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 .
DETAILED ACTION
Claims 1-7, 9, 11-14, 17, 19-21, 24, 26, 28-29, 31, 34, 36, 38, and 41 are pending in the instant application and being examined on the merit.
Objections to the Claims
Claim 2 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9-13, 26, 34, and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claims 9-13, administration to the subject of an amount of IL-2 as the IL-2 conjugate is claimed, but it is unclear if the claim is claiming the IL-2 protein weight alone in the absence of the PEG or the PEG conjugate. Further it is unclear if the conjugate is meant to be exchanged for IL-2. Thus, the claim is indefinite.
Regarding instant claims 26, 34, and 36, the claims list further details of IL-2 administration followed by the term “optionally” then describes details of cetuximab administration. It is not clear whether the recitation of the cetuximab administration are an optionally preferred example—and therefore not limiting—or further limitations of the scope of the claim.
Claim Rejections – 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-7, 9, 11-14, 17, 19-21, 24, 26, 28-29, 31, 34, 36, 38, and 41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding instant claims 1-7, 9, 11-14, 17, 19-21, 24, 26, 28-29, 31, 34, 36, 38, and 41, the methods of treating HNSCC do not require the cancer express the target of cetuximab, EGFR. If the cancer does not express EGFR then the cetuximab does not have a target to bind the cancer cells.
Scope of the claimed genus
Treatment of different forms of recurrent and/or metastatic HNSCC with a composition of an IL-2 conjugate and cetuximab are claimed, but the cancer is not required to express EGFR.
Summary of Species disclosed in the original specification
Effective administration of a composition of an IL-2 conjugate and cetuximab to HNSCC cancer cells that express EGFR and subjects that have HNSCC cancer cells that express EGFR are shown in Figs. 1-3 and summarized on page 86 [0325], wherein subjects treated with the combination of an IL-2 conjugate and cetuximab showed stable disease and a partial response. The disclosure does not describe possession of a method of treatment of a subject with HNSCC wherein the HNSCC does not express EGFR.
State of the prior art
The prior art describes cetuximab for treatment of HNSCC that expresses EGFR, but does not describe treatment is effective for patients wherein the cancer does not express the cetuximab target, EGFR. Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) taught Cetuximab is an immunoglobulin G1 monoclonal antibody, designed
specifically to block human EGFR (page 2172, left column, first paragraph). Vermorken JCI taught administration of a pharmaceutical composition of a pharmaceutically acceptable excipient and cetuximab in HNSCC patients with disease progression on platinum therapy, wherein cetuximab was administered as an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 (abstract), wherein the cetuximab was administered intravenously (page 2172, left column second paragraph). Vermorken JCI taught cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic HNSCC that progressed on platinum therapy (abstract). Vermorken JCI taught the study population’s characteristics were typical of this patient group, with a history of extensive previous therapy (page 2175, left to right bridging paragraph).
Claim Rejections – 35 USC § 103
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 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.
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.
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.
Claims 1-2, 5, 14, 17, 19-21, 24, 29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Hara M et al. (Cancer Sci. 2008 Apr 16;99(7):1471–1478, IDS reference), Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), and Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) and evidenced by WO 2022/174101 (Abbadessa G et al. IDS reference) and NCI dictionary pegenzileukin (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/pegenzileukin 2026)
Hara taught an effective method of treating a subject with gastric cancer or metastatic gastric cancer that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and cetuximab and IL-2, wherein the subject was not previously treated with cetuximab, wherein the administration of IL-2 and cetuximab was separately administered (Fig. 3 and 6).
Hara did not teach: 1) the IL-2 as an IL-2 conjugate of SEQ ID NO:1 wherein the amino acid at P64 is replaced by Formula I; and 2) the cancer as HNSCC, but this is obvious in view of Milla, ‘815, and Vermorken JCI.
Milla taught administration of THOR-707 demonstrated all critical actions of IL-2 for anti-tumoral responses without inducing VLS, including: (1) maximal extravasation and expansion of key CD8+ T and NK cell populations in mice and non-human primates (2) CD8+ T cell infiltration of tumor and lymph nodes in mouse tumor models, critical for antigen presentation by tumor cells and trans-presentation by antigen presenting cells and (3) induction of IFNγ release ex vivo by T cell receptor (TCR)-activated human T cells (abstract). Milla taught THOR-707 promoted an increase in the number of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells. Expression profiling of tumors revealed promotion of remodeling of cellular populations towards a composition favoring cytolytic phenotypes. Evaluation of TCR clonality revealed that treatment with THOR-707 increased intra-tumoral T cell diversity (abstract). THOR-707 is evidenced by NCI dictionary as a pegenzileukin (NCI dictionary, Table), which is evidenced by ‘101 as an IL-2 conjugate comprising ‘101 SEQ ID NO: 1, wherein position 64 is replaced by the structure of Formula (XII) or Formula (XIII), or a mixture of Formula (XII) and Formula (XIII), and a 30 kDa, linear mPEG chain (page 81-82, [0322]), wherein Formula (XII) and Formula (XIII) have the structure:
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and q is 1-3 (pages 27-28, [0169])
‘815 taught combination treatment of IL-2 or an IL-2 agonist mutein D10 with cetuximab increased NK cell lysis the EGFR-expressing squamous tumor cancer cell line SCC6, which is a HNSCC (page 8, [033], page 66-67, [0220-0221];, and Fig. 8).
Vermorken JCI taught administration of a pharmaceutical composition of a pharmaceutically acceptable excipient and cetuximab in HNSCC patients with disease progression on platinum therapy, wherein cetuximab was administered as an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 (abstract), wherein the cetuximab was administered intravenously (page 2172, left column second paragraph). Vermorken JCI taught cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic HNSCC that progressed on platinum therapy (abstract). Vermorken JCI taught the study population’s characteristics were typical of this patient group, with a history of extensive previous therapy (page 2175, left to right bridging paragraph).
Regarding instant claims 1-2, 5, 14, 17, 19-21, 24, 29, and 31, it would have been obvious for a person having ordinary skill in the art to modify the effective method of Hara of treating a subject with gastric cancer or metastatic gastric cancer that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and cetuximab and IL-2, wherein the subject was not previously treated with cetuximab, wherein the administration of IL-2 and cetuximab was separately administered – to:
1) exchange IL-2 for THOR-707 which is also known as pegenzileukin in view of Milla; 2) change the cancer to recurrent or metastatic HNSCC and wherein cetuximab was administered as an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 in view of ‘815 and Vermorken JCI; and 3) include patients that have platinum refractory HNSCC in view of Vermorken JCI.
