Filed on behalf of Petitioner COALITION FOR AFFORDABLE DRUGS IV LLC
`
`By:
`
`Jeffrey S. Ward (Reg. No. 32,774)
`MERCHANT & GOULD, P.C.
`10 E. Doty Street
`Suite 600
`Madison, WI 53703-3376
`Telephone: (608) 280-6751
`FAX: (612) 332-9081
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`COALITION FOR AFFORDABLE DRUGS IV LLC
`Petitioner
`
`v.
`
`PHARMACYCLICS, INC.
`Patent Owner
`
`_____________________
`
`Case No. To Be Assigned
`Patent No. 8,754,090
`_____________________
`
`DECLARATION BY DJORDJE ATANACKOVIC, M.D.,
`REGARDING U.S. PATENT NO. 8,754,090
`UNDER 37 C.F.R. § 42.63(a)
`
`Coalition for Affordable Drugs IV LLC – Exhibit 1021
`
`
`
`By:
`
`Jeffrey S. Ward (Reg. No. 32,774)
`MERCHANT & GOULD, P.C.
`10 E. Doty Street
`Suite 600
`Madison, WI 53703-3376
`Telephone: (608) 280-6751
`FAX: (612) 332-9081
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`COALITION FOR AFFORDABLE DRUGS IV LLC
`Petitioner
`
`v.
`
`PHARMACYCLICS, INC.
`Patent Owner
`
`_____________________
`
`Case No. To Be Assigned
`Patent No. 8,754,090
`_____________________
`
`DECLARATION BY DJORDJE ATANACKOVIC, M.D.,
`REGARDING U.S. PATENT NO. 8,754,090
`UNDER 37 C.F.R. § 42.63(a)
`
`Coalition for Affordable Drugs IV LLC – Exhibit 1021
`
`
`
`I, Djordje Atanackovic, M.D., declare and state as follows:
`
`I. Background and Experience
`1.
`
`I graduated from Free University of Berlin in Germany in 2000
`
`with a Doctorate of Medicine (M.D.) and completed my internal medicine
`
`residency in 2000 from the University Medical Center Hamburg-Eppendorf
`
`in Germany.
`
`2.
`
`I completed my postdoctoral training in tumor immunology in
`
`2003 from the Ludwig Institute for Cancer Research in New York.
`
`3.
`
`I am board certified in internal medicine, hematology and
`
`oncology.
`
`4.
`
`Between 2000 and 2014, I have held various research,
`
`development, and clinical position of increasing responsibility including
`
`positions at the University of Utah Huntsman Cancer Institute, the
`
`University Medical Center Hamburg-Eppendorf, and the Ludwig Institute
`
`for Cancer Research.
`
`5.
`
`At the University of Utah Huntsman Cancer Institute, I am the
`
`Director of the Multiple Myeloma Program and of Cancer Immunotherapy.
`
`In my role as Director, I manage several research projects including acting
`
`as the principal investigator of numerous clinical studies involving new
`
`drugs for the treatment of various cancers, including hematologic cancers.
`
`
`
`1
`
`
`
`6.
`
`I also treat patients with a variety of hematologic malignancies
`
`with a focus on Multiple Myeloma and B-cell lymphomas. Therapeutic
`
`regimens I use comprise of different types of chemotherapies including
`
`high-dose chemotherapy plus autotransplant, tyrosine kinase inhibitors,
`
`immunomodulatory drugs, proteasome inhibitors, and monoclonal
`
`antibodies.
`
`7. My research focuses on immunotherapeutic approaches for
`
`patients with hematologic malignancies, including multiple myeloma and B–
`
`cell non–Hodgkin’s lymphomas, such as mantle cell lymphoma. My
`
`research has developed numerous cellular and antibody based approaches for
`
`patients with blood cancer and as a result, many of those immunotherapeutic
`
`approaches have been introduced into the clinic as part of a treatment
`
`protocol.
`
`8.
`
`I am the principal investigator in multiple clinical trials in
`
`different human malignancies. One clinical study was a Phase 1/2 dose
`
`escalation safety, pharmacokinetic, and efficacy study of multiple
`
`intravenous administrations of a humanized monoclonal antibody
`
`(SAR640984) against CD38 in patients with selected CD38+ hematologic
`
`malignancies including different B-cell lymphomas.
`
`
`
`2
`
`
`
`9.
`
`I regularly publish peer-reviewed articles with my colleagues in
`
`medicine and science. I am the author of at least eighty (80) peer-reviewed
`
`publications.
