Ex Parte Bankiewicz et alDownload PDFPatent Trial and Appeal BoardMay 3, 201612603384 (P.T.A.B. May. 3, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/603,384 10/21/2009 24353 7590 05/05/2016 BOZICEVIC, FIELD & FRANCIS LLP Bozicevic, Field & Francis 1900 UNIVERSITY A VENUE SUITE 200 EAST PALO ALTO, CA 94303 FIRST NAMED INVENTOR Krystof S. Bankiewicz 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. UCSF-387DIV 6410 EXAMINER MACFARLANE, STACEY NEE ART UNIT PAPER NUMBER 1649 NOTIFICATION DATE DELIVERY MODE 05/05/2016 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): docket@bozpat.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte KRYSTOF S. BANKIEWICZ and SANDEEP KUNWAR Appeal2014-000778 Application 12/603,3841 Technology Center 1600 Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and RYAN H. FLAX, Administrative Patent Judges. FLAX, Administrative Patent Judge. DECISION ON APPEAL This is a decision on appeal under 35 U.S.C. § 134(a) involving claims directed to human central nervous system cancer treatment using a convection-enhanced delivery technique to infuse a topoisomerase inhibitor drug carried by a liposome. The Examiner rejects claims 1, 4, 7-10, 22, and 24 under 35 U.S.C. § 103(a). We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 The Real Party in Interest is Regents of the University of California. Br. 1. Appeal2014-000778 Application 12/603,384 STATEMENT OF THE CASE Claims 1, 4, 7-10, 22, and 24 are on appeal. 2 These claims can be found in the Claims Appendix of the Appeal Brief. Claim 1 is the sole independent claims and reads as follows: 1. A method of treating a human patient having cancer of the central nervous system (CNS), comprising: administering to said human patient a therapeutically effective dose of a pharmaceutical composition comprising a high molecular weight neurotherapeutic by convection enhanced delivery (CED) to the CNS; wherein said high molecular weight therapeutic comprises a carrier and topoisomerase inhibitor, and wherein said carrier is a liposome. Br. 8, Claims Appendix. The following ground of rejection is on appeal: Claims 1, 4, 7-10, 22, and 24 under 35 U.S.C. § 103(a) as being unpatentable over Kaiser, 3 Saito,4 and Krauze. 5 Final Action 3. 2 Claims, 2, 3, 5, 6, 11-21, and 23 are cancelled. Br. 8. 3 Kaiser et al., Tissue Distribution and Antitumor Activity of Topotecan Delivered by Intracerebral Clysis in a Rat Glioma Model, 47 NEUROSURGERY 1391-99 (Dec. 2000) (hereinafter "Kaiser"). 4 Saito et al., Distribution of Liposomes into Brain and Rat Brain Tumor Models by Convection-Enhanced Delivery Monitored with Magnetic Resonance Imaging, 64 CANCER RESEARCH 2572-79 (Apr. 1, 2004) (hereinafter "Saito"). 5 Krauze et al., Reflux-Free Cannula for Convection-Enhanced High-Speed Delivery of Therapeutic Agents, 103 J. NEUROSURGERY 923-29 (Nov. 2005) (hereinafter "Krauze"). 2 Appeal2014-000778 Application 12/603,384 FINDINGS OF FACT FF 1. Kaiser disclosed "brain tumor-bearing rats were treated with topotecan delivered systemically and by the intracerebral clysis method." Kaiser 1391 (Abstract); see also Ans. 4 (discussing Kaiser). FF2. Kaiser disclosed "[t]opotecan delivered by the intracerebral clysis method is effective for treatment of brain tumors in the rat gliomal model" and "[t ]hese studies provide compelling justification for further preclinical testing to formally evaluate toxicity and efficacy with variable dosing schedules." Kaiser 1391 (Abstract). FF3. Kaiser disclosed "[a] convection-enhanced drug delivery method" (ICC) developed to therapeutically "target brain tissue into which tumor has invaded grossly as well as microscopically." Id. FF4. Kaiser disclosed: The efficacy of ICC topotecan therapy in the C6 glioma model depends on adequate drug delivery and intrinsic sensitivity of C6 glioma cells to topotecan. In vitro, topotecan demonstrated a significant tumoricidal effect against the C6 cells during a 100-minute period. The median lethal dose (LDso) extrapolated from the dose response curve was 0.19 µmol/L (Fig. 1 ). This compares favorably with the reported LDso of the human glioma cell lines U87, U138, and U373, which ranges from 0.037 to 0.280 µmoVL (37). The LD99 of topotecan exposed to C6 glioma cells was 1.6 µmol/L. Id. 1393. FF5. Kaiser disclosed that topotecan convection-enhanced delivery "demonstrates that a conventional chemotherapeutic drug can effectively treat an intracerebral tumor when adequate delivery methods are implemented [in rats]." Id. 1395. 3 Appeal2014-000778 Application 12/603,384 FF6. Kaiser disclosed that its study on convection-enhanced topotecan delivery in rats was undertaken because "[ c ]linical trials evaluating intravenous administration of topotecan for patients with glioma demonstrated potential efficacy but were limited by systemic toxicity" and "[l]ocal delivery of the camptothecin class of drugs [e.g., topotecan] represents an alternative to systemic delivery, with the potential for increased efficacy and reduced toxicity." Kaiser 1396; see also Ans. 5 (discussing Kaiser). FF7. Kaiser disclosed: The inherent limitations of the rat model necessitate cautious interpretation before extrapolating these promising results to clinical success in humans. The C6 glioma cell line has been applicable to human studies because it mimics characteristics such as invasion, nuclear pleomorphism, hemorrhagic necrosis, and angiogenesis in human malignant glioma . . . . Although the antitumor efficacy of topotecan delivered using ICC is clearly demonstrated, the allogenicity of this C6 model \varrants consideration in the evaluation of studies claiming "cure" of intracerebral tumors . . . . In addition, the model limitations are related to the tumor and cerebral size disparity between rats and