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 .
Claim Status
Claims 1-124, 127, 131, and 133 have been cancelled and claims 125-126, 128, 135, 139, and 141 have been amended, as requested in the amendment filed on 12/11/2025. Following the amendment, claims 125-126, 128-130, 132, and 134-144 are pending in the instant application.
Claims 125-126, 128-130, 132, and 134-144 are under examination in the instant office action.
Independent claim 125 has been amended such that it now reads on a method of treating cancer in a human subject in need thereof comprising the active step of administering a lymphocyte activation gene-3 (LAG-3) antagonist to the subject; the wherein clauses of the claim passively recite how a subject is identified, however, it is noted the claim does not require one to actively identify a subject and test a tumor sample. Additionally, independent claim 126 has been amended such that it now reads on a method of treating cancer in a human subject in need thereof comprising the active step of administering a LAG-3 antagonist to the subject; it is noted that the wherein clauses of the claim passively recite how a subject is identified, but the claim does not require one to actively identify a subject and test a tumor sample and, furthermore, step (a) of amended claim 126 recites “identifying a subject as being suitable for treatment with a LAG-3 antagonist if a tumor sample from the subject has a LAG-3-D score of at least 5 cells/mm2 and/or a LAG-3-P score of at least 40%”, but this is an optional step as claimed and not a required active step of the method because the claim does not require one to actively identify a subject and test a tumor sample and administer the LAG-3 antagonist based on the scores of (a), but rather the LAG-3 antagonist is administered to the subject regardless of the scores of (a). In view of these amendments, the scope of the independent claims has changed, necessitating the new grounds of rejection detailed below.
Information Disclosure Statement
The information disclosure statement filed 12/15/2025 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein struckthrough, listed below, has not been considered.
NPL Citation #192: ROSENBERG, S.A., et al., "Cancer Immunotherapy in Cancer: Principles & Practice of Oncology", 332-344, LIPPINCOTT WILLIAMS & WILKINS (2011).
Specification - Objection Withdrawn
The specification was objected to for trade names or marks used in commerce. Applicant argued on Pages 12-13 of Remarks (12/11/2025) that the indicated terms NEXAVAR, LENVIMA, and STIVARGA, are all capitalized as well as followed by a symbol indicating use in commerce in paragraphs 168-169 of the specification as filed, and the trademarks are accompanied by their corresponding generic terminology (i.e., "tyrosine kinase inhibitor" as well as the generic terms sorafenib tosylate, lenvatinib mesylate, and regorafenib for NEXAVAR, LENVIMA, and STIV ARGA, respectively), such that the usage of these trademarks in the specification as filed is proper and complies with MPEP § 608.0l(v). Applicant further indicates that the trademark BIACORE was not capitalized or otherwise denoted with a symbol indicating use in commerce in paragraphs 155, 196, 220, and 233 of the specification as filed; those paragraphs have been amended to indicate the proprietary nature of the trademark and additionally, regarding accompanying generic terminology, paragraph 196 of the specification as filed, for example, discloses that BIACORE is a biosensor system that can be used to determine antibody binding by surface plasmon resonance. As such, the objection to the specification is withdrawn.
Claim Rejections - 35 USC § 101 - Withdrawn
Claim 127 was rejected under 35 U.S.C. § 101 as being directed to patent ineligible subject matter. Claim 127 has been cancelled, rendering the rejection moot. As such, the rejection of claim 127 under 35 U.S.C. § 101 as being directed to patent ineligible subject matter is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 128 and 131 were rejected under 35 U.S.C. § l 12(b) as being indefinite for the recitation of the term "about". Claim 128 has been amended to remove the term “about” and claim 131 has been cancelled, rendering the rejection moot. As such, the rejection of claims 128 and 131 35 U.S.C. § l 12(b) as being indefinite is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 125-131 and 133-144 were rejected under 35 U.S.C. § 103 as allegedly being
unpatentable over WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny") in view of WO 2018/145023 (previously cited on PTO-892; herein after referred to as "Bordeaux") and non-patent literature by Hemon et al. (J. Immunol., 2011, 186(9), 5173-5183; previously cited on PTO-892; herein after referred to as "Hemon").
Claim 132 was rejected under 35 U.S.C. § 103 as allegedly being unpatentable over WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny"), WO 2018/145023 (previously cited on PTO-892; herein after referred to as "Bordeaux"), and non-patent literature by Hemon et al. (J. Immunol., 2011, 186(9), 5173-5183; previously cited on PTO-892; herein after referred to as "Hemon") and further in view of non-patent literature by Melendez et al. (Transl. Lung Cancer Res., 2018, 7(6), 661-667; previously cited on PTO-892; herein after referred to as Melendez").
As noted above, independent claims 125 and 126 have been amended such that the claim scope is now different and claims 127, 131, and 133 have been cancelled. The instantly amended claim set thus renders the above-listed claim rejections under 35 U.S.C. § 103 moot. As such, the above-listed claim rejections under 35 U.S.C. § 103 are withdrawn.
Double Patenting - Withdrawn
Claims 125-144 were rejected on the grounds of nonstatutory obviousness-type double
patenting as allegedly being unpatentable over claims 1, 4-5, 10-12, 15-30, 32, 34-35, and 37 of
U.S. Patent No. 11,807,686 ("the '686 patent") and claims 1-2, 4-6, 8-19, and 21-30 of U.S. Patent No. 12,049,503 ("the '503 patent") in view of Novotny, Bordeaux, and Hemon, and/or Melendez.
Claims 125-144 were provisionally rejected on the grounds of nonstatutory obviousness-type double patenting as allegedly being unpatentable over claims 131, 133, 139-141, 143-149, and 151-153 of U.S. Patent Application No. 17/286,203, claims 177-191 and 198-200 of U.S. Patent Application No. 18/043,562, claims 185-203 of U.S. Patent Application No. 18/705, 171, claims 252-253 and 255-268 of U.S. Patent Application No. 18/745,399, claims 152-161 and 165-169 of U.S. Patent Application No. 18/833,472, and claims 93-100 and 103-111 of U.S. Patent Application No. 18/841,061 in view of Novotny, Bordeaux, and Hemon, and/or Melendez.
As noted above, independent claims 125 and 126 have been amended such that the claim scope is now different and claims 127, 131, and 133 have been cancelled. The instantly amended claim set thus renders the above-listed claim rejections under nonstatutory double patenting moot. As such, the above-listed claim rejections under nonstatutory double patenting are withdrawn.
New Rejections
(necessitated by amendments)
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 125-130, 134-139, and 142-144 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny").
Novotny discloses that recent studies have also shown that high LAG-3 expression on exhausted lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells contributes to their unresponsive state and limits CD8+ T cell antitumor responses; LAG-3 maintained tolerance to self and tumor antigens via direct effects on CD8+ T cells in two murine models (Paragraph 0004). Exhausted T cells are characterized by the expression of T cell negative regulatory receptors, predominantly Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), Programmed Cell Death I (PD-1), and LAG-3, whose action is to limit the cell's ability to proliferate, produce cytokines, and kill target cells and/or to increase Treg activity (Paragraph 0005). The invention relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. As such, Novotny anticipates claims 125-126.
With regard to claims 128-130 and 132, it is specifically noted that the claims further describe/limit the analysis of a tumor sample and/or the LAG-3-D and/or LAG-3-P scores determined therefrom, which are steps not required by the independent claims. As such, claims 128-130 and 132 are also anticipated by Novotny who teaches the required active steps of the instantly claimed methods of claims 125 and 126.