`
`10. My most recent publication relates to the expression of certain
`
`proteins in cancers cells of patients with multiple myeloma, a blood cancer.
`
`It was published in the Blood Cancer Journal in 2015.
`
`11.
`
`I am an active member of the medical and research community.
`
`I am an editor for BMC Cancer, a peer-reviewed medical journal that
`
`publishes original research on cancer. I am also a grant reviewer for several
`
`organizations including the European Commission, Leukemia &
`
`Lymphomas Research U.K., Cancer Research UK, FWF in Austria, the
`
`German Cancer Aid, the Research Foundation Flanders in Belgium, the
`
`Catalan Agency for Health Information in Spain, and the Italian Ministry of
`
`Health.
`
`12.
`
`I am a current member of the American Society of Hematology
`
`(ASH), the European Hematology Association (EHA), the American Society
`
`of Clinical Oncology (ASCO), the American Association for Cancer
`
`Research (AACR), and the European Association for Cancer Research
`
`(EACR).
`
`
`
`3
`
`
`
`13.
`
`I am also the named inventor on several patents and patent
`
`applications, including an issued patent directed to the diagnosis and therapy
`
`of hematological malignancies.
`
`14.
`
`I have won numerous awards for my research including the
`
`Science Award of the Hamburg Cancer Society, the Clinical Science Award
`
`of the German Society for Immune and Targeted Therapy, and the
`
`investigator award of the Cancer Research Institute (CRI).
`
`15. A copy of my CV is attached to this report as Exhibit 1022.
`
`16.
`
`I am not employed by, nor am I receiving grant support from
`
`the Petitioner or any of the other parties in interest. I am receiving
`
`compensation for my involvement in this matter based on my standard
`
`hourly consulting rate.
`
`17.
`
`I am competent to make this declaration based upon my
`
`personal knowledge and expertise in the area of treatment of and research
`
`into hematologic cancers, including B-cell non-Hodgkin’s lymphomas.
`
`II. Legal Principles Used In Analysis
`18.
`
`I have been asked to provide my opinion on whether the claims
`
`of the ’090 patent would have been anticipated or obvious to a person of
`
`ordinary skill in the art (“POSA”) at the time of the ’090 patent.
`
`
`
`4
`
`
`
`19.
`
`I understand that my analysis requires and understanding of the
`
`scope of the ’090 claims. I understand that claims subject to inter partes
`
`review are given the “broadest reasonable construction in light of the
`
`specification of the patent in which it appears.” 42 C.F.R. § 42.100(b).
`
`20.
`
`I understand that a claim is unpatentable if it is anticipated. I
`
`understand that the anticipation analysis involves comparing a claim to a
`
`prior art to determine whether each and every element of the claimed
`
`invention is disclosed in a single prior art, either expressly or inherently.
`
`21.
`
`I understand that a claim is unpatentable if it is obvious. I
`
`understand that the obviousness analysis involves comparing a claim to the
`
`prior art to determine whether the claimed invention would have been
`
`obvious to a POSA in view of the prior art and in light of the knowledge in
`
`the art. I also understand when a POSA would have reached the claimed
`
`invention through routine experimentation, the invention may be deemed
`
`obvious.
`
`22.
`
`I also understand that obviousness can be established by
`
`combining or modifying the teachings of the prior art. Specific teachings,
`
`suggestions, or motivations to combine any prior art reference with
`
`additional prior art references can be explicit or implicit. I understand that
`
`the references themselves may be one source of a specific teaching or
`
`
`
`5
`
`
`
`suggestion to combine features of the prior art, but that such suggestions or
`
`motivations to combine art may come from other sources as well.
`
`Specifically, the source may include logic, judgment, and common sense
`
`available to a person of ordinary skill rather than explicit statements in the
`
`prior art. I understand that it may not be proper to combine references when
`
`the prior art teaches away from such a combination. However, a reference’s
`
`mere disclosure of more than one alternative does not constitute teaching
`
`away from any of these alternatives.
`
`23.
`
`I further understand that whether there is a reasonable
`
`expectation of success from combining references in a particular way is also
`
`relevant to the analysis. I understand there may be a number of rationales
`
`that may support a reasonable expectation of success, including:
`
` Combining prior art elements according to known methods to
`
`yield predictable results;
`
` Substitution of one known element for another to obtain
`
`predictable results;
`
` Use of known technique to improve similar devices (methods,
`
`or products) in the same way;
`
` Applying a known technique to a known device (method, or
`
`product) ready for improvement to yield predictable results;
`
`
`
`6
`
`
`
` “Obvious to try” – choosing from a finite number of identified,
`
`predictable solutions, with a reasonable expectation of success;
`
`24.
