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 3-4, 6, 9, 11-13, 16, 19, 21-22, 24-25, 28-29, 32-34, 36, 38, 40, 42, 44, 46, 48 are cancelled.
Claims 1-2, 5, 7-8, 10, 14-15, 17-18, 20, 23, 26-27, 30-31, 35, 37, 39, 41, 43, 45 and 47 are amended.
Claims 1-2, 5, 7-8, 10, 14-15, 17-18, 20, 23, 26-27, 30-31, 35, 37, 39, 41, 43, 45, 47 are examined on the merits.
Priority
The applicant’s application is a U.S. National Stage application of PCT International Patent Application Serial No. PCT/EP2021/086761, filed December 20, 2021, which itself claims the benefit of PCT/EP2020/087467, filed December 21, 2020 is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objection
Claim 43 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Claims 1-2, 5, 7-8, 10, 14-15, 17-18, 20, 23, 26, 45 and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sahin et al. (“Sahin”, WO 2019/154985 A1, cited as reference 1 on IDS filed 06/20/2023).
Regarding claim 1, 5, 7, 14, Sahin teaches that outcomes of systemic IL2 administration in cancer patients are far from ideal. While 15 to 20 percent of patients respond objectively to high-dose IL2, the great majority do not, and many suffer severe, life threatening side effects, including nausea, confusion, hypotension, and septic shock. The severe toxicity associated with high-dose IL2 treatment is largely attributable to the activity of natural killer (NK) cells (e.g., lane 1, page 30). Sahin teaches formulation comprising a therapeutically effective agent, preferably together with pharmaceutically acceptable carriers, diluents and/or excipients. Said pharmaceutical composition is useful for treating, preventing, or reducing the severity of a disease or disorder by administration of said pharmaceutical composition to a subject (e.g., lane 27, page 51). Sahin teaches that IL2 is attached to a pharmacokinetic modifying group. The resulting molecule, hereafter referred to as "extended-pharmacokinetic (PK) IL2," has a prolonged circulation half-life relative to free IL2. The prolonged circulation half-life of extended-PK IL2 permits in vivo serum IL2 concentrations to be maintained within a therapeutic range, potentially leading to the enhanced activation of many types of immune cells, including T cells. Because of its favorable pharmacokinetic profile, extended-PK IL2 can be dosed less frequently and for longer periods of time when compared with unmodified IL2 (e.g., lane 9, page 30). Sahin teaches that the method comprises administering to the subject: a-1. the RNA encoding extended-PK IL2; a-2. the RNA encoding extended-PK IL7; b. the RNA encoding a peptide or protein comprising an epitope for inducing an immune response against an antigen in said subject; and c. the immune checkpoint inhibitor (e.g., lane 24, page 4). Sahin teaches that boost of tumor-specific T cell therapy and therapeutic efficacy with combination of mil12 and mlL2 targeted according to physiological function. Sahin teaches that mice were coinjected i.v. (intravenously) with 3 μg (1 μg from fourth treatment on) miIL12 mRNA (it reads on first dose) or irrelevant mRNA delivered as RNALPX (delivery to secondary lymphoid organs). Roughly 48 h later, 1 μg mRNA encoding mlL2-mAlb or 1 μg mAlb control formulated with Trans IT (delivery to liver for systemic availability) was injected i.v. (it reads on administration of the second dose after 2 Days, as required by claims 1, 5). The treatment schedule was repeated weekly for seven weeks (it reads on additional doses as required by instant claim 7). Furthermore, Sahin teaches IL12 treatment strongly improved the immunotherapy resulting in survival of 80 % of mice for more than 60 days. When either mil 12 or mll2 were omitted, only 45 % or 64 % of mice survived until day 60, respectively. Only 9 % of the control mice receiving control mRNA combined with PD-L 1 antibody were alive at this time point. In addition, the majority of mice receiving mRNA vaccination with PD-L 1 antibody and mil 12 combined with mAlb-mlL2, mil12 alone or mAlb-mlL2 alone showed signs of vitiligo, i.e. loss of fur pigmentation around the eyes as a result of strong autoimmunity against TRP-2 containing cells due to the treatment. (It reads on evaluating the subjects after administration of the mRNA cytokines, as required by instant claim 14). Due to ethical reasons, a control group testing administration of IL 12 delivered into the liver to show intolerable toxicity was not added in this experiment (e.g., Example 17, page 76; Fig. 24, lane 21, page 17). (It reads on increased reaction to mIL12 administration).