With regard to claims 134-139, Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). Thus, Novotny anticipates claims 134-139.
With regard to claim 142, Novotny teaches that in one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Thus, Novotny anticipates claim 142.
With regard to claim 143, exemplary cancers taught by Novotny are provided in Paragraph 0287 and include, for example, melanoma, hepatocellular carcinoma, lung cancer, and renal cancer. Thus, Novotny anticipates claim 143.
With regard to claim 144, Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350). Thus, Novotny anticipates claim 144.
Claims 125-130, 134-139, and 142-144 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by:
U.S. Patent No. 11,807,686;
U.S. Patent No. 12,049,503; or
US 2025/0043006 A1.
It is specifically noted that all of the above-listed U.S. Patent documents claim priority to WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny") wherein it is further noted that U.S. Patent No. 12,049,503 and US 2025/0043006 A1 are all continuations of U.S. Patent No. 11,807,686. As such, the disclosures of U.S. Patent No. 11,807,686, U.S. Patent No. 12,049,503, and US 2025/0043006 A1 are identical to that of Novotny, and therefore anticipate instant claims 125-130, 134-139, and 142-144 as detailed below.
Novotny discloses that recent studies have also shown that high LAG-3 expression on exhausted lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells contributes to their unresponsive state and limits CD8+ T cell antitumor responses; LAG-3 maintained tolerance to self and tumor antigens via direct effects on CD8+ T cells in two murine models (Paragraph 0004). Exhausted T cells are characterized by the expression of T cell negative regulatory receptors, predominantly Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), Programmed Cell Death I (PD-1), and LAG-3, whose action is to limit the cell's ability to proliferate, produce cytokines, and kill target cells and/or to increase Treg activity (Paragraph 0005). The invention relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. As such, Novotny anticipates claims 125-126.
With regard to claims 128-130 and 132, it is specifically noted that the claims further describe/limit the analysis of a tumor sample and/or the LAG-3-D and/or LAG-3-P scores determined therefrom, which are steps not required by the independent claims. As such, claims 128-130 and 132 are also anticipated by Novotny who teaches the required active steps of the instantly claimed methods of claims 125 and 126.
With regard to claims 134-139, Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). Thus, Novotny anticipates claims 134-139.
With regard to claim 142, Novotny teaches that in one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Thus, Novotny anticipates claim 142.
With regard to claim 143, exemplary cancers taught by Novotny are provided in Paragraph 0287 and include, for example, melanoma, hepatocellular carcinoma, lung cancer, and renal cancer. Thus, Novotny anticipates claim 143.
With regard to claim 144, Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350). Thus, Novotny anticipates claim 144.
Claims 125-130, 134-139, and 142-144 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by US 2021/0338813 A1 (herein after referred to as “Maurer”).
Maurer discloses method of inhibiting the growth of a metastatic melanoma tumor in a human patient, the method comprising administering to the patient an effective amount of: (a) a LAG-3 antagonist; and (b) a PD-1 pathway inhibitor; wherein the patient has not received prior treatment for metastatic melanoma (Paragraph 0006). In some embodiments, the LAG-3 antagonist is an anti-LAG-3 antibody, wherein said antibody may be a full-length antibody, a monoclonal, human, humanized, chimeric, or multispecific antibody (e.g., a dual-affinity re-targeting antibody (DART), a DVD-lg, or bispecific antibody), or a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide; in some embodiments, the anti-LAG-3 antibody is BMS-986016, IMP731 (H5L7BW), MK-4280 (28G-10), REGN3767, GSK2831781, humanized BAP050, IMP-701 (LAG-525), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb22841, MGD013, BI754111, FS118, P 13B02-30, or AVA-017 (Paragraph 0014). In some embodiments, the PD-1 pathway inhibitor is an anti-PD-1 or an anti-PD-L1 antibody; in certain embodiments, the anti-PD-1 antibody is selected from the group consisting of: nivolumab, pembrolizumab, pidilizumab, PDR00l, MEDI0680, TSR-042, REGN2810, JS00l, PF-06801591, BGB-A317, BI 754091, and SHR-1210 (Paragraph 0016). The anti-LAG-3 antibody or antagonist and anti-PD-1 antibody may be formulated for intravenous administration wherein, in some embodiments, the anti-LAG-3 antibody or antagonist and anti-PD-1 antibody are formulated together or are formulated separately (Paragraph 0018). Maurer further discloses therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-I antibody, such as nivolumab, in a therapeutically effective amount adapted for use in the preceding methods wherein the anti-LAG-3 antibody may be co-packaged with an anti-PD-1 antibody in unit dosage form; the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0213).
Examiner Suggestion: Amend the independent claims to require the active method steps of (i) identifying a subject as being suitable for treatment with a LAG-3 antagonist, which requires obtaining a tumor sample from the subject and from said tumor sample determining the LAG-3-D and/or LAG-3-P scores as instantly defined, and (ii) administering the LAG-3 antagonist to the subject identified as suitable for treatment with the LAG-3 antagonist.
New Rejections
(necessitated by amendments)
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 125-126, 132, and 134-144 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny").
Novotny discloses that recent studies have also shown that high LAG-3 expression on exhausted lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells contributes to their unresponsive state and limits CD8+ T cell antitumor responses; LAG-3 maintained tolerance to self and tumor antigens via direct effects on CD8+ T cells in two murine models (Paragraph 0004). Exhausted T cells are characterized by the expression of T cell negative regulatory receptors, predominantly Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), Programmed Cell Death I (PD-1), and LAG-3, whose action is to limit the cell's ability to proliferate, produce cytokines, and kill target cells and/or to increase Treg activity (Paragraph 0005). The invention relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). In one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Exemplary cancers taught by Novotny are provided in Paragraph 0287 and include, for example, melanoma, hepatocellular carcinoma, lung cancer, and renal cancer. Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350).
It is further noted that Novotny discloses (i) a method of treating a LAG-3 positive malignant tumor by administering a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) or a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor or (ii) administering an anti-CTLA4 antibody (Paragraphs 0117-0118). The invention provides an anti-CTLA-4 antibody according to a defined clinical dosage regimen, to treat subjects having a malignant tumor (e.g., an advanced refractory solid tumor); the anti-CTLA4 antibody can be ipilimumab, tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015 (Paragraph 0306). Thus, Novotny discloses that (i) LAG-3 inhibitors alone may be used to treat LAG-3 positive cancers, (ii) LAG-3 inhibitors in combination with PD-1 inhibitors may be used to treat LAG-3 positive cancers, (iii) PD-1 inhibitors in combination with immune checkpoint inhibitors (e.g., CTLA4 inhibitors) may be used to treat LAG-3 positive cancers, and (iv) CTLA4 inhibitors alone may be used to treat LAG-3 positive cancers.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of LAG-3 positive cancers. One would have been motivated to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of LAG-3 positive cancers to more effectively treat a LAG-3 positive tumor with a reasonable expectation of success because both LAG-3 inhibitors and CTLA4 inhibitors alone are useful in the treatment of LAG-3 positive cancers, as disclosed by Novotny.
Those of skill in the art recognize that the two classes of cancer therapeutics, LAG-3 inhibitor and CTLA4 inhibitor, both known to successfully, pharmaceutically treat LAG-3 positive cancers, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat LAG-3 positive cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in the treatment of LAG-3 positive cancers, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two classes of inhibitors, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating LAG-3 positive cancer.