humans, which differ by orders of magnitude. However, the advantage of ICC [e.g., CED] over diffusion-based delivery methods should be more pronounced as animal and brain size mcrease .... CONCLUSION Despite the limitations of rat glioma models, the success demonstrated in the present study may be predictive of topotecan efficacy in a clinical setting. These studies provide compelling justification for further preclinical testing to formally evaluate toxicity and efficacy with variable dosing schedules. The safe use of this delivery method has already been validated in human trials with a diphtheria toxin-transferrin conjugate . . . . Optimal 4 Appeal2014-000778 Application 12/603,384 infusion parameters have not yet been established, but clinically effective treatment concentrations are probably attainable. Kaiser 1396; see also Ans. 4--5 (discussing Kaiser). FF8. Comment included with the Kaiser article stated: All models for laboratory study of malignant glioma have drawbacks, and the authors have acknowledged the limitations of their C6 glioma model in Wistar rats. That said, the apparent "cure" of most of the animals treated with direct topotecan infusion seems impressive and very promising. That another group has demonstrated a similar benefit of direct topotecan infusion in a different model using human glioma cell lines ... , albeit at a much lower rate of infusion, provides additional reason to consider these findings significant. Kaiser 1398 (Comment by William C. Broaddus, Richmond, VA). FF9. Saito disclosed research performed by, among others, inventor Krystof S. Bankiewicz. Saito 2572. FFlO . Saito disclosed: . . . liposomes have been used as a vehicle for delivery of therapeutic agents in oncology, their efficacy in targeting brain tumors has been limited due to poor penetration through the blood-brain barrier. Because convection-enhanced delivery (CED) of liposomes may improve the therapeutic index for targeting brain tumors, we conducted a three-stage study: ... Stage 3 was designed to develop a clinically relevant treatment strategy in the 9L-2 model by infusing liposome containing Gd (Lip/Gd), prepared in the same size as Lip/Gd/DiI-DS, with Doxil, a liposomal drug of similar size used to treat several cancers. MRI detection of Lip/Gd coadministered with Doxil provided optimum CED parameters for complete coverage of 9L-2 tumors. By permitting in vivo monitoring of therapeutic distribution in brain tumors, this technique optimizes local drug 5 Appeal2014-000778 Application 12/603,384 delivery and may provide a basis for clinical applications in the treatment of malignant glioma. Saito 2572 (Abstract); see also Ans. 5 (discussing Saito). FFI 1. Saito disclosed that the mortality rate for patients with malignant glioma is 80% at 2 years and, so, "development of new local management strategies such as the CED [convection-enhanced delivery] of therapeutic liposomes may provide a therapeutic advantage in the adjuvant medical management of gliomas." Saito 2572; see also Ans. 5 (discussing Saito). FF12. Saito disclosed in vivo testing of liposome distribution in "[t]wo rat brain tumor models with quite different characteristics," disclosing infusing liposomes (Lip/Gd/DiI-DS) into C6 rat gliomal model animal brain tumors and 9L-2 rat gliosarcoma model animal brain tumors and live-tracking the liposomal distribution using MRI. Saito 257 6. Saito disclosed that the C6 brain tumor model "showed a heterogeneous tumor with multiple necrosis sites inside and a relatively clearly encapsulated border" and that "[l]iposomes, when infused into this heterogeneous tumor, became distributed in an irregular shape and leaked into the encapsulated tumor margin." Id. Saito disclosed that "the 9L-2 rat brain tumor model used showed a relatively homogeneous tumor with invasive chracteristics [sic]" and "[a]fter infusion of Lip/Gd/DiI-DS, almost the whole tumor mass was covered with Lip/Gd/DiI-DS." Id. FF13. Saito disclosed "CED infusion of Lip/Gd (in liposomes the same size as Lip/Gd/DiI-DS) and Doxil into rats with a 9L-2 brain tumor." Id. 6 Appeal2014-000778 Application 12/603,384 FF14. Saito disclosed "CED techniques, introduced in 1994, as a method to circumvent the blood-brain barrier and enhance distribution of therapeutic agents by local administration, represent promising technique for brain tumor therapy, and the safety and feasibility of CED have been well established." Id. 2577 (internal citations omitted). FF15. Saito disclosed "Liposomes have been extensively studied as a carrier of drugs for cancer therapy, including surrogate markers for visualization, and are a good candidate to fill this role." Id. FF16. Saito disclosed "CED effectively distributed the liposomes in the tumor and the surrounding normal brain tissue that contained isolated invasive tumor cells, implying the potential of a valuable therapeutic advantage in using CED for the treatment of human glioblastoma." Saito 2578; see also Ans. (discussing Saito). FF17. Saito disclosed "[ s ]everal key issues must be addressed, however, before clinical application of this method could be considered. Development of real-time MRI monitoring of liposome distribution during CED is now being developed in our laboratory using nonhuman primates." Saito 2578. FF18. Saito disclosed "we believe that the MRI-monitored in vivo detection of liposomes after CED is a first step toward successful clinical application of this technology." Id. FF19. Krauze disclosed the research performed by, among others, inventor Krystof S. Bankiewicz. Krauze 923. FF20. Krauze disclosed "[r]obust reflux-free [convection- enhanced] delivery and distribution of liposomes was achieved using the 7 Appeal2014-000778 Application 12/603,384 step-design cannula in brains in both rats