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.
Priority
The instant application, filed 10/20/2020, claims domestic benefit to US provisional application 62/924,044, filed 10/21/2019.
Status of Application, Amendments, and/or Claims
Applicant’s response of 10/14/2025 is acknowledged. No claims were amended. Claims 1, 3-5, 7, 10-90, 92-115, 121-124, and 129-130 are cancelled. Claims 2, 6, 8-9, 91, 116-120, 125-128, and 131-148 are currently pending and are examined on the merits herein.
The following rejections are maintained.
Nonstatutory 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
US Patent No 11,390,617 B2
Claims 2, 6, 8, 116-118, 125-127, 131-133, 136-138, 141-143, and 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 11,390,617 (herein US’617) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
US’617 claims a method of treating non-Hodgkin lymphoma comprising administering to a subject having NHL, a therapeutically effective amount of compounds 1, 2, or 3, having the recited formulas, or an enantiomer, mixture of enantiomers, tautomer, or pharmaceutically acceptable salt thereof. Compounds 1, 2, and 3 of US’617 match the compound of Formula (I) and the compound configurations of the instantly claimed invention. For instance, see compound 3 below:
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US’617 claims the further administration of a therapeutically effective amount of rituximab, which is an anti-CD20 antibody.
The claims of US’617 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of diagnosing patients who are likely to be responsive to treatment.
Girona teaches methods of identifying or selecting subjects who are likely to be responsive to treatment, predicting patient response, and methods of treating (columns 11 and 12) using cereblon (CRBN) as a biomarker (column 11, lines 63-64; column 243, line 43). The methods taught by Girona include obtaining biological samples from patients and measuring the presence or absence of CRBN before treatment to select patients as well as before and after treatment as a means of assessing patient response (column 11, lines, lines 63-64). Girona further teaches that an increased level of biomarker expression after treatment indicates the likelihood of an effective response (column 12, lines 25-35). Girona teaches that the patient is diagnosed as having a drug-sensitive cancer if a higher than baseline level of CBRN is determined to be present in the sample. The patient is then administered a therapeutically effective amount of the drug (column 243, claim 1).
Girona further teaches that the biomarker can be a gene or protein associated with CRBN including IRF4 (column 13, lines 5-9). Girona teaches that a higher baseline level of IRF4 indicates a higher likelihood that the cancer will be sensitive to treatment (column 12, lines 49-64).
Girona teaches that the biomarker is measured by gene or protein expression analysis (column 11, line 66 – column 12, line 1) and that the hematological cancer is chronic lymphocytic leukemia (CLL) (column 12, line 39) or non-Hodgkin’s lymphoma (column 12, lines 35-40). Girona further teaches that the cancer is relapsed or refractory diffuse large B-cell lymphoma (column 17, lines 5-15).
The treatment compounds taught by Girona include thalidomide, lenalidomide, and pomalidomide (column 8, lines 22-41).
Girona further teaches that compounds can be combined with other pharmacologically active compounds (“second active agents”) in the methods disclosed (column 35, lines 11-13). Girona discloses that antibodies that can be used in combination with the compound include monoclonal and polyclonal antibodies including rituximab (column 36, lines 10-14), which is an anti-CD20 antibody.
The compound of US’617 comprises a core structure of pomalidomide as evidenced by Hanaizi which teaches the structures of thalidomide, lenalidomide, and pomalidomide (page 331, Figure 1). A comparison of the structure claimed in US’617 and pomalidomide is shown below with the Pomalidomide core of the compound of US’617 identified with a gray box:
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Gandhi teaches that CRBN is required for the anti-proliferative activity of lenalidomide and pomalidomide in MM cells. CRBN also mediates the T cell co-stimulation by lenalidomide and pomalidomide because knockdown of CRBN expression in primary human T cells abrogates the drug-induced IL2 expression (paragraph bridging pages 811 and 812). Gandhi reports that members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos encoded by the IKZF1 and IKZF3 genes, respectively, are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment. Degradation of these substrates by lenalidomide or pomalidomide results in enhanced production of IL2 and other cytokines known to regulate T cell function. Ikaros and Aiolos are biologically relevant substrates because they are known negative regulators of IL2 expression (page 812, left column, paragraph 2).
