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` Paper 8
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` Entered: September 27, 2018
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`Trials@uspto.gov
`571-272-7822
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`APOTEX INC. and APOTEX CORP.,
`Petitioners,
`
`v.
`
`CELGENE CORPORATION,
`Patent Owner.
`
`
`Case IPR2018-00685
`Patent 8,741,929 B2
`
`
`
`Before TONI R. SCHEINER, GRACE KARAFFA OBERMANN, and
`TINA E. HULSE, Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 U.S.C. § 314(a)
`
`
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`IPR2018-00685
`Patent 8,741,929 B2
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`I. INTRODUCTION
`Apotex Inc. and Apotex Corp. (collectively, “Petitioner”)1 filed a
`Petition (Paper 2, “Pet.”) requesting an inter partes review of claims 1–4, 8,
`9, 15, and 20 of U.S. Patent No. 8,741,929 B2 (Ex. 1001, “the ’929 patent”).
`Celgene Corporation (“Patent Owner”) filed a Preliminary Response to the
`Petition (Paper 6, “Prelim. Resp.”). We have statutory authority under
`35 U.S.C. § 314, which provides that an inter partes review may not be
`instituted “unless . . . there is a reasonable likelihood that the petitioner
`would prevail with respect to at least 1 of the claims challenged in the
`petition.”
`For the reasons set forth below, we conclude that Petitioner has not
`established a reasonable likelihood that it would prevail in showing the
`unpatentability of any challenged claim of the ’929 patent. Accordingly, we
`do not institute an inter partes review of claims 1–4, 8, 9, 15, and 20 of
`the ’929 patent.
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`A. Related Proceedings
`The ’929 patent has been asserted in Celgene Corp. v. Apotex Inc.,
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`C.A. No. 18-cv-00461 (D.N.J. filed Jan. 11, 2018). Pet. 5; Paper 3, 1.
`
` B. The Asserted Grounds of Unpatentability
`Petitioner asserts that the challenged claims are unpatentable on the
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`following grounds:
`
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`1 According to Petitioner, “[a]dditional real parties-in-interest are Apotex
`Pharmaceutical Holdings Inc., and Apotex Holdings Inc.” Pet. 5.
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`Patent 8,741,929 B2
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`References
`
`Basis
`
`Claims Challenged
`
`Drach2 and Zeldis3
`Drach, Zeldis, and Querfeld4
`Celgene Press Release5
`
`§ 103(a) 1–4, 8, 9, 15, and 20
`§ 103(a) 4 and 20
`§ 102(a) 1–4, 8, 9, 15, and 20
`
`Petitioner supports its challenges with the Declaration of Michael J.
`Thirman, M.D, dated February 23, 2018 (Ex. 1002, “Thirman Declaration”).
`
`C. The ’929 Patent (Ex. 1001)
`
`The ’929 patent, titled “Methods Using 3-(4-amino-1-oxo-1,3-
`dihydro-isoindol-2-yl)-piperidine-2,6-dione for Treatment of Mantle Cell
`Lymphomas,” issued June 3, 2014, to inventor Jerome B. Zeldis. Ex. 1001
`(54), (75). The title compound is “an immunomodulatory compound . . .
`also known as lenalidomide, Revlimid® or Revimid®.” Id. at 1:19–23.
`
`2 Johannes Drach at al., Treatment of Mantle Cell Lymphoma: Targeting the
`Microenvironment, 5 EXPERT REV. ANTICANCER THER. 477–485 (2005) (Ex.
`1003, “Drach”). We refer to the page numbers of the exhibit, rather than the
`page numbers of the journal article.
`3 Jerome B. Zeldis, U.S. Patent Application Publication US 2004/0029832
`A1, published February 12, 2004 (Ex. 1004, “Zeldis”).
`4 Christiane Querfeld et al., Preliminary Results of a Phase II Study of CC-
`5013 (Lenalidomide, Revlimid®) in Patients with Cutaneous T-Cell
`Lymphoma, 106 BLOOD 3351 (2005) (Ex. 1005, “Querfeld”).