`
`I understand that it is not proper to use hindsight to combine
`
`references or elements of references to reconstruct the invention using the
`
`claims as a guide. My analysis of the prior art is determined at the time the
`
`invention was made.
`
`25.
`
`I understand that secondary considerations may be relevant to
`
`the determination of whether a claim is obvious should the patent owner
`
`allege such evidence. Such secondary considerations can include evidence of
`
`commercial success caused by an invention, evidence of a long-felt need that
`
`was solved by an invention, evidence that others copied an invention, or
`
`evidence that an invention achieved an unexpected result. I understand that
`
`such evidence must have a nexus, or causal relationship to the elements of a
`
`claim, in order to be relevant to the obviousness or non-obviousness of the
`
`claim. I am unaware of any such secondary considerations having a nexus to
`
`the claims at issue in this proceeding.
`
`26.
`
`I understand that for a reference to be used to show a claim is
`
`obvious, the reference must be analogous art to the claimed invention. In re
`
`Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004); see also KSR Int'l Co. v.
`
`Teleflex Inc., 550 U.S. 398, 420 (2007). I understand that a reference is
`
`
`
`7
`
`
`
`analogous to the claimed invention if the reference is from the same field of
`
`endeavor as the claimed invention, even if it addresses a different problem,
`
`or the reference is reasonably pertinent to the problem faced by the inventor,
`
`even if it is not in the same field of endeavor as the claimed invention. I
`
`understand that a reference is reasonably pertinent based on the problem
`
`faced by the inventor as reflected in the specification, either explicitly or
`
`implicitly.
`
`III. Materials Reviewed
`
`27.
`
`In preparing this Declaration, I reviewed the following
`
`documents and information:
`
`a. U.S. Patent No. 8,754,090, issued on June 17, 2014, to Buggy
`
`(“the ’090 patent”) (Ex. 1001);
`
`b. ClinicalTrials.gov Archive, Study of the Safety and Tolerability
`
`of PIC-32765 in Patients with Recurrent B-cell Lymphoma
`
`(February 23, 2009),
`
`https://clinicaltrials.gov/archive/NCT00849654/2009_02_23
`
`(“NCT00849654”) (Ex. 1002);
`
`c. U.S. Patent Application Publication No. 2008/0139582 (filed
`
`Dec. 26, 2007) (“the ‘582 publication”) (Ex. 1003); Press
`
`Release, Pharmacyclics, Pharmacyclics Initiates Phase I
`
`
`
`8
`
`
`
`Clinical Trial of Novel Oral Btk Inhibitor for Refractory B-Cell
`
`Non-Hodgkin’s Lymphoma (April 13, 2009) (“the 2009 Press
`
`Release”) (Ex. 1004); Zhengying Pan, et al., Discovery of
`
`Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase, 2
`
`ChemMedChem 58 (2007) (“Pan”) (Ex. 1005);
`
`d. Lee Honigberg et al., Targeting Btk in Lymphoma: PCI-32765
`
`Inhibits Tumor Growth in Mouse Lymphoma Models and a
`
`Fluorescent Analog of PCI-32675 Is an Active-Site Probe That
`
`Enables Assessment of Btk Inhibition In Vivo, Blood (ASH
`
`Annual Meeting Abstracts), November 2007, at 1592 (“Blood
`
`2007”) (Ex. 1006);
`
`e. Christophe Le Tourneau et al., Dose Escalation Methods in
`
`Phase I Cancer Clinical Trials, 101 J. Nat’L Cancer Inst. 708
`
`(2009) (Ex. 1007);
`
`f. Jonathan McConathy, Ph.D., & Michael J. Owens, Ph.D.,
`
`Stereochemistry in Drug Action, 5 Primary Care Companion J
`
`Clinical Psychiatry 70 (2003) (“McConathy”) (Ex. 1008);
`
`g. Stefano A. Pileri & Brunangelo Falini, Mantle Cell Lymphoma,
`
`94 Hematologica 1488 (2009) (Ex. 1009);
`
`
`
`9
`
`
`
`h. Agency For Toxic Substances and Disease Registry, Public
`
`Health Assessment Guidance Manual, (2005) (“the 2005
`
`Manual”) (Ex. 1010);
`
`i. MacPartlin et al., Bruton’s tyrosine kinase is not essential for
`
`Bcr-Abl-mediated transformation of lymphoid or myeloid cells,
`
`22 Leukemia 1354 (2008) (“Leukemia 2008”)(Ex. 1011);
`
`j. National Center for Biotechnology Information, PubChem
`
`Compound Database, CID=16126651, available at
`
`http://pubchem.ncbi.nlm.nih.gov/compound/16126651 (Ex.
