Trials@uspto.gov
`571-272-7822
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`Paper 10
`Date: April 30, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PFIZER, INC.,
`Petitioner,
`
`v.
`
`BIOGEN, INC. AND GENENTECH, INC.,
`Patent Owner.
`
`
`Case IPR2017-02126
`Patent 7,682,612 B1
`
`
`
`
`Before ERICA A. FRANKLIN, SHERIDAN K. SNEDDEN, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`571-272-7822
`
`
`
`
`
`
`
`
`Paper 10
`Date: April 30, 2018
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PFIZER, INC.,
`Petitioner,
`
`v.
`
`BIOGEN, INC. AND GENENTECH, INC.,
`Patent Owner.
`
`
`Case IPR2017-02126
`Patent 7,682,612 B1
`
`
`
`
`Before ERICA A. FRANKLIN, SHERIDAN K. SNEDDEN, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`Case IPR2017-02126
`Patent 7,682,612 B1
`
`I.
`
`INTRODUCTION
`Pfizer, Inc. (“Petitioner”) filed a Petition to institute an inter partes
`review of claims 1–13, 15–35, and 37–60 (Paper 1; “Pet.”) of U.S. Patent
`No. 7,682,612 B1 (Ex. 1001; “the ’612 patent”). Biogen, Inc. and
`Genentech, Inc. (collectively, “Patent Owner”) filed a Patent Owner
`Preliminary Response. Paper 8.
`We have authority to determine whether to institute an inter partes
`review under 35 U.S.C. § 314 and 37 C.F.R. § 42.4(a). Upon considering
`the Petition and the Preliminary Response, we determine that Petitioner has
`not shown a reasonable likelihood that it would prevail in showing the
`unpatentability of claims 1–13, 15–35, and 37–60. Accordingly, we deny
`the Petition and decline to institute an inter partes review.
`Related Proceedings
`A.
`Petitioner indicates that the ’612 patent is at issue in Genentech,
`Inc. v. Celltrion, Inc., Case No. 1:18-cv-00574 (D.N.J.), and Celltrion,
`Inc. v. Genentech, Inc., Case No. 3:18-cv-00276 (N.D. Cal.). Paper 7.
`Patent Owner state that the ’711 patent is at issue in Genentech, Inc., Biogen
`Inc., and City of Hope v. Sandoz, Inc. and Sandoz International GMBH,
`Case No. 2:17-cv-13507 (D.N.J.). Paper 6.
`The ’612 patent was the subject of IPR2017-01227 and IPR2017-
`01230, filed by a different Petitioner, Celltrion Inc., on March 31, 2017. The
`Board denied institution of these petitions on October 12, 2017 (IPR2017-
`01230) and October 23, 2017 (IPR2017-01230).
`Concurrently with this proceeding, Petitioner also filed a petition for
`inter partes review of U.S. Patent No. 8,206,711 (IPR2017-02127), which is
`
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`Case IPR2017-02126
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`related to the ’612 patent. Celltrion also filed a petition for inter partes
`review of the ’711 patent, IPR2017-01229, on March 31, 2017. The Board
`denied institution of that petition on October 23, 2017.
`The ’612 Patent (Ex. 1001)
`B.
`The ’612 patent discloses therapeutic regimens involving the
`administration of anti-CD20 antibodies for the treatment of chronic
`lymphocytic leukemia (CLL). Ex. 1001, Abst., 2:16–21. “[A] particularly
`preferred chimeric anti-CD20 antibody is RITUXAN® (rituximab), which is
`a chimeric gamma 1 anti-human CD20 antibody.” Id. at 3:18–20.
`With regard to dosing, the ’612 patent discloses that “[t]ypically
`effective dosages will range from about 0.001 to about 30 mg/kg body
`weight, more preferably from about 0.01 to 25 mg/kg body weight, and most
`preferably from about 0.1 to about 20 mg/kg body weight.” Id. at 3:50–54.
`“Such administration may be effected by various protocols, e.g., weekly, bi-
`weekly, or monthly, dependent on the dosage administered and patient
`response.” Id. at 3:55–57. “A particularly preferred dosage regimen will
`comprise administration of about 375 mg/m2 weekly for a total of four
`infusions.” Id. at 3:64–66.