Gandhi demonstrates that lenalidomide and pomalidomide promote the concentration and time-dependent degradation of Aiolos and Ikaros in activated T cells within hours of drug treatment. Drug binding to Cereblon promotes its coprecipitation with Aiolos and Ikaros. Furthermore, Gandhi demonstrates that Cereblon is required for Aiolos and Ikaros degradation by lenalidomide or pomalidomide as Cereblon knockdown in T cells protects the substrate proteins from drug-induced degradation. Additionally, lenalidomide and pomalidomide induced T cell co-stimulation can be the consequence of Aiolos and Ikaros degradation, consistent with effects mediated through increased association of these substrates to the E3 ligase complex during drug binding to Cereblon (page 819, paragraph bridging columns).
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’617 to include the methods of Girona in which patients are selected for the therapy based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. It would have further been obvious to one of ordinary skill in the art that the expression level of IRF4, IL-2, Ikaros and/or Aiolos would decrease following treatment in subjects who are responsive to therapy based on the teachings of Girona and Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and teachings of Gandhi with the methods claimed in US’617 in order to treat patients who are most likely to be responsive to the therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Gandhi with the methods of US’617 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’617.
Claims 9, 119, 128, 134, 139, and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 11,390,617 (herein US’617) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), US 2016/0222118 A1 (Chen, D.S., et al) 04 AUG 2016 and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’617 are as discussed above.
The claims of US’617 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of adjusting the dosage and frequency of treatment based on the biomarker assessment.
The teachings of Girona and Hanaizi are as discussed above.
Chen teaches a method in which a subject’s response to treatment with a PD-L1 axis binding antagonist is evaluated by (a) determining the level(s) of one or more biomarkers in a biological sample derived from the individual at a time point during or after administration of the PD-L1 antagonist and (b) maintaining, adjusting, or stopping the treatment of the individual based on a comparison of the level(s) of one or more biomarkers in the biological sample with reference levels, wherein a change in level(s) of one or more biomarkers in the biological sample compared to the reference levels is indicative of response to treatment (page 3, [0035]).
The teachings of Gandhi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’617 to include the methods of Girona and Chen in which treatment is monitored and dosages and/or frequencies of therapy are adjusted based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Chen and teachings of Gandhi with the methods claimed in US’617 in order to effectively treat patients who are identified as being non-responsive to therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona, Chen, and Gandhi with the methods of US’617 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’617.
Claims 91, 120, 135, 140, 145, and 148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 11,390,617 (herein US’617) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Li, S., et al (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation Blood advances 2(5); 492-504 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’617 are as discussed above.
The claims of US’617 differ from the instantly claimed invention in that the instant claims are drawn to the use of the biomarker Ikaros in methods of identifying subjects who are not likely to have cytotoxicity in non-cancerous cells.
The teachings of Girona and Hanaizi are as discussed above.
Li teaches that it has been previously shown that immunomodulatory drugs (IMiD) compounds induce a shift into immature myeloid precursors with a maturational arrest and subsequent neutropenia (abstract). Li teaches that IMiDs inhibit myeloma cell growth, block cytokine production, impair angiogenesis, and enhance T cell stimulation and proliferation leading to MM cell death and that such drugs include thalidomide and its derivatives lenalidomide and pomalidomide. Li further teaches that these compounds bind cereblon (CRBN) and that research has suggested that the compounds act by stabilizing CRBN substrates (page 492, paragraph 1). Li teaches that the down regulation of IKZF1 (Ikaros) contributes to the POM-induced cell lineage shift toward myelopoiesis. Therefore, inhibition of IKZF1 expression by IMiD compounds might also promote leukemogenesis in pre-B cells and subsequently contribute to second primary malignancy. Indeed, there is a slightly higher risk for leukemias and B-cell malignancies in patients treated with IMiD compounds (page 502, left column, paragraph 2). Li teaches the roles of CRBN and IKZF1 in IMiD induced effects providing the first evidence of pathomechanisms underlying the effects of LEN and POM on hematopoiesis and their induction of neutropenia, thrombocytopenia, and anemia (page 502, right column, paragraph 3). Li teaches that loss of IKZF1 is associated with a decrease of PU.1, critical for the development and maturation of neutrophils (abstract; Key points box).