Claims 125-126, 132, and 134-144 are rejected under 35 U.S.C. 103 as being unpatentable over:
U.S. Patent No. 11,807,686;
U.S. Patent No. 12,049,503; or
US 2025/0043006 A1.
It is specifically noted that all of the above-listed U.S. Patent documents claim priority to WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny") wherein it is further noted that U.S. Patent No. 12,049,503 and US 2025/0043006 A1 are all continuations of U.S. Patent No. 11,807,686. As such, the disclosures of U.S. Patent No. 11,807,686, U.S. Patent No. 12,049,503, and US 2025/0043006 A1 are identical to that of Novotny; as such each of the above-listed U.S. patent documents render obvious instant claims 125-126, 132, and 134-144 as detailed below.
Novotny discloses that recent studies have also shown that high LAG-3 expression on exhausted lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells contributes to their unresponsive state and limits CD8+ T cell antitumor responses; LAG-3 maintained tolerance to self and tumor antigens via direct effects on CD8+ T cells in two murine models (Paragraph 0004). Exhausted T cells are characterized by the expression of T cell negative regulatory receptors, predominantly Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), Programmed Cell Death I (PD-1), and LAG-3, whose action is to limit the cell's ability to proliferate, produce cytokines, and kill target cells and/or to increase Treg activity (Paragraph 0005). The invention relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). In one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Exemplary cancers taught by Novotny are provided in Paragraph 0287 and include, for example, melanoma, hepatocellular carcinoma, lung cancer, and renal cancer. Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350).
It is further noted that Novotny discloses (i) a method of treating a LAG-3 positive malignant tumor by administering a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) or a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor or (ii) administering an anti-CTLA4 antibody (Paragraphs 0117-0118). The invention provides an anti-CTLA-4 antibody according to a defined clinical dosage regimen, to treat subjects having a malignant tumor (e.g., an advanced refractory solid tumor); the anti-CTLA4 antibody can be ipilimumab, tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015 (Paragraph 0306). Thus, Novotny discloses that (i) LAG-3 inhibitors alone may be used to treat LAG-3 positive cancers, (ii) LAG-3 inhibitors in combination with PD-1 inhibitors may be used to treat LAG-3 positive cancers, (iii) PD-1 inhibitors in combination with immune checkpoint inhibitors (e.g., CTLA4 inhibitors) may be used to treat LAG-3 positive cancers, and (iv) CTLA4 inhibitors alone may be used to treat LAG-3 positive cancers.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of LAG-3 positive cancers. One would have been motivated to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of LAG-3 positive cancers to more effectively treat a LAG-3 positive tumor with a reasonable expectation of success because both LAG-3 inhibitors and CTLA4 inhibitors alone are useful in the treatment of LAG-3 positive cancers, as disclosed by Novotny.
Those of skill in the art recognize that the two classes of cancer therapeutics, LAG-3 inhibitor and CTLA4 inhibitor, both known to successfully, pharmaceutically treat LAG-3 positive cancers, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat LAG-3 positive cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in the treatment of LAG-3 positive cancers, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two classes of inhibitors, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating LAG-3 positive cancer.
Claims 125-126, 132, and 134-144 are rejected under 35 U.S.C. 103 as being unpatentable over US 2021/0338813 A1 (herein after referred to as “Maurer”).
Maurer discloses method of inhibiting the growth of a metastatic melanoma tumor in a human patient, the method comprising administering to the patient an effective amount of: (a) a LAG-3 antagonist; and (b) a PD-1 pathway inhibitor; wherein the patient has not received prior treatment for metastatic melanoma (Paragraph 0006). In some embodiments, the LAG-3 antagonist is an anti-LAG-3 antibody, wherein said antibody may be a full-length antibody, a monoclonal, human, humanized, chimeric, or multispecific antibody (e.g., a dual-affinity re-targeting antibody (DART), a DVD-lg, or bispecific antibody), or a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide; in some embodiments, the anti-LAG-3 antibody is BMS-986016, IMP731 (H5L7BW), MK-4280 (28G-10), REGN3767, GSK2831781, humanized BAP050, IMP-701 (LAG-525), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb22841, MGD013, BI754111, FS118, P 13B02-30, or AVA-017 (Paragraph 0014). In some embodiments, the PD-1 pathway inhibitor is an anti-PD-1 or an anti-PD-L1 antibody; in certain embodiments, the anti-PD-1 antibody is selected from the group consisting of: nivolumab, pembrolizumab, pidilizumab, PDR00l, MEDI0680, TSR-042, REGN2810, JS00l, PF-06801591, BGB-A317, BI 754091, and SHR-1210 (Paragraph 0016). The anti-LAG-3 antibody or antagonist and anti-PD-1 antibody may be formulated for intravenous administration wherein, in some embodiments, the anti-LAG-3 antibody or antagonist and anti-PD-1 antibody are formulated together or are formulated separately (Paragraph 0018). Maurer further discloses therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, in a therapeutically effective amount adapted for use in the preceding methods wherein the anti-LAG-3 antibody may be co-packaged with an anti-PD-1 antibody in unit dosage form; the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0213). It is further noted that Maurer also discloses that because anti-PD-1 and anti-PD-L1 target the same signaling pathway and have been shown in clinical trials to exhibit similar levels of efficacy in a variety of cancers, an anti-PD-L1 antibody may be substituted for the anti-PD-1 antibody in any of the therapeutic methods of the invention, and Maurer also of the invention for treating a subject afflicted with a tumor, e.g., SCLC, having a high TMB status comprising administering to the subject an anti-PD-L1 antibody alone ("monotherapy") or an anti-PD-L1 antibody in combination with an anti-CTLA-4 antibody (Paragraph 0169). The anti-CTLA-4 antibody binds to and inhibits CTLA-4 wherein, in some embodiments, the anti-CTLA-4 antibody is ipilimumab (YERVOY), tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015 (Paragraph 0179).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of cancer. One would have been motivated to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of cancer to more effectively treat said cancer with a reasonable expectation of success because both LAG-3 inhibitors and CTLA4 inhibitors alone are useful in the treatment of cancers, as disclosed by Maurer.
Those of skill in the art recognize that the two classes of cancer therapeutics, LAG-3 inhibitor and CTLA4 inhibitor, both known to successfully, pharmaceutically treat cancer, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in the treatment of cancer, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two classes of inhibitors, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating cancer.
New Rejections
(necessitated by amendments)
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.
Claims 125-126, 128-130, 132, 134-139, and 142-143 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-12, 15, 17-22, 24-26, 28, and 30 of U.S. Patent No. 11,807,686 (herein after referred to as “first reference patent”). Although the claims at issue are not identical, they are not patentably distinct from each other.