`Illustrative Claims
`C.
`Petitioner challenges claims 1–13, 15–35, and 37–60 of the ’612
`patent. Independent claims 1, 6, 23, 28, and 58 are illustrative of the
`challenged claims and are reproduced below:
`1. A method of treating chronic lymphocytic leukemia in a
`human patient, comprising administering an anti-CD20 antibody
`to the patient in an amount effective to treat the chronic
`lymphocytic leukemia, wherein the method does not include
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`treatment with a radiolabeled anti-CD20 antibody.
`
`6. A method of treating chronic lymphocytic leukemia in a
`human patient, comprising administering an anti-CD20 antibody
`to the patient in an amount effective to treat the chronic
`lymphocytic leukemia, wherein the anti-CD20 antibody is
`administered to the patient at a dosage of about 500 to about 1500
`mg/m2, wherein the method does not include treatment with a
`radiolabeled anti-CD20 antibody.
`
`23. A method of treating chronic lymphocytic leukemia in a
`human patient, comprising administering an anti-CD20 antibody
`to the patient in an amount effective to treat the chronic
`lymphocytic leukemia, wherein the anti-CD20 antibody therapy
`is combined with chemotherapy, wherein the method does not
`include treatment with a radiolabeled anti-CD20 antibody.
`
`28. A method of treating chronic lymphocytic leukemia in a
`human patient, comprising administering an anti-CD20 antibody
`to the patient in an amount effective to treat the chronic
`lymphocytic leukemia, wherein the anti-CD20 antibody is
`administered to the patient at a dosage of about 500 to about 1500
`mg/m2, wherein the anti-CD20 antibody therapy is combined
`with chemotherapy, and wherein the method does not include
`treatment with a radiolabeled anti-CD20 antibody.
`
`58. A method of treating chronic lymphocytic leukemia in a
`human patient, comprising administering an anti-CD20 antibody
`to the patient in an amount effective to treat the chronic
`lymphocytic leukemia, wherein the patient is refractory to
`fludarabine previously administered for the chronic lymphocytic
`leukemia, and wherein the method does not include treatment
`with a radiolabeled anti-CD20 antibody.
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`1
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`2
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`3
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`The Asserted Grounds
`D.
`Petitioner challenges claims 1–13, 15–35, and 37–60 of the ’612
`patent on the following grounds. Pet. 30–62.
`Ground
`Reference[s]
`Maloney 1994,1 Maloney Sept.
`19972 and Genentech Press
`Release3
`Maloney 1994, Maloney Sept.
`1997, Maloney Oct. 19974 and
`Genentech Press Release
`Maloney 1994, Maloney Sept.
`1997, Maloney Oct. 1997,
`Genentech Press Release and
`Kipps5
`
`46–57
`
`Basis Challenged Claims
`
`§ 103
`
`1–13, 15–22, 58, 60
`
`§ 103
`
`23–35, 37–45, 59
`
`§ 103
`
`
`1 Ex. 1003, David G. Maloney et al., Phase I Clinical Trial Using Escalating
`Single-Dose Infusion of Chimeric Anti-CD20 Monoclonal Antibody (IDEC-
`C2B8) in Patients with Recurrent B-Cell Lymphoma, 84(8) BLOOD 2457-
`2466 (Oct. 15, 1994) (“Maloney 1994”).
`2 Ex. 1004, David G. Maloney et al., “IDEC-C2B8 (Rituximab) Anti-CD20
`Monoclonal Antibody Therapy in Patients with Relapsed Low-Grade Non-
`Hodgkin’s Lymphoma,” BLOOD, 90(6):2188–2195 (1997) (“Maloney Sept.
`1997”).
`3 Ex. 1005, David G. Maloney et al., “IDEC-C2B8: Results of a Phase I
`Multiple-Dose Trial in Patients with Relapsed Non-Hodgkin’s Lymphoma,”
`15(10) J. CLINICAL ONCOLOGY 3266–3274 (1997) (“Maloney Oct. 1997”).