Regarding claim 2, 15, Sahin teaches high efficacy and reduced toxicity of mil15 encoding RNA targeted to secondary lymphoid organs compared to liver targeted cytokine production. Certain cytokines like IL15 and IL12 are very toxic when administered systemically. This toxicity is known to be largely dependent on secondary IFNy release which mediates for example gastrointestinal and liver dysfunction. Targeting mil15 into the secondary lymphoid organs should diminish systemic toxicity while retaining therapeutic efficacy. Four and seven days after tumor inoculation, mice were treated with mil15 RNA (mouse lnterleukin-15 fused to the murine lnterleukin-15 receptor a chain) either delivered via RNA-LPX into secondary lymphoid organs (40 μg RNA-LPX i.v.) or into the liver (3 μg RNA formulated in TranslT (Mirrus) i.v.). As hypothesized, liver targeted delivery which resulted in systemic availability of mil15 lead to severe toxicity. All mice in this group died after the second mRNA administration despite a very low dose. In contrast, mice that received mRNA delivered solely to secondary lymphoid organs stayed alive, even though 13 times more mRNA was administered (It reads on the second dose is greater than the first dose). All mice treated with mil15 mRNA delivered to secondary lymphoid organs were tumor free whereas up to several hundred tumor nodules were detected in control animals (it reads on mIL15 treatment does not cause a detectable unwanted response as required by instant claim 15) (e.g., Example 16, lane 21, page 75 to lane 12, page 76; Fig. 23).
Regarding claim 8, Sahin teaches pharmaceutical compositions described herein may be administered intravenously, intraarterially, subcutaneously, intradermally or intramuscularly (e.g., lane 1, page 54).
Regarding claim 10, Sahin teaches that outcomes of systemic IL2 administration in cancer patients are far from ideal. While 15 to 20 percent of patients respond objectively to high-dose IL2, the great majority do not, and many suffer severe, life threatening side effects, including nausea, confusion, hypotension, and septic shock. The severe toxicity
associated with high-dose IL2 treatment is largely attributable to the activity of natural killer (NK) cells. Attempts to reduce serum concentration by reducing dose and adjusting dosing regimen have been
attempted, and while less toxic, such treatments were also less efficacious (e.g., lane 1, page 30).
Regarding claim 17-18, Sahin teaches RNA for use in a method for treating or preventing cancer in a subject comprising administering to the subject: a. RNA encoding extended pharmacokinetic (PK) interleukin (IL)-2 and/or RNA encoding extended pharmacokinetic (PK) interleukin (IL)-7; and b. RNA encoding a peptide or protein comprising an epitope for inducing an immune response against a tumor-associated antigen in said subject. (e.g., lane 14, page 9).
Regarding claim 20, Sahin teaches IL2 is attached to a pharmacokinetic modifying group. The resulting molecule, hereafter referred to as "extended-pharmacokinetic (PK) IL2," has prolonged circulation half-life relative to free IL2. The prolonged circulation half-life of extended-PK IL2 permits in vivo serum IL2 concentrations to be maintained within a therapeutic range, potentially leading to the enhanced activation of many types of immune cells, including T cells. Because of its favorable
pharmacokinetic profile, extended-PK IL2 can be dosed less frequently and for longer periods of time when compared with unmodified IL2 (e.g., lane 9, page 30). Sahin teaches that IL7 is attached to a pharmacokinetic modifying group. The resulting molecule, hereafter referred to as "extended-pharmacokinetic (PK) IL7," has a prolonged circulation half-life relative to free IL7. The prolonged circulation half-life of extended-PK IL7 permits in vivo serum IL7 concentrations to be maintained within a therapeutic range, potentially leading to the enhanced survival of many types of immune cells, including T cells (e.g. lane 11, page 31).