First reference patent claims 1, 25-26, and 28 are generally drawn to methods of (i) treating a malignant tumor in a human patient comprising administering an immunotherapy to the human patient wherein the immunotherapy comprises a LAG-3 inhibitor and a PD-1 pathway inhibitor or (ii) selecting a patient/a malignant tumor in a human patient/a human patient with a malignant tumor for treatment with a LAG-3 therapy or an immunotherapy (i.e., comprising a LAG-3 inhibitor and a PD-1 pathway inhibitor) wherein the methods comprise (1) determining the level of LAG-3 expression in the patient or a sample of the patient’s tumor and (2) administering the LAG-3 therapy or immunotherapy to the patient based on the results of step (1). Thus, the first reference patent is drawn to methods of treating cancer in a human subject in need thereof comprising administering a LAG-3 therapy or an immunotherapy comprising a LAG-3 inhibitor (i.e., a LAG-3 antagonist). First reference patent claims 11-12 are drawn to the method of claim 1 wherein malignant tumors suitable for treatment are described (e.g., melanoma). First reference patent claim 15 is drawn to the method of claim 1 wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or antigen binding fragment thereof and the PD-1 pathway inhibitor is an anti-PD-1 antibody or antigen binding fragment thereof. First reference patent claims 17-21 are drawn to the method of claim 1, wherein the formulation/administration of the anti-LAG-3 antibodies and the anti-PD-1 antibodies are as follows: (i) they are formulated for intravenous injection, (ii) they are formulated together, (iii) they are formulated separately, (iv) the anti-PD-1 antibody is administered after administration of the anti-LAG-3 antibody, (v) the anti-PD-1 antibody is administered before administration of the anti-LAG-3 antibody, or (vi) the anti-PD-1 antibody is administered concurrently with the anti-LAG-3 antibody, respectively. First reference application claim 24 is drawn to the method of claim 1 further comprising administering at least one additional therapeutic agent.
As such, the first reference patent claims the methods of instant claims 125-126 and the additional limitations of instant claims 134-139 and 142-143. With regard to instant claims 128-130 and 132, it is specifically noted that the claims further describe/limit the analysis of a tumor sample and/or the LAG-3-D and/or LAG-3-P scores determined therefrom, which are not required by the instant independent claims 125-126. As such, instant claims 128-130 and 132 are also taught by the first reference patent which teaches the required active steps of the methods of instant claims 125 and 126.
Claims 125-126, 128-130, 132, 134-139, and 142-143 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-6, 8-10, 14, 17-19, 24, and 27-30 of U.S. Patent No. 12,049,503 (herein after referred to as “second reference patent”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Second reference patent claims 1, 19, and 28 are generally drawn to methods of treating a malignant tumor in a human patient comprising administering an immunotherapy to the human patient wherein the immunotherapy comprises (i) an anti-LAG-3 antibody or antigen binding fragment thereof and (ii) an anti-PD-1 antibody or antigen binding fragment thereof or an anti-PD-L1 antibody or antigen binding fragment thereof. Thus, the claims of the second reference patent are drawn to methods of treating cancer in a human subject in need thereof comprising administering an immunotherapy comprising an anti-LAG-3 antibody or antigen binding fragment thereof (i.e., a LAG-3 antagonist). Second reference patent claims 5-6 are drawn to the method of claim 1 wherein malignant tumors suitable for treatment are described (e.g., melanoma). Second reference patent claims 8-10 are drawn to the method of claim 1, wherein the formulation/administration of the anti-LAG-3 antibodies and the anti-PD-1 antibodies are as follows: (i) they are formulated together, (ii) they are formulated separately, or (iii) the anti-PD-1 antibody is administered concurrently with the anti-LAG-3 antibody, respectively. Second reference patent claims 14 and 17-18 are drawn to the method of claim 1 wherein the anti-LAG-3, anti-PD-1, and anti-PD-L1 antibodies, respectively, of the method are described (e.g., BMS-986016, pembrolizumab, and atezolizumab, respectively). Similarly, second reference patent claims 24 and 27 are drawn to the method of claim 19 and claims 29-30 are drawn to the method of claim 28 wherein the anti-LAG-3 and anti-PD-1/anti-PD-L1 antibodies, respectively, of the methods are described (e.g., BMS-986016, pembrolizumab, and atezolizumab, respectively).
As such, the second reference patent claims the methods of instant claims 125-126 and the additional limitations of instant claims 134-139 and 142-143. With regard to instant claims 128-130 and 132, it is specifically noted that the claims further describe/limit the analysis of a tumor sample and/or the LAG-3-D and/or LAG-3-P scores determined therefrom, which are not required by the instant independent claims 125-126. As such, instant claims 128-130 and 132 are also taught by the second reference patent which teaches the required active steps of the methods of instant claims 125 and 126.
Claims 140-141 and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-12, 15, 17-22, 24-26, 28, and 30 of U.S. Patent No. 11,807,686 (herein after referred to as “first reference patent”) in view of WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny").
First reference patent claims 1, 25-26, and 28 are generally drawn to methods of (i) treating a malignant tumor in a human patient comprising administering an immunotherapy to the human patient wherein the immunotherapy comprises a LAG-3 inhibitor and a PD-1 pathway inhibitor or (ii) selecting a patient/a malignant tumor in a human patient/a human patient with a malignant tumor for treatment with a LAG-3 therapy or an immunotherapy (i.e., comprising a LAG-3 inhibitor and a PD-1 pathway inhibitor) wherein the methods comprise (1) determining the level of LAG-3 expression in the patient or a sample of the patient’s tumor and (2) administering the LAG-3 therapy or immunotherapy to the patient based on the results of step (1). Thus, the first reference patent is drawn to methods of treating cancer in a human subject in need thereof comprising administering a LAG-3 therapy or an immunotherapy comprising a LAG-3 inhibitor (i.e., a LAG-3 antagonist). First reference patent claims 11-12 are drawn to the method of claim 1 wherein malignant tumors suitable for treatment are described (e.g., melanoma). First reference patent claim 15 is drawn to the method of claim 1 wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or antigen binding fragment thereof and the PD-1 pathway inhibitor is an anti-PD-1 antibody or antigen binding fragment thereof. First reference patent claims 17-21 are drawn to the method of claim 1, wherein the formulation/administration of the anti-LAG-3 antibodies and the anti-PD-1 antibodies are as follows: (i) they are formulated for intravenous injection, (ii) they are formulated together, (iii) they are formulated separately, (iv) the anti-PD-1 antibody is administered after administration of the anti-LAG-3 antibody, (v) the anti-PD-1 antibody is administered before administration of the anti-LAG-3 antibody, or (vi) the anti-PD-1 antibody is administered concurrently with the anti-LAG-3 antibody, respectively. First reference application claim 24 is drawn to the method of claim 1 further comprising administering at least one additional therapeutic agent.
However, the claims of the first reference patent do not teach/suggest methods for treating cancer in a human patient comprising administering to the patient a LAG-3 antagonist and a CTLA-4 inhibitor wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody or antigen binding fragment thereof, nor a kit for treating a subject afflicted with a tumor wherein the kit comprises (i) a dosage of a LAG-3 antagonist, or a dosage of a LAG-3 antagonist and a dosage of a PD-1 pathway inhibitor and (ii) instructions for using the LAG-3 antagonist is a method for treating cancer in a human patient in need thereof.
The invention of Novotny relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). In one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Exemplary cancers taught by Novotny are provided in Paragraph 0287 and include, for example, melanoma, hepatocellular carcinoma, lung cancer, and renal cancer. Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350).