`4 Ex. 1006, Press Release, Genentech, Inc. “Genentech and IDEC
`Pharmaceuticals to Collaborate on Anti-CD20 Monoclonal Antibody for B-
`Cell Lymphomas,” (March 16, 1995) (“Genentech Press Release”).
`5 Ex. 1008, Thomas J. Kipps, Chapter 106: Chronic lymphocytic leukemia
`and related diseases, in Williams Hematology Fifth Edition, 1017–1039
`(Ernest Beutler et al., eds., 1995) (“Kipps”).
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`Petitioner supports its challenge with the Declaration of Howard Ozer,
`M.D., Ph.D. (Ex. 1002).
`
`II. ANALYSIS
`Claim Interpretation
`A.
`We interpret claims using the “broadest reasonable construction in
`light of the specification of the patent in which [they] appear[].” 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs. LLC v. Lee, 136 S. Ct. 2131, 2144–46
`(2016). Under the broadest reasonable construction standard, claim terms
`are generally given their “ordinary and customary meaning,” as would be
`understood by one of ordinary skill in the art at the time of the invention. In
`re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007) (quoting
`Phillips v. AWH Corp, 415 F.3d 1303, 1313 (Fed. Cir. 2005)).
`We determine that no explicit construction of any claim term is
`necessary to determine whether to institute a trial in this case. See Nidec
`Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd., 868 F.3d 1013,
`1017 (Fed. Cir. 2017) (“[W]e need only construe terms ‘that are in
`controversy, and only to the extent necessary to resolve the controversy.’”
`(quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
`(Fed. Cir. 1999))).
`References Relied Upon
`B.
`1. Maloney 1994
`Maloney 1994 describes a phase I clinical trial dose escalation study
`to ascertain the toxicity of rituximab in human patients. Ex. 1003, 3.
`Patients with relapsed low-grade B-cell non-Hodgkin’s lymphoma,
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`including one small lymphocytic lymphoma (“SLL”) patient, received a
`single intravenous infusion of up to 500 mg/m2 rituximab.6 Id. at 5–6. All
`tested doses were well-tolerated, including the 500 mg/m2 dose, and “no
`dose-limiting toxicities were identified,” though some infusion-related side
`effects were observed. Id. at 9. Maloney 1994 reports that “[t]here was a
`does-dependent, rapid, and specific depletion of the B cells in all patients,
`especially those receiving doses of more than 100 mg.” Id. at 6. Maloney
`1994 goes on to suggest that “[e]xtension of these studies using multiple
`doses to achieve prolonged, tumor-saturating levels may lead to responses in
`patients with more extensive disease.” Id. at 11.
`In discussing treatment targets for NHL patients, Maloney 1994 states
`that, in contrast to other antigens, CD20 is “present on the surface of nearly
`all B cells” and, thus, “provides a more universal target for immunotherapy.”
`Ex. 1003, 3. For example, Maloney 1994 observes that “[m]ore than 90% of
`B-cell NHLs express this surface protein.” Id. With regard to CLL patients,
`however, Maloney 1994 notes that CD20 is “expressed at a lower density on
`B-cell chronic lymphocytic leukemia” than on B-cell NHLs. Id.
`2. Maloney Sept. 1997
`Maloney Sept. 1997 describes a “phase II, multicenter study
`evaluating four weekly infusions of 375 mg/m2 IDEC-C2B8 in patients with
`relapsed low-grade or follicular NHL.” Ex. 1004, 1. In that study, 17 of the
`37 patients enrolled exhibited clinical responses, i.e., partial or complete
`remission, to rituximab treatment. Id. at 5, Table 3.
`
`
`6 The SLL patient received a dose of 50 mg/m2. Ex. 1003, Table 1.
`7
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`Notably, however, “none of the 4 patients with small lymphocytic
`lymphoma (WF group A) responded.” Id. at 6; see also id. at 5. Maloney
`Sept. 1997 reasons that the absence of response in SLL patients may result
`from the decreased expression of CD20 on the B-cells of SLL patients
`relative to the B-cells of NHL patients. Id. at 6.
