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 .
Application Status
The amended claims filed on October 15, 2025 with the Response to the non-final Office Action are acknowledged. Claim 131, 138-139, and 147 has been amended. Claims 154-155 are newly added.
Claims 131, 133, and 135-155 are pending and under examination herein.
Claim Rejections Withdrawn
The rejection of claims 131, 133, and 135-153 under 35 U.S.C. § 103 as being unpatentable over Korman (WO 2015/042246 A1) in view of Long (Annals of Oncology (2018) 29(11): 2208-2213), and further in view of Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674) or Taube (Clinical Cancer Research (2015) 21(17): 3969-3976), are withdrawn in view of Applicant's amendment reciting that the administering step occurs “once about every four weeks”.
NEW CLAIM REJECTIONS NECESSITATED BY CLAIM AMENDMENT
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.
(1)
Claims 131, 133, 136-139, and 143-155 are rejected under 35 U.S.C. 103 as being obvious over Sadineni (US 2017/0143827 A1; published May 25, 2017; cited in IDS) in view of Korman (WO 2015/042246 A1; cited in PTO-892 mailed February 27, 2024). This is a new rejection necessitated by claim amendment.
Sadineni discloses pharmaceutical compositions comprising a combination of an anti-cancer agent which is a first antibody and a second antibody, which are administered as a flat dose (e.g., Abstract). Relevant to claims 131 and 147-149, Sadineni discloses pharmaceutical compositions comprising “an X amount of a first antibody or an antigen-binding fragment thereof”, e.g., about 480 mg of an anti-PD-1 antibody (nivolumab), and “a Y amount of a second antibody or an antigen-binding fragment thereof”, e.g., about 160 mg of an anti-LAG-3 antibody (BMS-986016), at a X:Y ratio of about 3:1 (e.g., ¶ 0008-0012, 0140-0152). Sadineni provides methods of treating a subject afflicted with metastatic melanoma with any composition of the invention, wherein the composition is administered at least about monthly (e.g., ¶ 0039-0044, 0187-0199). Sadineni recites a specific embodiment in which “480 mg of the anti-PD-1 antibody or antigen binding fragment is administered once about once every 4 weeks” (¶ 0198). Relevant to claims 143-146, the anti-LAG-3 antibody BMS-986016 is a mono-specific human monoclonal antibody comprising a Fab fragment, and the anti-PD-1 antibody BMS-936558 is a fully human mono-specific monoclonal antibody comprising a Fab fragment.
Relevant to claims 150-151, Sadineni teaches that compositions of the invention may be administered by intravenous, intraperitoneal, or other routes of administration (e.g., ¶ 0071, 0140-0143, 0191). Relevant to claim 152, Sadineni teaches that the first and second antibodies are formulated in a single composition (e.g., ¶ 0140-0145).
Relevant to claims 154-155, Sadineni discloses compositions comprising a third antibody, which may be any antibody recited in Sadineni’s disclosure (e.g., ¶ 0174, 0187-0190). Among these are the anti-CTLA-4 antibody ipilimumab (e.g., ¶ 0011, 0029-0030).
However, Sadineni does not appear to set forth that the treatment method of the invention additionally comprises the step of determining the level of LAG-3, PD-L1, and/or BRAF V600 in a patient-derived sample (as set forth in claims 133, 139 and 142); or whether the patient to be treated possesses the characteristics set forth in claims 136-138. Sadineni also does not teach the anti-PD-1 antibody and anti-LAG-3 antibody being separately formulated (as set forth in claim 153).
Korman discloses methods for clinical treatment of tumors using an anti-LAG-3 antibody in combination with an anti-PD-1 antibody. Korman teaches that the methods of the invention may be used to treat melanoma, and that the invention is also applicable to treatment of metastatic cancers (page 17). Relevant to claims 131 and 143-149, Korman discloses methods for treating tumors in a human patient that comprise administering to the patient a combination of an anti-LAG-3 antibody (e.g., BMS-986016, which comprises the anti-LAG-3 antibody VH and VL, with respective CDRs, set forth in claims 131, 147, and 149) and an anti-PD-1 antibody (e.g., BMS-936558 or nivolumab, which comprises the anti-PD-1 antibody VH and VL, with respective CDRs, set forth in claims 131 and 148-149) (pages 3-5). Relevant to claim 136, Korman recites that the combination treatment is administered as a first line treatment (e.g., pages 6, 18-20, 45).
Korman additionally describes a phase I clinical trial in which patients received combination treatment with anti-LAG-3 antibody (BMS-986016) and anti-PD-1 antibody (BMS-936558) (see Example 10, e.g., Parts B and C). Histologic confirmation of advanced (metastatic and/or unresectable) malignancy was carried out in melanoma patients prior to treatment (e.g., pages 44-47), relevant to claim 137. The target population further comprised patients with an ECOG status of 0 or 1 and with presence of at least one lesion with measurable disease as defined by RECIST v1.1 criteria for response assessment (e.g., pages 44-48), relevant to claim 138. Relevant to claims 133 and 139, exploratory biomarker assessment (e.g., immunohistochemistry) was also carried out in tumor biopsies collected from melanoma patients to be treated with the anti-LAG-3/anti-PD-1 antibody combination to assess levels of LAG-3 and PD-L1, including a characterization of tumor-infiltrating lymphocytes (TILs) expressing LAG-3 and PD-L1 (e.g., pages 57-65). Tumor biopsies were collected before treatment (screening), during treatment (e.g., cycle 1), and optionally upon progression (e.g., pages 57-59). Korman additionally teaches that gene mutation status of BRAF was determined in melanoma patients (e.g., pages 54-55).