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’617 to include the methods of Girona and Li and to monitor the expression of Ikaros in neutrophils during treatment to assess toxicity to non-cancerous cells. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Li with the methods claimed in US’617 in order to monitor the development of neutropenia, thrombocytopenia, and anemia and potentially additional second malignancy as Li teaches that IKZF1 is downregulated following treatment with IMiDs and that such downregulation causes these toxic side effects. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Li with the methods of US’617 as Girona and Li are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’617.
US Patent No 11,578,056 B2
Claims 2, 6, 8, 116-118, 125-127, 131-133, 136-138, 141-143, and 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No 11,578,056 B2 (herein “US’056”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’056 are drawn to a solid form of a free base or a salt of Compound 1 and a pharmaceutical composition comprising the compound. Compound 1 of US’056 matches the compound of Formula (I) of the instantly claimed invention and comprises a core structure that matches that of pomalidomide.
The claims of US’056 differ from the instantly claimed invention in that the instantly claimed invention is drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and using the recited biomarkers for identifying subjects as likely to respond to the compound.
The teachings of Girona, Gandhi, and Hanaizi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’056 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or r/r DLBCL. It would have been obvious to use the compound disclosed by US’056 in the treatment of CLL, NHL, or DLBCL as Girona teaches compounds, such as pomalidomide, which has the same core structure as the compound claimed by US’056 in the treatment of such diseases.
It would further have been obvious to have selected patients for the therapy based on the expression of CRBN related proteins relative to a baseline as taught by Girona and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. It would have further been obvious to one of ordinary skill in the art that the expression level of IRF4, IL-2, Ikaros and/or Aiolos would decrease following treatment in subjects who are responsive to therapy based on the teachings of Girona and Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and teachings of Gandhi with the methods claimed in US’056 in order to treat patients who are most likely to be responsive to the therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Gandhi with the methods of US’056 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’056.
Claims 9, 119, 128, 134, 139, and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No 11,578,056 B2 (herein “US’056”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), US 2016/0222118 A1 (Chen, D.S., et al) 04 AUG 2016 and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’056 are as discussed above.
The claims of US’056 differ from the instantly claimed invention in that the instant claims are drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and the use of the recited biomarkers in methods of adjusting the dosage and frequency of treatment based on the biomarker assessment.
The teachings of Girona, Hanaizi, Chen, and Gandhi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’056 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or DLBCL, and to include the methods of Chen in which treatment is monitored and dosages and/or frequencies of therapy are adjusted based. It would have further been obvious to use the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Chen and teachings of Gandhi with the methods claimed in US’056 in order to effectively treat patients who are identified as being non-responsive to therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona, Chen, and Gandhi with the methods of US’056 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’056.
Claims 91, 120, 135, 140, 145, and 148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No 11,578,056 B2 (herein “US’056”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Li, S., et al (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation Blood advances 2(5); 492-504 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’056 are as discussed above.
The claims of US’056 differ from the instantly claimed invention in that the instant claims are drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and the use of the biomarker Ikaros in methods of identifying subjects who are not likely to have cytotoxicity in non-cancerous cells.
The teachings of Girona, Hanaizi, and Li are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’056 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or DLBCL, and to monitor the expression of Ikaros in neutrophils during treatment to assess toxicity to non-cancerous cells. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Li with the compound claimed in US’056 in order to monitor the development of neutropenia, thrombocytopenia, and anemia and potentially additional second malignancy as Li teaches that IKZF1 is downregulated following treatment with IMiDs and that such downregulation causes these toxic side effects. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Li with the compound claimed in US’056 as Girona and Li are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’056.
US Patent No 11,504,378 B2
Claims 2, 6, 8, 116-118, 125-127, 131-133, 136-138, 141-143, and 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of U.S. Patent No 11,504,378 B2 (herein “US’378”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’378 are drawn to pharmaceutical compositions of compound 1. Compound 1 of US’378 matches the compound of Formula (I) of the instantly claimed invention and has a core structure that matches the structure of pomalidomide.
The claims of US’378 differ from the instantly claimed invention in that the instantly claimed invention is drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and using the recited biomarkers for identifying subjects as likely to respond to the compound.