`5 Celgene Press Release, titled “Revlimid® (Lenalidomide) Clinical Results
`in Non-Hodgkins Lymphoma Presented at the 11th Congress of the European
`Hematology Association” (2006) (Ex. 1006, “Celgene Press Release”).
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`The specification teaches that lymphomas comprise a heterogeneous
`group of neoplasms arising in the reticuloendothelial and lymphatic systems.
`Within that group, the term non-Hodgkin’s lymphoma (NHL) refers to a
`subset of neoplasms involving malignant monoclonal proliferation of
`lymphoid cells in the immune system, including the lymph nodes, bone
`marrow, spleen, liver, and gastrointestinal tract. Id. at 1:64–2:2. The
`specification further teaches that mantle cell lymphoma (MCL) is a
`lymphoproliferative disorder characterized by a specific chromosomal
`translocation which results in overexpression of the protein cyclin D1, which
`plays a key role in cell cycle regulation and progression of cells from G1
`phase to S phase by activation of cyclin-dependent kinases. Id. at 2:16–29.
`According to the specification, MCL “is a distinct entity among the
`non-Hodgkin’s lymphomas . . . account[ing] for 8% of all non-Hodgkin’s
`lymphomas” (id. at 2:4–5), and “is an incurable lymphoma with limited
`therapeutic options for patients with relapsed or refractory disease” (id.
`at 2:36–38).
`The specification describes the results of a Phase II clinical trial
`designed to evaluate the therapeutic potential and safety of oral lenalidomide
`monotherapy in patients with relapsed and refractory aggressive non-
`Hodgkin’s lymphoma. Id. at 23:12–20.
`Twenty-five patients age 45 to 80 years . . . with relapsed
`and refractory aggressive NHL and who had received a median
`of 2.5 prior treatments . . . were administered with lenalidomide
`in an amount of 25 mg orally once daily for 21 days in the
`treatment cycle. Sixteen patients with aggressive NHL were
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`evaluable for tumor assessment. Of the 16 patients, eight had
`diffuse large cell lymphoma, three had mantle cell lymphoma,
`two patients had follicular lymphoma, one had transformed
`lymphoma, and two had aggressive lymphomas of unknown
`histology.
`There were five (31 percent) patients who experienced
`objective responses to lenalidomide monotherapy . . . One
`patient with diffuse large cell lymphoma achieved complete
`response with progression free survival of more than 180 days.
`One patient with diffuse large cell lymphoma achieved partial
`response with progression free survival for 135 days. One
`patient with diffuse large cell lymphoma achieved partial
`response with progression free survival for 242 days. One
`patient with follicular lymphoma achieved partial response with
`progression free survival for more than 55 days. One patient
`with mantle cell lymphoma achieved partial response with
`progression free survival for more than 57 days.
`Id. at 23:24–48.
`Finally, the specification discloses “methods of treating, preventing or
`managing non-Hodgkin’s lymphomas, including . . . mantle cell lymphoma”
`(id. at 1:23–26), particularly disease that is “relapsed, refractory, or resistant
`to conventional chemotherapy” (id. at 2:47–48).
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`D. Illustrative Claim
`Petitioner challenges claims 1–4, 8, 9, and 20 of the ’929 patent, of
`which claim 1 is independent. Claim 1, reproduced below, is illustrative.
`Ex. 1001, 29:1–11.
`1. A method of treating mantle cell lymphoma in a human,
`which comprises (a) administering to a human having
`mantle cell lymphoma from about 5 mg to about 25 mg per
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`day of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-
`piperidine-2,6-dione or a pharmaceutically acceptable salt or
`hydrate thereof for 21 days followed by seven days rest in a
`28 day cycle; and (b) repeating step (a), wherein the mantle
`cell lymphoma is relapsed, refractory, or relapsed and
`refractory to conventional therapy.
`Ex. 1001, 23:63–24:4.
`
`II. ANALYSIS
`A. Claim Construction
`In an inter partes review, claim terms in an unexpired patent are given
`their broadest reasonable interpretation in light of the specification of the
`patent in which they appear. 37 C.F.R. § 42.100(b). Under this standard, we
`presume that a claim term carries its “ordinary and customary meaning,”
`which “is the meaning the term would have to a person of ordinary skill in
`the art in question” at the time of the invention. In re Translogic Tech., Inc.,
`504 F.3d 1249, 1257 (Fed. Cir. 2007); see also Trivascular, Inc. v. Samuels,
`812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under a broadest reasonable
`interpretation, words of the claim must be given their plain meaning, unless
`such meaning is inconsistent with the specification and prosecution
`history.”).
