DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/14/2025 has been entered.
Claims 1-2 are amended and claims 3-8, 11-27, 33-43, 46, 51-52, 55-56, 65-67, 69, 72-78, and 81-101 are canceled. Claims 1-2, 9-10, 28-32, 44-45, 47-50, 53-54, 57-64, 68, 70-71, and 79-80 are currently pending and are examined on the merits herein.
Priority
The instant application, filed 05/05/2022, is a 371 filing of PCT/US2020/059550, filed 11/06/2020, and claims domestic benefit to US provisional applications 63/016,977, filed 04/28/2020, and 62/932,500, filed 11/07/2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/14/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Rejections
In the Office action of 08/15/2025, claims 3-4 were rejected under 35 USC 103 and on the grounds of nonstatutory double patenting. The cancellation of the claims has rendered the rejections moot and the rejections are withdrawn.
The following grounds of rejection are modified as necessitated by applicant’s amendment to the claims.
Claim Objections
Claim 58 is objected to because of the following informalities: on line 2 of the claim there is a space missing between “SEQ ID NO: 1” and “or”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 28-32, 44-45, 47-50, 53-54, 64, 68, and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Otahal, P., et al (2016) Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells Oncoimmunology 5(4); e1115940, 1-10 in view of Matyskiela, M.E, et al (2018) A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos J. Med. Chem. 61; 535-542, and US 2014/0045843 A1 (Shafer, P.H. and A. Gandhi) 13 Feb 2014, as evidenced by Franco, R., et al (2016) Basic pharmacological and structural evidence for class A G-protein-coupled receptor heterodimerization Frontiers in Pharmacology 7(76); 1-10.
Otahal teaches that adoptive immunotherapy with autologous T lymphocytes genetically modified ex vivo to express chimeric antigen receptors is a promising treatment modality for cancer. At the time of publication, the most successful example of CAR-based immunotherapy achievements came from treating patients with B cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Successfully targeted antigens include CD19 and CD20, which are major B cell surface antigens and are strongly expressed by malignant B cells (page 1, left column, paragraph 1).
Despite promising results, resistance to CAR-based immunotherapy is frequently seen and several new approaches to enhance CAR-based therapies are being tested. One such approach is based on the targeted reversal of tumor immunomodulatory compounds, such as monoclonal antibodies that block particular inhibitor receptors, or small molecules belonging to the class of immunomodulatory agents (IMiDs), namely lenalidomide (LEN) (page 1, right column, paragraph 2). It had been previously demonstrated that LEN binds E3 ubiquitin ligase cereblon and induces degradation of transcription factors Ikaros and Aiolos and inhibits the growth of malignant B cells, inhibits angiogenesis, and augments antitumor T-cell responses. Otahal also teaches that LEN results in changed expression of various receptors on the surface of tumor cells (page 2, left column, paragraph 1; abstract).
Otahal studied the immunoadjuvant properties of LEN in combination with CD19 and CD20 CAR T cells (CAR19 and CAR20, respectively) in experimental therapy of aggressive B-cell lymphomas using various mouse xenograft models based on xenotransplantation of aggressive B-cell non-Hodgkin Lymphomas (page 2, left column, paragraph 2; abstract).
Otahal performed studies in which NSG mice received SC injection of 10 million Ramos cells (Burkitt lymphoma cells) followed with one dose of 5 million (5x106) CAR19 T cells. One group of the CAR19 treated mice also received daily injections of LEN following CAR T administration. After 3 weeks, mice were sacrificed and tumors were analyzed (page 4, left column, paragraphs 2-3). It is noted that, while Otahal does not specifically identify which day LEN administration began relative to the CAR19 cells, the teachings of Otahal indicate that the study was stopped after 3 weeks (21 days) indicating that administration of the IMiD began within 21 days following the CAR19 therapy. Otahal further teaches that the CAR T cells in the studies were intravenously injected (IV) (page 4, left column, paragraph 3).
Otahal teaches that LEN significantly enhances antitumor functions of CAR19 T cells in vivo. LEN enhanced production of interferon gamma by the CAR19 T cells and augmented cell signaling via the CAR19 protein in the T cells in vitro (abstract). Otahal concludes that CAR-based immunotherapy can be robustly enhanced by the concomitant application of the immunomodulatory agent, LEN, and that such combination might lead to highly effective cancer immunotherapy (page 8, left column, paragraph 3).
With regards to CAR structure, Otahal teaches that CARs typically encode an extracellular antibody-derived domain that binds to a surface antigen, such as CD19, linked with an intracellular signaling domain that mediates T cell activation such as TCRζ chain and costimulatory domains from CD28 or 4-1BB intracellular chains (page 1, left column, paragraph 1). In supplemental figure S1, Otahal provides a schematic of the CAR constructs used in the study (page 12). The schematic is duplicated below for convenience.
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Based on the schematic provided, the CD19 CAR used in the methods of Otahal comprised, in order, a CD8a leader; a scFv specific for CD19; a CD8 hinge, which meets the limitation of a spacer; a CD8 transmembrane domain; a 4-1BB costimulatory domain; and a TCR zeta intracellular signaling domain. The TCR zeta intracellular signaling domain disclosed by Otahal is another name for the CD3ζ signaling domain, which is an ITAM, as evidenced by Franco, Figure 1, page 3, which shows that the zeta signal transduction domain is an ITAM and is part of the TCR/CD3 signaling complex.
Otahal further teaches that CAR-based tumor immunotherapy is currently under intensive clinical investigation and that treatment induced long-term remission in patients with B cell acute and B cell chronic leukemia who were resistant to standard therapy including allogeneic bone marrow transplantation (page 5, right column, paragraph 2).