Relevant to claims 150-151, Korman teaches that the antibodies are formulated for intravenous administration (e.g., pages 6 and 16). Relevant to claims 152-153, Korman teaches that the antibodies are administered simultaneously (in a single formulation) or concurrently (as separate formulations) (e.g., pages 6 and 16). Korman teaches that either simultaneous or sequential administration of the therapeutic antibodies preferably results in both antibodies being simultaneously present in treated patients (pages 17-18).
Based on the teachings of Korman, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the combination treatment method taught by Sadineni (comprising administering about 160 mg of relatlimab and about 480 mg nivolumab about once per month/every four weeks) in order to optimize treatment for the specific population of patients suffering from an unresectable or metastatic melanoma tumor. The skilled artisan would have been motivated to carry out histological and exploratory biomarker assessments to determine LAG-3 and/or PD-L1 levels and to characterize the clinical status of the patient (relevant to claims 133 and 137-139) in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would have been motivated to administer the combination treatment as a first line treatment (as set forth in claim 136) because it is recognized that the patient has a clear need to be treated. The skilled artisan would have been motivated to try sequential, as opposed to simultaneous, administration of the anti-PD-1 and anti-LAG-3 antibodies (as suggested by Korman) because there are a finite number of ways in which to administer a combination treatment, and a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. There would have been a reasonable expectation of success because Sadineni and Korman each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab) for treating metastatic melanoma in a patient in need thereof.
Furthermore, as set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
(2)
Claims 131 and 135 are rejected under 35 U.S.C. 103 as being unpatentable over Sadineni (US 2017/0143827 A1; supra) in view of Korman (WO 2015/042246 A1; supra) as applied to claims 131, 133, 136-139, and 143-155 above, further in view of Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; cited in PTO-892 mailed July 16, 2025). This is a new rejection necessitated by claim amendment.
The teachings of Sadineni are recited in the 35 U.S.C. § 103 rejection above.
However, Sadineni does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor.
The teachings of Korman are recited in the 35 U.S.C. § 103 rejection above.
Sanlorenzo teaches that immunotherapies can be used as adjuvant therapy after complete surgical excision in patients with a high risk of disease relapse and as a treatment in advanced (unresectable or metastatic) stages in melanoma (Abstract). Sanlorenzo discloses that at least a few clinical trials evaluating the safety and efficacy of anti-CTLA-4 antibody ipilimumab as an adjuvant therapy in patients with resected advanced (stage III/IV) melanoma have been carried out (pages 669-670). Sanlorenzo discloses that a phase II trial in 75 patients with resected stage IIIC/IV melanoma showed that patients experienced improved outcomes with respect to relapse-free survival and overall survival after adjuvant ipilimumab therapy, and that immune-related adverse events (irAEs) were generally reversible and appeared to be associated with improved relapse-free survival (page 669). Per Sanlorenzo, immunotherapies targeting another immune checkpoint molecule, PD-1 (CD279), have also shown promise in the treatment of melanoma (page 670). Two exemplary anti-PD-1 monoclonal antibodies, BMS-936558 (nivolumab) and MK-3475, both displayed favorable response rates and fewer grade 3-4 irAEs (page 670). Sanlorenzo notes that in patients administered 3 mg/kg nivolumab biweekly appear to display higher response rates and a more beneficial side effects profile (e.g., lower incidence of irAEs, especially grade 3-4) relative to those patients administered ipilimumab (page 670).
In addition, Sanlorenzo teaches that studies have demonstrated synergy between PD-1 and LAG-3 pathways in inducing tolerance to self and tumor antigens, and that a dual blockade of these molecules represents a promising combinatorial strategy for cancer therapy (page 671). Sanlorenzo additionally notes that melanoma cells often express MHC class II molecules and that the LAG-3-MHC II interaction protects tumor cells from apoptosis.
In view of the further teachings of Sanlorenzo, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a combination method of treatment for metastatic or unresectable melanoma that comprises administering to a patient in need thereof about 160 mg of relatlimab and about 480 mg nivolumab once about every four weeks (as collectively taught by Sadineni and Korman), as an adjuvant therapy after surgery. The skilled artisan would have been motivated to do so because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
(3)
Claims 131, 133, and 139-142 are rejected under 35 U.S.C. 103 as being unpatentable over Sadineni (US 2017/0143827 A1; supra) in view of Korman (WO 2015/042246 A1; supra) as applied to claims 131, 133, 136-139, and 143-155 above, and further in view of Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; cited in PTO-892 mailed July 16, 2025).
