Thursday, March 23, 2017

Celltrion Files Three IPR Petitions Against Biogen's Rituximab Patents

             Last week Celltrion filed three IPR petitions against Biogen’s patents covering a method of treating lymphoma with rituximab, which is a chimeric anti-CD20 antibody:

Patent Number/IPR
Claim 1
8,557,244
IPR2017-01094
1. A method of treating a patient with diffuse large cell lymphoma, comprising administering an unlabeled chimeric anti-CD20 antibody and CHOP (cyclophosphamide, hydroxydaunorubicin/doxorubicin, vincristine, and prednisone/prednisolone) chemotherapy to the patient, wherein the patient is >60 years old and has bulky disease (tumor >10 cm in diameter).
8,329,172
IPR2017-01093
1. A method of treating low grade B-cell non-Hodgkin's lymphoma in a human patient comprising administering to the patient chemotherapy consisting of CVP therapy to which the patient responds, followed by rituximab maintenance therapy, wherein the maintenance therapy comprises four weekly administrations of rituximab at a dose of 375 mg/m.2 every 6 months, and wherein the maintenance therapy is provided for 2 years.
9,296,821
IPR2017-01095
1. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient a therapeutically effective amount of rituximab during a chemotherapeutic regimen, wherein the chemotherapeutic regimen consists of cyclophosphamide, vincristine, and prednisone (CVP therapy), wherein the method comprises administering 375 mg/m2 of rituximab, and wherein the method provides a beneficial synergistic effect in the patient.

8,329,172- IPR2017-01093

             Celltrion mainly relies on the following two prior art references in its petition: E1496 Patient Consent Form and E1496 Protocol.  E1496 is a specific clinical trial entitled “Randomized Phase III Study in Low Grade Lymphoma Comparing Cyclophosphamide/Fludarabine to Standard Therapy Followed by Maintenance Anti-CD20 Antibody.”  In IPR2015-00418, Boehringer attempted to rely on the E1496 Protocol as an anticipatory reference. In denying institution, the Board found that the petitioner had failed to show that the E1496 Protocol “was publicly accessible to the extent required to establish its status as a printed publication under either §311(b) or §102(b).” Celltrion argues that in contrast to Boehringer’s declarant in IPR2015-00418, Celltrion’s declarant (Dr. Walter Longo who enrolled patients in the ECOG 1496 study) “has specific, first-hand knowledge of the E1496 Protocol and Patient Consent Form and attests to the public accessibility of these documents beginning March 19, 1998.” 
GROUND 1
‘172 Claim 1
E1496 Patient Consent Form
A method of treating low grade B-cell non-Hodgkin’s lymphoma in a human patient
“It has been explained to you that you have a non-aggressive (low grade) lymphoma. You have been invited to participate in this study. This study involves treatment with one or two chemotherapy programs for six to eight cycles followed by maintenance therapy with an immunologic modifier (monoclonal antibody) in half of the patients.)”
comprising administering to the patient chemotherapy consisting of CVP therapy to which the patient responds,
“If you are assigned to the standard chemotherapy arm, CVP, you will receive cyclosphosphamide . . . and vincristine . . . and prednisone . . . These chemotherapy programs will be given for six to eight cycles depending on how quickly your tumor regresses. If your tumor remains the same or regresses with the chemotherapy you will then be assigned randomly to treatment with the monoclonal antibody, IDEC C2B8 (anti-CD20 antibody) or no maintenance therapy.”
followed by rituximab maintenance therapy,
“If your tumor remains the same or  regresses with the chemotherapy you will then be assigned randomly to treatment with the monoclonal antibody, IDEC C2B8 (anti-CD20 antibody), or no maintenance therapy.”
wherein the maintenance therapy comprises four weekly administrations of rituximab at a dose of 375 mg/m2 every 6 months, and wherein the maintenance therapy is provided for 2 years.
“The group receiving the antibody will
receive 375 mg/m2 of antibody weekly
for 4 weeks every 6 months for two
years. . . .” 