Regarding claim 23, Sahin teaches IL2 is fused to a heterologous polypeptide (i.e., a polypeptide that is not IL2). The heterologous polypeptide can increase the circulating half-life of IL2. The polypeptide that increases the circulating half-life may be serum albumin, such as human or mouse serum albumin (e.g., lane 26, page 30).
Regarding claim 26, Sahin teaches the therapeutic protein(s) is (are) joined to the albumin through (a) peptide linker(s). A linker peptide between the fused portions may provide greater physical separation between the moieties and thus maximize the accessibility of the therapeutic protein portion, for instance, for binding to its cognate receptor. The linker peptide may consist of amino acids such that it is flexible or more rigid. The linker sequence may be cleavable by a protease or chemically (e.g., lane 6, page 36). Sahin teaches Linkers suitable for fusing the extended-PK group to e.g. IL2 or IL7 are well known in the art. Exemplary linkers include glycine-serine-polypeptide linkers, glycine-praline-polypeptide linkers, and praline-alanine polypeptide linkers. In certain embodiments, the linker is a glycine-serine-polypeptide linker, i.e., a peptide that consists of glycine and serine residues (e.g., lane 20, page 38).
Regarding claim 45, 47, Sahin teaches the medical preparation is a kit. In one embodiment, the medical preparation comprises each RNA in a separate container (e.g. lane 25, page 6).
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.
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 27, 30-31, 35, 37, 39, 41 are rejected under 35 U.S.C. 103 as being unpatentable over Sahin et al. (“Sahin”, WO 2019/154985 A1, cited as reference 1 on IDS filed 06/20/2023) as applied to claims 1-2, 5, 7-8, 10, 14-15, 17-18, 20, 23, 26, 45 and 47 above, and further in view of Fidal et al. (“Fidal”, WO 2018/234862 A1) and Vasquez-Lombardi et al. (“Vasquez-Lombardi”, Nat. Commun. 2017).
Sahin does not teach IL2 variants, as required by claims 27, 30-31, 35, 37, 39, 41. However, this is cured by Fidal and Vasquez-Lombardi.
Regarding claims 27, 30-31, Fidal teaches IL-2 muteins (It reads on IL2 variants) that have an increased binding capacity for IL-2Rp receptor as compared to wild-type IL-2 for use in combination therapies (e.g., abstract). Fidal teaches providing combination therapies of IL-2 superagonists or agonists for the treatment of cancer, in particular combinations of anti-PD-I antibodies with IL-2 muteins comprising substitutions L80F [L=Leucine, F=Phenylalanine], R81D [R= Arginine, D=Aspartic acid], L85V [L=leucine, V=valine], I86V [I=isoleucine, V=valine] and I92F [I=isoleucine, F=Phenylalanine], numbered in accordance with wild-type IL-2 (e.g., paragraph 0005).
Regarding claim 35, Fidal teaches the IL-2 mutein exhibits increased binding capacity for IL-2Rβ as compared to wild-type human IL-2. In some embodiments, the IL-2 mutein exhibits a greater binding affinity for IL-2Rβ as compared to wild-type human IL-2 (e.g., paragraph 0016). Fidal teaches that the IL-2 mutein signals less and/or independently of CD25 (for example, has reduced or ablated CD25 binding) as compared to wild-type human IL-2. In some embodiments the reduced and/or independent signaling with regard to CD25 allows for preferential activation of effector T-cells while limiting the stimulation of Tregs (e.g., paragraph 00112).