`
`1012); and
`
`k. Elaine S. Jaffe, The 2008 WHO classification of lymphomas:
`
`implications for clinical practice and translational research,
`
`Hematology (2009)(“PubChem”)(Ex. 1013).
`
`IV. Opinions
`
`28.
`
`29.
`
`In sum, it is my opinion that claims 1 and 2 are anticipated.
`
`It is also my opinion that claims 1 and 2 would have been
`
`obvious to a POSA at the time the invention was made. The following
`
`sections and paragraphs provide the basis for my opinion.
`
`
`
`
`
`
`
`10
`
`
`
` Overview of United States Patent No. 8,754,090
`A.
`30. United States Patent No. 8,754,090 (“the ’090 patent”) is
`
`entitled “Use of Inhibitors of Bruton’s Tyrosine Kinase (BTK).” (Ex. 1001.)
`
`In general, the ’090 patent describes methods for treating hematological
`
`malignancies with a Btk inhibitor. The hematological malignancies
`
`identified in the specification of ’090 patent include B-cell lymphomas, such
`
`as mantle cell lymphoma (“MCL”), among others.
`
`31. The claims of the ’090 patent are narrower than the patent
`
`disclosure. Specifically, claim 1 recites: A method for treating mantle cell
`
`lymphoma in an individual who has already received at least one prior
`
`therapy for mantle cell lymphoma comprising administering to the
`
`individual once per day between about 420 mg to about 840 mg of an oral
`
`dose of an inhibitor of Bruton's tyrosine kinase (Btk) having the structure
`
`
`
`
`
`11
`
`
`
`32. Claim 2 depends from claim 1 and recites: The method of claim
`
`1, wherein the once per day oral dose is about 560 mg.
`
`33. The compound identified in the claims was also called
`
`Compound 13 in the prior art. It is now also called ibrutinib.
`
`
`Background and Overview of the Art
`B.
`34. The field of the invention relates to the treatment of and
`
`development of drugs used for treating hematologic cancers, including B-
`
`cell non-Hodgkin’s lymphomas (“NHL”). At the time of the ’090 patent,
`
`people in the field were looking for more effective ways to treat hematologic
`
`cancers, including B-cell NHLs like MCL.
`
`35. By way of scientific background, Bruton's tyrosine kinase
`
`(“Btk”) is a type of tyrosine kinase. A tyrosine kinase is an enzyme that
`
`functions as an “on” or “off” switch in many cellular functions. In healthy
`
`cells, tyrosine kinase enzymes are turned “on” and “off” as needed.
`
`Tyrosine kinases, however, can become mutated, which causes unregulated
`
`growth of the cell. Mutations can lead to the development of cancer. The
`
`inhibition of tyrosine kinases has been known to be an effective treatment
`
`for cancer.
`
`36. Btk plays a crucial role in B-cell development. (Ex.1003 at
`
`[0003].) A B-cell is a type of white blood cell that is produced in human
`
`
`
`12
`
`
`
`bone marrow. The right number of B-cells must be maintained for the
`
`human body to remain healthy. B-cell lymphomas are a type of NHL caused
`
`by uncontrolled growth of B-cells where activation of the B-cell receptor
`
`and Btk signaling play important roles. All B-cell NHLs are believed to be
`
`caused by this uncontrolled growth of B-cells. Thus, inhibiting this
`
`uncontrolled growth would be expected to inhibit B-cell NHLs.
`
`37. Mantle cell lymphoma (“MCL”) is a hematologic cancer. It is a
`
`type of B-cell NHL. MCL represents from 3-10% of all NHLs. (Ex. 1009 at
`
`1488-1489.) MCL is generally regarded as an aggressive, incurable disease
`
`with the median survival of affected patients being 3-4 years. (Id.) Because
`
`MCL is incurable, patients often relapse. Relapsed MCL patients have built
`
`up a tolerance to first-line therapies. Therefore, people practicing in the
`
`field were interested in finding new effective drug therapies for refractory or
`
`relapsed mantle cell lymphoma, among other B-cell NHLs.
