 7 of Beljanski '649 is reproduced below: 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 purine bases to pyrimidine bases [(G+A)/(C+U)] in said polyribonucleotides being between 1.0 and 2.5. (Beljanski '649 10:6-13). 4 Appeal2017-007033 Application 14/693,779 2. Beljanski '649 teaches: The "response" time varies with the route chosen and depends on the dose of product. ... 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. (Beljanski '649 8:5-18). 3. 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 ). 4. Beljanski (1990) teaches that "analysis of BLR activity at the cytological level indicated that they enhance leukocyte and platelet genesis" (Beljanski (1990) 148, col. 1). 5. 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). 5 Appeal2017-007033 Application 14/693,779 6. Figure 5 of Beljanski (1990) is reproduced below: -t lyrnphoblastic leukemia 0 1 I (:â€¢r :lll<>t:Nlflf~ _ <:<61X> BLRs: 1 d(l~$/d~y !3LRs l ,000 - - -- 0 R ll:li B B ~Â¢ "1:-R "'4. ~10 -1:i;t-~ ~ Â·M aa SB .3..-"7 ~ 34 3G ~e 40 S!att Oays; "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 per lingual route as indicated in the figure ( 1 dose = 15 mg ofBLRs)" (Beljanski (1990) 148). 7. Levi teaches "[t]o determine the effect of the fibrinogen-coated albumin microcapsules on thrombocytopenic bleeding, we used models of immune thrombocytopenia and of chemotherapy-induced thrombocytopenia in rabbits" (Levi, 107, col. 1 ). 8. Levi teaches "administration of fibrinogen-coated albumin microcapsules results in a significant reduction of enhanced bleeding in rabbits made thrombocytopenic with either platelet antiserum or with chemotherapy" (Levi 109, col. 2). 9. Natural Health Consult teaches "ReaLBuildÂ® 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 6 Appeal2017-007033 Application 14/693,779 the generation of white blood cells and platelets" (Natural Health Consult 1 ). 10. 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). Principles of Law "Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success." In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009). Analysis We adopt the Examiner's findings of fact and reasoning regarding the scope and content of the prior art (Non-Final Act. 5-7; FF 1-10) and agree that the claims are rendered obvious by Beljanski '649, Beljanski (1990), Levi, and Nature Health Consult. We address Appellant's arguments below. Claim 1 Appellant contends "[ n Jo evidence of record establishes that one of ordinary skill would have reasonable expectation of success in restoring platelet levels or curing ITP or alleviating its symptoms. The applied art does not [ establish such an expectation]. The art supplied to the Examiner prior to the first Office Action teaches accepted treatments recognized by those skilled in the art" (App. Br. 5). Appellant further contends the Beljanski patent and article describe model systems where low platelet levels are chemically induced and then restored to "normal" levels. The internet advertisement (Natural Health Consult) features ReaLBuildÂ®. There is no teaching of the chemically treated rabbit as being an art accepted model for either CIT or ITP. ITP is only mentioned in Levi et al. article as a known condition. 7 Appeal2017-007033 Application 14/693,779 (App. Br. 6). Appellant contends the "the Levi et al. article is not suggestive that ReaLBuildÂ® could treat both ITP and CIT. The treatment mechanisms of Levi et al and Beljanski are totally unrelated. The Levi et al. model systems deal with bleeding and improving clot formation in a platelet poor environment" (App. Br. 7). We do not find these arguments persuasive in view of the evidence in the prior art demonstrating efficacy of BLRs in treating leucocyte and platelet deficiencies, including experiments in animals (FF 4) and humans (FF 8). Beljanski (1990) teaches the "analysis of BLR activity at the cytological level indicated that they enhance leukocyte and platelet genesis" (FF 4), reasonably suggesting that the artisan would have expected a safe and effective treatment regimen of platelet deficiency diseases such as immune thrombocytopenia using the BLR composition of Beljanski '649 and Beljanski (1990). While Beljanski '649 is limited to cytopenias, in general, or chemotherapeutic thrombocytopenia (FF 1-2), Levi suggests that drugs used to treat chemotherapeutic thrombocytopenia also function to