and nonhuman primates." Krauze 923 (Abstract); see also Ans. 5---6 (discussing Krauze). FF21. Krauze disclosed "[r]ecently, CED has been used in clinical trial in patients [i.e., humans] with recurrent glioblastoma multiforme and in parkinsonian patients to deliver glial cell line-derived neurotrophic factor." Krauze 923. FF22. Krauze disclosed infusing DiIC 18-liposomes (fluorescent labeled liposomes) into the brains of Sprague-Dawley rats using CED. Id. 942. FF23. Krauze disclosed infusing rhodamine-labeled liposomes into the brains of cynomolgus monkeys (Macacafascicularis) using CED. Id. 925. FF24. Krauze disclosed "[d]espite the anatomical heterogeneity of the nonhuman primate brain, our step-design cannula permitted reflux- free delivery at different depths and in different regions of brain." Id. 926. FF25. Krauze disclosed "this study demonstrated effective reflux-free delivery of liposomes as a carrier for CED-mediated drug delivery in rat and nonhuman primate brains by using the step-design cannula." Id. 928. FF26. Krauze disclosed "[t]he flow rate providing safe and effective delivery ( < 5 µl/minute) was the same as that used in recent clinical trials. In current clinical trials, however, this flow rate required CED lasting several hours to days to deliver clinically significant volumes (36 ml) of drug to a targeted site." Id. 8 Appeal2014-000778 Application 12/603,384 FF27. Krauze disclosed "[i]mprovement of current CED methods is the key to broad clinical applicability of this promising therapeutic procedure. We developed a novel step-design cannula to overcome the present limitations of CED, primarily low infusion speed and reflux of the delivered agent." Krauze 928 (Conclusions); see also Ans. 6 (discussing Krauze). FF28. Dr. H. Christian Fibiger6 concluded "it is well known to scientists and drug developers that for a variety of reasons, reproducibility, extrapolability and generalizability of preclinical results are generally limited, in particular in the field of oncology" and ... the extrapolability to humans of experimental data generated with convection-enhanced delivery (CED) of potential anticancer agents in rodent models of human brain tumors, in particular malignant glioma, is specifically hampered by a number of confounding factors, including significant differences in (1) size; anatomy and architecture of the brain, (2) size, pathology and pathophysiology of the tumors, and (3) local tissue pharmacokinetics and pharmacodynamics of the pharmaceutical agents. Fibiger Deel. Under 37 C.F.R. § 1.132, i-fi-14--5 (dated Sept. 12, 2012) (hereinafter "Fibiger Deel."); see also Ans. 10-11 (discussing Fibiger Deel.). FF29. Dr. Fibiger concluded "CED-mediated drug distribution in brain can only be extrapolated from species to species if the underlying brain anatomy is comparable in the respective species." Fibiger Deel. i16. 6 Appellants hold Dr. Fibiger out as an expert witness. Br. 4. 9 Appeal2014-000778 Application 12/603,384 FF30. Dr. Fibiger concluded "fluid dynamics in the naturally growing glioblastoma multiforme are fundamentally different from experimental glioblastoma." Id. i-f 8. FF31. Dr. Fibiger concluded "[i]ndependent of the CED-related issues, drug metabolism and therefore, local tissue pharmacokinetics and pharmacodynamics of the pharmaceutical agents may vary significantly between species," which "can lead to substantially different local drug concentrations and qualitatively or quantitatively altered biological drug effects even if the distribution profiles are comparable between species." Id. ,-r 9. FF32. Dr. Fibiger's conclusions (see FF28-FF31) were based on the disclosures of the following nine (9) literature publications: 10 Appeal2014-000778 Application 12/603,384 Hutchinson7 · Begley8 · Allard9 · Vogelbaum10 · Bidros1i. Grahn12 · Husain13 · ' ' ' ' ' ' ' Kunwar14; and Sampson. 15 FF33. Hutchinson disclosed that "[ o ]nly 5% of agents that have anticancer activity in preclinical development are licensed after demonstrating sufficient efficacy in phase III testing" and identifies "[a] key drawback of animal models is that they do not represent the primary tumors 7 Lisa Hutchinson, High Drug Attrition Rates-Where are We Going Wrong?, 8 CLINICAL ONCOLOGY 189-190 (Apr. 2011) (hereinafter "Hutchinson"). 8 C. Glenn Begley & Lee M. Ellis, Raise Standards for Preclinical Cancer Research, 483 NATURE 531-533 (Mar. 29, 2012) (hereinafter "Begley"). 9 Allard et al., Convection-Enhanced Delivery of Nanocarriers for the Treatment of Brain Tumors, 30 BIOMATERIALS 2302-18 (2009) (hereinafter "Allard"). 10 M.A. Vogelbaum, Convection Enhanced Delivery for Treating Brain Titmors and Selected J.h/eitrological Disorders: Symposiitm 1?..e-vievv, 83 J. NEUROONCOL. 97-109 (2007) (hereinafter "Vogelbaum"). 11 Dani S. Bidros & Michael A. Vogelbaum, Novel Drug Delivery Strategies in Neuro-Oncology, 6 NEUROTHERAPEUTICS: J. AM. Soc. EXPERIMENTAL NEUROTHERAPEUTICS 539-546 (July 2009) (hereinafter "Bidros"). 12 Grahn et al., Non-PEGylated Liposomesfor Convection-Enhanced Delivery ofTopotecan and Gadodiamide in Malignant Glioma: Initial Experience, 95 J. NEUROONCOL. 185-97 (May 24, 2009) (hereinafter "Grahn"). 13 Husain et al., Interleukin-13 Receptor as a Unique Target for Anti- Glioblastoma Therapy, 92 INT. J. CANCER 168-75 (2001) (hereinafter "Husain"). 14 Kunwar et al., Phase III Randomized Trial of CED of IL13-PE38QQR vs Gliadel Wafers for Recurrent Glioblastoma, 12 NEURO-ONCOLOGY 871-81 (Feb. 4, 2010) (hereinafter "Kunwar"). 15 Sampson et al., Poor Drug Distribution as a Possible Explanation for the Results of the PRECISE Trial, 113 J. NEUROSURG 301---09 (Aug. 2010) (hereinafter "Sampson"). 