`According to Petitioner, “[t]he words of the claims at issue here
`should be given their plain meanings, because such a construction would be
`consistent with the specification and prosecution history.” Pet 14. Patent
`Owner “does not dispute Petitioners’ contention . . . that the claims do not
`require construction” at this stage of the proceeding. Prelim. Resp. 22. We
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`determine that no claim term requires express construction for purposes of
`deciding whether to institute a review in this case. See, e.g., Wellman, Inc.
`v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim
`terms need only be construed ‘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)).
`B. Level of Ordinary Skill in the Art
`Petitioner contends that a person of ordinary skill in the art “would
`
`have been a hematologist and/or oncologist, i.e., a medical doctor with
`hematology and/or oncology training, with several years of experience in
`treating blood cancers.” Pet. 7; Ex. 1002 ¶ 14. Patent Owner contends that
`“[t]he challenged claims each recite a method of treating MCL; accordingly,
`a POSA would be someone within Petitioners’ definition whose experience
`specifically included experience in treating MCL.” Prelim. Resp. 21.
`We adopt Petitioner’s definition for purposes of this decision, but note
`that our disposition of the case would not change under either definition.
`
`C. Overview of the Asserted Prior Art
`1. Zeldis (Ex. 1004)
`Zeldis discloses “methods of treating and preventing certain types of
`cancer, including primary and metastatic cancer, as well as cancers that are
`refractory or resistant to conventional chemotherapy” by administering an
`immunomodulatory compound. Ex. 1004 ¶ 17.
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`According to Zeldis, “the term ‘cancer’ includes, but is not limited to,
`solid tumors and blood born[e] tumors” (id. ¶ 107), for example, “Hodgkin’s
`lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma,
`cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, [and] low
`grade follicular lymphoma” (id.).
`Further according to Zeldis, the term “immunomodulatory
`compounds” refers to “small organic molecules that markedly inhibit
`TNF-α, LPS induced monocyte IL1β and IL12, and partially inhibit IL6
`production” (id. ¶ 31), and one of the “most preferred immunomodulatory
`compounds” is lenalidomide (Revimid) (id. ¶¶ 81, 82), a derivative or analog
`of thalidomide (id. ¶ 34).
`Zeldis teaches that in vitro studies demonstrate that lenalidomide “is
`similar to, but at least 200 times more potent than, thalidomide” with respect
`to “[i]nhibition of TNF-α production following LPS-stimulation of human
`PBMC and human whole blood.” Id. ¶ 219. In addition, “it has been shown
`that the compound is approximately 50–100 times more potent than
`thalidomide in stimulating the proliferation of T-cells following primary
`induction by T-cell receptor (TCR) activation” and lenalidomide “is also
`approximately 50 to 100 times more potent than thalidomide in augmenting
`the production of IL-2 and IFN-γ following TCR activation of PBMC (IL-2)
`or T-cells (IFN-γ).” Id. ¶ 220.
`Zeldis further describes several Phase I clinical studies designed to
`determine the maximum tolerated dose of lenalidomide in patients with
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`relapsed multiple myeloma (id. ¶¶ 238–243), malignant melanoma,
`carcinoma of the pancreas, renal carcinoma, breast carcinoma, non-small
`cell lung carcinoma, adrenal carcinoma, malignant mesothelioma (id.
`¶¶ 244–246), refractory solid tumors and/or lymphomas (id. ¶ 247).
`Additionally, 13 patients with metastatic melanoma were treated with
`escalating doses of lenalidomide (5 mg/day for 7 days, increasing every 7
`days to 10 mg/day, 25 mg/day, and 50 mg/day for a total of 4 weeks). Id.
`¶ 258. Five of the 13 melanoma patients showed either disease stabilization
`or a partial response, and the duration of response was approximately 6
`months. Id.