The teachings of Girona, Gandhi, and Hanaizi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’378 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or DLBCL. It would have been obvious to use the compound disclosed by US’378 in the treatment of CLL, NHL, or DLBCL as Girona teaches compounds, such as pomalidomide, which has the same core structure as the compound claimed by US’378 in the treatment of such diseases.
It would further have been obvious to have selected patients for the therapy based on the expression of CRBN related proteins relative to a baseline as taught by Girona and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. It would have further been obvious to one of ordinary skill in the art that the expression level of IRF4, IL-2, Ikaros and/or Aiolos would decrease following treatment in subjects who are responsive to therapy based on the teachings of Girona and Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and teachings of Gandhi with the methods claimed in US’378 in order to treat patients who are most likely to be responsive to the therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Gandhi with the methods of US’378 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’378.
Claims 9, 119, 128, 134, 139, and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of U.S. Patent No 11,504,378 B2 (herein “US’378”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), US 2016/0222118 A1 (Chen, D.S., et al) 04 AUG 2016 and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’378 are as discussed above.
The claims of US’378 differ from the instantly claimed invention in that the instant claims are drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and the use of the recited biomarkers in methods of adjusting the dosage and frequency of treatment based on the biomarker assessment.
The teachings of Girona, Hanaizi, Chen, and Gandhi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’378 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or DLBCL, and to include the methods of Chen in which treatment is monitored and dosages and/or frequencies of therapy are adjusted based. It would have further been obvious to use the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Chen and teachings of Gandhi with the methods claimed in US’378 in order to effectively treat patients who are identified as being non-responsive to therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona, Chen, and Gandhi with the methods of US’378 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’378.
Claims 91, 120, 135, 140, 145, and 148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of U.S. Patent No 11,504,378 B2 (herein “US’378”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Li, S., et al (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation Blood advances 2(5); 492-504 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’378 are as discussed above.
The claims of US’378 differ from the instantly claimed invention in that the instant claims are drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and the use of the biomarker Ikaros in methods of identifying subjects who are not likely to have cytotoxicity in non-cancerous cells.
The teachings of Girona, Hanaizi, and Li are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’378 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or DLBCL, and to monitor the expression of Ikaros in neutrophils during treatment to assess toxicity to non-cancerous cells. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Li with the composition claimed in US’378 in order to monitor the development of neutropenia, thrombocytopenia, and anemia and potentially additional second malignancy as Li teaches that IKZF1 is downregulated following treatment with IMiDs and that such downregulation causes these toxic side effects. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Li with the composition claimed in US’378 as Girona and Li are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’378.
US Patent No 11,666,579 B2
Claims 2, 6, 8, 116-118, 125-127, 131-133, 136-138, 141-143, and 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of US Patent No 11,666,579 B2 (herein “US’579”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
US’579 claims a method of treating a hematological malignancy, comprising to a subject having the hematological malignancy a therapeutically effective amount of Compounds 1-3 or an enantiomer, mixture of enantiomers, tautomer, isotoplog, or pharmaceutical salt thereof. Compounds 1-3 of US’579 match the compound of Formula (I) of the instantly claimed invention and comprises a core structure that matches pomalidomide.
US’579 further claims that the hematological malignancy is marginal zone lymphoma, which is a form (species) of Non-Hodgkin’s lymphoma. US’579 further claims that the hematological malignancy is relapsed or refractory.
The claims of US’579 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of diagnosing patients who are likely to be responsive to treatment.
The teachings of Girona, Gandhi, and Hanaizi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’579 to include the methods of Girona in which patients are selected for the therapy based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. It would have further been obvious to one of ordinary skill in the art that the expression level of IRF4, IL-2, Ikaros and/or Aiolos would decrease following treatment in subjects who are responsive to therapy based on the teachings of Girona and Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and teachings of Gandhi with the methods claimed in US’579 in order to treat patients who are most likely to be responsive to the therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Gandhi with the methods of US’579 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’579.
Claims 9, 119, 128, 134, 139, and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of US Patent No 11,666,579B2 (herein “US’579”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), US 2016/0222118 A1 (Chen, D.S., et al) 04 AUG 2016 and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’579 are as discussed above.
The claims of US’579 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of adjusting the dosage and frequency of treatment based on the biomarker assessment.