It is further noted that Novotny discloses (i) a method of treating a LAG-3 positive malignant tumor by administering a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) or a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor or (ii) administering an anti-CTLA4 antibody (Paragraphs 0117-0118). The invention provides an anti-CTLA-4 antibody according to a defined clinical dosage regimen, to treat subjects having a malignant tumor (e.g., an advanced refractory solid tumor); the anti-CTLA4 antibody can be ipilimumab, tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015 (Paragraph 0306). Thus, Novotny discloses that (i) LAG-3 inhibitors alone may be used to treat LAG-3 positive cancers, (ii) LAG-3 inhibitors in combination with PD-1 inhibitors may be used to treat LAG-3 positive cancers, (iii) PD-1 inhibitors in combination with immune checkpoint inhibitors (e.g., CTLA4 inhibitors) may be used to treat LAG-3 positive cancers, and (iv) CTLA4 inhibitors alone may be used to treat LAG-3 positive cancers.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of malignant tumors (e.g., LAG-3 positive cancers). One would have been motivated to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of LAG-3 positive cancers to more effectively treat a LAG-3 positive tumor with a reasonable expectation of success because both LAG-3 inhibitors and CTLA4 inhibitors alone are useful in the treatment of LAG-3 positive cancers, as disclosed by Novotny.
Those of skill in the art recognize that the two classes of cancer therapeutics, LAG-3 inhibitor and CTLA4 inhibitor, both known to successfully, pharmaceutically treat LAG-3 positive cancers, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat LAG-3 positive cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in the treatment of malignant tumors (e.g., LAG-3 positive cancers), thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two classes of inhibitors, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating LAG-3 positive cancer.
Additionally, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to provide the LAG-3 antagonist and PD-1 pathway inhibitors of the first reference patent in a kit for the treatment of malignant tumors, as disclosed by Novotny. Those of skill in the art would recognize that LAG-3 antagonists and PD-1 pathway inhibitors, in combination, are known to treat malignant tumors (e.g., LAG-3 positive cancers), and could have been provided said LAG-3 antagonists and PD-1 pathway inhibitors in a single kit wherein the kit is recognized as being used in the treatment of said malignant tumors, as disclosed by Novotny.
Claims 140-141 and 144 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-6, 8-10, 14, 17-19, 24, and 27-30 of U.S. Patent No. 12,049,503 (herein after referred to as “second reference patent”) in view of WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny").
Second reference patent claims 1, 19, and 28 are generally drawn to methods of treating a malignant tumor in a human patient comprising administering an immunotherapy to the human patient wherein the immunotherapy comprises (i) an anti-LAG-3 antibody or antigen binding fragment thereof and (ii) an anti-PD-1 antibody or antigen binding fragment thereof or an anti-PD-L1 antibody or antigen binding fragment thereof. Thus, the claims of the second reference patent are drawn to methods of treating cancer in a human subject in need thereof comprising administering an immunotherapy comprising an anti-LAG-3 antibody or antigen binding fragment thereof (i.e., a LAG-3 antagonist). Second reference patent claims 5-6 are drawn to the method of claim 1 wherein malignant tumors suitable for treatment are described (e.g., melanoma). Second reference patent claims 8-10 are drawn to the method of claim 1, wherein the formulation/administration of the anti-LAG-3 antibodies and the anti-PD-1 antibodies are as follows: (i) they are formulated together, (ii) they are formulated separately, or (iii) the anti-PD-1 antibody is administered concurrently with the anti-LAG-3 antibody, respectively. Second reference patent claims 14 and 17-18 are drawn to the method of claim 1 wherein the anti-LAG-3, anti-PD-1, and anti-PD-L1 antibodies, respectively, of the method are described (e.g., BMS-986016, pembrolizumab, and atezolizumab, respectively). Similarly, second reference patent claims 24 and 27 are drawn to the method of claim 19 and claims 29-30 are drawn to the method of claim 28 wherein the anti-LAG-3 and anti-PD-1/anti-PD-L1 antibodies, respectively, of the methods are described (e.g., BMS-986016, pembrolizumab, and atezolizumab, respectively).
However, the claims of the second reference patent do not teach/suggest methods for treating cancer in a human patient comprising administering to the patient a LAG-3 antagonist and a CTLA-4 inhibitor wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody or antigen binding fragment thereof, nor a kit for treating a subject afflicted with a tumor wherein the kit comprises (i) a dosage of a LAG-3 antagonist, or a dosage of a LAG-3 antagonist and a dosage of a PD-1 pathway inhibitor and (ii) instructions for using the LAG-3 antagonist is a method for treating cancer in a human patient in need thereof.
The invention of Novotny relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). In one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Exemplary cancers taught by Novotny are provided in Paragraph 0287 and include, for example, melanoma, hepatocellular carcinoma, lung cancer, and renal cancer. Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350).
It is further noted that Novotny discloses (i) a method of treating a LAG-3 positive malignant tumor by administering a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) or a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor or (ii) administering an anti-CTLA4 antibody (Paragraphs 0117-0118). The invention provides an anti-CTLA-4 antibody according to a defined clinical dosage regimen, to treat subjects having a malignant tumor (e.g., an advanced refractory solid tumor); the anti-CTLA4 antibody can be ipilimumab, tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015 (Paragraph 0306). Thus, Novotny discloses that (i) LAG-3 inhibitors alone may be used to treat LAG-3 positive cancers, (ii) LAG-3 inhibitors in combination with PD-1 inhibitors may be used to treat LAG-3 positive cancers, (iii) PD-1 inhibitors in combination with immune checkpoint inhibitors (e.g., CTLA4 inhibitors) may be used to treat LAG-3 positive cancers, and (iv) CTLA4 inhibitors alone may be used to treat LAG-3 positive cancers.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of malignant tumors (e.g., LAG-3 positive cancers). One would have been motivated to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of LAG-3 positive cancers to more effectively treat a LAG-3 positive tumor with a reasonable expectation of success because both LAG-3 inhibitors and CTLA4 inhibitors alone are useful in the treatment of LAG-3 positive cancers, as disclosed by Novotny.
Those of skill in the art recognize that the two classes of cancer therapeutics, LAG-3 inhibitor and CTLA4 inhibitor, both known to successfully, pharmaceutically treat LAG-3 positive cancers, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat LAG-3 positive cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in the treatment of malignant tumors (e.g., LAG-3 positive cancers), thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two classes of inhibitors, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating LAG-3 positive cancer.
Additionally, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to provide the LAG-3 antagonist and PD-1 pathway inhibitors of the second reference patent in a kit for the treatment of malignant tumors, as disclosed by Novotny. Those of skill in the art would recognize that LAG-3 antagonists and PD-1 pathway inhibitors, in combination, are known to treat malignant tumors (e.g., LAG-3 positive cancers), and could have been provided said LAG-3 antagonists and PD-1 pathway inhibitors in a single kit wherein the kit is recognized as being used in the treatment of said malignant tumors, as disclosed by Novotny.
Claims 125-126, 128-130, 132, 134-139, and 142-143 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. Although the claims at issue are not identical, they are not patentably distinct from each other.
Application No.
Brief Description of the Invention
Pertinent Claims
18043562
Method of Treating HCC Comprising Administering a LAG-3 Antagonist
177-191, 198-200
18705171
Method of Treating Hematological Cancer Comprising Administering a LAG-3 Antagonist
185-203
18833472
Method of Treating HCC Comprising Administering LAG-3 and PD-1 Antibodies
152-161, 165-169
The pertinent claims of the above-listed reference applications are all drawn to methods of treating cancer, wherein said cancer is recurrent, refractory, and/or metastatic, in a human patient comprising administering to the patient a LAG- 3 inhibitor and a PD-1 pathway inhibitor wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or antigen-binding fragment thereof and the PD-1 pathway inhibitor is an anti-PD-1 antibody or antigen-binding fragment thereof. The pertinent claims of the above-listed reference applications further claim specific anti-LAG-3 antibodies (e.g., BMS 986016) and specific anti-PD-1 antibodies (e.g., BMS 936558). The pertinent claims of the above-listed reference applications also claim the administration of the LAG-3 inhibitor and the PD-1 pathways inhibitor, as well as administering at least one additional therapeutic agent. Thus, the claims of the reference application are drawn to methods of treating cancer in a human subject in need thereof comprising administering a LAG-3 inhibitor (i.e., a LAG-3 antagonist).