Otahal differs from the instantly claimed invention in that Otahal teaches that the CD19 CAR T cells are administered with the IMiD lenalidomide. Otahal does not disclose the administration of a compound that is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-done or pharmaceutically acceptable salts, solvates, hydrates, co-crystal, clathrate, or polymorphs thereof or the claimed cycling regimen..
Matyskiela teaches that the drugs lenalidomide and pomalidomide bind the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Matyskiela describes the cereblon modulator compound CC-220, also referred to as compound 6 (abstract). CC-220 (compound 6) matches the structure of the instant claims with a structure of 3-[4-(4-Morpholin-4-ylmethyl-benzyloxy)-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione (page 5, right column, paragraph 4; Scheme 1) as depicted below:
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Matyskiela teaches that compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater. The crystal structure of cereblon in complex with DDB1 and compound 6 reveals that the increase in potency correlates with increased contacts between compound 6 and cereblon away from the modeled binding site for Ikaros/Aiolos. The results describe a new
cereblon modulator which achieves greater substrate degradation via tighter binding to the cereblon E3 ligase and provides an example of the effect of E3 ligase binding affinity with relevance to other drug discovery efforts in targeted protein degradation (abstract).
US’843 teaches methods of treating and/or managing cancers comprising administering to a patient a therapeutically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin 2-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (pages 4-5, [0041]-[0042]; page 45, claim 1). The structure for the compound taught by US’843 matches the structure of the compound disclosed by Matyskiela as shown below:
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US’843 teaches methods of administering of the compound in the treatment of lymphoma, non-Hodgkin lymphoma, DLBCL, the activated B-cell phenotype of DLBCL, follicular lymphoma, Burkitt’s lymphoma, mantle cell lymphoma, or multiple myeloma (page 5, [0047]-[0048]; page 45, claims 1, and 8-9).
US’843 further teaches that the compound is orally administered in an amount of about 0.1 to about 5 mg/day or 0.1, 0.2, 0.5, 1, 2, 2.5, 3, 4, 5, 7.5, 10, 15, 20, 25, 50, or 100 mg per day (page 45, claims 34-36). US’843 teaches dosages that overlap with (0.1 to 5 mg/day) and lie inside of (0.5 mg/day) the claimed ranges (0.3 mg to 0.6 mg) rendering the claimed ranges obvious per MPEP 2144.05 I, as it would be obvious to use any dosage within the range of US’843, including those claimed, with a reasonable expectation of success.
US’843 further teaches that the compound is administered for 21 days followed by seven days of rest in a 28 day cycle (page 45, claim 40). US’843 teaches that the compound can be used in combination with another therapy and that the number of cycles can range from about 1 to about 24, from about 2 to about 16, or from about 3 to about 4 cycles (pages 30-31, [0364]). Based on these teachings, any cycles of two or more would result in the claimed cycling regimen where the compound is administered daily for three consecutive weeks (21 days) followed by seven days of rest (first cycle) followed by additional administration periods in which the same cycle is repeated.
US’843 teaches that the compounds disclosed are potent co-stimulators of T cells and increase cell proliferation in a dose dependent manner and also exert anti-angiogenic and immune modulating effects (page 19, [0241]-[0242]). US’843 also studied the impact of the compounds on cytokine production by T cells (page 36, 6.2) and teaches that comparatively low concentrations of the compound, from 0.01 to 1 nM, enhanced IL-2, IL-3, IL-5, IL-10, IL-13, GM-CSF, IFN-γ, TNF-α, and RANTES production. Enhancement of most cytokines and chemokines peaked at 1 to 10 nM and either remained at that level or declined gradually as the concentration increased (page 37, [0426]).
US’843 further teaches that the compound can be administered in combination with a second active agent including immunotherapies, blood transfusions, or non-drug based therapies such as stem cell therapy (page 9, [0112]). Administration with one or more active agents can occur simultaneously or sequentially by the same or different routes of administration (page 26, [0300]).
US’843 teaches that the patient treated with the disclosed methods has been treated with anticancer therapy prior to the administration of the compound (page 24, [0288]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the lenalidomide in the method taught by Otahal with CC-220 (compound 6) taught by Matyskiela and as further supported by US’843 and to further use the administration regimens disclosed by US’843 for administration of the CC-220.
An ordinarily skilled artisan would have been motivated to substitute CC-220 in place of lenalidomide as Matyskiela teaches that CC-220 binds to cereblon with a higher affinity than lenalidomide causing more potent degradation of Ikaros and Aiolos, effects which Otahal teaches leads to enhanced production of IL-2 and other cytokines known to regulate T cell function. An ordinarily skilled artisan would have a reasonable expectation of success as Matyskiela demonstrates that CC-220 is an IMiD compound that degrades the same substrates as lenalidomide, but to a higher degree. Additionally, US’843 supports a reasonable expectation of success demonstrating that the chemical structure of CC-220 co-stimulates T cells and increases cell proliferation while enhancing expression of T cell cytokines including IL-2, IL-3, IL-5, IL-10, IL-13, GM-CSF, IFN-γ, TNF-α, and RANTES at comparatively low concentrations, which is similar to the functions of lenalidomide taught by Otahal in which lenalidomide is taught to enhance production of IL-2 and IFN-γ resulting in augmented CAR-19 T cell signaling.
It would have been obvious to an ordinarily skilled artisan to use the administration regimens disclosed by US’843 for administration of CC-220 as US’843 teaches that such dosages and administration cycles were known in the art for compounds with the structure of CC-220. An ordinarily skilled artisan would have had a reasonable expectation of success as US’843 teaches the use of the compound in the co-stimulation of T cells and in the treatment of diseases including multiple myeloma, NHL, and Burkitt Lymphoma demonstrating a nexus across the references.
It is further noted that the determination of optimal administration dosages and regimens are considered to be routine optimization where considerations and starting points were known in the prior art. MPEP 2144.05 (II) A. states that "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”. In this case, US’843 discloses administration cycles and dosages that could be used as a starting point for routine optimization to determine optimal administration regimens for the CC-220 compound used in the methods of Otahal, Matyskiela, and US’843.