treat immune thrombocytopenia (FF 8). To the extent that Levi is drawn to a different drug as tested in rabbits, that goes to the weight given the evidence, not the evidence itself. As claim 1 is not limited to human subjects, the animal tests disclosed in the prior art fall directly within the scope of the claim. While we agree that Levi tests a different drug for treatment of cytopenia, Levi demonstrates that a drug known to treat platelet deficiency caused by chemotherapeutic drugs can also treat platelet deficiency in immune thrombocytopenia (FF 7-8). Levi supports the Examiner's reasoning that increasing platelets would treat 8 Appeal2017-007033 Application 14/693,779 thrombocytopenia because "the therapeutic effects of RNA fragments in CIT treatment working examples of Beljanski's patent and 1990 reference are predictive of therapeutic effects of RNA fragments in ITP therapy" (Ans. 8, see FF 8). That is, both diseases are platelet deficiency diseases, Levi teaches a single agent can treat both immune and chemotherapeutic thrombocytopenia (FF 8), and Beljanski (1990) teaches BLRs are disclosed as functioning to "enhance ... platelet genesis" (FF 4), supporting the Examiner's finding of a reasonable expectation of success in treating immune thrombocytopenia with the known BLR composition (see Ans. 7- 8). Appellant contends "[ t ]here is no guidance provided in the applied references suggesting the selection of an agent that promotes platelet proliferation to treat ITP. There is no guidance that would lead to the identification of a result dependent variable, the optimization of which leads to the claimed dosage regimen" (App. Br. 8). We are not persuaded. The Specification acknowledges that in immune thrombocytopenia there is a "critical loss of platelets and that also appears to be a factor in reducing platelet production in the bone marrow" (Spec. 3:23-24). Immune thrombocytopenia has a similar etiology to chemotherapy induced thrombocytopenia because "the underlying pathology and the clinical symptoms of [immune thrombocytopenia] and drug-induced thrombocytopenia are consistent" (Spec. 4: 1-2). This commonality was recognized in the prior art as evidenced by Levi, which teaches that the same therapy treats both conditions (FF 8). Thus, Levi directly indicates that treatments directed to one of the thrombocytopenic conditions treats both conditions. 9 Appeal2017-007033 Application 14/693,779 Therefore, the ordinary artisan, aware ofBeljanksi (1990)'s teaching that "analysis of BLR activity at the cytological level indicated that they enhance leukocyte and platelet genesis" (FF 4), would have had reason to use this treatment on other thrombocytopenias including immune thrombocytopenia as taught by Levi (FF 8). To the extent that Appellant is arguing a dosing issue, we note that claim 1 does not require any specific dosing and claim 23 uses the 20 mg dose of Natural Health Consult that is taught to "naturally enhance the generation of white blood cells and platelets" (FF 9). Appellant contends they have also provided prior to the first Office Action journal articles, which listed accepted therapies for treating ITP. (The articles also indicated that ITP included a variety of conditions.) None of the therapies which employ compounds, e.g, prednisone, are remotely similar to the claimed small RNA fragment preparation ( chemical hydrolysates ). Without similarity to a successful compound, a reasonable expectation of success is absent. (App. Br. 9). We find this argument unpersuasive. The evidence of positive preclinical reports that demonstrate efficacy of BLRs in a human patient with thrombocytopenia in Beljanski (1990) (FF 5) provides a reasonable expectation of success for treatment of immune thrombocytopenia with this compound. In O 'Farrell, the court found that The admonition that "obvious to try" is not the standard under Â§ 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 10 Appeal2017-007033 Application 14/693,779 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 thrombocytopenic patients using BLR therapy and specifically teaches an example of such a treatment in a human patient (FF 5). 