11 Appeal2014-000778 Application 12/603,384 from which they are derived in terms of tumor heterogeneity and the mechanisms of drug resistance" and "[ x Jeno graft models lack the broad molecular transformation events that occur in human tumors" and "since the stromal component of the tumor is not human the effects of the microenvironment on drug response are often not reflective of the primary tumor." Hutchinson 189. FF34. Hutchinson expressed general dissatisfaction with all oncology animal research models and disclosed "[ fJor the cancer field to move forward, animal models more representative of the clinical situation should be used." Id. 190. FF35. Hutchinson expressed general dissatisfaction with then- current oncology research practices and disclosed "[c]learly, the reasons why antiangiogenic drugs have proved disappointing in the adjuvant setting are more complex than suboptimal animal model testing." Id. FF36. Begley disclosed that "historically, our ability to translate cancer research to clinical success has been remarkably low" and "clinical trials in oncology have the highest failure rate compared with other therapeutic areas." Begley 531. FF37. Begley disclosed that the haematology and oncology department of Amgen sought out to confirm and reproduce 53 "landmark" published research studies in cancer research, but could only do so in 11 % of the cases; Bayer HealthCare attempted a similar validation study project (70% of which was cancer research) and could only validate 25% of the published preclinical studies. Id. 532. 12 Appeal2014-000778 Application 12/603,384 FF38. Allard disclosed that molecular transport (e.g., per CED infusion) is influenced by brain-matter-type: gray matter (composed of somas of neurons and glial cells) exhibits diffusivity in all directions isotropically; white matter (composed of bundles of axons leading to the peripheral nervous system) exhibits permeability dependence on the directional alignment and density of axonal fibers and diffusion therein is anisotropic. Id. 2304. FF39. Allard disclosed "[b ]ecause rat brains have very limited white matter in their structure, this [diffusion] parameter would be better studied in larger animal models like primates, dogs and of course, in humans." Id. FF40. Allard disclosed "that as the volume of brain structure is larger in humans [as compared to rats and cats], there is a much higher flexibility concerning the infusion rates employed." Id. 2306-7. FF41. Allard disclosed that infusate volume of distribution (V d) with CED is characterized by a direct linear relationship with infusion volume (Vi) and that ... this information has been checked in different species such as cats, rats, pigs, dogs, non-human primates, and humans. The relationship between Vi and V d is linear, but the ratio V d/Vi is dependent on structural properties of the tissue on the one hand, and characteristics of the infusate on the other hand. Id. 2307 (internal citations omitted). FF42. Allard disclosed "[w]ith drug delivery [using a carrier, such as liposomes], the pharmacokinetic properties of the drug will no longer depend on the properties of the active molecule but on the physicochemical properties of the carrier." Id. 2308. 13 Appeal2014-000778 Application 12/603,384 FF43. Allard disclosed "[i]n the context of CED, nanocarriers [e.g., liposomes,] can be used as vectors to track infusion and/or as vectors to treat solid tumors" and "the results are different between species because of difference in brain structure, ... rodent brains and larger brain models including studies on non-human primate brains and dogs." Id. 2311. FF44. Allard disclosed delivering "nanoliposomal Topotecan" to rat brain tissue, which "revealed a dramatic improvement in brain retention of [the drug] compared to free drugs." Id. FF45. Allard disclosed delivering "Cationic liposomes HSV-1-tk (LIPO-HSV-1-tk) [herpes simplex virus type- I thymidine kinase] in humans," resulting in 50% tumor reduction in 2 of 8 patients. Id. 2312 (Table 3), 2315. FF46. Allard disclosed "[ d]ifferences have to be made between the diffusion of liposomes in rodents compared to primate brains since the brain anatomy [e.g., white matter proportion,] of each species is quite different" so "to consider such nanocarriers [e.g., liposomes,] in future clinical trials in the human brain, the transposition to a larger brain model is necessary." Id. 2313. FF47. Allard points to dog models as having characteristics similar to human brains and indicated that canine testing is an intermediary link between rodent and primate studies and human studies. Id. 2314. FF48. Vogelbaum disclosed "[a]natomy plays a role in determining diffusion." Vogelbaum 107. FF49. V ogelbaum disclosed that, as of the date of the Cleveland Clinic Brain Tumor Institute Symposium in February 2006, CED infusion 14 Appeal2014-000778 Application 12/603,384 studies (ofI-HSA or iodinated human serum albumin) in humans had shown some (19%) success and that liposome-based CED therapeutics were well- known. Id. 102. FF50. Vogelbaum disclosed that, as of the date of the Cleveland Clinic Brain Tumor Institute Symposium in February 2006, inventor Krys Bankiewicz described liposomes as "universal delivery vehicles" to carry drugs, such as topotecan, for tumors and that they diffused well. Id. 104-- 105. FF51. V ogelbaum disclosed that, as of the date of the Cleveland Clinic Brain Tumor Institute Symposium in February 2006, inventor Krys Bankiewicz noted that liposomal topotecan was a more effective treatment (in rats) than free form topotecan. Id. 105. FF52. Bidros disclosed "[c]onvection-enhanced delivery (CED) of substances within the human brain is becoming a more frequent experimental treatment option in the management of brain tumors." Bidros 541. FF53. Bidros disclosed both that "CED within the defined infusion measurements does not