The teachings of Girona, Hanaizi, Chen, and Gandhi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’579 to include the methods of Girona and Chen in which treatment is monitored and dosages and/or frequencies of therapy are adjusted based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Chen and teachings of Gandhi with the methods claimed in US’579 in order to effectively treat patients who are identified as being non-responsive to therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona, Chen, and Gandhi with the methods of US’579 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’579.
Claims 91, 120, 135, 140, 145, and 148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of US Patent No 11,666,579 B2 (herein “US’579”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Li, S., et al (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation Blood advances 2(5); 492-504 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’579 are as discussed above.
The claims of US’579 differ from the instantly claimed invention in that the instant claims are drawn to the use of the biomarker Ikaros in methods of identifying subjects who are not likely to have cytotoxicity in non-cancerous cells.
The teachings of Girona, Hanaizi, and Li are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’579 to include the methods of Girona and Li and to monitor the expression of Ikaros in neutrophils during treatment to assess toxicity to non-cancerous cells. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Li with the methods claimed in US’579 in order to monitor the development of neutropenia, thrombocytopenia, and anemia and potentially additional second malignancy as Li teaches that IKZF1 is downregulated following treatment with IMiDs and that such downregulation causes these toxic side effects. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Li with the methods of US’579 as Girona and Li are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’579.
US Patent No 11,583,536 B2
Claims 2, 6, 8, 116-118, 125-127, 131-133, 136-138, 141-143, and 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No 11,583,536 B2 (herein “US’536”) in view of in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’536 are drawn to methods of treating hematological malignancies comprising administering to a patient the compound of Compound 1 and a second active agent of an EZH2 inhibitor. US’536 further claim that the hematological malignancy is a non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia/small cell lymphocytic leukemia (CLL/SLL), DLBCL, or relapsed or refractory DLBCL. Compound 1 of US’536 is identical to that of the instant claims and comprises a core structure matching pomalidomide.
The claims of US’536 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of diagnosing patients who are likely to be responsive to treatment.
The teachings of Girona, Gandhi, and Hanaizi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’536 to include the methods of Girona in which patients are selected for the therapy based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. It would have further been obvious to one of ordinary skill in the art that the expression level of IRF4, IL-2, Ikaros and/or Aiolos would decrease following treatment in subjects who are responsive to therapy based on the teachings of Girona and Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and teachings of Gandhi with the methods claimed in US’536 in order to treat patients who are most likely to be responsive to the therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Gandhi with the methods of US’536 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’536.
Claims 9, 119, 128, 134, 139, and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No 11,583,536 B2 (herein “US’536”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), US 2016/0222118 A1 (Chen, D.S., et al) 04 AUG 2016 and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’536 are as discussed above.
The claims of US’536 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of adjusting the dosage and frequency of treatment based on the biomarker assessment.
The teachings of Girona, Hanaizi, Gandhi, and Chen are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’536 to include the methods of Girona and Chen in which treatment is monitored and dosages and/or frequencies of therapy are adjusted based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Chen and teachings of Gandhi with the methods claimed in US’536 in order to effectively treat patients who are identified as being non-responsive to therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona, Chen, and Gandhi with the methods of US’536 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’536.
Claims 91, 120, 135, 140, 145, and 148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No 11,583,536 B2 (herein “US’536”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Li, S., et al (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation Blood advances 2(5); 492-504 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’536 are as discussed above.
The claims of US’536 differ from the instantly claimed invention in that the instant claims are drawn to the use of the biomarker Ikaros in methods of identifying subjects who are not likely to have cytotoxicity in non-cancerous cells.
The teachings of Girona, Hanaizi, and Li are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’536 to include the methods of Girona and Li and to monitor the expression of Ikaros in neutrophils during treatment to assess toxicity to non-cancerous cells. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Li with the methods claimed in US’536 in order to monitor the development of neutropenia, thrombocytopenia, and anemia and potentially additional second malignancy as Li teaches that IKZF1 is downregulated following treatment with IMiDs and that such downregulation causes these toxic side effects. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Li with the methods of US’536 as Girona and Li are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’536.