`Finally, Zeldis teaches that lenalidomide “may be administered in an
`amount of from about 5 to 25 mg per day” (id. ¶ 113), and may be
`administered in four week cycles—25 mg/day for 21 days, with 7 days rest
`before resuming the next cycle (id. ¶ 229).
`2. Drach (Ex. 1003)
`Drach teaches that “[m]antle cell lymphoma is a distinct entity among
`the non-Hodgkin’s lymphomas” (Ex. 1003, 6), with an “aggressive clinical
`course, and . . . belongs to the lymphomas with the worst prognosis” (id.).
`According to Drach, “recent observations suggest that . . . the tumor
`microenvironment is crucial for survival and/or proliferation of the
`malignant B-cell clone” in several forms of non-Hodgkin’s lymphomas,
`including follicular lymphoma and B-cell chronic lymphocytic leukemia. Id.
`at 8. Although “[s]tudies exploring interactions between MCL cells and
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`their microenvironment have not yet been performed” (id. at 9), Drach
`suggests that “observations from B-cell entities . . . as well as from multiple
`myeloma (MM), where targeting the tumor cell and its microenvironment
`represents a new treatment paradigm, provide the framework for also
`exploring this treatment concept in MCL” (id.).
`In that regard, Drach notes that “thalidomide has pleiotropic effects”
`(id. at 10), and “[s]ome direct effects on tumor cells, including the induction
`of apoptosis, have been observed, but it appears that the modulation of
`interactions between tumor cells and stromal cells are even more important”
`(id.). Drach teaches that “[t]halidomide and its analogs (e.g., lenalidomide)
`are therefore important agents for the new treatment paradigm of targeting
`both the tumor cell and its microenvironment (mainly by interference with
`tumor-stromal cell interactions).” Id. According to Drach:
`Thalidomide as an agent with antilymphoma properties
`was first described in two case reports describing objective
`remissions in three patients with relapsed and chemotherapy-
`refractory MCL[6, 7]. In these case studies, single-agent
`thalidomide was used at a daily dose of between 100 and 800
`mg, and induced [a partial response] with a duration of several
`months.
`
`
`6 Edward A. Wilson et al., Response to Thalidomide in Chemotherapy-
`Resistant Mantle Cell Lymphoma: a Case Report, 119 BRITISH JOURNAL OF
`HAEMATOLOGY 128–130 (2002) (Ex. 2008, “Wilson”).
`7 G. Damaj et al., Thalidomide Therapy Induces Response in Relapsed
`Mantle Cell Lymphoma, 17 LEUKEMIA 1914–1915 (2003) (Ex. 2009,
`“Damaj”).
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`Ex. 1003, 10.
`Drach describes a third study,8 where thalidomide in combination with
`rituximab was evaluated in patients with pretreated MCL, and 83%
`“experienced an objective response.” Id. Rituximab is an antibody with
`previously “documented efficacy in MCL.” Ex. 2010, 2.
`In addition, Drach teaches that the thalidomide analog, lenalidomide,
`“has been evaluated in relapsed MM and appears to have a far more
`favorable toxicity profile than thalidomide” (id.), and that “[c]linical trials of
`lenalidomide are also underway in various malignant diseases outside of
`myeloma, including myelodysplastic syndromes, malignant melanoma and
`refractory solid tumors and lymphomas” (id.).
`
`3. Querfeld (Ex. 1005)
`Querfeld discloses the results of a Phase II clinical study in which
`lenalidomide was administered orally to patients with cutaneous T-cell
`lymphoma (CTCL). Patients received 25 mg daily for 21 days with 7 days
`rest in 28-day cycles. Three of eight patients experienced an objective
`response after 1 to 3 cycles. Ex. 1005, 2.
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`8 Hannes Kaufmann et al., Antitumor Activity of Rituximab Plus Thalidomide
`in Patients with Relapsed/Refractory Mantle Cell Lymphoma, 104 BLOOD
`2269–2271 (2004) (Ex. 2010, “Kaufmann”). We refer to the page numbers
`of the exhibit, rather than the page numbers of the journal article.
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`4. The Celgene Press Release (Ex. 1006)
`The Celgene Press Release, bearing a date of June 19, 2006, describes
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`a “Phase II clinical study evaluating single agent lenalidomide in patients
`with relapsed and refractory aggressive Non-Hodgkin’s lymphoma (NHL).”