produce cerebral edema or measurable increases in intracranial pressure" and, in the following paragraph, The volume of distribution achieved using CED into brain tumors differs markedly from the normal brain. This difference may be due to a number of factors including increased interstitial fluid pressure within and adjacent to brain tumors as compared to normal brain and an altered BBB. The increased interstitial fluid pressure observed in brain tumor creates a pressure gradient that can potentially drive infusate out of high-pressure areas within the tumor into relatively low-pressure areas in surrounding normal tissues. This pressure gradient and the 15 Appeal2014-000778 Application 12/603,384 Id. marked heterogeneity of drug distribution within the tumor itself are potential limiting factors in drug delivery by this method. FF54. Bidros disclosed "several key factors exist that affect the distribution of solutes delivered using CED. These include infusion rate, cannula size, infusion volume, interstitial fluid pressure, particle characteristics, and tumor tissue structure." Id. 542. FF55. Bidros disclosed: Initial studies of chronic topotecan infusion (a topoisomerase I inhibitorz [sic]) into rats bearing C6 gliomas showed more than a five-fold increase in survival times without significant neurological toxicity. 39 Based on these results, a phase I trial of topotecan delivery to patients with recurrent GBM was initiated, but outcomes have not yet been reported as of the time of this writing. CED of nanoparticle liposome containing topotecan has also been studied in vitro using rat models with experimental brain tumor. CED using liposomal topotecan resulted in extended tumor residence time as compared to free topotecan, as well as producing a significant survival benefit. 40 Id. 542. Bidros cites Kaiser (n.39 in the quote above) as disclosing a rat glioma study into the use of topotecan that spurred subsequent human glioblastoma multiforme CED studies with the same drug. Id. 542, 545. FF56 . Bidros disclosed . . . As exciting as many of these agents are in the laboratory, they face delivery hurdles imposed by the physical and biological properties of the normal brain, and the tumor infiltrated brain, which limit their clinical efficacy against malignant gliomas. Simultaneous development of novel drug delivery techniques will be required to realize the full potential of these new anti- cancer agents. Id. 544. 16 Appeal2014-000778 Application 12/603,384 FF57. Grahn disclosed that, as early as 1995 and no later than 2005, CED was a known process that "leads to reproducible distribution within a given target tissue and results in high and homogenous drug concentrations throughout the volume of distribution (V d)." Grahn 186. 16 FF58. Grahn disclosed that as of 1994 "CED allows tumors and other target tissues to be exposed to concentrations of TPT [ topotecan] that could not be achieved following systemic application, while providing a much wider distribution of the therapeutic agent across the target site than with simple diffusion." Id. 186. 17 FF59. Grahn disclosed that, as early as 1994 and no later than 2002, "[l]iposomal carriers have been shown to provide stable encapsulation for various anticancer drugs and offer distinct advantages over unencapsulated agents,"18 that, based on research published in 2006, "there 16 Grahn 186 citing Lieberman et al., Convection-enhanced Distribution of Large Molecules in Gray Matter During Interstitial Drug Infusion, 82 J. NEUROSURG. 1021-29 (1995); Croteau et al., Real-time in Vivo Imaging of the Convective Distribution of a Low-molecular-weight Tracer, 102 J. NEUROSURG. 90-97 (2005); Lonser et al., Successful and Safe Perfusion of the Primate Brainstem: in Vivo Magnetic Resonace Imaging of Macromolecular Distribution During Infusion, 97 J. NEUROSURG. 905-13 (2002). 17 Grahn 186 citing Bobo et al., Convection-enhanced Delivery of Macromolecules in the Brain, 91 PROC NAT'L ACAD. SCI. USA 2076-2080 (1994); Morrison et al., High-flow Microinfusion: Tissue Penetration and Pharmacodynamics, 266 AM. J. PHYSIOL. R292-R305 (1994). 18 Grahn 186 citing Morrison et al., High-flow Microinfusion: Tissue Penetration and Pharmacodynamics, 266 Am. J. Physiol. R292-R305 (1994); Moog et al, Change in Pharmacokinetics and Pharmacodynamic behavior of Gemcitabine in Human Tumor Xenografts Upon Entrapment in 17 Appeal2014-000778 Application 12/603,384 is good consistency within the class of topoisomerase I inhibitors for both antiglioma activity and the positive impact on efficacy of PEGylated liposomal encapsulation when delivered by CED." 19 Id. 186. FF60. Grahn disclosed that its rat study showed: . . . The distribution of topoCED in naive rat brain tissue is similar to liposome infusion by CED in normal non-human primate brain (Vd:Vi ratio of 2) [38], and in normal canine brain (Vd:Vi ratio range of 1.2-3.4) [39]. In the tumor-implanted animals, the corresponding Vd:Vi ratios were 1.6 in tumor tissue and 1.1 in naive brain tissue, right and left hemispheres respectively. CED fluid dynamics appear to be impacted by intracranial pressure, with high intracranial pressure due to excessive tumor growth leading to impaired drug distribution in both naive brain tissue and tumor tissue in the tumor implanted animals. Excellent co-convection of topoCED and gado-CED was observed in both tissue types with correlation coefficients between 0.97 and 0.99 (see Fig. 3). Id. 194--95. FF61. Grahn disclosed "[t]he overall results reported here warrant further investigation of topoCED co-administered with gadoCED by Vesicular Phospholipid Gels, 49 CANCER CHEMOTHER. PHARMACOL. 356-66 (2002). 19 Grahn 186 citing Moog et al, Change in Pharmacokinetics and Pharmacodynamic Behavior of Gemcitabine in Human Tumor Xenografts Upon Entrapment in Vesicular Phospholipid Gels, 49 Cancer Chemother. Pharmacol. 