Claims 44-45, 47-50, 53-54, 57-64, 68, 70-71, and 79-80 are rejected under 35 U.S.C. 103 as being unpatentable over Otahal, P., et al (2016) Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells Oncoimmunology 5(4); e1115940, 1-10 in view of Matyskiela, M.E, et al (2018) A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos J. Med. Chem. 61; 535-542, and US 2014/0045843 A1 (Shafer, P.H. and A. Gandhi) 13 Feb 2014 as applied to claim 2 above, and in further view of WO 2017/214207 A2 (Turtle, C.J.) 14 Dec 2017.
It is noted that claims 44-45, 47-50, 53-54, 64, 68, and 70 were rejected above over Otahal in view of Matyskiela and US’843. The claims are also rejected here to demonstrate further obviousness over the prior art.
The combination of Otahal, Matyskiela, and US’843 teach the method of claim 2 as discussed in detail above.
The combination of applied references, however, do not teach the sequences of instant claims 57-63 or that, immediately prior to the administration of the T cells, a lymphodepleting therapy is administered as recited in instant claims 79-80.
WO’207 teaches adoptive cell therapies, such as cells expressing CARs, and methods of administering doses of the cells in the treatment of B cell malignancies. In some embodiments the methods also involve prior administration of a lymphodepleting therapy. The features of the methods include an increase in the complete remission, overall survival, and/or progression free survival of subjects treated (abstract).
WO’207 teaches CARs targeting the B cell antigen CD19 (page 7, [0028]), and teaches that the CAR comprises, in order, an scFv specific for the antigen, a spacer, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, which optionally is or includes a 4-1BB signaling domain, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, which optionally is or includes a CD3 zeta signaling domain. WO’207 further teaches that the spacer is a peptide spacer that contains or consists of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified version thereof or contains about 15 amino acids or less (page 10, [0040]).
WO’207 teaches that the transmembrane domain is the transmembrane domain of human CD28, for example, Accession No. P01747.1, or a variant thereof and comprises the amino acid sequence set forth in SEQ ID NOs: 8 or 9 (page 71, [0231]). WO’207, SEQ ID NOs: 8 and 9 are identical to instant SEQ ID NOs: 8 and 9, respectively, as shown in the ABSS alignments below:
Instant SEQ ID NO: 8 aligned with WO’207 SEQ ID NO: 8
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Instant SEQ ID NO: 9 aligned with WO’207 SEQ ID NO: 9
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WO’207 further teaches that the spacer has or consists of the sequence of SEQ ID NO: 1, a sequence encoded by SEQ ID NO: 2, or SEQ ID NO:s 30-34 (page 10, [0040]). The sequences disclosed by WO’207 for the spacer are identical to those recited in instant claim 58 as shown in the ABSS alignments below:
Instant SEQ ID NO: 1 aligned with WO’207 SEQ ID NO: 1
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Instant SEQ ID NO: 2 aligned with WO’207 SEQ ID NO: 2
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Instant SEQ ID NO: 30 aligned with WO’207 SEQ ID NO: 30
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Instant SEQ ID NO: 31 aligned with WO’207 SEQ ID NO: 31
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Instant SEQ ID NO: 32 aligned with WO’207 SEQ ID NO: 32
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Instant SEQ ID NO: 33 aligned with WO’207 SEQ ID NO: 33
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Instant SEQ ID NO: 34 aligned with WO’207 SEQ ID NO: 34
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US’207 further teaches that the costimulatory domain contains SEQ ID NO: 12 (page 10, [0040]), which is identical to instant SEQ ID NO: 12 as shown in the ABSS alignment below:
Instant SEQ ID NO: 12 aligned with WO’207 SEQ ID NO: 12
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US’207 further teaches that the primary signaling domain contains SEQ ID NOs: 13, 14, or 15 (pages 10-11, [0040]), which are identical to instant SEQ ID NOs: 13, 14, and 15, respectively, as shown in the ABSS alignments below:
Instant SEQ ID NO: 13 aligned with WO’207 SEQ ID NO: 13
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Instant SEQ ID NO: 14 aligned with WO’207 SEQ ID NO: 14
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Instant SEQ ID NO: 15 aligned with WO’207 SEQ ID NO: 15
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WO’207 further teaches that the scFv contains a CDRL1-CDRL3 of SEQ ID NOs: 35, 36, and 37, respectively, and CDRH1-CDRH3 of SEQ ID NOs: 38, 39, and 40, respectively (pages 10-11, [0040]), which are identical to the instantly claimed CDRs as shown in the ABSS alignments below:
Instant SEQ ID NO: 35 aligned with WO’207 SEQ ID NO: 35
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Instant SEQ ID NO: 36 aligned with WO’207 SEQ ID NO: 36
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Instant SEQ ID NO: 37 aligned with WO’207 SEQ ID NO: 37
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Instant SEQ ID NO: 38 aligned with WO’207 SEQ ID NO: 38
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Instant SEQ ID NO: 39 aligned with WO’207 SEQ ID NO: 39
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Instant SEQ ID NO: 40 aligned with WO’207 SEQ ID NO: 40
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US’207 further teaches that the scFv contains, in order, a VH, a linker, and a VL, where the VH comprises SEQ ID NO: 41 and the VL comprises SEQ ID NO: 42 (pages 10-11, [0040]; page 64, [0206]), which are identical to instant SEQ ID NOs: 41 and 42, as shown in the ABSS alignments below:
Instant SEQ ID NO: 41 aligned with WO’207 SEQ ID NO: 41
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Instant SEQ ID NO: 42 aligned with WO’207 SEQ ID NO: 42
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US’207 further teaches that the scFv comprises the sequence of amino acids set forth in SEQ ID NO: 43 (page 64, [0206]), which is identical to instant SEQ ID NO: 43, as shown in the ABSS alignment below:
Instant SEQ ID NO: 43 aligned with WO’207 SEQ ID NO: 43
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WO’207 teaches that the methods involve treating a subject having non-Hodgkin lymphoma (NHL), such as an aggressive NHL and/or an NHL of a particular sub-type such as a DLBCL, a primary mediastinal large B cell lymphoma (PMBCL), a T cell/histocyte-rich large B cell lymphoma (TCHRBCL), a Burkitt’s lymphoma, and/or other aggressive NHL, a mantle cell lymphoma (MCL), and/or follicular lymphoma (FL) (pages 3-4, [0011]). WO’207 teaches that a subject that has NHL is administered a dose of between at or about 1x107 and at or about 1.5x108 total CAR expressing T cells (page 8, [0033]). WO’207 further teaches that the CAR expressing cells are administered parenterally, including intravenously (page 9, [0037]).