`Ex. 1006, 1. “Patients in the study received 25 mg of REVLIMID orally
`once daily for days 1-21 in a 28-day cycle and continued therapy for 52
`weeks as tolerated or until disease progression.” Id. at 2.
`Of the 16 evaluable patients, 1 patient achieved an unconfirmed
`complete response (CRu) and 4 patients achieved partial
`responses (PR) to Revlimid monotherapy. Four patients
`exhibited stable disease and 7 patients had disease progression
`after a median follow-up of 2 months (range 1–7 months). Of
`the 16 patients, 8 had diffuse large cell lymphoma, 3 patients
`had mantle cell lymphoma, 2 patients had follicular lymphoma,
`1 patient had transformed lymphoma, and 2 patients had
`aggressive lymphoma of unknown histology.
`Id. One of the patients with mantle cell lymphoma achieved a partial
`response with progression free survival for more than 57 days. Id.
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`D. Obviousness of Claims 1–4, 8, 9, 15, and 20 over Drach and
`Zeldis; and Claims 4 and 20 over Drach, Zeldis, and Querfeld
`Petitioner contends that claims 1–4, 8, 9, 15, and 20 are unpatentable
`
`over Drach and Zeldis, and that claims 4 and 20 are unpatentable over
`Drach, Zeldis, and Querfeld. Pet. 16–30.
`
`Patent Owner contends, inter alia, that both obviousness grounds
`should be denied under 35 U.S.C. § 325(d) because Petitioner “simply
`replaces art considered during prosecution with art containing the same
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`disclosures” (Prelim. Resp. 17), and moreover, “present[s] substantially the
`same arguments that were overcome during prosecution,” without providing
`“a compelling reason to readjudicate them” (id. at 12).
`For the reasons discussed below, we exercise our discretion under
`§ 325(d) to decline institution on these grounds because the same or
`substantially the same prior art or arguments were previously presented to
`the Office during prosecution.
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`1. 35 U.S.C. § 325(d)
`
`Institution of inter partes review is discretionary. See Harmonic Inc.
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`v. Avid Tech, Inc., 815 F.3d 1356, 1367 (Fed. Cir. 2016) (“the PTO is
`permitted, but never compelled, to institute an IPR proceeding”). In
`particular, § 325(d) states “[i]n determining whether to institute or order a
`proceeding under this chapter . . . The Director may take into account
`whether, and reject the petition or request because, the same or substantially
`the same prior art or arguments previously were presented to the Office.”
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`In evaluating whether the same or substantially the same prior art or
`arguments were previously presented to the Office under § 325(d), the Board
`has considered a number of non-exclusive factors, including, for example:
`(a) the similarities and material differences between the asserted
`art and the prior art involved during examination; (b) the
`cumulative nature of the asserted art and the prior art evaluated
`during examination; (c) the extent to which the asserted art was
`evaluated during examination, including whether the prior art
`was the basis for rejection; (d) the extent of the overlap between
`the arguments made during examination and the manner in
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`which Petitioner relies on the prior art or Patent Owner
`distinguished the prior art; (e) whether Petitioner has pointed
`out sufficiently how the Examiner erred in its consideration of
`the asserted prior art; and (f) the extent to which additional
`evidence and facts presented in the Petition warrant
`reconsideration of the asserted prior art or arguments.
`Becton, Dickenson & Co. v. B. Braun Melsungen AG, Case IPR2017-01586,
`slip op. 17–18 (PTAB Dec. 15, 2017) (Paper 8) (Informative).
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`2. Prosecution History of the ’929 Patent
`The Examiner issued a final office action rejecting the claims that
`
`ultimately issued as challenged claims 1–4, 8, 9, 15, and 20 as obvious over
`Zeldis (Ex. 1004) in view of three additional references: Damaj, Wilson, and
`Kaufmann.9 Ex. 2007, 10–19.