`Although patients with chronic lymphocytic leukemia (CLL)
`were excluded from this trial (based on the presence of >5,000
`lymphocytes/µL for this histologic subgroup), it is possible that
`the decreased response rate in this [SLL] subgroup was due to a
`lower expression of the CD20 surface antigen that has been
`observed in cases of CLL.
`Id. at 6.
`
`3. Maloney Oct. 1997
`Maloney Oct. 1997 describes a phase I trial to evaluate the safety,
`pharmacokinetics, and biologic effect of four weekly infusions of rituximab,
`administered in doses of 125 mg/m2 to 375 mg/m2, to patients with relapsed
`NHL. Ex. 1005, 3. Maloney Oct. 1997 reports a 33% rituximab response
`rate (partial remission) for patients who completed the study protocol, at
`each dose tested. Id. at Table 6. Notably, treatment was discontinued for
`two patients, including an SLL patient who experienced “[g]rade 4-related
`thrombocytopenia occurred within 24 hours of the first infusion” of
`rituximab. Id. at 6.
`In summarizing prior in vitro work, Maloney Oct. 1997 reports that
`rituximab “increases sensitivity to the cytotoxic effect of
`chemotherapy/toxins in some resistant human lymphoma cell lines.”
`Ex. 1005, 3–4.
`
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`4. Genentech Press Release
`The Genentech Press Release discloses that “IDEC-C2B8 is being
`developed for certain lymphomas and leukemias characterized by excessive
`B-cell proliferation, including low grade and follicular non-Hodgkin’s B-cell
`lymphomas.” Ex. 1006, 1. The Genentech Press Release goes on to explain:
`Phase II studies of IDEC-C2B8 in NHL reveal encouraging
`results indicating that it may provide an effective and
`well-tolerated treatment. IDEC, in cooperation with Genentech,
`will conduct a Phase III trial scheduled to begin by mid-1995 to
`attempt to confirm these results. Genentech and IDEC are
`planning additional studies with IDEC-C2B8 to support this
`primary indication in NHL and in other B-cell mediated cancers
`such as intermediate grade NHL and chronic lymphocytic
`leukemia.
`
`Id.7
`
`5. Kipps
`Kipps is a textbook reference, which discloses the use of
`chlorambucil, cyclophosphamide, COP, CHOP, fludarabine, and cisplatin to
`treat CLL. Ex. 1008, 34–36.
`
`
`7 Because we determine that Petitioner has not established a reasonable
`likelihood of prevailing on its assertion that an ordinarily skilled artisan
`would have had a reasonable expectation of success in combining the cited
`references to arrive at the claimed invention, we need not address whether
`Petitioner has sufficiently established that the Genentech Press Release
`qualifies as a printed publication. Nevertheless, we highlight, as Patent
`Owners point out, that Petitioner failed to submit a declaration from the
`Internet Archive attesting to the date the Genentech Press Release was
`captured by the Way Back Machine (Prelim. Resp. 17–18).
`9
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`C.
`
`Challenges Based on the Combination of Maloney 1994,
`Maloney Sept. 1997, and Genentech Press Release
`On the record before us, and for purposes of this decision, we agree
`with Patent Owners that Petitioner has not met its burden to establish a
`reasonable likelihood of success that it would prevail in showing that an
`ordinarily skilled artisan would have had a reasonable expectation of success
`in using any dosage of rituximab to treat CLL. Rather, as explained below,
`although the evidence of record suggests a rationale for exploring the
`possibility of treating CLL with rituximab, such suggestion amounts to no
`more than an invitation to experiment, and is, therefore, inadequate to
`establish a reasonable expectation of success in CLL treatment for purposes
`of this decision.
`1. Reasonable expectation of success
`“An obviousness determination requires finding both ‘that a skilled
`artisan would have been motivated to combine the teachings of the prior art
`references to achieve the claimed invention, and that the skilled artisan
`would have had a reasonable expectation of success in doing so.’” CRFD
`Research, Inc. v. Matal, 876 F.3d 1330, 1340 (Fed. Cir. 2017) (quoting
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367–
`1368 (Fed. Cir. 2016)).
`“The reasonable expectation of success requirement refers to the
`likelihood of success in combining references to meet the limitations of the
`claimed invention.” Intelligent Bio-Sys. 821 F.3d at 1367. A reasonable
`expectation of success “does not require a certainty of success.” Medichem,
`S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006).