`
`38. One company exploring such treatments was Pharmacyclics,
`
`the owner of the ’090 patent. Pharmacyclics published much of its drug
`
`development work in the area, including patent applications, press releases,
`
`articles, abstracts, and clinical study recruitment documents detailing its
`
`development of a compound called PCI-32675 and its use for the treatment
`
`of relapsed or refractory B-cell NHL.
`
`
`
`13
`
`
`
`39.
`
`In 2007, Pharmacyclics filed a patent application on compounds
`
`that inhibit Btk and uses of those compounds. That patent application is
`
`United States Patent Application 11/964,285, which was published as U.S.
`
`Patent Application Publication Pub. No. 2008/0139582 (“the ’582
`
`publication”) (Ex. 1003). The ’582 publication discloses and tests
`
`compounds that inhibit Btk among 12 other named and tested compounds.
`
`(Id. at Table 2.) The ’582 publication refers to “Compound 4” and
`
`“Compound 13,” among others, and provides their chemical structures. (Id.)
`
`The ’582 publication data shows that Compound 13 is the most potent Btk
`
`inhibitor of all compounds tested by the applicant and is a highly selective
`
`compound. (Id.) The ’582 publication further teaches that the disclosed
`
`compounds are a “medicament for the inhibition of Bruton’s tyrosine kinase
`
`(Btk) activity” that can be “orally administered” to a “human” (Id. at [0029],
`
`[0030]) for the treatment of cancer, including “mantle cell lymphoma.” (Id.
`
`at [0041].) The ’582 publication also teaches a dose range of “1-1500 mg
`
`per day.” (Id. at [0399].)
`
`40.
`
`In 2007, Honigberg, a researcher at Pharmacyclics, presented
`
`his research at the American Society of Hematology (“ASH”) Annual
`
`Meeting. (Ex. 1006.) The ASH annual meeting is the most important
`
`conference in the field of hematology and only the most important research
`
`
`
`14
`
`
`
`is accepted for presentation. Honigberg’s abstract was also published in
`
`Blood, the leading journal in the field hematology. The abstract is called
`
`Targeting Btk in Lymphoma: PCI-32765 Inhibits Tumor Growth in Mouse
`
`Lymphoma Models and a Fluorescent Analog of PCI-32675 Is an Active-Site
`
`Probe That Enables Assessment of Btk Inhibition In Vivo (“Blood 2007”).
`
`(Ex. 1006.)
`
`41. Blood 2007 disclosed that there “is increasing evidence
`
`indicating that B-cell receptor (BCR) signaling is required for survival of
`
`non-Hodgkin’s lymphoma (NHL) cells” and that “there have been few
`
`highly selective small molecule inhibitors of Btk,” but now Pharmacyclics
`
`has “developed a series of covalent Btk inhibitors that target Cys-481 in
`
`Btk.” (Id.) Blood 2007 further discloses that “PCI-32765 is a Cys-481
`
`targeting Btk inhibitor that has been optimized for potency, selectivity and
`
`pharmacokinetics.” (Id.) Importantly, Blood 2007 reports that Btk inhibition
`
`by PCI-32765 induces apoptotic cell death and inhibits the growth of a
`
`variety of tumor cell lines derived from patients with different low-grade
`
`(cell line DHL-4) and high-grade (cell lines DHL-6, WSU-DLCL2, OCI-
`
`Ly10, DOHH2) B-cell lymphomas in vitro and in vivo. (Id.) That PCI-
`
`32765 was shown to be effective against both low-grade and high-grade B-
`
`cell lymphoma cell lines was particularly important for the treatment of
`
`
`
`15
`
`
`
`MCL because MCL exhibits characteristics of both low-grade and high-
`
`grade lymphoma.
`
`42. Based on Blood 2007, practitioners in the field would have
`
`understood that Pharmacyclics developed a new compound that showed
`
`significant potential as a treatment of B-cell NHL and that the new agent
`
`would soon be evaluated in clinical trials for B-cell NHL. This research
`
`would have led researchers to look closely at Pharmacyclics’ development
`
`of PCI-32765 as a treatment for B-cell NHL.