`The Examiner found, in relevant part, that “Zeldis teaches methods of
`treating, preventing, and/or managing cancer comprising administration of
`an immunomodulatory compound,” and that “[t]he instantly claimed 3-(4-
`amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (i.e.,
`Lenalidomide; Revlimid™; Revimid™) is disclosed as a preferred
`compound.” Ex. 2007, 62 (citing Ex. 1004, Abstract, Fig. 1, ¶¶ 16, 34, 37).
`In addition, the Examiner found that Zeldis teaches that lenalidomide is at
`least 200 times more potent than thalidomide in inhibiting TNF-α production
`in vitro (id. at 64 (citing Ex. 1004 ¶ 219)); 50–100 times more potent than
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`9 See supra notes 6–8.
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`thalidomide in stimulating proliferation of T-cell following primary
`induction by T-cell receptor activation (id. at 65 (citing Ex. 1004 ¶ 220));
`and more potent than thalidomide against multiple myeloma cell
`proliferation in vitro (id. (citing Ex. 1004 ¶ 222)). The Examiner further
`found that Zeldis teaches oral administration of lenalidomide in an amount
`of 5, 10, or 25 mg per day for 21 to 28 days followed by 1 week of rest in a
`four or six week cycle. Id. at 63 (citing Ex. 1004 ¶ 173). The Examiner also
`noted that lenalidomide provided a clinical benefit in some patients. Id. at
`69–70 (citing Ex. 1004 ¶¶ 244–249, 257–258).
`The Examiner found that Zeldis teaches that “the term ‘cancer’
`includes, but is not limited to solid tumors and blood born[e] tumors”
`(Ex. 2007, 62 (citing Ex. 1004 ¶ 107)), in particular, “‘various types of
`lymphoma’, including, but not limited to, Hodgkin’s lymphoma, non-
`Hodgkin’s lymphoma, cutaneous T-cell lymphoma, cutaneous B-Cell
`lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low
`grade follicular lymphoma” (id. (citing Ex. 1004 ¶ 107)). The Examiner
`acknowledged that Zeldis does not disclose treatment of mantle cell
`lymphoma. Ex. 2007, 66.
`The Examiner cited Damaj as teaching that thalidomide induced a
`response in relapsed mantle cell lymphoma (Ex. 2007, 66 (citing Ex. 2009,
`1914)); Wilson as teaching that thalidomide produced partial remission in a
`patient with relapsed mantle cell lymphoma (id. at 66–67 (citing Ex. 2008,
`130)); and Kauffman as teaching that a combination of lenalidomide and
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`rituximab has beneficial activity in treatment of relapsed/refractory mantle
`cell lymphoma (id. at 67 (citing Ex. 2010, Abstract)).
`The Examiner concluded that it would have been obvious to treat
`mantle cell lymphoma with lenalidomide because Zeldis “explicitly teaches,
`suggests, and motivates one skilled in the art to treat cancer using
`[lenalidomide], including ‘various types of lymphoma’ such as non-
`Hodgkin’s lymphoma and B-cell lymphomas” (id. at 69); “mantle cell
`lymphoma is a type of non-Hodgkin’s lymphoma/B-cell lymphoma” (id.);
`Damaj, Wilson, and Kaufmann teach that “thalidomide was . . . effective in
`the treatment of mantle cell lymphoma” (id.); and Zeldis teaches that
`lenalidomide “is significantly more potent tha[n] thalidomide” in various in
`vitro assays (id.), and provides a clinical benefit in some patients with other
`forms of cancer (id. at 69–70).
`Finally, according to the Examiner, “[t]he skilled artisan would thus
`have been imbued with at least a reasonable expectation that [lenalidomide]
`would be effective in treating mantle cell lymphoma given the broad
`spectrum anticancer [activity] of this compound as demonstrated by Zeldis.”
`Id. at 69.
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`Applicant, supported by the Declaration of Dr. Lei Zhang,10 contested
`the final rejection, arguing, in relevant part:
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`10 Declaration of Lei Zhang, M.D., submitted under 37 C.F.R. § 1.132, and
`dated October 15, 2013 (Ex. 1008, “Zhang Declaration” or “Zhang Decl.”).