`
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`However, to have a reasonable expectation of success, one must
`be motivated to do more than merely to vary all parameters or try
`each of numerous possible choices until one possibly arrived at
`a successful result, where the prior art gave either no indication
`of which parameters were critical or no direction as to which of
`many possible choices is likely to be successful. Similarly, prior
`art fails to provide the requisite reasonable expectation of success
`where it teaches merely to pursue a general approach that seemed
`to be a promising field of experimentation, where the prior art
`gave only general guidance as to the particular form of the
`claimed invention or how to achieve it.
`Id. (internal quotations omitted).
`Each of the three grounds of unpatentability presented by Petitioner
`relies on the same arguments concerning the existence of a reasonable
`expectation of success in treating CLL with rituximab. Pet. 32–53. Namely,
`Petitioner contends that Maloney 1994, Maloney (Sept.) 1997, and the
`Genentech Press Release would have provided an ordinarily skilled artisan
`with a reasonable expectation of success for methods of using rituximab to
`treat CLL patients at the claimed doses. Id. at 33–34, 49.
`As Petitioner acknowledges, NHL and CLL are different cancers.
`Pet. 9 (“[L]ike NHL, another type of cancer, CLL patients experience the
`uncontrollable growth of the body’s B-cells.”). Indeed, Petitioner highlights
`two important differences between CLL and NHL that would have been
`known to an ordinarily skilled artisan at the time of invention of the ’612
`patent, and would have influenced such an artisan’s expectation of success
`in applying an NHL therapy to treat CLL. First, “generally speaking, CLL
`patients have a higher tumor burden” (Pet. 10), with “about 100 times more
`cancerous B-cells than NHL patients” (id.; see also Ex. 1002 ¶ 33). Second,
`CD20, the antigen to which rituximab binds, is expressed at a lower density
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`on CLL B-cells than on NHL B-cells or normal B-cells. Pet. 42 (citing
`Ex. 1002 ¶ 48); see also Ex. 2003, 1, 5. “[T]he weaker density of CD20 [in
`CLL] is akin to having a smaller ‘target’ for rituximab to hit, making it less
`likely that any given unit of rituximab successfully binds to the CD20
`antigen.” Pet. 39 (citing Ex. 1002 ¶ 77). Taken together, these
`characteristics of CLL mean that a CLL patient has 100-fold more cancerous
`B-cells than an NHL patient, and rituximab is significantly less likely to bind
`to any one of those cancerous CLL B-cells than it would be to bind an NHL
`B-cell.
`Despite the acknowledged differences in tumor burden and rituximab
`antigen expression between CLL B-cells and NHL B-cells, none of the
`references on which Petitioner relies describes studies of, or treatment
`parameters for, the use of rituximab to treat CLL. Nor do those studies
`discuss the specifics of how rituximab treatment might be modified to
`address the characteristics of CLL. Rather, the cited rituximab references
`simply disclose studies employing rituximab to treat NHL. Indeed, the
`rituximab trial described in Maloney Sept. 1997 expressly excludes CLL
`patients, based on their high tumor burden relative to NHL patients.
`Ex. 1004, 6 (“patients with chronic lymphocytic leukemia (CLL) were
`excluded from this trial (based on the presence of >5,000 lymphocytes/µL
`for this histologic subgroup)”). Furthermore, when the four SLL patients
`who took part in the Maloney Sept. 1997 study failed to respond to
`rituximab treatment, the investigators reasoned that “it is possible that the
`decreased response rate in this [SLL] subgroup was due to a lower
`expression of the CD20 surface antigen that has been observed in cases of
`
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`CLL.” Ex. 1004, 6. Similarly, in the Maloney Oct. 1997 study, rituximab
`treatment was discontinued for an SLL patient who experienced grade 4
`thrombocytopenia subsequent to rituximab infusion. Ex. 1005, 6.