US Patent No 12,103,923 B2
Claims 2, 6, 8, 116-118, 125-127, 131-133, 136-138, 141-143, and 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No 12,103,923 B2 (herein “US’923”) in view of in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’923 are drawn to methods of treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL), comprising administering to a subject having the relapsed or refractory DLBCL a therapeutically effective amount of compound 1. Compound 1 of US’923 is identical to that of the instant claims and comprises a core structure matching pomalidomide.
The claims of US’923 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of diagnosing patients who are likely to be responsive to treatment.
The teachings of Girona, Gandhi, and Hanaizi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’923 to include the methods of Girona in which patients are selected for the therapy based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. It would have further been obvious to one of ordinary skill in the art that the expression level of IRF4, IL-2, Ikaros and/or Aiolos would decrease following treatment in subjects who are responsive to therapy based on the teachings of Girona and Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and teachings of Gandhi with the methods claimed in US’923 in order to treat patients who are most likely to be responsive to the therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Gandhi with the methods of US’923 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’923.
Claims 9, 119, 128, 134, 139, and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No 12,103,923 B2 (herein “US’923”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), US 2016/0222118 A1 (Chen, D.S., et al) 04 AUG 2016 and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’923 are as discussed above.
The claims of US’923 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of adjusting the dosage and frequency of treatment based on the biomarker assessment.
The teachings of Girona, Hanaizi, Gandhi, and Chen are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’923 to include the methods of Girona and Chen in which treatment is monitored and dosages and/or frequencies of therapy are adjusted based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Chen and teachings of Gandhi with the methods claimed in US’923 in order to effectively treat patients who are identified as being non-responsive to therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona, Chen, and Gandhi with the methods of US’536 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’923.
Claims 91, 120, 135, 140, 145, and 148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No 12,103,923 B2 (herein “US’923”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Li, S., et al (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation Blood advances 2(5); 492-504 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’923 are as discussed above.
The claims of US’923 differ from the instantly claimed invention in that the instant claims are drawn to the use of the biomarker Ikaros in methods of identifying subjects who are not likely to have cytotoxicity in non-cancerous cells.
The teachings of Girona, Hanaizi, and Li are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’923 to include the methods of Girona and Li and to monitor the expression of Ikaros in neutrophils during treatment to assess toxicity to non-cancerous cells. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Li with the methods claimed in US’923 in order to monitor the development of neutropenia, thrombocytopenia, and anemia and potentially additional second malignancy as Li teaches that IKZF1 is downregulated following treatment with IMiDs and that such downregulation causes these toxic side effects. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Li with the methods of US’923 as Girona and Li are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’923.
US Patent No 11,628,172 B2
Claims 2, 6, 8, 116-118, 125-127, 131-133, 136-138, 141-143, and 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No 11,628,172 B2 (herein “US’172”) in view of in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’172 are drawn to methods of treating CLL or SLL, comprising administering to a subject having CLL/SLL a therapeutically effective amount of compound 3. Compound 3 of US’172 is identical to that of the instant claims and comprises a core structure matching pomalidomide.
The claims of US’172 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of diagnosing patients who are likely to be responsive to treatment.
The teachings of Girona, Gandhi, and Hanaizi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’172 to include the methods of Girona in which patients are selected for the therapy based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. It would have further been obvious to one of ordinary skill in the art that the expression level of IRF4, IL-2, Ikaros and/or Aiolos would decrease following treatment in subjects who are responsive to therapy based on the teachings of Girona and Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and teachings of Gandhi with the methods claimed in US’172 in order to treat patients who are most likely to be responsive to the therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Gandhi with the methods of US’172 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’172.
Claims 9, 119, 128, 134, 139, and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No 11,628,172 B2 (herein “US’172”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), US 2016/0222118 A1 (Chen, D.S., et al) 04 AUG 2016 and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’172 are as discussed above.
The claims of US’172 differ from the instantly claimed invention in that the instant claims are drawn to the use of the recited biomarkers in methods of adjusting the dosage and frequency of treatment based on the biomarker assessment.
The teachings of Girona, Hanaizi, Gandhi, and Chen are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’172 to include the methods of Girona and Chen in which treatment is monitored and dosages and/or frequencies of therapy are adjusted based on the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Chen and teachings of Gandhi with the methods claimed in US’172 in order to effectively treat patients who are identified as being non-responsive to therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona, Chen, and Gandhi with the methods of US’172 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’172.