356-66 (2002); Saito et al., Convection-enhanced Deliver of Ls- TPT Enables an Effective, Continuous, Low-dose Chemotherapy Against Malignant Glioma Xenograft Model, 8 NEUROONCOLOGY 205-214 (2006); Noble et al., Novel Nano-liposomal CPT-11 Infused by Convection- enhanced Delivery in Intracranial Tumors: Pharmacology and Efficacy, 66 CANCER RES. 2801---06 (2006). 18 Appeal2014-000778 Application 12/603,384 CED in non-human primate tumor models with the goal of treating patients with malignant glioma in the near future." Id. 195. FF62. Husain disclosed "A wide array of human glioblastoma cell lines expressing the receptor for IL-13 were effectively killed by an IL- 13 cytotoxin, a chimeric protein composed of human IL-13 and a mutated form of Pseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin)" and "[ o Jn the basis of these [mice] studies, we have initiated a Phase I clinical trial using IL13-PE38QQR in patients with recurrent glioblastoma." Husain 168 (Abstract). FF63. Husain disclosed "[t]he chemically conjugated or recombinant immunotoxins or cytotoxins have shown remarkable antitumor activity in animal models of several human cancers" and "[t ]herefore, it is reasonable to predict that IL-13 toxin will have significant antitumor activity in the clinic." Id. 1 73. FF64. Husain disclosed "[w]e have performed preclinical safety studies in mice and monkeys using IL-13-PE38QQR." Id. 174. FF65. Husain disclosed "[w]e have recently initiated a Phase 1 clinical trial using IL13-PE38QQR for the treatment of recurrent glioblastoma." Id. 174. FF66. Kunwar disclosed a clinical study, called PRECISE, comparing clinical patients treated with cintradekin besudotox (CB, aka IL13-PE38QQR) via CED to patients treated with Gliadel wafers (GB) and disclosed: ... For the efficacy evaluable population, the median survival was 45.3 weeks (11.3 months) for CB and 39.8 weeks (10 months) for GW (P 5 .310). . . . This is the first randomized 19 Appeal2014-000778 Application 12/603,384 phase III evaluation of an agent administered via CED and the first with an active comparator in GBM patients. There was no survival difference between CB administered via CED and GW. Kunwar 871. FF67. Kunwar disclosed that 32% of patients in the PRECISE study were not treated in accordance with protocol guidelines on CED catheter placement. Id. 877. FF68. Kunwar disclosed that the PRECISE study experienced a surprising 40% improvement in control arm survival over prior experience. Id. 879. FF69. Sampson disclosed an analysis of "the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial." Sampson 301 (Abstract). FF70. Sampson disclosed catheter placement score and the number of optimally positioned catheters had a significant effect on PPS. Unfortunately, few catheters met all positioning criteria. As a result, estimated coverage of areas at risk for tumor recurrence was low, suggesting that limited drug delivery may have led to the limited efficacy of CB. Id. 302. FF71. Sampson disclosed that "[a] number of factors related to catheter positioning may have resulted in poor [drug] coverage [and disappointing results]." Id. 307. FF72. Sampson disclosed that "[b ]etween March 2004 and December 2005, 294 adult patients with a first recurrence of GBM were randomized in a 2: 1 ratio to receive either postoperative CED of CB or 20 Appeal2014-000778 Application 12/603,384 carmustine wafers, respectively, at 52 sites in the US, Canada, Europe, and Israel. Id. 302. FF73. The Specification described, In practice, the amount of high molecular weight neurotherapeutic will depend on the nature of the target tissue (e.g., necrosis associated with tumors or stroke; trophically deprived cells and damaged tissue, as in neurodegenerative disease), the nature of the active agent (e.g., antitumor agent, or growth factor), the volume of the target tissue, and additional factors, as recognized by one of skill in the art. The Vi: V d ratio of high molecular weight neurotherapeutic when administered to the CNS by CED Is great [sic] than or equal to 1: 1. The ratio varies to between regions of the CNS, and Vi will be adjusted accordingly without undue experimentation. Spec. ,-r 134. FF74. The Specification described "[a]ctive agents include therapeutic proteins. Therapeutic proteins include biologically active variants. The active agents according to this invention may be isolated or generated by any means known to those skilled in the art." Spec. i-f 148. FF75. The Specification described "[t]he optimal pharmaceutical formulation will be determined by one skilled in the art" and "the Vi: V d ratio varies between CNS regions, and Vi will be adjusted accordingly without undue experimentation." Spec. i-f 154 FF76. The Specification described "[t]he desired infusion volume, desired amount of active agent, and duration of infusion are largely determined by target tissue volume and the type of agent used, and are readily determined by one of skill in the art without undue experimentation." Spec. ,-r 163. 