Regarding claim 39, Fidal teaches that the IL-2 mutein has increased capabilities to stimulate one or more signaling pathways that are dependent on IL-2Rβ/IL-2Ryc heterodimerization. In some embodiments, the subject IL-2 mutein has an enhanced capability to stimulate STAT5 phosphorylation in an IL-2Rβ+ cell as compared to wild-type human IL-2 (e.g., paragraph 00107). Fidal teaches that the IL-2Rβ+ cell is a T cell. The T cell is a CD8+ T cell. The CD8+ T cell is a freshly isolated CD8+ T cell. The CD8+ T cell T cell is an activated CD8+ T cell. The IL-2Rβ+ cell is a natural killer (NK) cell (e.g., paragraph 00107). Fidal teaches that IL-2 mutein signals less and/or independently of CD25 (for example, has reduced or ablated CD25 binding) as compared to wild-type human IL-2. In some embodiments the reduced and/or independent signaling with regard to CD25 allows for preferential activation of effector T-cells while limiting the stimulation of Tregs (e.g., paragraph 00112).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Sahin -comprising the administration of two or multiple doses of cytokine RNAs (IL2, IL15, IL12, IL7) , where the cytokine is attached to a pharmacokinetic modifying group, like albumin. The resulting molecule, "extended-pharmacokinetic (PK) cytokine" has prolonged circulation half-life relative to free cytokine, with the teachings of Fidal -IL-2 muteins that have an increased binding capacity for IL-2Rp receptor as compared to wild-type IL-2 and IL-2 mutein exhibits reduced binding affinity for CD25 as compared to wild-type human IL-2. The IL-2 muteins comprising substitutions L80F, R81D, L85V, I86V and I92F, numbered in accordance with wild-type IL-2; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing a method to comprising the administration of two or multiple doses of the mutein IL2 RNAs (L80F, R81D, L85V, and I92F), where the IL2 mutein is attached to a pharmacokinetic modifying group, like albumin.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to develop the pharmaceutical composition RNA IL-2 muteins (L80F, R81D, L85V, 186V and I92F) that have an increased binding capacity for IL-2Rp receptor as compared to wild-type IL-2 and that exhibits reduced binding affinity for CD25 as compared to wild-type human IL-2.
Regarding claim 37, Vasquez-Lombardi teaches generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25+ regulatory T-cells (Tregs) and results in strong expansion of CD25- cytotoxic subsets (e.g., abstract). Vasquez-Lombardi teaches introduction of charge-reversal substitutions directly into bivalent IL-2-Fc constructs, thus differing from previous approaches that have targeted both charged and aromatic residues in monovalent unfused IL-2 (e.g., paragraph 3rd, column right, page 2). Vasquez-Lombardi teaches that binding was considerably reduced, residual affinity to CD25 was observed for all designed single mutations, as well as for a previously reported F42A mutant, particularly when expressed bivalently in an Fc-fusion format (e.g., paragraph 3rd, column right page 2; Supplementary Fig. 1).
Supplemental Fig. 1:
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Vasquez-Lombardi teaches that to further reduce CD25 interactions, combined single mutations in a step-wise manner, first into double, and then into triple mutants. Single dose IL-23XFc (R38D [R=Arginine, D=Aspartic acid], K43E [K=lysine, E=Glutamic acid], E61R [E= Glutamic acid, R=Arginine]) induced robust expansion of MP CD8 and NK cell subsets in the spleens of C57BL/6 mice, substantially higher than what was observed not only for IL-2WTFc, but also for treatment with IL-2/mAb immune complexes (e.g., paragraph 4th, column right, page 2; Fig. 1; Supplementary Figs 1–3)
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Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Sahin -comprising the administration of two or multiple doses of cytokine RNAs (IL2, IL15, IL12, IL7), where the cytokine is attached to a pharmacokinetic modifying group, like albumin. The resulting molecule, "extended-pharmacokinetic (PK) cytokine" has prolonged circulation half-life relative to free cytokine, with the teachings of Vasquez-Lombardi teachings that IL2 muteins (R38D, K43E, E61R) to further reduce CD25 interactions, combined single mutations in a step-wise manner, first into double and then into triple mutants; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing a method to comprising the administration of two or multiple doses of the mutein IL2 RNAs (K43E, E61R), where the IL2 mutein is attached to a pharmacokinetic modifying group, like albumin.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to develop the pharmaceutical composition RNA IL-2 mutein (K43E, E61R) that have an increased binding capacity for IL-2Rp receptor as compared to wild-type IL-2 and that exhibits reduced binding affinity for CD25 as compared to wild-type human IL-2.