The teachings of Sadineni are recited in the 35 U.S.C. § 103 rejection above.
However, Sadineni does not expressly teach determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3.
The teachings of Korman, with respect to determining the expression of LAG-3 and PD-L1 in tumor samples prior to and during treatment, are recited in the 35 U.S.C. § 103 rejection above.
Taube teaches that aberrant expression of PD-L1 in cancers facilitates adaptive immune resistance, and that research suggests PD-L1 expression on tumor cells and/or leukocytes in the tumor microenvironment (TME) may predict response to PD-1 pathway blockade (Introduction). Taube further discloses that a recent study suggests that leukocyte expression of PD-L1 is most predictive of response to an anti-PD-L1 antibody (Introduction). Taube previously found that PD-L1+ melanomas express PD-L1 on both tumor and monocytic cells (Introduction). Taube recites, “understanding TME factors that coordinately influence PD-L1 expression on tumor cells and/or leukocytes is essential in augmenting the clinical impact of anti-PD-1/PD-L1 therapies. Such factors may warrant further study as candidate biomarkers of clinical outcomes to PD-1 blockade, or as cotargets for developing synergistic combination therapies with anti-PD-1/PD-L1” (Introduction). Taube additionally teaches that antibodies that interrupt the PD-1/PD-L1 pathway have durable efficacy in patients with advanced melanoma and other cancers (Introduction).
Relevant to claims 133 and 139, Taube characterized expression of PD-L1 and LAG-3 in metastatic melanoma specimens (Methods). “PD-L1+” was defined as ≥5% of tumor cells showing cell surface staining with a murine anti-human PD-L1 antibody, and the geographic association of PD-L1 expression with TILs was also noted (Methods). Cases where ≥5% of TILs expressed LAG-3 were considered LAG-3 positive (Methods).
Taube discloses that while there is a general association between the presence of TILs and PD-L1 expression, a significant number of TIL-infiltrated tumors do not express PD-L1 (relevant to claim 142), and PD-L1(-) melanoma cases had more modest immune infiltrates (Results, page 3971). Taube also discloses that PD-1 (PDCD1) and LAG-3 are coordinately expressed in the PD-L1+ (CD274+) TME (e.g., Results, page 3972; Figure 2). Relevant to claims 140-141, Taube discloses, “Eleven of 12 cases (92%) demonstrating tumor cell PD-L1 protein expression at the interface between tumor and lymphocytes also showed LAG-3 protein expression by at least 5% of those lymphocytes (Fig. 3 and Supplementary Fig. S1). In contrast, only 2 of 13 (15%) of cases that were PD-L1(-) expressed LAG-3 (P = 0.0002, Fisher exact test). Thus, LAG-3+ TILs significantly colocalized with PD-L1+ melanoma cells” (Results, page 3972; Figure 3; Supplementary Figure S1). Taube teaches that although LAG-3 appears to be subdominant in the hierarchy of intratumoral immunosuppression, it may nevertheless provide a bypass mechanism for melanoma tumor cells to evade anti-PD-1/PD-L1 therapies, suggesting opportunities for cotargeted combination treatment regimens (Discussion). Taube further teaches that LAG-3 blockade synergizes with anti-PD-1 in murine tumor models (Discussion).
Based on the further teachings of Taube, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a combination method of treatment for metastatic or unresectable melanoma that comprises administering to a patient in need thereof about 160 mg of relatlimab and about 480 mg nivolumab once about every four weeks (as collectively taught by Sadineni and Korman), which further comprises the step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and wherein at least about 5% of cells are TILs expressing LAG-3. The skilled artisan would have been motivated to do so because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
NEW CLAIM REJECTIONS
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.
(1)
Claims 131, 133, 135, and 139-155 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 10,081,681 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The reference patent claims a method of treating melanoma in a human patient who has previously been treated with anti-PD-1 or anti-PD-L1 antibody therapy, which comprises administering 80 mg of an anti-LAG-3 antibody and 240 mg of an anti-PD-1 antibody over at least one two-week administration cycle, wherein the respective antibodies have heavy chain and light chain amino acid sequences (and corresponding CDRs) sharing 100% sequence identity to those recited in claims 131 and 143-149 (patented claims 1 and 10-16). Relevant to claims 150-151, the anti-PD-1 and anti-LAG-3 antibodies are formulated for intravenous administration (patented claim 3). Relevant to claims 152-153, the anti-PD-1 and anti-LAG-3 antibodies are formulated together or separately (patented claims 4-5 and 7-8).
The reference patent further claims that the method further comprises administering ipilimumab (patented claims 2 and 18), relevant to claims 154-155.
While the reference patent does not expressly claim treating unresectable or metastatic melanoma, by administering a dose of about 160 mg of the anti-LAG-3 antibody and about 480 mg of the anti-PD-1 antibody once about every four weeks, this deficiency is remedied by Sadineni (supra) and the skilled artisan could have arrived at such a method through the process of routine optimization. One of ordinary skill in the art would also recognize that patients with unresectable or metastatic melanoma have a clear need to be treated. There would have been a reasonable expectation of success because the reference patent and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), in a dosing ratio of 3:1, for treating metastatic melanoma in a patient in need thereof.