This is obvious because:
1a) Milla taught administration of THOR-707 demonstrated all critical actions of IL-2 for anti-tumoral responses without inducing VLS, including: (a) maximal extravasation and expansion of key CD8+ T and NK cell populations in mice and non-human primates (b) CD8+ T cell infiltration of tumor and lymph nodes in mouse tumor models, critical for antigen presentation by tumor cells and trans-presentation by antigen presenting cells and (c) induction of IFNγ release ex vivo by T cell receptor (TCR)-activated human T cells; and (d) promoted an increase in the number of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells;
2a) ‘815 taught combination treatment of IL-2 or an IL-2 agonist mutein D10 with cetuximab increased NK cell lysis the EGFR-expressing squamous tumor cancer cell line SCC6, which is a HNSCC; Thus, the combination of cetuximab and IL-2 was known to be effective in HNSCC.
2b-3) Vermorken JCI taught cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic HNSCC that progressed on platinum therapy, wherein cetuximab was administered as an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2, wherein the cetuximab was administered intravenously, wherein the patients had extensive previous therapy. Thus, cetuximab was known to be effective in recurrent or metastatic HNSCC.
There is a reasonable expectation of success because:
1a) Milla taught administration of THOR-707 demonstrated all critical actions of IL-2 for anti-tumoral responses without inducing VLS, including: (a) maximal extravasation and expansion of key CD8+ T and NK cell populations in mice and non-human primates (b) CD8+ T cell infiltration of tumor and lymph nodes in mouse tumor models, critical for antigen presentation by tumor cells and trans-presentation by antigen presenting cells and (c) induction of IFNγ release ex vivo by T cell receptor (TCR)-activated human T cells; and (d) promoted an increase in the number of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells. Thus, THOR-707 would be expected to be effective in the combination;
2a) ‘815 taught combination treatment of IL-2 or an IL-2 agonist mutein D10 with cetuximab increased NK cell lysis the EGFR-expressing squamous tumor cancer cell line SCC6, which is a HNSCC. Thus, the combination would be expected to be effective in HNSCC patients;
2b-3) Vermorken JCI taught cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic HNSCC that progressed on platinum therapy, wherein cetuximab was administered as an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2, wherein the cetuximab was administered intravenously, wherein the patients had extensive previous therapy. Thus, the combination would be expected to be effective in recurrent and/or metastatic HNSCC patients that is platinum refractory at this dose of cetuximab.
This would produce a method of treating a subject with platinum refractory (instant claim 5) recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
An IL-2 conjugate THOR-707 which is also known as pegenzileukin, which is an IL-2 conjugate comprising ‘101 SEQ ID NO: 1, which is identical to instant SEQ ID NO:1, wherein position 64 is replaced by the structure of Formula (XII) or Formula (XIII), or a mixture of Formula (XII) and Formula (XIII), and a 30 kDa, linear mPEG chain, wherein Formula (XII) and Formula (XIII) have the structure:
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and q is 1-3 (instant claims 14, 17, 19-21, and 24), wherein the attachment point would further attach to L-amino acids with the structure
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143
103
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, wherein X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue; and
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab (instant claim 29),
wherein the administration of IL-2 and cetuximab was separately administered (instant claim 31) (instant claims 1-2 ).
Claims 1-3, 5, 9-14, 17, 19-21, 24, 26, 29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Hara M et al. (Cancer Sci. 2008 Apr 16;99(7):1471–1478, IDS reference), Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), and Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) as applied to claims 1-2, 5, 14, 17, 19-21, 24, 29, and 31 above, and further in view of ZacksSCR et al. (https://scr.zacks.com/news/news-details/2020/MDNATO-Encouraging-MDNA19-Data-in-Non-Human-Primates-Financing-Funds-Company-Through-End-of-2022/default.aspx).
Hara, Milla, and Vermorken JCI are described above.
Hara does not teach: 1) the concentration of an IL-2 conjugate between about 8 and 32 µg/kg, but this is obvious in view of ZacksSCR.
ZacksSCR taught administration of a pharmaceutical composition comprising IL-2 agents MDNA19 or THOR-707 to non-human primates wherein: 1) lymphocyte expansion of THOR-707 dosed at 0.1 mg/kg is effective very similar to the same dose of MDNA19 (page 2, last paragraph and page 3 top figure); 2) CD8+ T cell proliferation as measured by Ki67 expression was similar for THOR-707 and MDNA19 wherein 30 µg/kg and 100 µg/kg was dose-dependently effective (page 3, first paragraph and middle figure). ZacksSCR taught 10 µg/kg of MDNA19 was effective in non-human primates to increase CD8+ T cell proliferation (page 3, middle figure). ZacksSCR taught administration of THOR-707 as Q2W which is an administration once every two weeks as effective to increase lymphocytes (page 3, top figure).
Regarding instant claims 3 and 9-13, it would have been obvious for a person having ordinary skill in the art to modify the effective method of Hara, Milla, and Vermorken JCI above – to:
1) administer about 10 µg/kg to about 100 µg/kg of THOR-707 which is also known as pegenzileukin once every two weeks in view of ZacksSCR
This is obvious because:
1a) ZacksSCR taught administration of a pharmaceutical composition comprising IL-2 agents MDNA19 or THOR-707 to non-human primates wherein: i) lymphocyte expansion of THOR-707 dosed at 0.1 mg/kg (100 µg/kg) is effective and very similar to the same dose of MDNA19; ii) CD8+ T cell proliferation as measured by Ki67 expression was similar for THOR-707 and MDNA19 wherein 30 µg/kg and 100 µg/kg was dose-dependently effective; and iii) 10 µg/kg of MDNA19 was effective in non-human primates to increase CD8+ T cell proliferation. Thus, if MDNA19 and THOR-707 have similar pharmacokinetics, then it would be obvious with a reasonable expectation of success that 10 µg/kg of THOR-707 would be similarly effective in increasing CD8+ T cell proliferation at this dosage; and
1b) ZacksSCR taught administration of THOR-707 as Q2W which is an administration once every two weeks as effective to increase lymphocytes.