21 Appeal2014-000778 Application 12/603,384 FF77. The Specification described "[ o ]ne of skill in the art could readily determine which general area of the CNS is an appropriate target." Spec. ,-r 167. FF78. The Specification described "[t]he skilled artisan can readily ascertain therapies that may be used in a regimen in combination with the treatment methods of the invention." Spec. i-f 175. FF79. The Specification described, The specific dose is typically calculated according to the predetermined tissue distribution volume. The calculations necessary to determine the appropriate dosage for treatment involving pharmaceutical formulations is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them without undue experimentation. Spec. ,-r 176. CLAIM INTERPRET A TI ON During examination, the PTO must interpret terms in a claim using "the broadest reasonable meaning of the words in their ordinary usage as they would be understood by one of ordinary skill in the art, taking into account whatever enlightenment by way of definitions or otherwise that may be afforded by the written description contained in the applicant's specification." In re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997). We conclude that, when read in light of the Specification, the broadest reasonable interpretation of the claim language, "therapeutically effective dose of a pharmaceutical composition" is interpreted to mean "a dose of a pharmaceutical composition effective in reducing or preventing the severity or symptoms of the subject disorder." See Spec. i-f 171. "The optimal 22 Appeal2014-000778 Application 12/603,384 pharmaceutical formulation will be determined by one skilled in the art" and "[t]he calculations necessary to determine the appropriate dosage for treatment involving pharmaceutical formulations is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them without undue experimentation." Spec. i-fi-f 154 and 176. DISCUSSION The rejection of claims 1, 4, 7-10, 22, and 24 under 35 U.S.C. § 103(a) as being unpatentable over Kaiser, Saito, and Krauze. Appellants do not dispute that all elements of claim 1 were disclosed by or obvious in view of the cited prior art combination. 20 Br. 2---6. Applicants do not dispute that there would have been a motivation to combine. Id. We find that the Examiner has made a prima facie case for obviousness. Final Action 3--4; Ans. 4--7. Applicants' arguments focus on whether there was a reasonable expectation of success in practicing the claimed invention based on the prior art combination. See, e.g., Br. 3. The question presented is whether the person of ordinary skill in the art would have had a reasonable expectation of success in practicing a method of treating a human patient's cancer of the central nervous system based upon combined references that disclose the invention's methodology, but used to treat rats and nonhuman primates. See FF 1-FF2 7, supra (discussing the disclosures of the combined prior art); see also, Ans. 4--10 (discussing the prior art combination). Put differently, as the difference 20 Appellants have not argued that any claims are separately patentable; therefore, our analysis of independent claim 1 covers all claims. 23 Appeal2014-000778 Application 12/603,384 between the cited prior art and the claimed invention is the claims' reciting treating cancer in humans rather than rodents or nonhuman primates, and the level of ordinary skill in the art is high,21 we must determine if a preponderance of the evidence establishes that rodents and nonhuman primates would not have been considered predictive test subjects for successful human treatments so as to rebut the prima facie case for obviousness. Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966) (setting forth the factors to analyze obviousness); In re. O'Farrell, 853 F.2d 894, 903--4 (Fed. Cir. 1988) (obviousness does not require absolute predictability of success and there is always at least a possibility of unexpected results that could provide an objective basis to show nonobviousness). Although there is no dispute that the prior art combination discloses and suggests the claimed invention, we find it important to identify certain teachings within the cited references because they educate on the use of the claimed treatment on humans based on animal research. As determined by 21 Neither Appellants nor the Examiner expressly set forth what the ordinary level of skill in the art would have been. However, understanding that such a skilled artisan would have conducted research in oncological pharmacology pertaining to the central nervous system, based on the knowledge such an artisan would possess as described in the Specification (of, e.g., neurotherapeutic formulating, isolation and generation of biologically active agents, optimizing pharmaceutical formulations, infusion parameters per target tissue volume and type of agent, catheter or cannula positioning for infusion, providing supplemental therapies, and calculating dose of pharmaceutical formulation (see Spec. i-fi-f 134, 148, 154, 163, 167, 175)), and based on the prior art and literature of record, which establish that those working and publishing in the relevant field held medical degrees, doctorate degrees, or both, and possessed significant experience, the level of ordinary skill in the art is undeniably very high. 24 Appeal2014-000778 Application 12/603,384 the Examiner, Kaiser taught CED delivery of topotecan to effectively treat glioma in rat models. See FFI-FF8, supra; see also, Ans. 4--5 (discussing Kaiser). Kaiser disclosed that results of its research compared favorably to findings reported for research on human glioma cell lines, that its research was undertaken specifically because the drug topotecan was known to be potentially effective in humans but for its systemic toxicity limitations, that perceived limitations related to the size discrepancy in rat versus human tumor and cerebrum was likely overcome by the advantages of the CED delivery method, and that the CED delivery method (already validated in human trials) was potentially predictive of topotecan efficacy in a clinical setting. See FF4-FF8, supra. As determined by the Examiner, Saito disclosed the inventor Bankiewicz's own research confirming as effective cancer drug delivery in rats via liposome carrier and CED infusion. See FF9-FF18, supra; see also, Ans. 5 (discussing Saito). Saito disclosed and tracked CED liposomal