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`[T]he efficacy of lenalidomide in relapsed, refractory, or
`relapsed and refractory mantle cell lymphoma, as demonstrated
`by the response rates, median duration of response and median
`overall survival in a Phase II clinical study [described in an
`accompanying article by Goy11], would have been unexpected
`and surprising at the time the claimed invention was made.
`Ex. 1007, 8–9 (citing Ex. 1008 generally).
`
`The Examiner, after considering the Zhang Declaration (Ex. 1008)
`and the underlying Goy reference (Ex. 2006), was “persuaded by
`Applicant’s argument of unexpected results as it pertains to the treatment of
`mantle cell lymphoma relapsed, refractory, or relapsed and refractory to
`conventional therapy comprising administration of lenalidomide in the
`[claimed] dosing regimen.” Ex. 2007, 81.
`Specifically, as set forth in the [Zhang] Declaration filed
`12/18/2013, prior to June 2013 there was only one drug
`approved by the FDA for the treatment of patients with relapsed
`
`11 Andre Goy et al., Single-Agent Lenalidomide in Patients with Mantle-Cell
`Lymphoma Who Relapsed or Progressed After or Were Refractory to
`Bortezomib: Phase II MCL-001 (EMERGE) Study, 31 JOURNAL OF CLINICAL
`ONCOLOGY 3688–3695 (2013) (Ex. 2006, “Goy”).
`Goy is a post-filing date reference describing a clinical trial in which
`lenalidomide was administered to 134 patients with relapsed or refractory
`mantle cell lymphoma “on days 1 through 21 every 28 days until disease
`progression or intolerance.” Ex. 2006, 3688. The overall response rate with
`lenalidomide was 28% (7.5% CR/Cru), exceeding the prespecified 15%
`target, with prolonged responses showing a median duration of response of
`16.6 months, including 18 patients who responded for ≥ 6 months and 10
`who responded for ≥ 12 months (maximum, 29.2+ months). Id. at 3694.
`
`
`17
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`IPR2018-00685
`Patent 8,741,929 B2
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`
`or refractory MCL (bortezomib). Surprisingly, Applicant
`demonstrated that lenalidomide administered in the claimed
`dosing regimen was effective in treating heavily pretreated
`MCL patients, including patients previously treated with
`bortezomib.
`
`Given the extremely poor prognosis of mantle cell
`lymphoma patients relapsed, refractory, or relapsed and
`refractory to conventional therapy and the lack of available
`effective therapies for such patients, it is surprising and
`unexpected that lenalidomide elicits an overall response rate of
`28% in heavily pretreated MCL patients.
`Ex. 2007, 81–82.
`
`In summary, as indicated by the prosecution history of the ’929
`patent, the Examiner ultimately concluded that Applicant’s evidence of
`unexpected results—i.e., the 28% overall response rate elicited by
`lenalidomide in pretreated relapsed and/or refractory mantle cell lymphoma
`patients—outweighed the evidence supporting his initial determination that
`it would have been prima facie obvious for one of ordinary skill in the art to
`use lenalidomide to treat mantle cell lymphoma. Ex. 2007, 81–82.
`3. Petitioner’s Obviousness Challenges
`Petitioner contends that claims 1–4, 8, 9, 15, and 20 would have been
`
`obvious over the combined teachings of Drach and Zeldis, and that claims 4
`
`18
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`and 20 would have been obvious over the combined teachings of Drach,
`Zeldis, and Querfeld.12
`Petitioner contends that Drach discloses “thalidomide’s use in
`treatment of relapsed and refractory MCL for human patients,” and makes
`“an explicit suggestion for using lenalidomide in MCL treatment.” Pet. 16
`(citing Ex. 1003, 10). Petitioner further contends that Zeldis teaches that
`lenalidomide is “one of the ‘most preferred’ immunomodulatory compounds
`for treating cancers that are refractory or resistant to conventional
`chemotherapy” (Pet. 17 (citing Ex. 1004 ¶¶ 17, 34, 81, 82)), and that both
`Drach and Zeldis disclose “lenalidomide’s use in treating relapsed and/or
`refractory cancers related to MCL” (id. at 16 (citing Ex. 1003, 10; Ex. 1004
`¶¶ 238–243)). Finally, Petitioner contends that Zeldis discloses that
`lenalidomide can be administered according to the same dosing and cycling
`protocol required by the claims. Id. at 17 (citing Ex. 1004 ¶¶ 113, 171, 173,
`229, 239–243).