`The paucity of record evidence concerning clinical trials of rituximab
`in CLL patients, or other results from, or treatment parameters for, studies of
`rituximab in CLL is consistent with the evidence before us suggesting that
`no such studies had been performed in the relevant time frame.8 For
`example, Jensen,9 confirms that as of mid-1998, the “[e]fficacy and safety in
`the treatment of chronic lymphocytic leukemia (CLL) and other blood-born
`tumors [with rituximab] ha[d] not been investigated.” Ex. 1009, 1.
`Nevertheless, Petitioner asserts that “Maloney 1994 suggested that
`anti-CD20 antibodies (e.g., rituximab) could be useful therapies for both
`NHL and CLL cancers, because both diseases manifested in CD20-positive
`B-cells.” Id. at 32. Petitioner also contends that an ordinarily skilled artisan
`would have had a reasonable expectation of success in using rituximab to
`treat CLL based on the Genentech Press Release’s “reporting on Patent
`Owners’ further development of rituximab to treat patients with CLL.” Id.
`at 33.
`
`
`8 Petitioner states “The earliest priority date to which the claims of the ’612
`patent is entitled is the filing date of the ’658 provisional patent
`application—i.e., November 9, 1998.” Pet. 20–21.
`
` M. Jensen et al., Rapid Tumor Lysis in a Patient with B-cell Chronic
`Lymphocytic Leukemia and Lymphocytosis Treated with an Anti-CD20
`Monoclonal Antibody (IDEC-C2B8, Rituximab), 77 ANN. HEMATOLOGY 89–
`91 (1998) (Ex. 1009) (“Jensen”).
`
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`Consistent with the discussion of the record evidence above, however,
`neither Maloney 1994 nor the Genentech Press Release reports any study
`results, clinical endpoints, treatment parameters, or other information
`relating to how one would treat CLL with rituximab, or why one would
`reasonably expect such treatment to be successful in view of the higher
`tumor burden and lower expression of CD20 observed in CLL relative to
`NHL. Ex. 1004, 6; Ex. 1005, 7; Ex. 1023 ¶ 14; Ex. 1002 ¶ 101; Ex. 1033 ¶¶
`22–24 (stating that that higher tumor burden “serves in part to distinguish
`CLL from small lymphocytic lymphoma,” that “CLL and NHL also
`typically affect different patient populations,” and that “[c]linicians approach
`CLL and NHL with different expectations for therapy and different
`treatment plans.”). Maloney 1994, at best, indicates that CD20 is a “more
`universal target for immunotherapy” than patient-specific anti-idiotype
`monoclonal antibodies (Ex. 1003, 3), and that rituximab treatment warrants
`further study in “patients with more extensive disease” (id. at 11).
`Maloney 1994 does not, however, disclose any study of rituximab in
`CLL patients, or teach any treatment parameters for using rituximab in CLL
`patients. In fact, the only explicit discussion of CLL in Maloney 1994 is the
`disclosure that CD20, the target for rituximab, is “expressed at a lower
`density on B-cell chronic lymphocytic leukemia.” Id. at 3. Thus, to the
`extent Maloney 1994 suggests anything at all regarding CLL treatment, it is
`that there is a lower probability that rituximab would be useful to treat CLL
`than NHL, because CLL cancer cells are a smaller target that is more
`difficult for rituximab to hit.
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`Moreover, although Maloney 1994 states that LG-NHL patients
`treated with rituximab in doses of 10 mg/m2 up to 500 mg/m2 exhibited a
`“dose-dependent, rapid, and specific depletion of the B cells” (Ex. 1003, 6),
`that reference does not report a positive “maximal response” result for the
`sole SLL patient enrolled in the study (id. at Table 1).10 Nor does it discuss
`any particulars as to how the trial results, or rituximab treatment more
`broadly, might be applied in the context of CLL. Accordingly, at most,
`Maloney 1994 might be said to encourage investigation of using rituximab
`to treat CLL; it does not provide, however, any reasonable expectation of
`success in such treatment.
`Akin to Maloney 1994, the Genentech Press Release is devoid of any
`study results or parameters for the treatment of CLL. Furthermore, the
`Genentech Press Release does not, as Petitioner suggests, disclose “that
`Patent Owners were conducting rituximab clinical trials with CLL patients”
`(Pet. 33). Ex. 1006, 1–2. Rather, the rituximab clinical trials discussed in
`the press release relate exclusively to the treatment of NHL patients. Id.