There is a reasonable expectation of success because:
1a) ZacksSCR taught administration of a pharmaceutical composition comprising IL-2 agents MDNA19 or THOR-707 to non-human primates wherein: i) lymphocyte expansion of THOR-707 dosed at 0.1 mg/kg (100 µg/kg) is effective and very similar to the same dose of MDNA19; ii) CD8+ T cell proliferation as measured by Ki67 expression was similar for THOR-707 and MDNA19 wherein 30 µg/kg and 100 µg/kg was dose-dependently effective; and iii) 10 µg/kg of MDNA19 was effective in non-human primates to increase CD8+ T cell proliferation. Thus, if MDNA19 or THOR-707 have similar pharmacokinetics, then it would be obvious with a reasonable expectation of success that 10 µg/kg of THOR-707 would be similarly effective in increasing CD8+ T cell proliferation at this dosage. Thus a dosage of about 10 to 100 µg/kg would be expected to be effective; and
1b) ZacksSCR taught administration of THOR-707 as Q2W which is an administration once every two weeks as effective to increase lymphocytes. Thus this timing is expected to be effective.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
a dosage of 10 µg/kg to 100 µg/kg of an IL-2 conjugate THOR-707 which is also known as pegenzileukin, which overlaps with the dosage of 8 to 32 µg/kg and includes 16, 24, and 32 µg/kg (instant claims 3 and 9-13) once every two weeks (instant claim 26),
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered.
Claims 1-2, 4-7, 14, 17, 19-21, 24, 29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Hara M et al. (Cancer Sci. 2008 Apr 16;99(7):1471–1478, IDS reference), Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), and Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) as applied to claims 1-2, 5, 14, 17, 19-21, 24, 29, and 31 above, and further in view of Vermorken JB et al. (NEJM 2008, 359 11 1116-1127).
Hara, Milla, and Vermorken JCI are described above.
Hara does not teach: 1) wherein the HNSCC patient was not previously treated with cetuximab or wherein the previous treatment for HNSCC comprised failure of no more than two regimens, but this is obvious in view of Vermorken NEJM.
Vermorken NEJM taught administration of a pharmaceutical composition comprising cetuximab to recurrent or metastatic HNSCC patients was effective as a first line treatment (abstract).
Regarding instant claims 4 and 6-7, it would have been obvious for a person having ordinary skill in the art to modify the effective method of Hara, Milla, and Vermorken JCI above – to:
1) administer cetuximab wherein the recurrent or metastatic HNSCC patient was not previously treated with cetuximab or wherein the previous treatment for HNSCC comprised failure of no more than two regimens in view of Vermorken NEJM.
This is obvious because:
1a) Vermorken NEJM taught administration of a pharmaceutical composition comprising cetuximab to recurrent or metastatic HNSCC patients was effective as a first line treatment. Thus patients not previously treated with cetuximab are effectively treated with cetuximab; and
1b) If cetuximab is effective in first line treatment of recurrent or metastatic HNSCC as taught by Vermorken NEJM and effective in platinum refractory recurrent or metastatic HNSCC then it would be obvious with a reasonable expectation that the combination would be effective in platinum refractory recurrent or metastatic HNSCC wherein the previous treatment comprised failure of at least one regimen containing a platinum.
There is a reasonable expectation of success because:
1a) Vermorken NEJM taught administration of a pharmaceutical composition comprising cetuximab to recurrent or metastatic HNSCC patients was effective as a first line treatment. Thus patients not previously treated with cetuximab are effectively treated with cetuximab and the combination would be expected to be effective; and
1b) If cetuximab is effective in first line treatment of recurrent or metastatic HNSCC as taught by Vermorken NEJM and effective in platinum refractory recurrent or metastatic HNSCC then it would be obvious with a reasonable expectation that the combination would be effective in platinum refractory recurrent or metastatic HNSCC wherein the previous treatment comprised failure of at least one regimen containing a platinum.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR, wherein the subject was not previously treated with cetuximab (instant claim 4), or wherein the subject has platinum-refractory HNSCC and the subject's previous treatment for HNSCC comprised failure of one or two regimens (instant claim 6-7), comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is also known as pegenzileukin,
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered.
Claims 1-2, 5, 14, 17, 19-21, 24, 28-29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Hara M et al. (Cancer Sci. 2008 Apr 16;99(7):1471–1478, IDS reference), Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), and Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) as applied to claims 1-2, 5, 14, 17, 19-21, 24, 29, and 31 above, and further in view of Mattijssen V et al. (Annals of Oncology 1994 5(10) 957-960, IDS reference).
Hara, Milla, and Vermorken JCI are described above.
Hara does not teach: 1) an IL-2 conjugate solvate, but this is obvious in view of Mattijssen.
Mattijssen taught administration of PEG-IL-2 was beneficial for some HNSCC patients (abstract). Mattijssen taught PEG-IL-2 in an aqueous solution of normal saline, which is thus solvated with water (page 958, left column, second paragraph).
Regarding instant claim 28, it would have been obvious for a person having ordinary skill in the art to modify the effective method of Hara, Milla, and Vermorken JCI above – to:
1) administer an IL-2 conjugate solvate in view of Mattijssen.
This is obvious because:
1) Mattijssen taught PEG-IL-2 in an aqueous solution of normal saline, which is thus solvated with water. It would be obvious to administer the IL-2 conjugate in an aqueous solution which would solvate the conjugate.
There is a reasonable expectation of success because:
1) Mattijssen taught PEG-IL-2 in an aqueous solution of normal saline, which is thus solvated with water. It would be obvious to administer the IL-2 conjugate in an aqueous solution which would solvate the conjugate and be expected to be effective as seen in other PEG-IL-2 conjugates.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is also known as pegenzileukin in an aqueous solution which would solvate the IL-2 conjugate (instant claim 28),
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered.
Claims 1-2, 5, 14, 17, 19-21, 24, 29, 31, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Hara M et al. (Cancer Sci. 2008 Apr 16;99(7):1471–1478, IDS reference), Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), and Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) as applied to claims 1-2, 5, 14, 17, 19-21, 24, 29, and 31 above, and further in view of Mahmoudpour SH et al. (Sci Rep 2019 9(1):7145).