`
`43. Pharmacyclics also issued an April 2009 Press Release (“the
`
`2009 Press Release”) promoting its work with PCI-32765. (Ex. 1004.) The
`
`2009 Press Release reports that Pharmacyclics “has begun treating patients
`
`in a Phase I dose-escalation study to evaluate the safety and tolerability of
`
`PCI-32765, an orally available, selective inhibitor of Bruton’s tyrosine
`
`kinase, or Btk, as a potential treatment for patients with relapsed or
`
`refractory B-cell non-Hodgkin’s lymphoma (NHL).” (Id.) The 2009 Press
`
`Release further discloses that in “preclinical studies, PCI-32765 has the
`
`remarkable ability to selectively inhibit human B-cell activation without
`
`effecting T-cells.” (Id.) The 2009 Press Release further reports that
`
`“[p]reliminary results from the Phase I trial [with PCI-32765] shows good
`
`patient tolerability under conditions of Btk-drug occupancy with potent
`
`
`
`16
`
`
`
`bioactivity in targeted cell populations derived from the B-Cell lymphoma
`
`patients.” (Id.) A POSA would understand from the 2009 Press Release that
`
`PCI-32765 was potent and selective in inhibiting Btk and provided positive
`
`clinical response in patients with B-cell lymphoma.
`
`44. The prior art also includes Pharmacyclics’ Phase I clinical study
`
`with PCI-32765 recruitment publication (“NCT00849654”). (Ex. 1002.)
`
`NCT00849654 discloses that Pharmacyclics is conducting a “[s]tudy on the
`
`Safety and Tolerability of PCI-32765 in Patients with Recurrent B-cell
`
`Lymphoma” and that the “purpose of the study is to establish the safety and
`
`optimal dose of orally administered PCI-32765 in patients with recurrent B-
`
`cell lymphoma.” (Id.) NCT00849654 describes the primary outcomes of the
`
`study to measure “adverse events” and “pharmacokinetic /
`
`pharmacodynamics.” (Id.) The secondary outcome of the study was “tumor
`
`response.” (Id.) The doses to be administered in the study included 1.25,
`
`2.5, 5.0, 8.3, 12.5 and 17.5 mg/kg/day orally once per day. (Id.) The study
`
`anticipated enrolling 36 patients. (Id.)
`
`45. Thus, as of 2009, Pharmacyclics’ own prior art publications
`
`disclosed PCI-32765 and its clinical use for the treatment of B-cell NHL,
`
`including MCL, at a dose of about 560 mg.
`
`
`
`
`
`17
`
`
`
`C.
`
`The Identity of PCI-32765
`46. The ’582 publication identifies PCI-32765 as Compound 4.
`
`(Ex. 1003 at Table 6.) Compound 4 is a racemate of Compound 13 and
`
`Compound 14. (Id. at Table 2.) Another reference—PubChem— also
`
`identifies PCI-32765 as Compound 4. (Ex. 1013.)
`
`47. Although the ’582 publication and PubChem references
`
`disclose PCI-32765 as being Compound 4, a POSA would be able to deduce
`
`that the correct identity of PCI-32765 is Compound 13. In fact, other prior
`
`art references support the identity of PCI-32765 as Compound 13, the R-
`
`enantiomer of Compound 4.
`
`48. Pan and MacPartlin combine with Blood 2007 to disclose the
`
`chemical structure of PCI-32765. Pan discloses Compound 4. (Ex. 1005 at.
`
`59.) MacPartlin states that Compound 4 from Pan is known as PCI-
`
`31523. (Ex. 1011 at 1354.) MacPartlin also discloses another compound,
`
`PCI-33380, which is the “pure R-enantiomer of PCI-31523” linked to the
`
`fluorophore Bodipy-FL. (Id. at 1355.) MacPartlin cites Blood 2007 in
`
`support of this proposition. Blood 2007 discloses that to test the potency of
`
`PCI-32765, PCI-33380 was developed. PCI-33380 is a covalent Btk
`
`inhibitor linked to Bodipy-FL. (Ex. 1006.) In other words, a POSA would
`
`understand from the combination of Blood 2007, Pan and MacPartlin that, to
`
`
`
`18
`
`
`
`test the potency of PCI-32765, a probe was developed containing PCI-32765
`
`and Bodipy-FL. A POSA would further understand that PCI-32765 is the R-
`
`enantiomer of PCI-31523 (i.e., the R-enantiomer of Compound 4 in Pan,
`
`which itself is Compound 13 in Pan). (Id.) The R-enantiomer of Compound
`
`4 in Pan is now known as ibrutinib, which is Compound 13. Thus, the
`
`combination of Blood 2007, Pan and MacPartlin discloses the structure of
`
`ibrutinib in the prior art. (Id.)
`
`V. A Person of Ordinary Skill in the Art
`49.
`
`I understand that a person of ordinary skill in the art (“POSA”)
`
`is a hypothetical person who is presumed to be aware of all pertinent art.