`at 1. With regard to CLL, the Genentech Press Release indicates only that
`rituximab “is being developed for certain lymphomas and leukemias
`characterized by excessive B-cell proliferation” (Ex. 1006, 1), and that
`“Genentech and IDEC are planning additional studies with IDEC-C2B8 to
`support this primary indication in NHL and in other B-cell mediated cancers
`such as intermediate grade NHL and chronic lymphocytic leukemia” (id.).
`
`
`10 As explained above with regard to Maloney Sept. 1997, SLL B-cells, like
`CLL B-cells, express CD20 at lower levels that NHL B-cells. See, e.g.,
`Ex. 2003, 4.
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`Thus, although we agree with Petitioner that the Genentech Press Release
`invites investigation of what “seem[s] to be a promising field of
`experimentation,” we nevertheless find that the press release provides “only
`general guidance as to the particular form of the claimed invention or how to
`achieve it.” Medichem, 437 F.3d at 1165. The Genentech Press Release is,
`therefore, insufficient to establish a reasonable expectation of success in
`treating CLL with rituximab for purposes of this decision.
`Furthermore, because Maloney 1994 and the Genentech Press Release
`suffer from the same shortcomings, namely, an absence of any meaningful
`disclosure concerning studies of, or parameters for, treating CLL with
`rituximab, those references together also would have failed to supply an
`ordinarily skilled artisan with a reasonable expectation of success in arriving
`at the claimed invention.
`We also find unavailing Petitioner’s reliance on law pertaining to the
`utility requirement set forth in 35 U.S.C. § 101, to support the proposition
`that the purported initiation of clinical trials by Genentech warrants a
`presumption “that the subject matter of that trial is reasonably predictive of
`having the asserted therapeutic utility” (Pet. 33–34 (quoting Eli Lilly & Co.
`v. Teva Pharm. USA, Inc., 619 F.3d 1329, 1343 (Fed. Cir. 2010) (quoting
`MPEP § 2107.03 at IV(2008)))). As explained above, Petitioner has not
`adequately established, for purposes of this decision, that Patent Owners had
`initiated clinical trials of rituximab in human CLL patients. By Petitioner’s
`own logic, it would at best be entitled to a presumption that rituximab is
`useful to treat NHL, but not CLL. Moreover, Petitioner does not identify
`any authority or provide a persuasive rationale for employing a § 101 utility
`
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`Case IPR2017-02126
`Patent 7,682,612 B1
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`analysis to satisfy the § 103 requirement for a reasonable expectation of
`success.
`Neither are we persuaded by Petitioner’s reference to Soft Gel
`Technologies., Inc., v. Jarrow Formulas, Inc., 864 F.3d 1334 (Fed.
`Cir. 2017), in which our reviewing court rejected the argument that the
`performance of confirmatory or follow-up studies evinces the absence of any
`reasonable expectation of success in arriving at the invention claimed
`(Pet. 34). The court’s determination in Soft Gel that “[a]n incentive to
`conduct a confirmatory study frequently exists even when one has every
`reason to expect success,” 864 F.3d at 1342, is inapposite here, as Petitioner
`has not adequately established, for purposes of this decision, that any study
`of rituximab treatment in CLL patients had been performed prior to the
`invention of the ’612 patent, much less a confirmatory study.
`Similarly, Petitioner’s resort to the Board’s finding in Biomarin
`Pharmaceutical. Inc., v. Genzyme Therapeutic Products Ltd. Partnership,
`Case IPR2013-00534, Paper 81, at 17 (PTAB Feb. 23, 2015)) (Pet. 34),
`serves to underscore what is lacking from the instant Petition. In Biomarin,
`the Board explained that an ordinarily skilled artisan would have had a
`reasonable expectation of success when “[w]hat remained was the execution
`of human clinical trials, arguably ‘routine’ to a person of ordinary skill in the
`art, to verify the expectation that a specific dosage (within a previously
`suggested dosage range) and corresponding dosage regimen would have
`been safe and effective.” Biomarin, IPR2013-00534, Paper 81, at 17. Here,
`the prior art fails to provide guidance concerning clinical endpoints,
`treatment parameters, or other information relating to how one would treat
`
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`Case IPR2017-02126
`Patent 7,682,612 B1
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`CLL with rituximab, or why one would reasonably expect such treatment to
`be successful, but instead invites experimentation to determine whether
`rituximab may in fact treat CLL.