Claims 91, 120, 135, 140, 145, and 148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No 11,628,172 B2 (herein “US’172”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Li, S., et al (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation Blood advances 2(5); 492-504 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’172 are as discussed above.
The claims of US’172 differ from the instantly claimed invention in that the instant claims are drawn to the use of the biomarker Ikaros in methods of identifying subjects who are not likely to have cytotoxicity in non-cancerous cells.
The teachings of Girona, Hanaizi, and Li are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’172 to include the methods of Girona and Li and to monitor the expression of Ikaros in neutrophils during treatment to assess toxicity to non-cancerous cells. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Li with the methods claimed in US’172 in order to monitor the development of neutropenia, thrombocytopenia, and anemia and potentially additional second malignancy as Li teaches that IKZF1 is downregulated following treatment with IMiDs and that such downregulation causes these toxic side effects. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Li with the methods of US’172 as Girona and Li are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’172.
US Patent No 12,178,822 B2
Claims 2, 6, 8, 116-118, 125-127, 131-133, 136-138, 141-143, and 146-147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No 12,178,822 B2 (herein “US’822”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’822 are drawn to a method of treating a hematological malignancy comprising administering to a subject in need thereof an effective amount of compound 1. Compound 1 of US’822 matches the compound of Formula (I) of the instantly claimed invention and has a core structure that matches the structure of pomalidomide.
The claims of US’822 differ from the instantly claimed invention in that the instantly claimed invention is drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and using the recited biomarkers for identifying subjects as likely to respond to the compound.
The teachings of Girona, Gandhi, and Hanaizi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’822 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or DLBCL. It would have been obvious to use the compound disclosed by US’822 in the treatment of CLL, NHL, or DLBCL as Girona teaches compounds, such as pomalidomide, which has the same core structure as the compound claimed by US’822 in the treatment of such diseases.
It would further have been obvious to have selected patients for the therapy based on the expression of CRBN related proteins relative to a baseline as taught by Girona and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. It would have further been obvious to one of ordinary skill in the art that the expression level of IRF4, IL-2, Ikaros and/or Aiolos would decrease following treatment in subjects who are responsive to therapy based on the teachings of Girona and Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and teachings of Gandhi with the methods claimed in US’822 in order to treat patients who are most likely to be responsive to the therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Gandhi with the methods of US’822 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’822.
Claims 9, 119, 128, 134, 139, and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No 12,178,822 B2 (herein “US’822”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”), US 2016/0222118 A1 (Chen, D.S., et al) 04 AUG 2016 and Gandhi, A.K., et al (2013) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN British Journal of Haematology 164; 811-821 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’822 are as discussed above.
The claims of US’822 differ from the instantly claimed invention in that the instant claims are drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and the use of the recited biomarkers in methods of adjusting the dosage and frequency of treatment based on the biomarker assessment.
The teachings of Girona, Hanaizi, Chen, and Gandhi are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’822 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or DLBCL, and to include the methods of Chen in which treatment is monitored and dosages and/or frequencies of therapy are adjusted based. It would have further been obvious to use the expression of CRBN related proteins relative to a baseline and to have used IRF4 as taught by Girona or Ikaros and/or Aiolos as taught by Gandhi as the CRBN associated markers. Alternatively, it would have been obvious to use IL-2 as the marker based on the teachings of Gandhi. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Chen and teachings of Gandhi with the methods claimed in US’822 in order to effectively treat patients who are identified as being non-responsive to therapy. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona, Chen, and Gandhi with the methods of US’822 as Girona and Gandhi are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’822.
Claims 91, 120, 135, 140, 145, and 148 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No 12,178,822 B2 (herein “US’822”) in view of US 9,365,640 B2 (Lopez-Girona, A., et al) 14 JUN 2016 (herein “Girona”) and Li, S., et al (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation Blood advances 2(5); 492-504 as evidenced by Hanaizi, Z., et al (2015) The European Medicines Agency review of Pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use The Oncologist 20; 329-334.
The claims of US’822 are as discussed above.
The claims of US’822 differ from the instantly claimed invention in that the instant claims are drawn to the use of the compound in methods of treating subjects having a hematological cancer, specifically NHL, CLL, or SLL, and the use of the biomarker Ikaros in methods of identifying subjects who are not likely to have cytotoxicity in non-cancerous cells.