Furthermore, regarding claims 133 and 139-142, although the reference patent does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and to administer the combination therapy when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Furthermore, regarding claim 135, although the reference patent does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
(2)
Claims 131, 133, and 135-155 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of U.S. Patent No. 10,266,591 in view of Sadineni (US 2017/0143827 A1; supra) and Korman (WO 2015/042246 A1; supra), and further in view of Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The reference patent claims a method of stimulating an immune response which comprises administering a full-length human anti-LAG-3 antibody or antigen-binding fragment thereof comprising identical CDRs/variable regions to those recited in claims 131, 143-147, and 149 (patented claims 1-6, 9, 35-37), which further comprises additionally administering an anti-PD-1 antibody (nivolumab), relevant to claims 131 and 148-149 (patented claims 14-15, 18-19, 33). Relevant to claims 152-153, the reference patent recites that the antibodies may be administered separately or concurrently as a single composition (patented claims 20-22).
While the reference patent does not expressly claim that the combination of antibodies are intravenously administered to treat unresectable or metastatic melanoma, at a dose of about 160 mg of the anti-LAG-3 antibody and about 480 mg of the anti-PD-1 antibody once about every four weeks, or that a third immune checkpoint inhibitor (ipilimumab) is administered, relevant to claims 131, 150-151, and 154-155, these deficiencies are remedied by Sadineni (supra) and Korman (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization. The skilled artisan would have been motivated to do so because Sadineni and Korman teach that the combined administration of nivolumab (anti-PD-1 antibody) and relatlimab (anti-LAG-3 antibody) is effective for treating metastatic melanoma. There would have been a reasonable expectation of success because, as set forth by Sadineni and Korman, PD-1 and LAG-3 are both implicated in melanoma.
Furthermore, regarding claims 133 and 136-139, although the reference patent does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies.
Furthermore, regarding claims 133 and 139-142, although the reference patent does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and carry out the administration method when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Furthermore, regarding claim 135, although the reference patent does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
(3)
Claims 131, 133, and 135-155 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10,377,824 in view of Sadineni (US 2017/0143827 A1; supra) and Korman (WO 2015/042246 A1; supra), and further in view of Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The reference patent claims methods of inhibiting growth of melanoma tumor cells/treating melanoma, comprising administering a full-length and/or bispecific anti-LAG-3 antibody or antigen-binding fragment thereof comprising identical CDRs/variable regions to that set forth in claims 131, 143-147, and 149, in combination with at least one or both of nivolumab (further relevant to claims 131 and 148-149) and ipilimumab (relevant to claims 154-155) (patented claims 1-6, 8-11, 13, 15-20, 22-26, 28-30). Relevant to claims 152-153, the antibodies are administered as separate formulations or as a single formulation (patented claims 14, 27).
While the reference patent does not expressly claim that the combination of antibodies are intravenously administered to treat metastatic melanoma, at a dose of about 160 mg of the anti-LAG-3 antibody and about 480 mg of the anti-PD-1 antibody once about every four weeks, relevant to claims 131, 150-151, and 154-155, these deficiencies are remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization. The skilled artisan would have been motivated to do so because Sadineni teaches that the combined administration of about 480 mg nivolumab (anti-PD-1 antibody) and about 160 mg relatlimab (anti-LAG-3 antibody), at a 3:1 dosage ratio, is effective for treating metastatic melanoma. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both implicated in metastatic melanoma.
Further regarding claims 133 and 136-139, although the reference patent does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would further have been motivated to treat a patient who has not received any prior systemic treatment, as the patient has a clear need to be treated.
Further regarding claims 133 and 139-142, although the reference patent does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and carry out the administration method when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Further regarding claim 135, although the reference patent does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
(4)
Claims 131, 133, and 135-155 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,274,152 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra) or Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra).
The reference patent claims a pharmaceutical composition comprising 80 mg of an anti-LAG-3 antibody comprising an identical structure to that recited in claims 131, 147, and 149, and 240 mg of an anti-PD-1 antibody comprising an identical structure to that recited in claims 131 and 148-149 (patented claims 1-10). Relevant to claims 150-151, patented claim 11 recites that the pharmaceutical composition is formulated for intravenous administration. Patented claim 12 recites a kit for treating a solid tumor in a human patient, comprising 80 mg of said anti-LAG-3 antibody, 240 mg of said anti-PD-1 antibody, and instructions for use in a method of treatment.
While the reference patent does not expressly claim a method that comprises administering said pharmaceutical composition for the purpose of treating metastatic melanoma, or that the dosages of the anti-LAG-3 antibody and the anti-PD-1 antibody are about 160 mg and about 480 mg, respectively, and administered once about every four weeks, this deficiency is remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization, as the ratio of anti-PD-1 antibody to anti-LAG-3 antibody is comparable (3:1) between the formulations described in the reference patent and by Sadineni. Furthermore, the limitations set forth in claims 143-146 and 152-155, which are not recited in the patented claims, are also taught by Sadineni. With respect to the limitations of claims 143-146 and 152-153, the skilled artisan would have recognized that there are a finite number of antibody formats or formulations which can be administered in a treatment method, and with respect to claims 154-155, the skilled artisan would have been motivated to target additional immune checkpoint proteins that are similarly implicated in metastatic melanoma to maximize the efficacy of the treatment. There would have been a reasonable expectation of success because the reference patent and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), in a dosing ratio of 3:1, for treating metastatic melanoma in a patient in need thereof.