As such, the pertinent claims of the above-listed reference applications read on the methods of instant claims 125-126 and the additional limitations of instant claims 134-139 and 142-143. With regard to instant claims 128-130 and 132, it is specifically noted that the claims further describe/limit the analysis of a tumor sample and/or the LAG-3-D and/or LAG-3-P scores determined therefrom, which are not required by the instant independent claims 125-126. As such, instant claims 128-130 and 132 are also taught by the pertinent claims of the above-listed reference applications, which teach the required active steps of the methods of instant claims 125 and 126.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 125-126, 128-130, 132, 134-139, and 142-144 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 252-253, 257, and 260-266, and 268 of copending Application No. 18/745,399 (herein after referred to as “reference application”) Although the claims at issue are not identical, they are not patentably distinct from each other.
Reference application claims 252-253 are drawn to a method of treating a malignant tumor in a human patient comprising administering an immunotherapy to the patient, wherein a sample of the patient’s tumor is LAG-3 positive and wherein the immunotherapy comprises: (i) a LAG- 3 inhibitor and a PD-1 pathway inhibitor, (ii) a LAG-3 inhibitor, (iii) a PD-1 pathway inhibitor, (iv) an anti-CTLA-4 antibody, or (v) a PD-1 pathway inhibitor and an immune checkpoint inhibitor. Reference application claim 257 is drawn to the method of claim 253 wherein the malignant tumors for treatment of the method are described (e.g., melanoma). Reference application claim 258 is drawn to the method of 253, comprising administering to the patient a therapeutically effective amount of the LAG-3 inhibitor and the PD-1 pathway inhibitor, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or antigen-binding fragment thereof and the PD-1 pathway inhibitor is an anti-PD-1 antibody or antigen-binding fragment thereof. Reference application claims 260-261 are drawn to the method of claim 258, further comprising administering at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is a chemotherapeutic agent or an immune checkpoint inhibitor. Reference application claim 262 is drawn to a kit for treating a patient with a malignant tumor, the kit comprising: (a) (i) a dose of a LAG-3 inhibitor and a dose of a PD-1 pathway inhibitor, (ii) a dose of a LAG-3 inhibitor, (iii) a dose of a PD-1 pathway inhibitor, (iv) a dose of an anti-CTLA-4 antibody, or (v) a dose of a PD-1 pathway inhibitor and a dose of an immune checkpoint inhibitor; and (b) instructions for using the LAG-3 inhibitor and PD-1 pathway inhibitor, LAG-3 inhibitor, PD-1 pathway inhibitor, anti-CTLA-4 antibody, or PD-1 pathway inhibitor and immune checkpoint inhibitor, respectively, in the method of claim 252. Reference application claims 263-265 are drawn to a method of selecting a patient for treatment with a LAG-3 therapy, the method comprising: (a) determining the level of LAG-3 expression in the patient; and (b) administering the LAG-3 therapy to the patient if the level of LAG-3 expression is increased in the patient following treatment with a PD-1 pathway inhibitor, relative to the level of LAG-3 expression prior to treatment with the PD-1 pathway inhibitor wherein the LAG-3 therapy is an anti-LAG-3 antibody or antigen-binding fragment thereof, or a combination therapy and the combination therapy is a combination of an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof. Reference application claims 266 and 268 are drawn to a method of selecting a malignant tumor in a human patient for immunotherapy, comprising: (a) determining the level of LAG-3 expression in a sample of the patient's tumor; and (b) administering an immunotherapy to the patient if the sample is LAG-3 positive and wherein the immunotherapy comprises contacting the tumor with a therapeutically effective amount of: (i) a LAG-3 inhibitor and a PD-1 pathway inhibitor, (ii) a LAG-3 inhibitor, (iii) a PD-1 pathway inhibitor, (iv) an anti-CTLA-4 antibody, or (v) a PD-1 pathway inhibitor and an immune checkpoint inhibitor. Thus, the claims of the reference application are drawn to methods of treating cancer in a human subject in need thereof comprising administering an immunotherapy comprising a LAG-3 inhibitor (i.e., a LAG-3 antagonist).
As such, the reference application claims the methods of instant claims 125-126 and the additional limitations of instant claims 134-139 and 142-144. With regard to instant claims 128-130 and 132, it is specifically noted that the claims further describe/limit the analysis of a tumor sample and/or the LAG-3-D and/or LAG-3-P scores determined therefrom, which are not required by the instant independent claims 125-126. As such, instant claims 128-130 and 132 are also taught by the reference application which teaches the required active steps of the methods of instant claims 125 and 126.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 125-126, 128-130, 132, 134-139, and 140-143 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. Although the claims at issue are not identical, they are not patentably distinct from each other.
Application No.
Brief Description of the Invention
Pertinent Claims
17286203
Method of Treating Metastatic or Unresectable Melanoma Comprising Administering LAG-3 and PD-1 Antibodies
131, 133, 139-141, 143-149, 151-153
18841061
Method of Treating CRC Comprising Administering LAG-3 and PD-1/PD-L1 Antibodies
93-100, 103-111
The pertinent claims of the above-listed reference applications are all drawn to methods of treating cancer, wherein said cancer is recurrent, refractory, and/or metastatic, in a human patient comprising administering to the patient a LAG- 3 inhibitor and a PD-1 pathway inhibitor wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or antigen-binding fragment thereof and the PD-1 pathway inhibitor is an anti-PD-1 antibody or antigen-binding fragment thereof. The pertinent claims of the above-listed reference applications further claim specific anti-LAG-3 antibodies (e.g., BMS 986016) and specific anti-PD-1 antibodies (e.g., BMS 936558). The pertinent claims of the above-listed reference applications also claim the administration of the LAG-3 inhibitor and the PD-1 pathways inhibitor. The pertinent claims of the above-listed reference applications further disclose administering at least one additional therapeutic agent, wherein the additional therapeutic agent is an immune checkpoint inhibitor, including an anti-CTLA-4 antibody (e.g., ipilimumab). Thus, the claims of the reference application are drawn to methods of treating cancer in a human subject in need thereof comprising administering a LAG-3 inhibitor (i.e., a LAG-3 antagonist).
As such, the pertinent claims of the above-listed reference applications read on the methods of instant claims 125-126 and the additional limitations of instant claims 134-139 and 140-143. With regard to instant claims 128-130 and 132, it is specifically noted that the claims further describe/limit the analysis of a tumor sample and/or the LAG-3-D and/or LAG-3-P scores determined therefrom, which are not required by the instant independent claims 125-126. As such, instant claims 128-130 and 132 are also taught by the pertinent claims of the above-listed reference applications, which teach the required active steps of the methods of instant claims 125 and 126.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 140-141 and 144 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. in view of WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny").
Application No.