Hara, Milla, and Vermorken JCI are described above.
Hara does not teach: 1) subcutaneous administration of an IL-2 conjugate but this is obvious in view of Mahmoudpour.
Mahmoudpour taught use of subcutaneous recombinant IL-2 on top of the standard of care is well tolerated and does not appear to increase the risk of developing thromboembolic events in patients with various conditions, notably cancer (page 5, Discussion, first paragraph).
Regarding instant claim 34, it would have been obvious for a person having ordinary skill in the art to modify the effective method of Hara, Milla, and Vermorken JCI above – to:
1) administer an IL-2 conjugate subcutaneously in view of Mahmoudpour.
This is obvious because:
1) Mahmoudpour taught use of subcutaneous recombinant IL-2 on top of the standard of care is well tolerated and does not appear to increase the risk of developing thromboembolic events in patients with various conditions, notably cancer. Thus, subcutaneous administration of an IL-2 conjugate is obvious.
There is a reasonable expectation of success because:
1) Mahmoudpour taught use of subcutaneous recombinant IL-2 on top of the standard of care is well tolerated and does not appear to increase the risk of developing thromboembolic events in patients with various conditions, notably cancer. Thus, subcutaneous administration of an IL-2 conjugate has a reasonable expectation of success.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is also known as pegenzileukin wherein the IL-2 conjugate is administered via subcutaneous injection (instant claim 34),
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered.
Claims 1-2, 5, 14, 17, 19-21, 24, 29, 31, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Hara M et al. (Cancer Sci. 2008 Apr 16;99(7):1471–1478, IDS reference), Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), and Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) as applied to claims 1-2, 5, 14, 17, 19-21, 24, 29, and 31 above, and further in view of Bentebibel S-E et al. (Cancer Discov (2019) 9 (6): 711–721).
Hara, Milla, and Vermorken JCI are described above.
Hara does not teach: 1) intravenous administration of an IL-2 conjugate but this is obvious in view of Bentebibel.
Bentebibel taught NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients (abstract), wherein NKTR-214 (bempegaldesleukin) is a human recombinant IL-2 attached to PEG (page 712, left column, second paragraph) administered via intravenous infusion (page 719, patients and study design).
Regarding instant claim 36, it would have been obvious for a person having ordinary skill in the art to modify the effective method of Hara, Milla, and Vermorken JCI above – to:
1) administer an IL-2 conjugate intravenously in view of Bentebibel.
This is obvious because:
1) Bentebibel taught NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients, wherein NKTR-214 (bempegaldesleukin) is a human recombinant IL-2 attached to PEG administered via intravenous infusion. Thus, intravenous administration of an IL-2 conjugate is obvious.
There is a reasonable expectation of success because:
1) Bentebibel taught NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients, wherein NKTR-214 (bempegaldesleukin) is a human recombinant IL-2 attached to PEG administered via intravenous infusion. Thus, intravenous administration of an IL-2 conjugate has a reasonable expectation of success.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is also known as pegenzileukin wherein the IL-2 conjugate is administered via intravenous injection (instant claim 36),
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered.
Claims 1-2, 5, 14, 17, 19-21, 24, 29, 31, 38, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Hara M et al. (Cancer Sci. 2008 Apr 16;99(7):1471–1478, IDS reference), Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), and Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) as applied to claims 1-2, 5, 14, 17, 19-21, 24, 29, and 31 above, and further in view of Tra F et al. (JCI 2008 26 15 suppl 17040).
Hara, Milla, and Vermorken JCI are described above.
Hara does not teach: 1) administration of a composition comprising acetaminophen, diphenhydramine, and ondansetron before cetuximab, but this is obvious in view of Tra.
Tra taught administration of a pretreatment composition comprising diphenhydramine, acetaminophen, and ondansetron was effective to prevent infusion-related reactions before administration of cetuximab to patients, which contrasts with the known infusion-related side effects of cetuximab (abstract).
Regarding instant claims 38 and 41, it would have been obvious for a person having ordinary skill in the art to modify the effective method of Hara, Milla, and Vermorken JCI above – to:
1) administer a composition comprising acetaminophen, diphenhydramine, and ondansetron before cetuximab in view of Tra.
This is obvious because:
1) Tra taught administration of a pretreatment composition comprising diphenhydramine, acetaminophen, and ondansetron was effective to prevent infusion-related reactions before administration of cetuximab to patients, which contrasts with the known infusion-related side effects of cetuximab. Thus, administration before cetuximab is obvious.
There is a reasonable expectation of success because:
1) Tra taught administration of a pretreatment composition comprising diphenhydramine, acetaminophen, and ondansetron was effective to prevent infusion-related reactions before administration of cetuximab to patients, which contrasts with the known infusion-related side effects of cetuximab. Thus, administration before cetuximab to prevent infusion-related reactions has a reasonable expectation of success.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is also known as pegenzileukin,
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered, and wherein diphenhydramine, acetaminophen, and ondansetron are administered before administration of cetuximab (instant claims 38 and 41).
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 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 13, 19, 21-22, 24, 27, and 30-37 of copending Application No. 19/305,326 in view of Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), and Vermorken JB et al. (JCI 2007, 25(16) 2171-2177) and evidenced by WO 2022/174101 (Abbadessa G et al., IDS reference) and NCI dictionary pegenzileukin (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/pegenzileukin 2026)
‘326 taught methods of cancer treatment of an anti-EGFR antibody and an IL-2 conjugate in pending claims 1, 4-9, 13, 19, 21-22, 24, 27, and 30-37.
‘326 taught a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (a) an IL-2 conjugate, and (b) an anti-EGFR antibody, wherein the IL-2 conjugate comprises the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (I)
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W is a PEG group of about 30 kDa, X has the structure
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X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue; wherein the position is P64 in copending claim 1,
wherein the structure of Formula I has the structure of Formula (IV) or (V) or the IL-2 conjugate is provided as a mixture of Formula (IV) and (V):
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Formula (V)
wherein W is a PEG group of about 30 kDa and q is 1, 2, or 3, and X has the structure
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X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue in copending claim 9,
wherein the IL-2 conjugate is administered to the subject once every two weeks in copending claim 19,
wherein the IL-2 conjugate is administered intravenously in copending claim 21,
wherein the IL-2 conjugate and anti-EGFR conjugate are administered separately in copending claim 22,
wherein the cancer is HNSCC in copending claim 24,
wherein the antibody is cetuximab in copending claim 27.