Further regarding claims 133 and 136-139, although the reference patent does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would further have been motivated to treat a patient who has not received any prior systemic treatment, as the patient has a clear need to be treated.
Further regarding claims 133 and 139-142, although the reference patent does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and carry out the administration method when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Further regarding claim 135, although the reference patent does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
(5)
Claims 131, 133, and 135-155 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No. 11,807,686 in view of in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The reference patent claims a method of treating a malignant tumor (e.g., melanoma) in a human patient, which comprises administering a LAG-3 inhibitor (e.g., 80 mg of an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., 240 mg of an anti-PD-1 antibody), wherein at least about 1% of nucleated cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3 (patented claims 1, 10-12, 15-16), relevant to claims 131, 140-141, and 144-149. The reference patent claims further recite determining the level of LAG-3 expression and/or PD-L1 expression in the sample (patented claims 4-5 and 25-29), relevant to claims 133 and 139-141. Relevant to claim 142, the reference patent recites that the sample is PD-L1 negative (patented claim 3).
Relevant to claim 136, the reference patent claims that the antibodies are administered as a first line of treatment (patented claim 23). Relevant to claims 150-151, patented claims 15 and 17-18 recite that the antibodies are formulated for intravenous administration. Relevant to claims 152-153, patented claims 15 and 18-21 recite that the antibodies are formulated together or separately.
Relevant to claims 154-155, patented claims 15, 24, and 30 recite further administering an additional immune checkpoint inhibitor.
While the reference patent does not expressly claim treating metastatic melanoma, by administering a dose of about 160 mg of the anti-LAG-3 antibody and about 480 mg of the anti-PD-1 antibody once about every four weeks, or that the additional immune checkpoint inhibitor administered is ipilimumab, this deficiency is remedied by Sadineni (supra) and the skilled artisan could have arrived at such a method through the process of routine optimization. One of ordinary skill in the art would also recognize that patients with unresectable or metastatic melanoma have a clear need to be treated. There would have been a reasonable expectation of success because the reference patent and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), in a dosing ratio of 3:1, for treating metastatic melanoma in a patient in need thereof.
Furthermore, regarding claim 135, although the reference patent does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to do so because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
Furthermore, regarding claims 137-138, although the reference patent does not expressly claim that the human patient to be treated possesses the qualities set forth in the instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. There would have been a reasonable expectation of success because the reference patent and Korman each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab) for treating metastatic melanoma in a patient in need thereof.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
(6)
Claims 131, 133, and 135-155 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12,049,503 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The reference patent claims a method of treating a melanoma, comprising administering an anti-LAG-3 antibody (e.g., relatlimab) comprising an identical structure to that recited in claims 131, 143-147, and 149, and an anti-PD-1 antibody (e.g., nivolumab) comprising an identical structure to that recited in claims 131 and 143-146, and 148-149 (patented claims 1, 6, 12-17, 19, and 22-30). Regarding claims 133 and 139-141, the reference patent claims the further step of determining LAG-3 expression in a sample of the patient’s sample and that about 1% to about 5% or about 20% of nucleated cells in the sample of the patient’s tumor are TILs expressing LAG-3 (patented claims 1-2, 19, 21). Regarding claim 142, patented claims 3 and 20 further recite that the tumor is PD-L1 negative.
Relevant to claims 135-136, patented claim 11 recites that the antibodies are administered as a first line or second line treatment. Regarding claims 152-153, patented claims 8-10 recite that the antibodies are either formulated together or separately.
While the reference patent does not expressly claim a method of treating metastatic melanoma, or that the dosages of the anti-LAG-3 antibody and the anti-PD-1 antibody are about 160 mg and about 480 mg, respectively, and administered parenterally (e.g., intravenously) once about every four weeks, these deficiencies are remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization. Furthermore, with respect to claims 154-155, the skilled artisan would have been motivated to target additional immune checkpoint proteins that are similarly implicated in metastatic melanoma to maximize the efficacy of the treatment. There would have been a reasonable expectation of success because the reference patent and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), in a dosing ratio of 3:1, for treating metastatic melanoma in a patient in need thereof.
Further regarding claims 137-138, although the reference patent does not expressly claim that the human patient to be treated possesses the qualities set forth in the instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. There would have been a reasonable expectation of success because the reference patent and Korman each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab) for treating metastatic melanoma in a patient in need thereof.