Brief Description of the Invention
Pertinent Claims
18043562
Method of Treating HCC Comprising Administering a LAG-3 Antagonist
177-191, 198-200
18705171
Method of Treating Hematological Cancer Comprising Administering a LAG-3 Antagonist
185-203
18833472
Method of Treating HCC Comprising Administering LAG-3 and PD-1 Antibodies
152-161, 165-169
The pertinent claims of the above-listed reference applications are all drawn to methods of treating cancer, wherein said cancer is recurrent, refractory, and/or metastatic, in a human patient comprising administering to the patient a LAG- 3 inhibitor and a PD-1 pathway inhibitor wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or antigen-binding fragment thereof and the PD-1 pathway inhibitor is an anti-PD-1 antibody or antigen-binding fragment thereof. The pertinent claims of the above-listed reference applications further claim specific anti-LAG-3 antibodies (e.g., BMS 986016) and specific anti-PD-1 antibodies (e.g., BMS 936558). The pertinent claims of the above-listed reference applications also claim the administration of the LAG-3 inhibitor and the PD-1 pathways inhibitor, as well as administering at least one additional therapeutic agent. Thus, the claims of the reference application are drawn to methods of treating cancer in a human subject in need thereof comprising administering a LAG-3 inhibitor (i.e., a LAG-3 antagonist).
However, the pertinent claims of the above-listed reference applications do not teach/suggest methods for treating cancer in a human patient comprising administering to the patient a LAG-3 antagonist and a CTLA-4 inhibitor wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody or antigen binding fragment thereof, nor a kit for treating a subject afflicted with a tumor wherein the kit comprises (i) a dosage of a LAG-3 antagonist, or a dosage of a LAG-3 antagonist and a dosage of a PD-1 pathway inhibitor and (ii) instructions for using the LAG-3 antagonist is a method for treating cancer in a human patient in need thereof.
The invention of Novotny relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). In one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Exemplary cancers taught by Novotny are provided in Paragraph 0287 and include, for example, melanoma, hepatocellular carcinoma, lung cancer, and renal cancer. Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350).
It is further noted that Novotny discloses (i) a method of treating a LAG-3 positive malignant tumor by administering a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) or a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor or (ii) administering an anti-CTLA4 antibody (Paragraphs 0117-0118). The invention provides an anti-CTLA-4 antibody according to a defined clinical dosage regimen, to treat subjects having a malignant tumor (e.g., an advanced refractory solid tumor); the anti-CTLA4 antibody can be ipilimumab, tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015 (Paragraph 0306). Thus, Novotny discloses that (i) LAG-3 inhibitors alone may be used to treat LAG-3 positive cancers, (ii) LAG-3 inhibitors in combination with PD-1 inhibitors may be used to treat LAG-3 positive cancers, (iii) PD-1 inhibitors in combination with immune checkpoint inhibitors (e.g., CTLA4 inhibitors) may be used to treat LAG-3 positive cancers, and (iv) CTLA4 inhibitors alone may be used to treat LAG-3 positive cancers.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of malignant tumors (e.g., LAG-3 positive cancers). One would have been motivated to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of LAG-3 positive cancers to more effectively treat a LAG-3 positive tumor with a reasonable expectation of success because both LAG-3 inhibitors and CTLA4 inhibitors alone are useful in the treatment of LAG-3 positive cancers, as disclosed by Novotny.
Those of skill in the art recognize that the two classes of cancer therapeutics, LAG-3 inhibitor and CTLA4 inhibitor, both known to successfully, pharmaceutically treat LAG-3 positive cancers, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat LAG-3 positive cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in the treatment of malignant tumors (e.g., LAG-3 positive cancers), thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two classes of inhibitors, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating LAG-3 positive cancer.
Additionally, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to provide the LAG-3 antagonist and PD-1 pathway inhibitors of the above-listed reference applications in a kit for the treatment of malignant tumors, as disclosed by Novotny. Those of skill in the art would recognize that LAG-3 antagonists and PD-1 pathway inhibitors, in combination, are known to treat malignant tumors (e.g., LAG-3 positive cancers), and could have been provided said LAG-3 antagonists and PD-1 pathway inhibitors in a single kit wherein the kit is recognized as being used in the treatment of said malignant tumors, as disclosed by Novotny.
This is a provisional nonstatutory double patenting rejection.
Claims 140-141 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 252-253, 257, and 260-266, and 268 of copending Application No. 18/745,399 (herein after referred to as “reference application”) in view of WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny").
Reference application claims 252-253 are drawn to a method of treating a malignant tumor in a human patient comprising administering an immunotherapy to the patient, wherein a sample of the patient’s tumor is LAG-3 positive and wherein the immunotherapy comprises: (i) a LAG- 3 inhibitor and a PD-1 pathway inhibitor, (ii) a LAG-3 inhibitor, (iii) a PD-1 pathway inhibitor, (iv) an anti-CTLA-4 antibody, or (v) a PD-1 pathway inhibitor and an immune checkpoint inhibitor. Reference application claim 257 is drawn to the method of claim 253 wherein the malignant tumors for treatment of the method are described (e.g., melanoma). Reference application claim 258 is drawn to the method of 253, comprising administering to the patient a therapeutically effective amount of the LAG-3 inhibitor and the PD-1 pathway inhibitor, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or antigen-binding fragment thereof and the PD-1 pathway inhibitor is an anti-PD-1 antibody or antigen-binding fragment thereof. Reference application claims 260-261 are drawn to the method of claim 258, further comprising administering at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is a chemotherapeutic agent or an immune checkpoint inhibitor. Reference application claim 262 is drawn to a kit for treating a patient with a malignant tumor, the kit comprising: (a) (i) a dose of a LAG-3 inhibitor and a dose of a PD-1 pathway inhibitor, (ii) a dose of a LAG-3 inhibitor, (iii) a dose of a PD-1 pathway inhibitor, (iv) a dose of an anti-CTLA-4 antibody, or (v) a dose of a PD-1 pathway inhibitor and a dose of an immune checkpoint inhibitor; and (b) instructions for using the LAG-3 inhibitor and PD-1 pathway inhibitor, LAG-3 inhibitor, PD-1 pathway inhibitor, anti-CTLA-4 antibody, or PD-1 pathway inhibitor and immune checkpoint inhibitor, respectively, in the method of claim 252. Reference application claims 263-265 are drawn to a method of selecting a patient for treatment with a LAG-3 therapy, the method comprising: (a) determining the level of LAG-3 expression in the patient; and (b) administering the LAG-3 therapy to the patient if the level of LAG-3 expression is increased in the patient following treatment with a PD-1 pathway inhibitor, relative to the level of LAG-3 expression prior to treatment with the PD-1 pathway inhibitor wherein the LAG-3 therapy is an anti-LAG-3 antibody or antigen-binding fragment thereof, or a combination therapy and the combination therapy is a combination of an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof. Reference application claims 266 and 268 are drawn to a method of selecting a malignant tumor in a human patient for immunotherapy, comprising: (a) determining the level of LAG-3 expression in a sample of the patient's tumor; and (b) administering an immunotherapy to the patient if the sample is LAG-3 positive and wherein the immunotherapy comprises contacting the tumor with a therapeutically effective amount of: (i) a LAG-3 inhibitor and a PD-1 pathway inhibitor, (ii) a LAG-3 inhibitor, (iii) a PD-1 pathway inhibitor, (iv) an anti-CTLA-4 antibody, or (v) a PD-1 pathway inhibitor and an immune checkpoint inhibitor. Thus, the claims of the reference application are drawn to methods of treating cancer in a human subject in need thereof comprising administering an immunotherapy comprising a LAG-3 inhibitor (i.e., a LAG-3 antagonist).