`2. Dosage limitations
`With regard to the recited dosages of rituximab, Petitioner contends
`that Maloney 1994 reference discloses doses ranging from 10 mg/m2 to 500
`mg/m2 were safe and achieved a “dose-dependent, rapid, and specific
`depletion of the B cells in all patients.” Pet. 37 (citing Ex. 1003, 6).
`Petitioner further contends as follows:
`Maloney 1994 taught that the amount of B-cell depletion was
`“dose-dependent,” meaning the greater the dose, the greater the
`effect. Ex. 1003, 6. Maloney (Sept.) 1997 taught that 375 mg/m2
`was the dose of choice for treating NHL patients. Ex. 1004, 2.
`The teachings from these two references, when combined with
`the knowledge of a [person of ordinary skill in the art] that CLL
`patients had approximately 100 times more tumor cells than
`NHL patients, suggested that a higher rituximab dose likely
`would be needed to treat CLL. Ex. 1002 ¶ 75; compare Ex. 1008,
`Kipps at 28 (CLL defined as more than 10,000 lymphocytes/μl),
`with Ex. 1012, McLaughlin at 7–8 & Fig 3 (low-grade NHL
`patients had average of about 100 lymphocytes/μl).
`The only dose above 375 mg/m2 disclosed as safe and
`effective in Maloney was 500 mg/m2. That claimed dose,
`therefore, would have been obvious for use in CLL patients. Ex.
`1002 ¶ 86.
`Id. at 38.
`In view of the 100-fold increase in tumor burden and significant
`decrease in CD20 expression observed in CLL relative to NHL, however, we
`are unpersuaded by Petitioner’s contention that an ordinarily skilled artisan
`would have had a reasonable expectation of success in administering
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`Case IPR2017-02126
`Patent 7,682,612 B1
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`rituximab in a dose of 500 mg/m2 to treat CLL. Even accepting Petitioner’s
`contention that Maloney 1994 and Maloney Sept. 1997 taught the
`administration of rituximab in a dose of 500 mg/m2 to treat NHL (id.),
`Petitioner does not adequately explain why, given the 100-fold increase in
`tumor burden and significant decrease in CD20 expression observed in CLL
`relative to NHL, an ordinarily skilled artisan would have expected a
`rituximab dose of 500 mg/m2 to treat CLL. Rather, Petitioner assumes that
`an ordinarily skilled artisan would have considered the dose-dependent
`depletion of B-cells in NHL patients to be predictive of B-cell depletion in
`CLL patients, but does not endeavor to justify that assumption, or explain
`why an ordinarily skilled artisan would reasonably expect that increasing the
`rituximab dose effective to treat NHL by about a third (from 375 mg/m2 to
`500 mg/m2) would treat a disease with 100-fold more cancerous B-cells to
`which rituximab is less likely to bind. For example, Petitioner’s statement
`that these differences between CLL and NHL would have “suggested that a
`higher rituximab dose likely would be needed to treat CLL” (id.) is
`insufficient to support the contention that an ordinarily skilled artisan would
`have had a reasonable expectation of success in treating CLL with
`500 mg/m2 of rituximab. Petitioner’s assertion that it would have been
`obvious to use 500 mg/m2 of rituximab to treat CLL because that is the
`“only dose above 375 mg/m2 disclosed as safe and effective in Maloney
`[1994]” (id.) similarly misses the mark.11
`
`
`11 It is also factually incomplete, as Maloney 1994 does not identify any
`theoretical maximum dose for rituximab. To the contrary, Maloney 1994
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`Case IPR2017-02126
`Patent 7,682,612 B1
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`In addition, Petitioner’s reliance on the dictate that “where there is a
`range disclosed in the prior art, and the claimed invention falls within that
`range, there is a presumption of obviousness” (Pet. 38 (quoting Iron Grip
`Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 20
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