‘326 did not teach: 1) treatment of recurrent or metastatic HNSCC or 2) an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab, but this is obvious in view of Milla, ‘815, and Vermorken.
Milla taught administration of THOR-707 demonstrated all critical actions of IL-2 for anti-tumoral responses without inducing VLS, including: (1) maximal extravasation and expansion of key CD8+ T and NK cell populations in mice and non-human primates (2) CD8+ T cell infiltration of tumor and lymph nodes in mouse tumor models, critical for antigen presentation by tumor cells and trans-presentation by antigen presenting cells and (3) induction of IFNγ release ex vivo by T cell receptor (TCR)-activated human T cells (abstract). Milla taught THOR-707 promoted an increase in the number of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells. Expression profiling of tumors revealed promotion of remodeling of cellular populations towards a composition favoring cytolytic phenotypes. Evaluation of TCR clonality revealed that treatment with THOR-707 increased intra-tumoral T cell diversity (abstract). THOR-707 is evidenced by NCI dictionary as a pegenzileukin (NCI dictionary, Table), which is evidenced by ‘101 as an IL-2 conjugate comprising ‘101 SEQ ID NO: 1, wherein position 64 is replaced by the structure of Formula (XII) or Formula (XIII), or a mixture of Formula (XII) and Formula (XIII), and a 30 kDa, linear mPEG chain (page 81-82, [0322]), wherein Formula (XII) and Formula (XIII) have the structure:
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and q is 1-3 (pages 27-28, [0169])
‘815 taught combination treatment of IL-2 or an IL-2 agonist mutein D10 with cetuximab increased NK cell lysis the EGFR-expressing squamous tumor cancer cell line SCC6, which is a HNSCC (page 8, [033], page 66-67, [0220-0221];, and Fig. 8).
Vermorken JCI taught administration of a pharmaceutical composition of a pharmaceutically acceptable excipient and cetuximab in HNSCC patients with disease progression on platinum therapy, wherein cetuximab was administered as an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 (abstract), wherein the cetuximab was administered intravenously (page 2172, left column second paragraph). Vermorken JCI taught cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic HNSCC that progressed on platinum therapy (abstract). Vermorken JCI taught the study population’s characteristics were typical of this patient group, with a history of extensive previous therapy (page 2175, left to right bridging paragraph).
Regarding instant claims 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, and 36, it would have been obvious for a person having ordinary skill in the art to modify the method of the combined copending claims 1, 9, 19, 21-22, 24, and 27 of ‘326 of a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (a) an IL-2 conjugate, and (b) an anti-EGFR antibody, wherein the IL-2 conjugate comprises the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (I)
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W is a PEG group of about 30 kDa, X has the structure
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X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue; wherein the position is P64, wherein the structure of Formula I has the structure of Formula (IV) or (V) or the IL-2 conjugate is provided as a mixture of Formula (IV) and (V):
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Formula (V)
wherein W is a PEG group of about 30 kDa and q is 1, 2, or 3, and X has the structure
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118
86
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X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue, wherein the IL-2 conjugate is administered to the subject once every two weeks, wherein the IL-2 conjugate is administered intravenously, wherein the IL-2 conjugate and anti-EGFR conjugate are administered separately, wherein the cancer is HNSCC, and wherein the antibody is cetuximab – and modify to:
treat recurrent or metastatic HNSCC in view of Milla, ‘815, and Vermorken; and
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab in view of Vermorken.
This is obvious because THOR-707 is identical to the IL-2 conjugate in copending claims 1 and 9 and:
1a) Milla taught administration of THOR-707 demonstrated all critical actions of IL-2 for anti-tumoral responses without inducing VLS, including: (a) maximal extravasation and expansion of key CD8+ T and NK cell populations in mice and non-human primates (b) CD8+ T cell infiltration of tumor and lymph nodes in mouse tumor models, critical for antigen presentation by tumor cells and trans-presentation by antigen presenting cells and (c) induction of IFNγ release ex vivo by T cell receptor (TCR)-activated human T cells; and (d) promoted an increase in the number of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells;
1b) ‘815 taught combination treatment of IL-2 or an IL-2 agonist mutein D10 with cetuximab increased NK cell lysis the EGFR-expressing squamous tumor cancer cell line SCC6, which is a HNSCC. Thus, the combination of cetuximab and IL-2 was known to be effective;
1c-2) Vermorken JCI taught cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic HNSCC that progressed on platinum therapy, wherein cetuximab was administered as an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2, wherein the cetuximab was administered intravenously, wherein the patients had extensive previous therapy. Thus, cetuximab was known to be effective in recurrent and/or metastatic HNSCC.
There is a reasonable expectation of success because:
1a) Milla taught administration of THOR-707 demonstrated all critical actions of IL-2 for anti-tumoral responses without inducing VLS, including: (a) maximal extravasation and expansion of key CD8+ T and NK cell populations in mice and non-human primates (b) CD8+ T cell infiltration of tumor and lymph nodes in mouse tumor models, critical for antigen presentation by tumor cells and trans-presentation by antigen presenting cells and (c) induction of IFNγ release ex vivo by T cell receptor (TCR)-activated human T cells; and (d) promoted an increase in the number of infiltrating tumor-killing NK and CD8+ T cells without expansion of suppressive CD4+ Treg cells. Thus, THOR-707 would be expected to be effective in the combination;
1b) ‘815 taught combination treatment of IL-2 or an IL-2 agonist mutein D10 with cetuximab increased NK cell lysis the EGFR-expressing squamous tumor cancer cell line SCC6, which is a HNSCC. Thus, the combination of cetuximab and IL-2 was known to be effective;
1c-2) Vermorken JCI taught cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic HNSCC that progressed on platinum therapy, wherein cetuximab was administered as an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2, wherein the cetuximab was administered intravenously, wherein the patients had extensive previous therapy. Thus, cetuximab was known to be effective in recurrent and/or metastatic HNSCC.