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 3---6). Levi teaches that a compound that treated chemotherapeutic induced thrombocytopenia also treated immune thrombocytopenia (FF 7-8). We agree with the Examiner that the ordinary artisan would have reasonably found it obvious to optimize the BLR dose in humans for treatment of the immune thrombocytopenia because Beljanski '649 teaches "[t]he 'response' time varies with the route chosen and depends on the dose of product" (FF 2; cf Ans. 19). Appellant contends "[t]he claimed use cannot be deemed [to have] been obvious when three decades lapsed before Appellant used it successfully to treat chronic and severe patients with the condition. The Examiner's conclusion is based on hindsight. The successful outcome is only reported in the present specification" (App. Br. 9). Appellant contends the "Examiner[' s] total disregard of the EPO and JPO patentability findings is not appreciated" (App. Br. 9-10). 11 Appeal2017-007033 Application 14/693,779 We are not persuaded. While we are aware that hindsight bias may plague determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36 (1966), we are also mindful that the Supreme Court has stated that the "combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR, 550 U.S. at 416. In the instant case, the prior art suggests the use of the composition for treatment ofthrombocytopenias in general (FF 16, 9, 10), and teaches that compounds useful in chemotherapeutic induced thrombocytopenia also function to treat immune thrombocytopenia (FF 7, 8). Thus, applying the known platelet therapy of BLRs to a known thrombocytopenic disease condition of immune thrombocytopenia reasonably represents the predictable use of known elements, not improper hindsight. With respect to Appellant's argument that other national patent offices considered the claims "inventive," we are not persuaded because we evaluate patentability of claims based on their own merit following U.S. patent law and U.S. caselaw. See, e.g., In re Gyurik, 596 F.2d 1012, 1018 n.15 (CCPA 1979) ("In reviewing specific rejections of specific claims, this court does not consider allowed claims in other applications or patents." Appellant contends the "claimed invention is a treatment method for curing a subject having ITP. There is no formal claim construction section in the Examiner's Answer" (Reply Br. 2). Appellant contends that "Curing the subject of ITP is required by the definition of 'treating"' (Reply Br. 3). We find this argument unpersuasive because the Specification states "[b ]y 'treating' or 'treatment' is meant to prevent or reduce the risk of occurrences of a disease or condition- or inhibit or ameliorate the symptoms 12 Appeal2017-007033 Application 14/693,779 of a disease or conditions or accelerate the recovery from a disease or condition" (Spec. 5:28-30). Thus, Appellant's attempts to now limit the word "treating" to "curing" is directly inconsistent with the express definition of "treating" provided in the Specification. Appellant points to no persuasive basis to limit "treating" to "curing." Claims 2 3 and 2 6 Appellant reiterates the contentions regarding the relevance of the Levi reference that we found unpersuasive, as discussed above (see App. Br. 11 ). Appellant's only argument somewhat specific to claims 23 and 26, which deal with a dosage of 20 mg/week and a chronic or severe ITP, respectively, is that the "present specification teaches different dosage regimens for ITP and CIT. CIT is disclosed by Appellant as having a threshold dosage amount. The frequencies of administration also differ. None of the art relied upon would suggest this" (App. Br. 12). We find this argument unpersuasive for several reasons. First, Beljanski '649 recognizes dosing as an optimizable variable, teaching the "'response' time varies with the route chosen and depends on the dose of product" (FF 2). Second, the claimed dose overlaps that claimed by Beljanski '649 of 2 to 100 mg (FF 1). Third, Appellant provides no evidence of unexpected result or any other secondary consideration for non- obviousness regarding the dosing amounts. Conclusion of Law The evidence of record supports the Examiner's conclusion that the prior art renders claims 1, 23, and 24 obvious. 13 Appeal2017-007033 Application 14/693,779 SUMMARY In summary, we affirm the rejection of claims 1, 23, and 24 under 35 U.S.C. Â§ 103(a) as obvious over Beljanski '649, Beljanski (1990), Levi, and Nature Health Consult. Claims 22 and 25-31 fall with claims 1, 23, and 24. 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 14