WO’207 teaches that the engineered cells are T cells, optionally CD4+ and CD8+ and that the T cells are autologous or allogeneic to the subject (page 15, [0052]).
WO’207 further teaches that preconditioning the subject with lymphodepleting therapy can improve the effects of adoptive cell therapy. Preconditioning with lymphodepleting agents, including combinations of cyclophosphamide and fludarabine, have been effective in improving the efficacy of transferred TIL cells in cell therapy, including improving response and/or persistence of the transferred cells. Such preconditioning can also be carried out to reduce the risk of one or more various outcomes that could dampen the effectiveness of the therapy including cytokine sink (page 28, [0098]). Thus, the methods comprise administration of a chemotherapeutic agent, e.g., conditioning chemotherapeutic agent, for example, to reduce tumor burden prior to administering the dose of cells. In some embodiments, the methods include administering a preconditioning agent, such as a lymphodepleting or chemotherapeutic agent, such as cyclophosphamide, fludarabine, or combinations thereof. The subject may be administered a preconditioning agent at least 2 days prior, such as at least 3, 4, 5, 6, or 7 days prior to the administration of the cells and is administered or initiated at least 48 hours before the cells (pages 28-29, [0099]). WO’207 teaches that the cyclophosphamide is administered at about 300 mg/m2 daily for 3 days prior to the cell therapy and the fludarabine is administered at about 30 mg/m2 for 3 days prior to the cell therapy (pages 29-30, [0101]-[0102]).
WO’207 exemplifies the CD19 CAR T cells disclosed administered to 41 adult human subjects with CD19+ NHL, including subjects with DLBCL, PMBCL, TCHRBCL, Burkitt lymphoma, and patients with mantle cell lymphoma and follicular lymphoma (page 126, Example 2). Among the 27 patients preconditioned with both cyclophosphamide and fludarabine, the ORR was 74% with 44% of patients achieving complete remission (page 127 [0363]).
In the examples provided by WO’207, patients had been previously treated. For instance, in the treatment of NHL outlined in example 2, subjects had received a median number of four prior treatments ranging from 1 to 11 (page 126, [0359]). WO’207 further teaches that, prior to the administration of the dose of cells, the subject has been treated with two or more, optionally 3, 4, 5, 6, 7, 8, or 9, therapies (page 5, [0021]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the CD19 CAR T cells in the method taught by the combination of Otahal, Matyskiela, and US’843 with the autologous or allogeneic CD19 CAR T cells of WO’207 and to have administered a lymphodepleting therapy immediately prior to the administration of the T cell therapy according to the methods disclosed by WO’207.
An ordinarily skilled artisan would have been motivated to substitute the CD19 CAR T cells of WO’207 in place of the CD19 CAR T cells of Otahal, Matyskiela, and US’843 as WO’207 demonstrates their effective use in clinical studies. An ordinarily skilled artisan would have had a reasonable expectation of success as, like in the method of Otahal, the CAR T cells of WO’207 target CD19. Additionally, WO’207 teaches the use of the CARs in methods of treating NHL, including subtypes also taught by Otahal, Matyskiela, and US’843. The CAR taught by WO’207 also comprises a 4-1BB costimulatory and CD3 zeta intracellular signaling domain, which is the same combination of signaling domains used in the CAR disclosed by Otahal.
An ordinarily skilled artisan would be motivated to administer the lymphodepletion therapy disclosed by WO’207 prior to the administration of the CAR T cells in order to reduce tumor burden prior to administration of the T cells and to improve the efficacy of the transferred cells as disclosed by WO’207. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’207 demonstrates the use of the disclosed lymphodepletion regimens prior to the administration of CD19 CAR T cells, which is the same CAR T cell target of Otahal, in the treatment of NHL cancers, including subtypes also taught by Otahal, Matyskiela, and US’843.
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Otahal, P., et al (2016) Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells Oncoimmunology 5(4); e1115940, 1-10 in view of Matyskiela, M.E, et al (2018) A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos J. Med. Chem. 61; 535-542, and US 2014/0045843 A1 (Shafer, P.H. and A. Gandhi) 13 Feb 2014, as applied to claim 2 above, and in further view of Works, M., et al (2017) 652. Abstract, Lenalidomide enhances anti-BCMA chimeric antigen receptor T cell function against multiple myeloma Blood 130 (Suppl_1): 1794; 1-3.
The combination of Otahal, Matyskiela, and US’843 teaches the method of claim 2 as discussed above.
The combination of Otahal, Matyskiela, and US’843, however, do not explicitly disclose that the IMiD compound administration begins on the same day as the T cell therapy or that the administration period begins between at or about 1 day and at or about 15 days, inclusive, after administering the T cell therapy.