`
`Factors I have considered in determining the level of ordinary skill in the art
`
`include: (A) the “type of problems encountered in the art;” (B) “prior art
`
`solutions to those problems;” (C) “rapidity with which innovations are
`
`made;” (D) “sophistication of the technology;” and (E) “educational level of
`
`active workers in the field.”
`
`50.
`
`In my opinion, a POSA at the time of the alleged invention of
`
`the ’090 patent is a medical doctor specializing in hematology and having
`
`several years of experience treating patients with B-cell NHL, including
`
`MCL. A person of ordinary skill in the art may also include a medical
`
`
`
`19
`
`
`
`doctor or researcher with a Ph.D. in biochemistry or related field having
`
`several years of experience researching treatments for B-cell NHLs.
`
`VI. Claim Construction
`51.
`
`I understand that in this proceeding claim terms are given their
`
`broadest reasonable interpretation in light of the specification of the patent.
`
`Unless noted otherwise in the discussions below, all claim terms that I
`
`discuss should be given their broadest reasonable interpretation in light of
`
`the specification as commonly understood by those of ordinary skill in the
`
`art.
`
`52. Claims 1 and 2 use the term “treating.” The ’090 patent defines
`
`“treating” as “alleviating, abating or ameliorating a disease or condition, or
`
`symptoms thereof; managing a disease or condition, or symptoms thereof;
`
`preventing additional symptoms; ameliorating or preventing the underlying
`
`metabolic causes of symptoms; inhibiting the disease or condition, e.g.,
`
`arresting the development of the disease or condition; relieving the disease
`
`or condition; causing regression of the disease or condition, relieving a
`
`condition caused by the disease or condition; or stopping the symptoms of
`
`the disease or condition. The terms "treat," "treating" or "treatment",
`
`include, but are not limited to, prophylactic and/or therapeutic
`
`treatments.” (Ex. 1001 col. 27:26-37.) A POSA would understand that
`
`
`
`20
`
`
`
`under the broadest reasonable construction of “treating,” this definition
`
`includes causing any positive clinical response in an individual with relapsed
`
`or refractory MCL. In fact, “ameliorating or preventing the underlying
`
`metabolic causes of symptoms” would simply require inhibiting Btk in a
`
`patient.
`
`53. Claims 1 and 2 also use the term “about” in the context of the
`
`dose to be administered. Claim 1 states that the dose is “about 420 mg to
`
`about 840 mg” and claim 2 provides a dose of “about 560 mg.” (Ex. 1001 at
`
`149:5.)
`
`54. A POSA would understand “about” to mean of
`
`“approximately.” “Approximately” would include doses that are not
`
`materially different from the named dose. In this field, a POSA would
`
`understand that a difference in dose of 10% or less would have no material
`
`effect on patient treatment, especially given that patients come in various
`
`sizes and the maximum tolerated dose of PCI-327465 has a high upper limit.
`
`(Ex. 1002.) Furthermore, the ’090 patent makes no distinction between
`
`doses of even greater difference in terms of efficacy, tolerability or anything
`
`else. In fact, the ’090 patent does not distinguish a 560 mg dose from either
`
`a 420 mg dose or an 840 g dose. Thus, “about” would include any dose that
`
`is 10% or less different from the specific dose named in the claims.
`
`
`
`21
`
`
`
`A.
`
`VII. Grounds for Anticipation
` Claims 1 and 2 of the ‘090 Patent are anticipated by
`NCT00849654.
`55. The claims of the ’090 patent would have been anticipated
`
`based on the NCT00849654 reference. To demonstrate anticipation, I will
`
`address the disclosure of the claims on and element by element basis.
`
`
`A method for treating mantle cell lymphoma in an
`individual who has already received at least one prior
`therapy for mantle cell lymphoma.
`
`1.
`
`
`
`56. NCT00849654 discloses this claim element. NCT00849654 is
`
`a Phase I clinical study recruitment document involving the administration
`
`of PCI-32765 to patients with “recurrent B-cell lymphoma.” (Ex. 1002.)
`
`Recurrent B-cell lymphoma meant that patients enrolling on the study were
`
`required to “have failed ≥1 previous treatment for lymphoma.” (Id.)
`
`57. Based on the classification systems of lymphomas used by
`
`numerous clinicians and researchers, a POSA would understand “B-cell
`
`lymphomas” necessarily includes all of its subtypes. One subtype is MCL.
`
`(Ex. 1013.)