The teachings of Girona, Hanaizi, and Li are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of US’822 with the methods taught by Girona including the use of the compound in the treatment of hematological malignancies, including CLL, NHL, or DLBCL, and to monitor the expression of Ikaros in neutrophils during treatment to assess toxicity to non-cancerous cells. An ordinarily skilled artisan would have been motivated to use the methods of Girona and Li with the composition claimed in US’822 in order to monitor the development of neutropenia, thrombocytopenia, and anemia and potentially additional second malignancy as Li teaches that IKZF1 is downregulated following treatment with IMiDs and that such downregulation causes these toxic side effects. An ordinarily skilled artisan would have had a reasonable expectation of success in using the methods of Girona and Li with the composition claimed in US’822 as Girona and Li are teaching biomarkers and methods for therapies including pomalidomide, which is the core structure in the compound claimed in US’822.
Response to Arguments
Applicant’s arguments in the response filed 10/14/2025 have been fully considered, but were not persuasive.
With regards to the nonstatutory double patenting rejections, applicant argues that the specific biomarkers for the specific compound in the claims were unknown and could not have been predicted based on structurally different compounds. Applicant argues that, contrary to the Office’s assertion, a first compound that comprises the structure of a second compound does not necessarily have the same biomarker as the second compound. Applicant argues that even small differences in overall structure can have different biomarkers and presents compound 5-hydroxythalidomide and thalidomide as an example. As discussed in the response, 5-hydroxythalidomide includes a hydroxy (-OH) moiety to the dioxopiperidine ring of thalidomide. Applicant argues that Costacurta indicates that PLZF and SALL4 degradation is mediated by both 5-hydroxythalidomide and thalidomide, but IKZF1 (Ikaros) is only degraded by thalidomide. The compounds compared by applicant are duplicated below for convenience.
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These arguments, however, are not persuasive.
As discussed in detail in the rejections of record, the claimed compound comprises the structure of pomalidomide, which is known to degrade Ikaros and Aiolos. A comparison of the structures is shown in the rejection and is duplicated below for convenience.
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As shown, the compound claimed in the US patents cited in the nonstatutory double patenting rejections differ from pomalidomide in an additional moiety that has been attached to the amino group of pomalidomide.
While the compounds cited by applicant from Costacurta may demonstrate that adding a moiety to the dioxopiperidine ring of thalidomide changes the degradation of Ikaros, these teachings do not suggest that a moiety on the opposite end of pomalidomide, attached to the amino group, would have a similar effect. Rather, the comparison of 5-hydroxythalidomide and thalidomide suggests that the structure of the dioxopiperidine ring is required for Ikaros and Aiolos degradation. This is also suggested by Figure 9 of Ghandi which shows this group interacting with CRBN, Aiolos, and Ikaros. The dioxopiperidine ring group is also shared by pomalidomide, thalidomide, and lenalidomide, all of which degrade Ikaros and Aiolos. Furthermore, the amino group on pomalidomide, to which the claimed structure has an additional moiety attached, is not present in thalidomide, suggesting that the NH2 group is not responsible for the degradation of Ikaros and Aiolos and could be altered without negatively impacting such degradation. As such, the teachings of Costacurta discussed by applicant do not demonstrate unpredictability in using Ikaros or Aiolos as biomarkers for the compound of the US patents cited.
Per MPEP 2143.02 (I), obviousness only requires a reasonable expectation of success and conclusive proof of efficacy is not required. In order to sufficiently refute the reasonable expectation of success, applicant must show that the properties are not expected. The compound referenced by applicant in Costacurta does not comprise the structure of pomalidomide, or a modification on the amino group of pomalidomide, and; therefore, the results referenced do not demonstrate a lack of predictability regarding compounds that comprise pomalidomide. Additionally, it is noted that the instant claims do not limit the degree of degradation that is required and any change to Ikaros or Aiolos, or one of the other biomarkers suggested by the applied references, could be used as a means to determine the effect of the treatment and would result in the same determination.
If applicant has data demonstrating that a compound comprising pomalidomide, modified on the amino group, does not retain the function of degrading Ikaros or Aiolos, then such data could be submitted and would be considered.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693