GROUND 2
‘172 Claim 1
E1496 Protocol 
A method of treating low grade B-cell non-Hodgkin’s lymphoma in a human patient
“Eastern Cooperative Oncology Group[:] Randomized Phase III Study in Low Grade Lymphoma Comparing
Cyclophosphamide/Fludarabine to Standard Therapy Followed by Maintenance Anti-CD20 Antibody”

“Selection of Patients . . . [n]o prior
chemotherapy, radiotherapy, or
immunotherapy.” (Ex. 1009 at 007-08.)
comprising administering to the patient chemotherapy consisting of CVP therapy to which the patient responds,
“Patients randomized [in first randomization to treatment regimen B] (standard therapy) will receive cyclophosphamide 1000 mg/m2 . . ., vincristine 1.4 mg/m2 . . . and prednisone 100 mg/m2 . . . . Cycles will be repeated q 21 days.
. . .
All patients who have not progressed on induction chemotherapy will be randomized to either maintenance
therapy with chimeric anti-CD20 antibody or observation.”
followed by rituximab maintenance therapy,
“Patients randomized [in second randomization to treatment regimen C] will receive Anti-CD20 . . . .”
wherein the maintenance therapy comprises four weekly administrations of rituximab at a dose of 375 mg/m2
every 6 months, and wherein the maintenance therapy is provided for 2 years
“at a dose of 375 mg/m2 weekly x 4 every 6 months for a total of 2 years beginning 4 weeks after the last
chemotherapy” 

9,296,821 – IPR2017-01095
Patent Number
Claim 1
9,296,821
1. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient a therapeutically effective amount of rituximab during a chemotherapeutic regimen, wherein the chemotherapeutic regimen consists of cyclophosphamide, vincristine, and prednisone (CVP therapy), wherein the method comprises administering 375 mg/m2 of rituximab, and wherein the method provides a beneficial synergistic effect in the patient.

                For the ‘821 Patent, Celltrion’s main prior art reference is Marcus, which is a publication describing the results of a clinical trial comparing CVP with CVP plus rituximab in previously untreated patients with advanced follicular lymphoma. Patients assigned to the rituximab- CVP arm received 375 mg/m2 of rituximab every three weeks for eight total doses.  Marcus discloses that patients who received CVP plus rituximab demonstrated “major improvement in all clinical endpoints.”   Celltrion further argues that Marcus inherently discloses rituximab’s amino acid sequence, since “under the doctrine of inherent disclosure, a reference that describes an invention with “certain undisclosed yet inherent properties” is deemed to inherently disclose the invention’s inherent properties.”  As a back-up, Celltrion argues obviousness in view of the combination of Marcus and US Patent  5,736,137, which teaches the sequence of rituximab. 

Ground 1
’821 Claim
Marcus
A method for treating low grade or follicular non-Hodgkin’s lymphoma (NHL)
“Eligible patients were 18 years or older with untreated CD20+ follicular lymphoma”
comprising administering to a patient a therapeutically effective amount of rituximab during a chemotherapeutic regimen, wherein the chemotherapeutic regimen consists of cyclophosphamide, vincristine, and prednisone (CVP therapy),
“Patients . . . [treated] with CVP plus
rituximab (R-CVP) or CVP alone.”
(Id.)
wherein the method comprises administering 375 mg/m2 of rituximab,
“Patients treated with R-CVP also received 375 mg/m2 of rituximab intravenously on day 1 of each therapy cycle.”
and wherein the method provides a beneficial synergistic effect in the patient.
“Treatment with R-CVP significantly lengthened [time to treatment failure]. . . the addition of rituximab to CVP reduced the risk of experiencing disease progression across all patient subgroups . . . compared with CVP.”


8,557,244-IPR2017-01094
Patent Number
Claim 1
8,557,244
1. A method of treating a patient with diffuse large cell lymphoma, comprising administering an unlabeled chimeric anti-CD20 antibody and CHOP (cyclophosphamide, hydroxydaunorubicin/doxorubicin, vincristine, and prednisone/prednisolone) chemotherapy to the patient, wherein the patient is >60 years old and has bulky disease (tumor >10 cm in diameter).

            For the ‘244 Patent, Celltrion does not have an anticipatory reference and relies on obviousness based on the combination of three separate references: Link, McNeil, and “The FDA Transcript.”  Link describes a study investigating the safety and efficacy of rituximab.  Patients enrolled in this trial received rituximab 375 mg/m2 on day 1 of each 21 day cycle followed 48 hours later by CHOP.   McNeil discusses the ongoing E4494 clinical trial investigating the combination of rituximab and CHOP in 630 elderly (60+ years old) patients with intermediate-grade lymphoma.  According to Celltrion, McNeil teaches the use of rituximab and CHOP in combination to treat elderly patients with intermediate grade NHL. The FDA Transcript is a transcript of the July 25, 1997 public proceedings before the FDA’s Biological Response Modifiers Advisory Committee, in which Dr. Grillo-López stated: “Suffice it to say that we do have some preliminary data from the separate study that we conducted including patients with lesions greater than 10 cm and that preliminary data . . . shows a 48% response rate.”

         The Patent Trial and Appeal Board has not yet made a decision on these three petitions

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