`
`58. Furthermore, MCL accounts for 3-10% of all NHL. (Ex.1009
`
`at1488.) Because it is incurable, MCL relapses after first-line therapy were
`
`common. Consequently, a POSA would expect that at least some patients of
`
`
`
`22
`
`
`
`the 36 patients anticipated to be enrolled in the Phase I clinical trial
`
`contemplated in NCT00849654 had refractory or relapsed MCL.
`
`59. Although it is not clear whether at the time NCT00849654 was
`
`published the enrolled patients had received doses of PCI-32765, a POSA
`
`would expect that PCI-32765 will “treat” the B-cell Lymphoma by
`
`inhibiting Btk activity if administered. In other words, a POSA would
`
`expect that treatment is inherent in the administration of PCI-32765. It is
`
`my understanding that actual administration is not necessary for anticipation
`
`when the result of the administration is inherent.
`
`2.
`
`Administering an inhibitor of Bruton's tyrosine kinase (Btk)
`having the structure:
`
`
`60. This structure corresponds to Compound 13 in the ’582
`
`publication. (Ex. 1003 at Table 2.) NCT00849654 discloses that it is a
`
`“Phase I Dose-Escalation Study of Bruton’s Tyrosine Kinase (Btk) Inhibitor
`
`
`
`23
`
`
`
`PCI-32765.” (Ex. 1002.) Although NCT00849654 does not further identify
`
`PCI-32765, a POSA would have known from other prior art references that
`
`PCI-32765 was at least one of two compounds—Compound 4 from the ’582
`
`publication, or its R-enantiomer, Compound 13.
`
`61. As noted about in Section IV.C, a POSA would deduce that
`
`PCI-32765 is actually Compound 13 after reviewing MacPartlin, Pan, and
`
`Blood 2007.
`
`3.
`
`Administering to the individual once per day between about
`420 mg to about 840 mg of an oral dose.
`
`
`62. NCT00849654 discloses that “PCI-32765 will be administered
`
`in 1.25, 2.5, 5.0, 8.3, 12.5 and 17.5 mg/kg/day dose cohorts orally once per
`
`day for 28 days” in order to establish the “optimal dose of . . . PCI-32765.”
`
`(Ex. 1002.)
`
`63. A POSA with knowledge of NCT00849654 seeking to find an
`
`appropriate dose amount would try the identified dosage levels to determine
`
`the optimal dose. Determining the appropriate dose would have been a
`
`matter of standard and routine experimentation. For example, the phase I
`
`dose escalation study performed by Pharmacyclics used a methodology
`
`similar to that explained in a prior art reference called “Dose Escalation
`
`Methods in Phase I Cancer Clinical Trials.” (Ex. 1007.) In fact, a POSA
`
`would follow the same standard and routine experimentation performed by
`
`
`
`24
`
`
`
`the researchers conducting the NCT00849654 clinical trial to find the
`
`appropriate dose. A POSA would have a reasonable expectation that at least
`
`one of the identified doses would “treat” relapsed or refractory MCL.
`
`Pharmacyclics confirmed in the 2009 Press Release that the study showed
`
`efficacy using PCI-32675 for the treatment of relapsed or refractory B-cell
`
`NHL in at least one of the doses used in the study. (Ex. 1004.)
`
`64. A person of ordinary skill in the art would further understand
`
`that 70 kg is the weight used for the standard man in calculating drug doses.
`
`(Ex. 1010 at ch.7, p.16.) This standard man construct is discussed in many
`
`publications. For example, a January 2005 Public Health Assessment
`
`Guidance Manual (“the 2005 Manual”) document explains that with respect
`
`to body weight the “default assumption is that the average adult weighs 70
`
`kg (154 pounds).” (Id.) Therefore, to determine the daily dose given in
`
`NCT00849654, a POSA would multiple the doses by 70 kg. The daily dose
`
`for the 8.3 mg/kg/day cohort would be 580 mg. This is within the dose
`
`range of claim 1.
`
`4. Wherein the once per day oral dose is about 560 mg.
`
`65. Claim 2 adds that the “once per day oral dose is about 560 mg.”
`
`As explained above, the 8.3 mg/kg/day equates to 580 mg in a 70 kg person.
`
`580 mg differs from the stated dose of 560 mg by 20 mg or 3%. A 560 mg
`
`
`
`25
`
`
`
`dose in a 70 kg individual would be 8.0 mg/kg/day. A POSA would
`
`understand that doses different by 10% or less will have
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