Further regarding claim 135, although the reference patent does not expressly teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
(7)
Claims 131, 133, and 135-155 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-43 of co-pending Application No. 17/682,986 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The co-pending reference application recites a method for treating a patient for metastatic and/or unresectable melanoma, comprising administering to the patient a pharmaceutical composition comprising 80 mg of a human anti-LAG-3 antibody comprising a structure identical to that recited in claims 131, 143-144, 147, and 149 and 240 mg of a human anti-PD-1 antibody comprising a structure identical to that recited in claims 131, 143-144, and 148-149 (co-pending claims 24-25, 27-36, and 43). Regarding claim 136, co-pending claim 37 recites that the pharmaceutical composition is administered as a first line treatment. Regarding claims 150-151, co-pending claims 40-41 recite that the pharmaceutical composition is formulated for intravenous or intraperitoneal administration among others.
While the co-pending reference application does not expressly teach administering a dose of about 160 mg of the anti-LAG-3 antibody and about 480 mg of the anti-PD-1 antibody once about every four weeks, or that the additional immune checkpoint inhibitor administered is ipilimumab, this deficiency is remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization, as the ratio of anti-PD-1 antibody to anti-LAG-3 antibody is comparable (3:1) between the formulations described in the co-pending reference application and by Sadineni. Furthermore, the limitations set forth in claims 143-146 and 152-155, which are not recited in the co-pending claims, are also taught by Sadineni. With respect to the limitations of claims 143-146 and 152-153, the skilled artisan would have recognized that there are a finite number of antibody formats or formulations which can be administered in a treatment method, and with respect to claims 154-155, the skilled artisan would have been motivated to target additional immune checkpoint proteins that are similarly implicated in metastatic melanoma to maximize the efficacy of the treatment. There would have been a reasonable expectation of success because the co-pending reference application and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), in a dosing ratio of 3:1, for treating metastatic melanoma in a patient in need thereof.
Further regarding claims 133 and 136-139, although the reference patent does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would further have been motivated to treat a patient who has not received any prior systemic treatment, as the patient has a clear need to be treated.
Further regarding claims 133 and 139-142, although the reference patent does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and carry out the administration method when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Further regarding claim 135, although the reference patent does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
This is a provisional nonstatutory double patenting rejection.
(8)
Claims 131, 133, and 135-155 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 150-168 of co-pending Application No. 18/336,889 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
Co-pending claims 150-153 and 158-164 recite a pharmaceutical composition comprising about 80 mg or about 160 mg of an anti-LAG-3 antibody comprising an identical structure to that recited in claims 131, 147, and 149, and about 240 mg or about 480 mg of an anti-PD-1 antibody comprising an identical structure to that recited in claims 131 and 148-149. Relevant to claims 150-151, co-pending claims 165-166 recite that the pharmaceutical composition is formulated for intravenous or intramuscular administration, among others.
While the co-pending reference application does not expressly recite a method that comprises parenterally (e.g., intravenously) administering said pharmaceutical composition for the purpose of treating metastatic melanoma, or that the dosages of the anti-LAG-3 antibody and the anti-PD-1 antibody are about 160 mg and about 480 mg, respectively, and administered once about every four weeks, this deficiency is remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization, as the ratio of anti-PD-1 antibody to anti-LAG-3 antibody is comparable (3:1) between the formulations described in the co-pending reference application and by Sadineni. Furthermore, the limitations set forth in claims 143-146 and 152-155, which are not recited in the co-pending claims, are also taught by Sadineni. With respect to the limitations of claims 143-146 and 152-153, the skilled artisan would have recognized that there are a finite number of antibody formats or formulations which can be administered in a treatment method, and with respect to claims 154-155, the skilled artisan would have been motivated to target additional immune checkpoint proteins that are similarly implicated in metastatic melanoma to maximize the efficacy of the treatment. There would have been a reasonable expectation of success because the co-pending reference application and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), in a dosing ratio of 3:1, for treating metastatic melanoma in a patient in need thereof.
Further regarding claims 133 and 136-139, although the co-pending reference application does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would further have been motivated to treat a patient who has not received any prior systemic treatment, as the patient has a clear need to be treated.
Further regarding claims 133 and 139-142, although the co-pending reference application does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and carry out the administration method when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Further regarding claim 135, although the co-pending reference application does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
This is a provisional nonstatutory double patenting rejection.
(9)
Claims 131, 133, and 135-155 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 252-268 of co-pending Application No. 18/745,399 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The co-pending reference application recites a method of treating a melanoma tumor, wherein a sample of the tumor is LAG-3 positive, by administering a LAG-3 inhibitor (e.g., 80 mg of an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., 240 mg of an anti-PD-1 antibody), relevant to claim 131 (co-pending claims 252-259, 266-268). Relevant to claims 133 and 139-141, co-pending claims 255-256 recite determining LAG-3 and/or PD-L1 expression in the tumor sample prior to the administration step, and that at least 1% or at least about 20% of the total number of TILs in the sample express LAG-3. Relevant to claim 142, co-pending claim 154 recites that the tumor sample is PD-L1 negative.
Relevant to claims 154-155, co-pending claims 260-261 recite further administering an additional immune checkpoint inhibitor.