Works studied the combination of anti-BCMA CAR T cells with lenalidomide and teaches that lenalidomide, a small molecule immunomodulatory agent approved for use in MM, can have both direct tumoricidal and T cell modulatory effects. Recently publications had also highlighted the ability of lenalidomide to enhance T cell and CAR-T function in preclinical models (page 1, paragraph 1). The immunomodulatory drug was investigated in combination with an autologous cellular drug product transduced to express a BCMA-specific CAR with 4-1BB costimulatory and CD3 zeta endodomains (page 1, paragraph 2).
In vivo activity of daily administration of lenalidomide in combination with the anti-BCMA CAR T cells in NSG mice injected with multiple myeloma cells was evaluated. Two dosing strategies were evaluated to determine the effect of dosing lenalidomide either concurrently with CAR-T cell administration or two weeks following CAR T cell administration. Both lenalidomide dosing schedules enhanced function of sub-curative doses of CAR-T cells, as demonstrated by decreased tumor burden and increased animal survival (page 2, paragraph 3).
Works also studied the combination in vitro and teaches that lenalidomide increased CAR-T cell cytokine production across stimulation conditions and CAR-T cells exposed to low levels of antigen demonstrated the most marked increase in cytokine production and activation with the addition of lenalidomide in culture (page 1, paragraph 2). Additionally, differential expression and accessibility results demonstrated an enriched involvement of immune synapse associated genes, cytokine signaling, and T cell activation pathways consistent with the functional gains measured in the presence of lenalidomide (page 2, paragraph 1).
Works further studied the effect of lenalidomide on CAR-T cell cytolytic activity, cytokine production, and proliferation in co-culture with MM cells displaying a range of BCMA expression. The addition of lenalidomide during co-culture increased CAR-T cell effector cytokine production and cytolytic activity. Lenalidomide also increased CAR-T cell performance over 4 weeks in a repeat serial stimulation of BCMA CAR-T cells with MM1.S cells, an assay designed to predict CAR-T cell product fitness. The lenalidomide-associated increase in persistence and proliferation correlated with an increase in IL-2 production and activation marker expression (page 2, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Otahal, Matyskiela, and US’843 to administer the CC-220 on the same day or two weeks (14 days) following the administration of the CAR T cells as taught by Works. It would have been obvious to begin administering the CC-220 on the same day or 14 days following the CD19 CAR T cells as Works teaches that both dosing schedules enhanced the function of CAR-T cells, as demonstrated by both tumor burden and increased animal survival. An ordinarily skilled artisan would have had a reasonable expectation of success as, like Otahal, Works is teaching the combination of IMiDs and CAR-T cells as a means to increase CAR-T cell activation, proliferation, cytolytic activity, and cytokine production. Additionally, Works teaches that the administration increased cytokine production and proliferation which is also taught by Otahal for lenalidomide and US’843 for a compound with the structure of CC-220 when the IMiDs are put in combination with T cells.
It is further noted that the determination of optimal administration times are considered to be routine optimization where considerations and starting points were known in the prior art. See MPEP 2144.05 (II) A. In this case, Works demonstrates that administration of IMiDs on days 0 and 14 were known to improve CAR T cell function and activity. It would have been obvious to one of ordinary skill in the art to use the teachings of Works as a starting point for routine optimization to determine the optimal starting day for the CC-220 administration in the methods disclosed by Otahal, Matyskiela, and US’843.
Response to Arguments
Applicant’s arguments in the response filed 11/14/2025 have been fully considered, but were not persuasive.
Applicant argues that the examples of the disclosure demonstrate unexpected performance attributable to the claimed methods. Specifically, applicant argues that the working examples of the disclosure demonstrate that CC-220 is able to improve CAR T cell activity even under conditions involving chronic stimulation or exhaustion and do so at low amounts. Applicant argues that one of ordinary skill in the art would not have expected the beneficial therapeutic effects resulting from the claimed methods.
Arguments concerning unexpected results were discussed in the Office action of 08/15/2025 and, in response to the arguments, it was considered that applicant does not provide a comparison to the closest prior art in order to demonstrate that the claimed method results in unexpected outcomes, as required by MPEP 716.02(b)(III) and 716.02(e). Specifically, applicant provides a comparison to compound B, which is disclosed as having the structure 3-(5-amino-2-methyl-4-oxo-4H- quinazolin-3-yl)-piperidine-2,6-dione, not lenalidomide, which has a structure of 3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
With regards to this response, applicant argues that compound B is a more appropriate comparator than lenalidomide. Applicant argues that the examples compare CC-220 (designated “Compound A”) with CC-122 (designated “Compound B”) which are both known as cereblon modulators (CELMoD) whereas lenalidomide is an IMiD. Applicant argues that IMiDs exhibit lower selectivity compared to a CELMoD. Applicant cites Matyskiela as emphasizing the distinctions in activity and mechanisms of action between IMiDs and CELMoDs on page 536, left column, second paragraph. Specifically, applicant argues that Matyskiela explains that IMiDs exhibit broader substrate activity because they target both CRBN and CK1α. Applicant further argues that Ribrag (cited on the IDS of 11/14/2025) shows that CC-122 is more potent than lenalidomide, having 10-fold greater immunomodulator effect than lenalidomide.
While the art cited by applicant does suggest that CC-122 is more potent than lenalidomide, the degree to which Ikaros/Aiolos is degraded does not necessarily indicate that CC-122 is a closer prior art or more appropriate comparison than lenalidomide in combination with CAR T cells. For instance, as discussed in the rejection, Otahal studied lenalidomide in combination with CD19 CAR T cells prior to the effective filing date and specifically identifies the downregulation of transcription factors Ikaros and Aiolos as contributing to the observed results. As Otahal identifies Ikaros and Aiolos degradation caused by lenalidomide as enhancing the CD19 CAR T cell therapy, and CC-220 is known to degrade these substrates, lenalidomide is considered to be a closest prior art comparison.