drug delivery in both heterogeneous and homogeneous tumors and that its research implied a valuable therapeutic advantage for treatment of human glioblastoma, but indicated that its methods and results were a first step toward clinical applications and that planned intervening research would study nonhuman primates. See FF12-FF18, supra. As determined by the Examiner, Krauze disclosed the inventor Bankiewicz's research confirming as effective CED delivery of liposomes in both rat and nonhuman primate brains. See FF19-FF27, supra; see also, Ans. 5---6 (discussing Krauze ). Krauze disclosed that CED had already been used in human clinical trials, that CED delivery was effective in spite of 25 Appeal2014-000778 Application 12/603,384 anatomical nonhuman primate brain heterogeneity, that its research method's infusion flow rate was safe and effective and the same as that used in human clinical trials, and that its research results were likely the "key to broad clinical applicability" of CED liposomal infusion. See FF21-27, supra. As the Examiner determined, the combined references taught and suggested effective CED-infusion of liposome-carried topotecan. See Ans. 4--7. Further, while the combination did not disclose actually treating human neurological cancer with this method and identified the reality that all models for cancer research have drawbacks (see, e.g., FF8, supra), as the Examiner also determined, the combination does point to an expectation of clinical success in humans. See Ans. 4--6, 9-10. Moreover, the combined references address potential shortcomings (for example differences in brain size and differences in tumor composition) of using rodent model (or nonhuman primate model) research to extrapolate findings to human patients and, nevertheless, indicate that the rodent/nonhuman primate results are predictive of human patient efficacy. For example, the combined references indicated that the drug topotecan was believed effective in humans, that CED delivery of liposomes was known to be effective in human brains, that CED delivery of liposomes could be achieved and tracked in homogeneous and heterogeneous tumors, and that size discrepancy was a surmountable issue. See FF1-FF27. A reasonable expectation of success is assessed from the perspective of one of ordinary skill in the art at the time the invention was made. Verlander v. Garner, 348 F.3d 1359, 1365 (Fed. Cir. 2003) citing Life 26 Appeal2014-000778 Application 12/603,384 Techs., Inc. v. Clontech Labs., Inc., 224 F.3d 1320, 1326 (Fed.Cir.2000). The facts here generally track those of the Ver lander case, where there was no dispute that the invention was taught by the properly combined prior art, the determination ofunpatentability of a biotechnology-focused invention as obvious came down to whether there would have been a reasonable expectation of success in producing the invention based on the prior art of record, and the patentee's arguments were supported by expert witness declarations. We follow the guidance of Verlander. As in Ver lander, here the testimony of the expert witness, Dr. Fibiger, can be accorded weight only where corroborated by the literature he cites. See Verlander, 348 F.3d at 1371 (citing Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 787-88 (Fed. Cir. 1988) (weight to be accorded evidence is within discretion of trier of fact) and Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 294 (Fed. Cir. 1985) (within Board's discretion to accord printed publications greater weight than conclusory statements of expert)). Therefore, we have undertaken a review of Dr. Fibiger's declaration and cited literature. The Examiner determined that the expert testimony was conclusory and presented no specific data as evidence of a lack of reasonable expectation of success or of unexpected results. Ans. 10. While we find Dr. Fibiger's credibility sound and conclusions (see FF28-FF31, supra) to be generally supported by the cited literature (see, e.g., FF33, FF36-FF37, FF38-FF39,FF46-FF48,FF53-FF54,FF56,FF61,FF62-FF66,supra),we also find the expert testimony picks-and-chooses among the literatures' disclosures, relying on favorable points and overlooking contradictions. 27 Appeal2014-000778 Application 12/603,384 These contradictions in the literature (see FF35, FF40-FF43, FF45, FF49- FF53, FF55-FF60, FF63, FF67-71, supra), on balance, support the Examiner's position that a person of ordinary skill in the art would have had a reasonable expectation of success in achieving the claimed invention based on the prior art combination. For example, in some instances, skilled practitioners moved ahead with human treatments (clinical research) based on results of rodent models. See FF45, FF55-FF56, FF62, FF65, supra. In determining obviousness, When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that is was obvious under§ 103. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007). \Ve find these factors met for the reasons set forth above. The claimed invention would have been obvious to try because there was undeniable market pressure, finite and predictable (and tested) solutions, which would have given the person of ordinary skill a good reason to pursue the invention, and there would have been a reasonable expectation of success. The Examiner's determination that the claimed invention would have been obvious is supported by a preponderance of the evidence. For these reasons, the rejection of claims 1, 4, 7-10, 22, and 24 under 35 U.S.C. § 103(a) is affirmed. 28 Appeal2014-000778 Application 12/603,384 SUMMARY The rejection of claims 1, 4, 7-10, 22, and 24 under 35 U.S.C. § 103(a) is affirmed. TIME PERIOD FOR RESPONSE 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 29 Copy with citationCopy as parenthetical citation