However, the claims of the reference application do not teach/suggest methods for treating cancer in a human patient comprising administering to the patient a LAG-3 antagonist and a CTLA-4 inhibitor wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody or antigen binding fragment thereof.
The invention of Novotny relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). In one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Exemplary cancers taught by Novotny are provided in Paragraph 0287 and include, for example, melanoma, hepatocellular carcinoma, lung cancer, and renal cancer. Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350).
It is further noted that Novotny discloses (i) a method of treating a LAG-3 positive malignant tumor by administering a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) or a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor or (ii) administering an anti-CTLA4 antibody (Paragraphs 0117-0118). The invention provides an anti-CTLA-4 antibody according to a defined clinical dosage regimen, to treat subjects having a malignant tumor (e.g., an advanced refractory solid tumor); the anti-CTLA4 antibody can be ipilimumab, tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015 (Paragraph 0306). Thus, Novotny discloses that (i) LAG-3 inhibitors alone may be used to treat LAG-3 positive cancers, (ii) LAG-3 inhibitors in combination with PD-1 inhibitors may be used to treat LAG-3 positive cancers, (iii) PD-1 inhibitors in combination with immune checkpoint inhibitors (e.g., CTLA4 inhibitors) may be used to treat LAG-3 positive cancers, and (iv) CTLA4 inhibitors alone may be used to treat LAG-3 positive cancers.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of malignant tumors (e.g., LAG-3 positive cancers). One would have been motivated to combine a LAG-3 inhibitor and a CTLA4 inhibitor in the treatment of LAG-3 positive cancers to more effectively treat a LAG-3 positive tumor with a reasonable expectation of success because both LAG-3 inhibitors and CTLA4 inhibitors alone are useful in the treatment of LAG-3 positive cancers, as disclosed by Novotny.
Those of skill in the art recognize that the two classes of cancer therapeutics, LAG-3 inhibitor and CTLA4 inhibitor, both known to successfully, pharmaceutically treat LAG-3 positive cancers, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat LAG-3 positive cancer and have additive effects through the combination of the two agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in the treatment of malignant tumors (e.g., LAG-3 positive cancers), thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two classes of inhibitors, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of treating LAG-3 positive cancer.
This is a provisional nonstatutory double patenting rejection.
Claim 144 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. in view of WO 2018/222718 (previously cited on PTO-892; herein after referred to as "Novotny").
Application No.
Brief Description of the Invention
Pertinent Claims
17286203
Method of Treating Metastatic or Unresectable Melanoma Comprising Administering LAG-3 and PD-1 Antibodies
131, 133, 139-141, 143-149, 151-153
18841061
Method of Treating CRC Comprising Administering LAG-3 and PD-1/PD-L1 Antibodies
93-100, 103-111
The pertinent claims of the above-listed reference applications are all drawn to methods of treating cancer, wherein said cancer is recurrent, refractory, and/or metastatic, in a human patient comprising administering to the patient a LAG- 3 inhibitor and a PD-1 pathway inhibitor wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or antigen-binding fragment thereof and the PD-1 pathway inhibitor is an anti-PD-1 antibody or antigen-binding fragment thereof. The pertinent claims of the above-listed reference applications further claim specific anti-LAG-3 antibodies (e.g., BMS 986016) and specific anti-PD-1 antibodies (e.g., BMS 936558). The pertinent claims of the above-listed reference applications also claim the administration of the LAG-3 inhibitor and the PD-1 pathways inhibitor. The pertinent claims of the above-listed reference applications further disclose administering at least one additional therapeutic agent, wherein the additional therapeutic agent is an immune checkpoint inhibitor, including an anti-CTLA-4 antibody (e.g., ipilimumab).
However, the pertinent claims of the above-listed reference applications do not teach/suggest a kit for treating a subject afflicted with a tumor wherein the kit comprises (i) a dosage of a LAG-3 antagonist, or a dosage of a LAG-3 antagonist and a dosage of a PD-1 pathway inhibitor and (ii) instructions for using the LAG-3 antagonist is a method for treating cancer in a human patient in need thereof.
The invention of Novotny relates to a method of selecting a malignant tumor in a human patient for treating with a PD-1 pathway inhibitor, a LAG-3 inhibitor, a combination of a PD-1 pathway inhibitor and an immune checkpoint inhibitor, or a combination of a LAG-3 inhibitor (i.e., LAG-3 antagonist; e.g., anti-LAG-3 antibody) and a PD-1 pathway inhibitor and methods of treating LAG-3 positive tumors in a human patient comprising administering a LAG-3 inhibitor and a PD-1 pathway inhibitor (Paragraph 0009). In certain embodiments, identifying a patient suitable for a LAG-3 inhibitor/PD-1 pathway inhibitor combination therapy, a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody therapy, or an anti-CTLA-4 antibody therapy for the present methods includes measuring or assessing a LAG-3 expression in a sample, for example, a malignant tumor test tissue sample comprising tumor cells and tumor infiltrating inflammatory cells (Paragraph 0195). Thus, Novotny teaches that from a tumor sample a patient can be identified as having a LAG-3 positive tumor and a method of treating a LAG-3 positive malignant tumor comprising administering a LAG-3 inhibitor, either alone or in combination with a PD-1 pathway inhibitor. Novotny further teaches treating a human patient with unresectable or metastatic melanoma in need thereof with a combination of a PD-1 pathway inhibitor and a LAG-3 inhibitor; in certain embodiments, the PD-1 pathway inhibitor is an anti-PD-1 antibody and can be nivolumab and the LAG-3 inhibitor is an anti-LAG-3 antibody that can be BMS-986016 (Paragraph 0194). In one aspect, suitable treatment protocols for treating a malignant tumor in a human patient include administering to the patient an effective amount of each of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody) and a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) (Paragraph 0316); the anti-LAG-3 and anti-PD-1 antibodies can be formulated for separate administration and are administered concurrently or sequentially (e.g., one antibody is administered within about 30 minutes prior to administration of the second antibody) (Paragraph 0309) and the anti-LAG-3 and/or anti-PD-1 antibodies can be formulated for intravenous administration (Paragraph 0327). Novotny also provides therapeutic kits which include a pharmaceutical composition containing an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1 antibody, such as nivolumab, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods; in certain embodiments of a therapeutic kit, the anti-LAG-3 antibody is co-packaged with an anti-PD-1 antibody in unit dosage form wherein the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor) (Paragraph 0350).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to provide the LAG-3 antagonist and PD-1 pathway inhibitors of the above-listed reference applications in a kit for the treatment of malignant tumors, as disclosed by Novotny. Those of skill in the art would recognize that LAG-3 antagonists and PD-1 pathway inhibitors, in combination, are known to treat malignant tumors (e.g., LAG-3 positive cancers), and could have been provided said LAG-3 antagonists and PD-1 pathway inhibitors in a single kit wherein the kit is recognized as being used in the treatment of said malignant tumors, as disclosed by Novotny.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments with respect to claims 125-126, 128-130, 132, and 134-144 have been fully considered, but are moot in view of the instant claim amendments which significantly change the scope of the claims to which the arguments pertain. The new grounds of rejection above address the claims as presently amended.
Conclusion
Claims 125-126, 128-130, 132, and 134-144 are pending. Claims 125-126, 128-130, 132, and 134-144 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642