This would produce a method of treating a subject with platinum refractory (instant claim 5) recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
An IL-2 conjugate THOR-707 which is an IL-2 conjugate comprising ‘326 SEQ ID NO: 3, which is identical to instant SEQ ID NO:1, wherein position 64 is replaced by the structure of wherein the structure of Formula I has the structure of Formula (IV) or (V) or the IL-2 conjugate is provided as a mixture of Formula (IV) and (V):
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Formula (V), wherein W is a PEG group of about 30 kDa and q is 1, 2, or 3, and X has the structure
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X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue, (instant claims 14, 17, 19-21, and 24); and
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab (instant claim 29),
wherein the administration of IL-2 and cetuximab was separately administered (instant claim 31), wherein the IL-2 conjugate is administered to the subject once every two weeks (instant claim 26), wherein the IL-2 conjugate is administered intravenously (instant claim 36) (instant claims 1-2 ).
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 5, 9-14, 17, 19-21, 24, 26, 29, 31, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 13, 19, 21-22, 24, 27, and 30-37 of copending Application No. 19/305,326 in view of Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), Vermorken JB et al. (JCI 2007, 25(16) 2171-2177), and ZacksSCR et al. News Details 3/3/2020 (https://scr.zacks.com/news/news-details/2020/MDNATO-Encouraging-MDNA19-Data-in-Non-Human-Primates-Financing-Funds-Company-Through-End-of-2022/default.aspx) and evidenced by WO 2022/174101 (Abbadessa G et al. IDS reference) and NCI dictionary pegenzileukin (https://www.cancer.gov/publications/dictionaries/cancer-drug/def/pegenzileukin 2026)
The claims of the copending ‘326 in view of Milla, ‘815, and Vermorken JCI and evidenced by ‘101 and NCI dictionary teach the limitations of claims 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, and 36 for the reasons set forth above.
‘326, Milla, ‘815, Vermorken JCI, ‘101, and NCI dictionary are described above.
‘326 did not teach: 1) the concentration of an IL-2 conjugate between about 8 and 32 µg/kg, but this is obvious in view of ZacksSCR.
ZacksSCR taught administration of a pharmaceutical composition comprising IL-2 agents MDNA19 or THOR-707 to non-human primates wherein: 1) lymphocyte expansion of THOR-707 dosed at 0.1 mg/kg is effective very similar to the same dose of MDNA19 (page 2, last paragraph and page 3 top figure); 2) CD8+ T cell proliferation as measured by Ki67 expression was similar for THOR-707 and MDNA19 wherein 30 µg/kg and 100 µg/kg was dose-dependently effective (page 3, first paragraph and middle figure). ZacksSCR taught 10 µg/kg of MDNA19 was effective in non-human primates to increase CD8+ T cell proliferation (page 3, middle figure). ZacksSCR taught administration of THOR-707 as Q2W which is an administration once every two weeks as effective to increase lymphocytes (page 3, top figure).
Regarding instant claims 3 and 9-13, it would have been obvious for a person having ordinary skill in the art to modify the effective method of copending claims 1, 9, 19, 21-22, 24, and 27 of ‘326, Milla, and Vermorken JCI above – to:
1) administer about 10 µg/kg to about 100 µg/kg of THOR-707 which is also known as pegenzileukin in view of ZacksSCR.
This is obvious because:
1) ZacksSCR taught administration of a pharmaceutical composition comprising IL-2 agents MDNA19 or THOR-707 to non-human primates wherein: i) lymphocyte expansion of THOR-707 dosed at 0.1 mg/kg (100 µg/kg) is effective and very similar to the same dose of MDNA19; ii) CD8+ T cell proliferation as measured by Ki67 expression was similar for THOR-707 and MDNA19 wherein 30 µg/kg and 100 µg/kg was dose-dependently effective; and iii) 10 µg/kg of MDNA19 was effective in non-human primates to increase CD8+ T cell proliferation. Thus, if MDNA19 and THOR-707 have similar pharmacokinetics, then it would be obvious with a reasonable expectation of success that 10 µg/kg of THOR-707 would be similarly effective in increasing CD8+ T cell proliferation at this dosage.
There is a reasonable expectation of success because:
1) ZacksSCR taught administration of a pharmaceutical composition comprising IL-2 agents MDNA19 or THOR-707 to non-human primates wherein: i) lymphocyte expansion of THOR-707 dosed at 0.1 mg/kg (100 µg/kg) is effective and very similar to the same dose of MDNA19; ii) CD8+ T cell proliferation as measured by Ki67 expression was similar for THOR-707 and MDNA19 wherein 30 µg/kg and 100 µg/kg was dose-dependently effective; and iii) 10 µg/kg of MDNA19 was effective in non-human primates to increase CD8+ T cell proliferation. Thus, if MDNA19 or THOR-707 have similar pharmacokinetics, then it would be obvious with a reasonable expectation of success that 10 µg/kg of THOR-707 would be similarly effective in increasing CD8+ T cell proliferation at this dosage. Thus a dosage of about 10 to 100 µg/kg would be expected to be effective.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
a dosage of 10 µg/kg to 100 µg/kg of an IL-2 conjugate THOR-707 which is an IL-2 conjugate comprising ‘326 SEQ ID NO: 3, which is identical to instant SEQ ID NO:1, wherein position 64 is replaced by the structure of wherein the structure of Formula I has the structure of Formula (IV) or (V) or the IL-2 conjugate is provided as a mixture of Formula (IV) and (V):
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Formula (V), wherein W is a PEG group of about 30 kDa and q is 1, 2, or 3, and X has the structure
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X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue, which overlaps with the dosage of 8 to 32 µg/kg and includes 16, 24, and 32 µg/kg (instant claims 3 and 9-13); and
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered, wherein the IL-2 conjugate is administered to the subject once every two weeks, wherein the IL-2 conjugate is administered intravenously.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4-7, 14, 17, 19-21, 24, 26, 29, 31, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 13, 19, 21-22, 24, 27, and 30-37 of copending Application No. 19/305,326 in view of Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), Vermorken JB et al. (JCI 2007, 25(16) 2171-2177), and Vermorken JB et al. (NEJM 2008, 359 11 1116-1127) and evidenced by WO 2022/174101 (Abbadessa G et al. IDS reference) and NCI dictionary pegenzileukin (https://www.cancer.gov/publications/dictionaries/cancer-drug/def/pegenzileukin 2026)
The claims of the copending ‘326 in view of Milla, ‘815, and Vermorken JCI and evidenced by ‘101 and NCI dictionary teach the limitations of claims 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, and 36 for the reasons set forth above.