While the co-pending reference application does not expressly recite a method that comprises parenterally (e.g., intravenously) administering the combination of an anti-LAG-3 antibody such as relatlimab and an anti-PD-1 antibody such as nivolumab for the purpose of treating metastatic melanoma, or that the dosages of the anti-LAG-3 antibody and the anti-PD-1 antibody are about 160 mg and about 480 mg, respectively, and administered once about every four weeks, this deficiency is remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization, as the ratio of anti-PD-1 antibody to anti-LAG-3 antibody is comparable (3:1) between the formulations described in the co-pending reference application and by Sadineni. Furthermore, the limitations set forth in claims 143-146 and 152-155, which are not recited in the co-pending claims, are also taught by Sadineni. With respect to the limitations of claims 143-146 and 152-153, the skilled artisan would have recognized that there are a finite number of antibody formats or formulations which can be administered in a treatment method, and with respect to claims 154-155, the skilled artisan would have been motivated to target additional immune checkpoint proteins such as CTLA-4 (via ipilimumab) that are similarly implicated in metastatic melanoma to maximize the efficacy of the treatment. There would have been a reasonable expectation of success because the co-pending reference application and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), in a dosing ratio of 3:1, for treating metastatic melanoma in a patient in need thereof.
Further regarding claims 136-138, although the co-pending reference application does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would further have been motivated to treat a patient who has not received any prior systemic treatment, as the patient has a clear need to be treated.
Further regarding claim 135, although the co-pending reference application does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), "[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). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
This is a provisional nonstatutory double patenting rejection.
(10)
Claims 131, 133, and 135-155 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 133-155 of co-pending Application No. 18/870,218 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The co-pending reference application at claims 133-134, 136, 138, 140, and 142, recites a method of treating a metastatic or unresectable melanoma, comprising administering an anti-PD-1 antibody (e.g., nivolumab, at a dosage of “about 480 mg”) and an anti-LAG-3 antibody (e.g., relatlimab, e.g., at a dosage of “about 160 mg”), relevant to claims 131 and 143-149. Relevant to claims 154-155, co-pending claims 142-146 recite that the method further comprises administering ipilimumab.
While the co-pending reference application does not expressly recite that the antibodies are formulated separately or together (relevant to claims 152-153), or formulated for parenteral (e.g., intravenous) administration (relevant to claims 150-151), or administered “once about every four weeks”, these deficiencies are remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization. Furthermore, with respect to the limitations of claims 150-153, the skilled artisan would have recognized that there are a finite number of ways to administer or formulate a combination of antibodies used in a treatment method, and one of ordinary skill in the art has reason to pursue options within their technical grasp. There would have been a reasonable expectation of success because the co-pending reference application and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), at respective doses of about 480 mg and about 160 mg, for treating metastatic melanoma in a patient in need thereof.
Further regarding claims 133 and 136-139, although the co-pending reference application does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would further have been motivated to treat a patient who has not received any prior systemic treatment, as the patient has a clear need to be treated.
Further regarding claims 133 and 139-142, although the co-pending reference application does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and carry out the administration method when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Further regarding claim 135, although the co-pending reference application does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), “[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). Moreover, it is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants’ invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
This is a provisional nonstatutory double patenting rejection.
(11)
Claims 131, 133, and 135-155 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 167-186 of co-pending Application No. 19/025,264 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
Relevant to claims 131 and 143-149, the co-pending reference application recites a method of treating a melanoma tumor in a human patient by administering a LAG-3 inhibitor (e.g., relatlimab), a PD-1 pathway inhibitor (e.g., nivolumab), and an immunotherapeutic agent (e.g., ipilimumab), as set forth in co-pending claims 167-170, 172-173, 176-179, and 184.
While the co-pending reference application does not expressly recite that the antibodies are formulated separately or together (relevant to claims 152-153), or formulated for parenteral (e.g., intravenous) administration (relevant to claims 150-151), or administered “once about every four weeks” to treat a metastatic melanoma tumor, these deficiencies are remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization. Furthermore, with respect to the limitations of claims 150-153, the skilled artisan would have recognized that there are a finite number of ways to administer or formulate a combination of antibodies used in a treatment method, and one of ordinary skill in the art has reason to pursue options within their technical grasp. There would have been a reasonable expectation of success because the co-pending reference application and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), at respective doses of about 480 mg and about 160 mg, for treating metastatic melanoma in a patient in need thereof.
Further regarding claims 133 and 136-139, although the co-pending reference application does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would further have been motivated to treat a patient who has not received any prior systemic treatment, as the patient has a clear need to be treated.
Further regarding claims 133 and 139-142, although the co-pending reference application does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and carry out the administration method when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Further regarding claim 135, although the co-pending reference application does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), “[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). Moreover, it is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants’ invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
This is a provisional nonstatutory double patenting rejection.
(12)
Claims 131, 133, and 135-155 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 150-169 of co-pending Application No. 19/025,919 in view of Sadineni (US 2017/0143827 A1; supra), and further in view of Korman (WO 2015/042246 A1; supra) or Taube (Clinical Cancer Research (2015) 21(17): 3969-3976; supra) or Sanlorenzo (Cancer Biology & Therapy (2014) 15(6): 665-674; supra).