Even if CC-122 were considered to be an equally close comparison to lenalidomide, MPEP 716.02 (e) II states that “Showing unexpected results over one of two equally close prior art references will not rebut prima facie obviousness unless the teachings of the prior art references are sufficiently similar to each other that the testing of one showing unexpected results would provide the same information as to the other. In re Johnson, 747 F.2d 1456, 1461, 223 USPQ 1260, 1264 (Fed. Cir. 1984).”
In the examples, applicant studies CC-122 for the same effect as those discussed by Otahal for lenalidomide, specifically the degradation of Ikaros and Aiolos and the effect of such degradation of CD19 CAR T cells. It is not clear from applicant’s arguments, or the disclosure, that the results shown provide the same information as a comparison to lenalidomide would. For instance, applicant argues that CC-220 provides an effect at an unexpectedly low amount of CC-220; however, applicant does not provide any data on comparative amounts, for instance IC50, only activity. Matyskiela, however, compares CC-220 to lenalidomide, including both the degree of Ikaros and Aiolos degradation as well as IC50 values (page 536, right column), allowing for a comparison between lenalidomide and CC-220 and active concentrations beyond activity alone.
Applicant further argues that the present claims are based on the problem that upon administration of the CAR T cell therapy to the subject and activation of the CAR, that there is a risk that the T cells may become exhausted as a result of chronic antigen stimulation. Applicant argues that this is problematic because exhausted T cells lose their persistence and therapeutic effectiveness. Applicant argues that the present application reveals that the activity of the CAR T cells can be improved, such as by reducing exhaustion or even rescuing their activity after the cells have undergone chronic stimulation and exhaustion. Applicant further argues that it is surprising that the effect can be achieved with an unexpectedly low amount of CC-220 that is substantially lower than what would be anticipated based on known potency. Applicant cites Examples 1, 3, and 4 of the specification for support.
Applicant argues that, in example 1, it is shown that CC-220 is 10-20 fold more potent than CC-122, based on the degradation of Aiolos and Ikaros transcription factors in CAR T cells, citing Fig. 1. Applicant further argues that it was surprisingly found that the activity of CC-220 on CAR T cells was even more striking with an amount of CC-220 approximately 100 fold or more lower than that of CC-122 achieving comparable or superior activity. Applicant cites Fig. 3C for support stating that improved cytolytic function of CD19 CAR T cells against tumor cells was superior to CC-122 even at amounts that were 100 fold (0.01 μM) or 1000 fold (0.001 μM) lower than the amount of CC-122 (1 μM) in the same assay. Applicant argues that this is surprising in view of the much lower fold increase in potency for CC-220 compared to CC-122 in Aiolos and Ikaros. Applicant argues that similar results were observed in a rescue model as described in Example 4. Applicant argues that treatment with CC-220 improved CAR T cell cytolytic function to reduce growth of CD19 expressing tumor spheroids in a manner that was superior to CC-122, even at amounts that were 100 fold (0.01 μM) or 1000 fold (0.001 μM) lower than the amount of CC-122 (1 μM). Applicant argues that the cited references do not suggest the superior activity of CC-220 on CD19 CAR T cells for reducing or reversing CAR T cell exhaustion when administered subsequently to the CD19 CAR T cells or that such result could be achieved at such low amounts.
It is first noted that the instant claims do not require that the CAR T cells be in an exhausted state or have lost persistence or therapeutic effectiveness. Rather, the claims only require that CC-220 be administered subsequently to CD19 CAR T cell therapy according to the recited regimen.
Furthermore, the reduction in exhaustion of the administered CAR T cells would flow naturally from following the suggestions of the prior art in which CC-220 is administered subsequently to CAR T cell therapy and; therefore, cannot be the basis of patentability when the differences would have otherwise been obvious. See MPEP 2145 II., which states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Additionally, to such an extent that exhaustion of the CD19 CAR T cells is the result of antigen exposure resulting from administration of the CAR T cells, an improvement of CAR T cell function with the addition of CC-220 would have been expected in view of the teachings of the prior art.
MPEP 716.02 states “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” The MPEP chapter further states that “A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent.”
As discussed in detail in the rejection, Otahal demonstrates that the administration of the immunomodulatory drug lenalidomide (LEN) subsequent to CAR T cell administration significantly enhances the antitumor functions of CAR19 and CAR20 T cells in vivo. Otahal teaches that the data supports use of LEN for augmentation of CAR based immunotherapy in the clinical grounds (abstract). The results provided by Otahal demonstrate that the additional of LEN to CD19 CAR T cells led to significant reductions in tumor weight compared to either agent alone or controls as well as a significant increase in CD8+ T cells (page 5, Figure 6 A and B). Otahal also discloses that LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors (abstract). Matyskiela demonstrates that the claimed compound CC-220, was known in the art and, like lenalidomide, had been demonstrated as a cereblon modulator. Matyskiela also teaches that the compound binds cereblon with higher affinity than lenalidomide and, consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater (abstract). As CC-220 is shown to bind cereblon with higher affinity and result in more potent degradation of the substrates Ikaros and Aiolos, one of ordinary skill in the art would have expected similar, or even better, outcomes when lenalidomide is substituted with CC-220 in the method taught by Otahal.
Applicant argues that the results observed in the instant examples were at concentrations of CC-220 that were surprisingly low; however, it was known in the art that CC-220 had a significantly lower IC50 value compared to lenalidomide and; therefore, it would have been expected that CC-220 would have been effective at significantly lower concentrations. Additionally, the prior art, specifically US’843, demonstrates that CC-220 would have been expected to be effective at the claimed mg/day administration as well as the demonstrated μM concentrations.