‘326, Milla, ‘815, Vermorken JCI, ‘101, and NCI dictionary are described above.
‘326 did not teach: 1) wherein the HNSCC patient was not previously treated with cetuximab or wherein the previous treatment for HNSCC comprised failure of no more than two regimens, but this is obvious in view of Vermorken NEJM.
Vermorken NEJM taught administration of a pharmaceutical composition comprising cetuximab to recurrent or metastatic HNSCC patients was effective as a first line treatment (abstract).
Regarding instant claims 4 and 6-7, it would have been obvious for a person having ordinary skill in the art to modify the effective method of copending claims 1, 9, 19, 21-22, 24, and 27 of ‘326, Milla, and Vermorken JCI above – to:
1) administer cetuximab wherein the recurrent or metastatic HNSCC patient was not previously treated with cetuximab or wherein the previous treatment for HNSCC comprised failure of no more than two regimens in view of Vermorken NEJM.
This is obvious because:
1a) Vermorken NEJM taught administration of a pharmaceutical composition comprising cetuximab to recurrent or metastatic HNSCC patients was effective as a first line treatment. Thus patients not previously treated with cetuximab are effectively treated with cetuximab; and
1b) If cetuximab is effective in first line treatment of recurrent or metastatic HNSCC as taught by Vermorken NEJM and effective in platinum refractory recurrent or metastatic HNSCC then it would be obvious with a reasonable expectation that the combination would be effective in platinum refractory recurrent or metastatic HNSCC wherein the previous treatment comprised failure of at least one regimen containing a platinum.
There is a reasonable expectation of success because:
1a) Vermorken NEJM taught administration of a pharmaceutical composition comprising cetuximab to recurrent or metastatic HNSCC patients was effective as a first line treatment. Thus patients not previously treated with cetuximab are effectively treated with cetuximab and the combination would be expected to be effective; and
1b) If cetuximab is effective in first line treatment of recurrent or metastatic HNSCC as taught by Vermorken NEJM and effective in platinum refractory recurrent or metastatic HNSCC then it would be obvious with a reasonable expectation that the combination would be effective in platinum refractory recurrent or metastatic HNSCC wherein the previous treatment comprised failure of at least one regimen containing a platinum.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR, wherein the subject was not previously treated with cetuximab (instant claim 4), or wherein the subject has platinum-refractory HNSCC and the subject's previous treatment for HNSCC comprised failure of one or two regimens (instant claim 6-7) comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is an IL-2 conjugate comprising ‘326 SEQ ID NO: 3, which is identical to instant SEQ ID NO:1, wherein position 64 is replaced by the structure of wherein the structure of Formula I has the structure of Formula (IV) or (V) or the IL-2 conjugate is provided as a mixture of Formula (IV) and (V):
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Formula (V), wherein W is a PEG group of about 30 kDa and q is 1, 2, or 3, and X has the structure
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118
86
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X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue; and
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered, wherein the IL-2 conjugate is administered to the subject once every two weeks, wherein the IL-2 conjugate is administered intravenously.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5, 14, 17, 19-21, 24, 26, 28-29, 31, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 13, 19, 21-22, 24, 27, and 30-37 of copending Application No. 19/305,326 in view of Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), Vermorken JB et al. (JCI 2007, 25(16) 2171-2177), and Mattijssen V et al. (Annals of Oncology 1994 5(10) 957-960, IDS reference) and evidenced by WO 2022/174101 (Abbadessa G et al. IDS reference) and NCI dictionary pegenzileukin (https://www.cancer.gov/publications/dictionaries/ cancer-drug/def/pegenzileukin 2026)
The claims of the copending ‘326 in view of Milla, ‘815, and Vermorken JCI and evidenced by ‘101 and NCI dictionary teach the limitations of claims 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, and 36 for the reasons set forth above.
‘326, Milla, ‘815, Vermorken JCI, ‘101, and NCI dictionary are described above.
‘326 did not teach: 1) an IL-2 conjugate solvate, but this is obvious in view of Mattijssen.
Mattijssen taught administration of PEG-IL-2 was beneficial for some HNSCC patients (abstract). Mattijssen taught PEG-IL-2 in an aqueous solution of normal saline, which is thus solvated with water (page 958, left column, second paragraph).
Regarding instant claim 28, it would have been obvious for a person having ordinary skill in the art to modify the effective method of copending claims 1, 9, 19, 21-22, 24, and 27 of ‘326, Milla, and Vermorken JCI above – to:
1) administer an IL-2 conjugate solvate in view of Mattijssen.
This is obvious because:
1) Mattijssen taught PEG-IL-2 in an aqueous solution of normal saline, which is thus solvated with water. It would be obvious to administer the IL-2 conjugate in an aqueous solution which would solvate the conjugate.
There is a reasonable expectation of success because:
1) Mattijssen taught PEG-IL-2 in an aqueous solution of normal saline, which is thus solvated with water. It would be obvious to administer the IL-2 conjugate in an aqueous solution which would solvate the conjugate and be expected to be effective as seen in other PEG-IL-2 conjugates.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is an IL-2 conjugate comprising ‘326 SEQ ID NO: 3, which is identical to instant SEQ ID NO:1, wherein position 64 is replaced by the structure of wherein the structure of Formula I has the structure of Formula (IV) or (V) or the IL-2 conjugate is provided as a mixture of Formula (IV) and (V):
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Formula (V), wherein W is a PEG group of about 30 kDa and q is 1, 2, or 3, and X has the structure
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X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue in an aqueous solution which would solvate the IL-2 conjugate (instant claim 28); and
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered, wherein the IL-2 conjugate is administered to the subject once every two weeks, wherein the IL-2 conjugate is administered intravenously.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, 34, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 13, 19, 21-22, 24, 27, and 30-37 of copending Application No. 19/305,326 in view of Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), Vermorken JB et al. (JCI 2007, 25(16) 2171-2177), and Mahmoudpour SH et al. (Sci Rep 2019 9(1):7145) and evidenced by WO 2022/174101 (Abbadessa G et al. IDS reference) and NCI dictionary pegenzileukin (https://www.cancer.gov/publications/dictionaries/cancer-drug/def/pegenzileukin 2026)
The claims of the copending ‘326 in view of Milla, ‘815, and Vermorken JCI and evidenced by ‘101 and NCI dictionary teach the limitations of claims 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, and 36 for the reasons set forth above.