The co-pending reference application recites a pharmaceutical composition, and a method of use thereof for treating a melanoma, comprising about 80 mg or about 160 mg of an anti-LAG-3 antibody (e.g., relatlimab) and about 240 mg or about 480 mg of an anti-PD-1 antibody (e.g., nivolumab), relevant to claims 131 and 143-149 (co-pending claims 150-153, 158-167).
While the co-pending reference application does not expressly recite that the antibodies are formulated separately or together (relevant to claims 152-153), or formulated for parenteral (e.g., intravenous) administration (relevant to claims 150-151), or administered “once about every four weeks” to treat a metastatic melanoma tumor, these deficiencies are remedied by Sadineni (supra), and the skilled artisan could have arrived at such a method through the process of routine optimization. Furthermore, with respect to the limitations of claims 150-153, the skilled artisan would have recognized that there are a finite number of ways to administer or formulate a combination of antibodies used in a treatment method, and one of ordinary skill in the art has reason to pursue options within their technical grasp. Furthermore, with respect to claims 154-155, the skilled artisan would have been motivated additionally target another immune checkpoint protein such as CTLA-4 via co-administration of ipilimumab, as taught by Sadineni, to maximize the efficacy of the treatment. There would have been a reasonable expectation of success because the co-pending reference application and Sadineni each recognized the suitability of the specific combination of an anti-PD-1 antibody (nivolumab) and an anti-LAG-3 antibody (relatlimab), at respective doses of about 480 mg and about 160 mg or at a dosage ratio of 3:1, for treating metastatic melanoma in a patient in need thereof.
Further regarding claims 133 and 136-139, although the co-pending reference application does not expressly claim that the subject possesses the qualities set forth in these instant claims, this deficiency is remedied by Korman (supra). The skilled artisan would have been motivated to carry out histological staging and to characterize the clinical status of the patient in order to determine the severity of disease in the patient and determine whether the patient is more likely to be responsive to the anti-LAG-3 and/or anti-PD-1-specific therapies. The skilled artisan would further have been motivated to treat a patient who has not received any prior systemic treatment, as the patient has a clear need to be treated.
Further regarding claims 133 and 139-142, although the co-pending reference application does not expressly claim determining the level of LAG-3, PD-L1, and/or BRAF V600, nor that about 1 to about 20% of cells in a sample of the patient’s tumor are tumor-infiltrating lymphocytes expressing LAG-3, this deficiency is remedied by Taube (supra). The skilled artisan would have been motivated to perform the additional step of determining the level of LAG-3 and PD-L1 in a sample of the patient’s tumor prior to treatment, and carry out the administration method when at least about 5% of cells are TILs expressing LAG-3, because Taube teaches that LAG-3 and PD-1 expression could be predictive of individual treatment response to anti-PD-1/PD-L1 blockade therapies, and that combinatorial blockade of LAG-3 and PD-1 shows a synergistic effect in preclinical tumor models. There would have been a reasonable expectation of success that LAG-3 and PD-1 expression are predictive of treatment response because LAG-3 and PD-1 correlate with PD-L1 expression in the TME of metastatic melanoma, and PD-L1 is expressed on both tumor and monocytic cells in PD-L1+ melanoma, as taught by Taube.
Further regarding claim 135, although the co-pending reference application does not teach that the combination anti-PD-1/anti-LAG-3 antibody therapy is for adjuvant therapy after surgery for the metastatic melanoma tumor, this deficiency is remedied by Sanlorenzo (supra). The skilled artisan would have been motivated to carry out the instantly claimed method for adjuvant therapy after surgery because Sanlorenzo teaches that immunotherapies can be used as an adjuvant treatment after complete surgical excision in metastatic melanoma. While Sanlorenzo describes findings based on adjuvant administration of an anti-CTLA-4 antibody (ipilimumab), it would have been obvious to try adjuvant administration of an alternative immunotherapy such as an anti-PD-1 antibody (e.g., nivolumab) because Sanlorenzo teaches that, relative to ipilimumab, patients treated with nivolumab have greater response rates and fewer incidences of serious adverse events than those administered ipilimumab. One of ordinary skill in the art would have been further motivated to combine adjuvant nivolumab with an anti-LAG-3 antibody because Sanlorenzo teaches that the PD-1 and LAG-3 pathways act synergistically. There would have been a reasonable expectation of success because PD-1 and LAG-3 are both involved in tumor immune escape mechanisms and have been implicated in melanoma.
As set forth in MPEP § 2144.05(II)(A), “[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). Moreover, it is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). Optimal drug dosages are an art-recognized result-effective variable that is routinely determined and optimized in the pharmaceutical art, and it is conventional and within the skill of those in the art to identify the optimal dosages and treatment intervals necessary to achieve desired working concentrations and therapeutic efficacy. Accordingly, it would have been obvious to one of ordinary skill in the art at the time Applicants’ invention was made to determine all operable and optimal therapeutic doses and schedules, and one of ordinary skill in the art would have arrived at the dosages of 160 mg relatlimab and 480 mg nivolumab, administered once about every four weeks, through the process of routine optimization.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643