Regarding claim 41, Fidal teaches that the IL-2 muteins are characterized by amino acid insertions, deletions, substitutions and modifications at one or more sites in or at the other residues of the native IL-2 polypeptide chain. In accordance with this disclosure, any such
insertions, deletions, substitutions and modifications result in an IL-2 mutein that retains the IL-2R~ binding activity. Exemplary muteins can include substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids (e.g., paragraph 0071). Fidal teaches that muteins also include conservative modifications and substitutions at other positions of IL-2 (i.e., those that have a minimal effect on the secondary or tertiary structure of the mutein). Fidal teaches the following groups represent conservative changes: Group I: ala, pro, gly, gln, asn, ser, thr; Group II: cys, ser, tyr, thr; Group 111: val, ile, leu, met, ala, phe; Group IV: lys, arg, his; Group V: phe, tyr, trp, his; and Group VI: asp, glu (e.g., paragraph 0072). Fidal teaches a mutation (whether conservative or non-conservative, by way of addition(s) or deletion(s)) can be made at one or more of positions. For example, the mutation can be: I24V, P65H, Q74R, Q74H, Q74N, Q74S, L80F, L80V, R81I, R8IT, R8ID, L85V, I86V, I89V, I92F, V93I (e.g., paragraph 00102).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Sahin -comprising the administration of two or multiple doses of cytokine RNAs (IL2, IL15, IL12, IL7) , where the cytokine is attached to a pharmacokinetic modifying group, like albumin. The resulting molecule, "extended-pharmacokinetic (PK) cytokine" has prolonged circulation half-life relative to free cytokine, with the teachings of Fidal -IL-2 muteins that have an increased binding capacity for IL-2Rp receptor as compared to wild-type IL-2 and IL-2 mutein exhibits reduced binding affinity for CD25 as compared to wild-type human IL-2. For example, the mutation can be: I24V, P65H, Q74R, Q74H, Q74N, Q74S, L80F, L80V, R81I, R8IT, R8ID, L85V, I86V, I89V, I92F, V93I. Exemplary muteins can include substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids and a mutation (whether conservative or non-conservative, by way of addition(s) or deletion(s)) can be made at one or more of positions, with the teachings of Vasquez-Lombardi that IL2 muteins (R38D, K43E, E61R) to further reduce CD25 interactions, combining single mutations in a step-wise manner, first into double and then into triple mutants; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of developing a method to comprising the administration of two or multiple doses of the mutein IL2 RNAs (K43 E [K=Lysine, E=Glutamic acid], E61K [E=Glutamic acid, K=Lysine], Q74H [Q=Glutamine, H=Histidine], L80F [L=Leucine, F=Phenylalanine], R81E [R=Arginine, E=Glutamic acid], L85V [L=leucine, V=Valine], and I92F [I=Isoleucine, F=Phenylalanine]), where the IL2 mutein is attached to a pharmacokinetic modifying group, like albumin.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do develop the pharmaceutical composition RNA IL-2 muteins (K43 E, E61K, Q74H, L80F, R81E, L85V, and I92F) that have an increased binding capacity for IL-2Rp receptor as compared to wild-type IL-2 and that exhibits reduced binding affinity for CD25 as compared to wild-type human IL-2.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637