`Petitioner contends that one of ordinary skill in the art “would have
`been motivated to substitute thalidomide with lenalidomide . . . for MCL
`treatment” (Pet. 19), because “Drach teaches that thalidomide was being
`used to treat relapsed and/or refractory MCL as of June 2005” (Pet. 18
`
`
`12 Petitioner does not specifically address 35 U.S.C. § 325(d), but does
`indicate that Drach and Querfeld were not considered by the Examiner
`during prosecution of the ’929 patent. Pet. 15.
`
`
`19
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`Patent 8,741,929 B2
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`(citing Ex. 1002 ¶ 68; Ex. 1003, 10)); “thalidomide and its analogs inhibit
`cytokines and are immunomodulatory, both of which were thought to be
`relevant pathways to address for MCL treatment” (Pet. 18 (citing Ex. 1002
`¶ 68; Ex. 1003, 10)); “lenalidomide had a better toxicity profile than
`thalidomide” (Pet. 18 (citing Ex. 1002 ¶¶ 71, 76; Ex. 1004, ¶¶ 220, 222,
`238–243, Fig. 1)); Zeldis teaches that “lenalidomide was known to be more
`potent than thalidomide” (Pet. 20 (citing Ex. 1002 ¶ 68; Ex. 1003, 10)); and
`“Drach explicitly taught that lenalidomide was an important agent for the
`new treatment paradigm of MCL at the time” (Pet. 18 (citing Ex. 1002
`¶ 68; Ex. 1003, 10)).
`Petitioner also contends that one of ordinary skill in the art “would
`have expected success in treating MCL with lenalidomide based on its
`structural similarity to thalidomide.” Pet. 19 (citing Ex. 1002 ¶ 65). In
`addition, Petitioner contends that “Zeldis teaches that . . . lenalidomide was
`more potent than thalidomide in the inhibition of MM [multiple myeloma]
`cell proliferation” (id. at 20 (citing Ex. 1002 ¶ 75; Ex. 1004 ¶¶ 222, 238–
`243, Fig. 1)), and “it was known that both MM and MCL were B-cell
`cancers that utilized a common biochemical pathway” (id. (citing Ex. 1002
`¶ 75 (Dr. Thirman testifying that “one of the pathways involved in MM
`(support of the microenvironment) was thought to potentially be involved in
`MCL”); Ex. 1010, 3; Ex. 1011, 4; Ex. 1003, 11)).
`
`Petitioner acknowledges that “[d]uring prosecution, Patent Owner
`argued that the clinical results achieved by lenalidomide in relapsed,
`
`20
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`refractory, or relapsed and refractory MCL patients were unexpected” (Pet.
`28 (citing Ex. 1007, 7)), but asserts “based on what was known prior to the
`critical date, those results would have been entirely expected” (Pet. 28). In
`support of this assertion, Petitioner relies on the following testimony of Dr.
`Michael Thirman:
`The prior art teaches, at least, the following: (1) thalidomide
`was being used to treat relapsed and/or refractory MCL
`(Drach), (2) thalidomide had undesirable side effects (Drach),
`(3) lenalidomide was a less toxic, more potent, structurally
`similar analogue of thalidomide being suggested for MCL
`treatment (Drach and Zeldis), and (4) lenalidomide could be
`used for MCL treatment in the dosages, dosage forms and
`cycling regimen claimed by the challenged claims of the ’929
`patent (Zeldis, Querfield, Celgene Press Release).
`Ex. 1002 ¶ 109. “Thus,” Dr. Thirman asserts, “the alleged unexpected
`properties would have been expected.” Ex. 1002 ¶ 110.
`Moreover, Petitioner argues that “a long-felt and unmet need must be
`satisfied by the invention” (Pet. 29), but “Dr. Thirman opines, the ’929
`patent’s claims did not satisfy any unmet need because there is still a need
`for new MCL therapy” (id. at 30 (citing Ex. 1002 ¶ 113; Ex. 1015, 1313)).
`
`
`13 Martin Dreyling et al., Treatment for P
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