For instance, Matyskiela teaches that treatment with Compound 6, which is the same as CC-220, results in loss of Ikaros protein levels with an IC50 of 1 nM compared to 67 nM for lenalidomide and 24 nM for pomalidomide. Compound 6 is similarly potent toward Aiolos, with an EC50 of 0.5 nM compared to 87 nM for lenalidomide and 2 for pomalidomide. In addition, the extent of substrate degradation is more dramatic with compound 6, indicating more efficient substrate degradation relative to the rate or protein resynthesis (page 536, right column, paragraph 1). The difference in IC50 values are also demonstrated by US’843 which teaches that compound I-S (CC-220) was tested in cereblon ubiquitination assays and showed an IC50 value of 0.19 μM, while the IC50 values for lenalidomide and pomalidomide were 12.9 μM and 21.6 μM, respectively.
Additionally, US’843 teaches the claimed mg/day and also demonstrates that the μM concentrations of CC-220 used in the examples were known to be effective. For instance, US’843 teaches that compound I-S at a concentration of 0.1 μM resulted in approximately 50% less CRBN bound to affinity beads, while pomalidomide at a concentration of 3 μM resulted in approximately 50% less CRBN bound to affinity beads (pages 42-43, [0492]). US’843 also provides plots of cytokine/chemokine production as a function of the compound concentration (Figures 1-9) and demonstrates that concentrations as low as 0.001 μM, and for some cytokines/chemokines even 0.0001 μM, were effective in modulating cytokine/chemokine production.
Based on the IC50 data provided by Matyskiela and US’843, and the results provided by US’843 regarding CC-220 concentrations and effects, an ordinarily skilled artisan would have reasonably expected that CC-220 would be efficacious at lower concentrations.
Furthermore, the results discussed by applicant are not commensurate with the full scope of the instantly claimed invention.
MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
The examples of the instant disclosure studied T cells expressing a CD19 CAR, comprising an scFv, immunoglobulin derived spacer, CD28 transmembrane domain, 4-1BB costimulatory domain, and CD3-zeta intracellular signaling domain, used in combination with the claimed compound, at specific dosages in the treatment of specific types of cells. These results, however, are not commensurate in scope with the claimed invention. For instance, the independent claims encompass any type of CD19 CAR expressing T cells and the treatment of any type of B cell malignancy. Additionally, the claims recite dosages of the CC-220 compound in mg/day, not μM and applicant does not provide a correlation to demonstrate that the dosages claimed and those discussed in the response are equivalent.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 12,263,190 B2
Claims 1-2, 9-10, 28-32, 44-45, 47-50, 53-54, 57-64, 68, 70-71, and 79-80 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 12,263,190 in view of WO 2017/214207 A2 (Turtle, C.J.) 14 Dec 2017.
US’190 claims a method of treatment comprising (a) administering a T cell therapy to a subject having a cancer, said T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds a target antigen; and (b) administering to the subject an immunomodulatory compound, wherein the compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydroisoindol-2-yl]-piperidine-2,6,dione or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof (claim 1). US’190 claims that the immunomodulatory compound is administered at a daily dose of from or from about 0.1 mg to 5 mg per day (claim 2), and is initiated subsequently to the T cell therapy within 90 days (claims 2-4) or prior to the T cell compound from about 0-30 days prior (claims 5-6). US’190 claims that the cancer is a B cell malignancy (claim 7), that the target antigen is CD19, and the cancer is lymphoma (claims 9-10). Claim 13 recites that the compound administration is continued for a period greater than 1 month and is administered orally (claims 13 and 17). US’190 claims that the CAR is administered at a dose of 1x105 to 5x108 total CAR expressing cells, inclusively, and are autologous or allogeneic to the subject (claims 20-24). US’190 further claims that the subject is administered a lymphodepleting therapy immediately prior to the T cells comprising cyclophosphamide at 200-400 mg/m2, inclusive, and/or fludarabine at about 20-40 mg/m2, daily for 2-4 days (claims 25 and 33).
US’190 further claims that the immunomodulatory compound is administered in an effective amount of 0.4 mg, 0.5 mg, 0.7 mg, 0.8 mg, or 1.0 mg and is administered daily for a period of time in a cycling regimen (claims 28-29). US’190 claims that the cycling regimen is once daily for 21 days over a 28 day treatment cycle, wherein the administration continues for greater than three, four, five, or six months (claims 29-31). US’190 also claims that the administration of the immunomodulatory compound is initiated concurrently with the T cell therapy administration (claim 32).
The claims of US’190 differ from those of the instantly claimed invention in that US’190 does not claim that the subject has received more than one, two, three, four, five, or six prior therapies. Additionally US’190 does not claim that the cancer is from those recited in claim 45, that the CAR T cells are administered intravenously, or the claimed components of the CD19 CAR.
The teachings of WO’207 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the method of US’190 to include subjects who have been treated with two or more, optionally 3, 4, 5, 6, 7, 8, or 9 prior therapies as taught by WO’207 . It would have further been obvious to use the CD19 CAR T cells of WO’207 administered intravenously and to treat cancers including those disclosed by WO’207.
It would have been obvious to administer the combination to a patient who has been treated with two or more, optionally 3, 4, 5, 6, 7, 8, or 9 prior therapies with a reasonable expectation of success as WO’207 demonstrates the use of anti-CD19 CAR T cells for the treatment of this population of patients. An ordinarily skilled artisan would have been motivated to use the CD19 CAR T cells of WO’207, administered intravenously, as WO’207 demonstrates their effective use in human studies. An ordinarily skilled artisan would have had a reasonable expectation of success as, like in the method claimed by US’190, the CAR T cells of WO’207 target CD19. Additionally, WO’207 teaches the use of the CARs in methods of treating B cell lymphomas which is the disease treated by the claims of US’190. It would have been obvious to treat the specific B cell malignancies disclosed by WO’207 with the methods claimed in US’190 as WO’207 teaches that such malignancies can be treated with CD19 targeting CAR T cells.