‘326, Milla, ‘815, Vermorken JCI, ‘101, and NCI dictionary are described above.
‘326 did not teach: 1) subcutaneous administration of an IL-2 conjugate but this is obvious in view of Mahmoudpour.
Mahmoudpour taught use of subcutaneous recombinant IL-2 on top of the standard of care is well tolerated and does not appear to increase the risk of developing thromboembolic events in patients with various conditions, notably cancer (page 5, Discussion, first paragraph).
Regarding instant claim 34, it would have been obvious for a person having ordinary skill in the art to modify the effective method of copending claims 1, 9, 19, 21-22, 24, and 27 of ‘326, Milla, and Vermorken JCI above – to:
1) administer an IL-2 conjugate subcutaneously in view of Mahmoudpour.
This is obvious because:
1) Mahmoudpour taught use of subcutaneous recombinant IL-2 on top of the standard of care is well tolerated and does not appear to increase the risk of developing thromboembolic events in patients with various conditions, notably cancer. Thus, subcutaneous administration of an IL-2 conjugate is obvious.
There is a reasonable expectation of success because:
1) Mahmoudpour taught use of subcutaneous recombinant IL-2 on top of the standard of care is well tolerated and does not appear to increase the risk of developing thromboembolic events in patients with various conditions, notably cancer. Thus, subcutaneous administration of an IL-2 conjugate has a reasonable expectation of success.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is an IL-2 conjugate comprising ‘326 SEQ ID NO: 3, which is identical to instant SEQ ID NO:1, wherein position 64 is replaced by the structure of wherein the structure of Formula I has the structure of Formula (IV) or (V) or the IL-2 conjugate is provided as a mixture of Formula (IV) and (V):
PNG
media_image5.png
282
465
media_image5.png
Greyscale
Formula (V), wherein W is a PEG group of about 30 kDa and q is 1, 2, or 3, and X has the structure
PNG
media_image4.png
118
86
media_image4.png
Greyscale
X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue; and
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered, wherein the IL-2 conjugate is administered to the subject once every two weeks, wherein the IL-2 conjugate is administered intravenously or wherein the IL-2 conjugate is administered via subcutaneous injection (instant claim 34).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, 36, 38, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-9, 13, 19, 21-22, 24, 27, and 30-37 of copending Application No. 19/305,326 in view of Milla ME et al. (Annals of Oncology 2019 30 Suppl 5 v501), WO 2015/164815 (Garcia KC et al.), Vermorken JB et al. (JCI 2007, 25(16) 2171-2177), and Tra F et al. (JCI 2008 26 15 suppl 17040) and evidenced by WO 2022/174101 (Abbadessa G et al. IDS reference) and NCI dictionary pegenzileukin (https://www.cancer.gov/publications/dictionaries/cancer-drug/def/pegenzileukin 2026)
The claims of the copending ‘326 in view of Milla, ‘815, and Vermorken JCI and evidenced by ‘101 and NCI dictionary teach the limitations of claims 1-2, 5, 14, 17, 19-21, 24, 26, 29, 31, and 36 for the reasons set forth above.
‘326, Milla, ‘815, Vermorken JCI, ‘101, and NCI dictionary are described above.
‘326 did not teach: 1) administration of a composition comprising acetaminophen, diphenhydramine, and ondansetron before cetuximab, but this is obvious in view of Tra.
Tra taught administration of a pretreatment composition comprising diphenhydramine, acetaminophen, and ondansetron was effective to prevent infusion-related reactions before administration of cetuximab to patients, which contrasts with the known infusion-related side effects of cetuximab (abstract).
Regarding instant claims 38 and 41, it would have been obvious for a person having ordinary skill in the art to modify the effective method of copending claims 1, 9, 19, 21-22, 24, and 27 of ‘326, Milla, and Vermorken JCI above – to:
1) administer a composition comprising acetaminophen, diphenhydramine, and ondansetron before cetuximab in view of Tra.
This is obvious because:
1) Tra taught administration of a pretreatment composition comprising diphenhydramine, acetaminophen, and ondansetron was effective to prevent infusion-related reactions before administration of cetuximab to patients, which contrasts with the known infusion-related side effects of cetuximab. Thus, administration before cetuximab is obvious.
There is a reasonable expectation of success because:
1) Tra taught administration of a pretreatment composition comprising diphenhydramine, acetaminophen, and ondansetron was effective to prevent infusion-related reactions before administration of cetuximab to patients, which contrasts with the known infusion-related side effects of cetuximab. Thus, administration before cetuximab to prevent infusion-related reactions has a reasonable expectation of success.
This would produce a method of treating a subject with platinum refractory recurrent or metastatic HNSCC that expressed EGFR comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and
an IL-2 conjugate THOR-707 which is an IL-2 conjugate comprising ‘326 SEQ ID NO: 3, which is identical to instant SEQ ID NO:1, wherein position 64 is replaced by the structure of wherein the structure of Formula I has the structure of Formula (IV) or (V) or the IL-2 conjugate is provided as a mixture of Formula (IV) and (V):
PNG
media_image5.png
282
465
media_image5.png
Greyscale
Formula (V), wherein W is a PEG group of about 30 kDa and q is 1, 2, or 3, and X has the structure
PNG
media_image4.png
118
86
media_image4.png
Greyscale
X-1 indicates the point of attachment to the preceding amino acid residue and X + 1 indicates the point of attachment to the following amino acid residue; and
an initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2 cetuximab,
wherein the administration of IL-2 and cetuximab was separately administered, wherein the IL-2 conjugate is administered to the subject once every two weeks, wherein the IL-2 conjugate is administered intravenously, and wherein diphenhydramine, acetaminophen, and ondansetron are administered before administration of cetuximab (instant claims 38 and 41).
This is a provisional nonstatutory double patenting rejection.
Conclusion
All claims are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
