Ex Parte Bankiewicz et al

Patent Trial and Appeal Board

May 3, 2016

12603384 (P.T.A.B. May. 3, 2016)

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").
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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.
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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
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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
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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.
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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
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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.
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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.
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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:
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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").
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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.
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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.
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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
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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
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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.
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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
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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).
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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
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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
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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.
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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
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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.
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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.
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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
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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
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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.
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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.
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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