16/609,733
Claims 1-2, 9-10, 28-32, 44-45, 47-50, 53-54, 57-64, 68, 70-71, and 79-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 222, 235-237, 239-240, 245, 247-250, 252, 260-267, 269, 276-290, and 293-299 of copending Application No. 16/609,733 in view of Otahal, P., et al (2016) Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells Oncoimmunology 5(4); e1115940, 1-10, Matyskiela, M.E, et al (2018) A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos J. Med. Chem. 61; 535-542, US 2014/0045843 A1 (Shafer, P.H. and A. Gandhi) 13 Feb 2014, and WO 2017/214207 A2 (Turtle, C.J.) 14 Dec 2017.
App’733 claims a method of treatment comprising administering an immunomodulatory compound to a subject having a disease or condition wherein, at the time of administration of the compound, the subject has been previously administered a T cell therapy for the treatment of the disease. App’733 teaches that the compound is selected from the group consisting of thalidomide analogs, thalidomide derivatives, compounds that interact and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex, inhibitors of Ikaros, inhibitors of Aiolos, and compounds that enhance or promote ubiquitination and/or degradation of Ikaros or Aiolos. App’733 also claims a method of treatment in which a patient is administered a T cell therapy and administered the immunomodulatory compound. Wherein initiation of the compound is carried out from 7-42 days after the initiation of the T cell therapy.
App’733 further recites a structure for the immunomodulatory compound and claims that the compound is administered in an amount from or from about 0.1 mg to about 100 mg.
App’733 further claims that the T cell therapy is a therapy comprising genetically engineered cells that express a CAR that binds to an antigen expressed by cells of the disease or condition. The disease is a tumor or cancer and the antigen is CD19.
App’733 claims that the cancer treated is MCL, MM, ALL, CLL, NHL, DLBCL, or FL.
App’733 differs from the instantly claimed invention in that App’733 does not claim that the immunomodulatory compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-done or pharmaceutically acceptable salts, solvates, hydrates, co-crystal, clathrate, or polymorphs thereof or the instantly claimed administration regimen. App’733 also does not claim that the subject has received lymphodepleting therapy with fludarabine and cyclophosphamide as is instantly claimed.
The teachings of Otahal, Matyskiela, US’843, and WO’207 are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’733 to use CC-220 (compound 6) taught by Matyskiela as the immunomodulator as further supported by Otahal and US’843 and to use the administration regimens disclosed by US’843 for administration of the CC-220.
An ordinarily skilled artisan would have been motivated to use CC-220 as the IMiD as Matyskiela teaches that CC-220 binds to cereblon with a higher affinity than lenalidomide and pomalidomide causing more potent degradation of Ikaros and Aiolos, effects which Otahal teaches leads to enhanced production of IL2 and other cytokines known to regulate T cell function. An ordinarily skilled artisan would have a reasonable expectation of success as Matyskiela demonstrates that CC-220, like lenalidomide and pomalidomide, is an IMiD compound that degrades the same substrates, namely Ikaros and Aiolos, but to a higher degree. Additionally, US’843 supports a reasonable expectation of success demonstrating that CC-220 would be expected to co-stimulate T cells and increase cell proliferation while enhancing expression of T cell cytokines including IL-2, IL-3, IL-5, IL-10, IL-13, GM-CSF, IFN-γ, TNF-α, and RANTES at comparatively low concentrations, which is similar to the functions of lenalidomide taught by Otahal in which lenalidomide is taught to enhance production of IL-2 and IFN-γ resulting in augmented CAR-19 T cell signaling.
It would have been obvious to an ordinarily skilled artisan to use the administration regimens disclosed by US’843 for administration of CC-220 in the methods of App’733 as US’843 teaches that such dosages and administration cycles were known in the art for compounds with the structure of CC-220. An ordinarily skilled artisan would have had a reasonable expectation of success as US’843 teaches the use of the compound in the co-stimulation of T cells and in the treatment of diseases including multiple myeloma, NHL, and Burkitt Lymphoma demonstrating a nexus across the references.
Regarding 47-50, 53-54, 57-64, 68, 70-71, and 79-80, it would have been prima facie obvious to one of ordinary skill in the art to modify the method of App’733 modified by Otahal, Matyskiela, US’843, and WO’207 to use the CD19 CAR T cells of WO’207 and to have administered fludarabine and cyclophosphamide lymphodepleting therapy immediately prior to the administration of the T cell therapy according to the methods disclosed by WO’207.
An ordinarily skilled artisan would have been motivated to use the CD19 CAR T cells of WO’207 as WO’207 demonstrates their effective use in human studies. An ordinarily skilled artisan would have had a reasonable expectation of success as, like in the method claimed by App’337, the CAR T cells of WO’207 target CD19. Additionally, WO’207 teaches the use of the CARs in methods of treating NHL, including subtypes claimed by App’733. The CAR taught by WO’207 also comprises a 4-1BB costimulatory and CD3 zeta intracellular signaling domain, which is the same combination of signaling domains used in the CAR disclosed by Otahal and taught to synergize with the immunomodulatory agent lenalidomide.
An ordinarily skilled artisan would be motivated to administer the lymphodepletion therapy disclosed by WO’207 prior to the administration of the CAR T cells in order to reduce tumor burden prior to administration of the T cells and to improve the efficacy of the transferred cells as disclosed by WO’207. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’207 demonstrates the use of the disclosed lymphodepletion regimens prior to the administration of CD19 CAR T cells, which is the same CAR T cell target claimed in App’733, in the treatment of NHL cancers, including subtypes also claimed in App’733.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant does not provide any response concerning the rejection of the claims under nonstatutory double patenting in the response filed 11/14/2025 and the rejections are maintained.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693