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 .
Election/Restriction
Applicant’s election without traverse of Invention II and/or species G85E (i.e., IL7-VAR21), in the reply filed on 12DEC2025 is acknowledged.
Upon further consideration, the species election of G85E as set forth in the election of species requirement mailed 15SEP2025 has been withdrawn. Examiner has expanded the search to include K81X substitutions in the human IL-7.
Claim Status
Claim 5 has been amended.
Claims 1-4, 7, 11-13, and 23-29 have been cancelled.
Claims 40-42 are new.
Claims 5-6, 8-10, 14-22, and 40-42 are pending and examined on the merits in the instant application (i.e., Claim(s) 5 is/are independent).
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/EP2021/059473, filed 13APR2021, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of EP Application No. 20169510.3 filed on 15APR2020 has been received and is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 15NOV2023 is/are acknowledged and the references cited therein have been considered.
Specification
The disclosure is objected to because of the following informalities:
Typographical error, p 34, line 12, “…wild type IL2 sequence…” should be updated to “…wild type IL7 sequence….”
Typographical error, p 153, line 2, the unit of dose, presumably mg/kg needs to be added between “…with 1” and “iv qw….”
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p 19). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The lengthy specification has not been checked to the extent necessary to determine the presence of and to catalog all possible minor errors. Applicant’s assistance and cooperation in finding and correcting any errors of which the applicant may become aware of in the specification is appreciated.
Claim Objections
Claims 5, 15, 21, and 40 are objected to because of the following informalities:
Claim 1 should be updated to include “consisting” between “group” and “of” in line 4 of the claim for the purpose of reciting proper Markush-type language.
Claim 15 contains “…Currently amended of the first subunit…” which should be updated to “…of the first subunit…” in the last line of the claim.
Claims 21 and 40 should be updated to include “consisting” between “group” and “of” in line 2 of the claims for the purpose of reciting proper Markush-type language.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 16-17 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.
Claim 16, recites the phrase "optionally," which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(h)(II). Claim 17 is also rejected since it depends from claim 16, but does not remedy this deficiency.
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.
Scope of Enablement
Claims 5-6, 8-10, 14-22, and 40-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
“An immunoconjugate comprising (i) a mutant IL7 and (ii) an antibody that binds to PD1;
wherein the mutant IL7 comprises at least one amino acid substitution selected from the group of E13A, E13K, V15A, V15K, V18A, V18K, D21A, D21K, Q22A, Q22K, D25A, D25K, T72A, L77A, L77K, K81A, K81E, E84A, G85K, G85E, I88K, Q136A, Q136K, K139A, K139E, N143K and M147A of human IL7 according to SEQ ID NO: 52; and
wherein the antibody that binds to PD1 comprises
(a) a heavy chain variable region (VH) comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO:1, a HVR-H2 comprising the amino acid sequence of SEQ ID NO:2, a HVR-H3 comprising the amino acid sequence of SEQ ID NO:3, and a FR-H3 comprising the amino acid sequence of SEQ ID NO:7 at positions 71-73 according to Kabat numbering, and (b) a light chain variable region (VL) comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO:4, a HVR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a HVR-L3 comprising the amino acid sequence of SEQ ID NO:6; or
the antibody comprises (c) a heavy chain variable region (VH) comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO:8, a HVR-H2 comprising the amino acid sequence of SEQ ID NO:9, and a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 10, and (d) a light chain variable region (VL) comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 13; and
a Fc domain;” does not reasonably provide enablement for more.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Scope of the claim:
In the instance of claim 1, the nature of the invention drawn to a mutant IL7 comprising at least one amino acid substitution (i.e., 19 naturally occurring amino acids) at 16 different positions of wild type IL7 (i.e., SEQ ID NO: 52) and essentially any antibody that binds to PD1 is not fully enabled. Claim 1 is not fully enabled because:
The breadth of mutant IL7 polypeptides (i.e., 1916 or 1.1 x 1020 sequence combinations);
The breadth of anti-PD1 antibodies;
The lack of support in the specification and working examples for all permutations of mutant IL7 in combination with PD1 antibodies (inclusive of Fc domain) in all proposed formats (i.e., Fig 1A-E);
The screening of the PD1-IL7v immunoconjugates;
The lack of predictability in the art; and
Therefore the undue experimentation for one of ordinary skill in the art to make the immunoconjugate as currently claimed.
Claims 6, 8-10, 14-22, and 40-42 are also rejected since they depend from claim 5, but do not remedy this deficiency.
Direction provided by the inventor and existence of working examples:
The specification teaches that the invention of the instant application encompasses an immunoconjugate comprising a mutant IL7 polypeptide and an anti-PD1 antibody, which allows for targeting CTLs rather than tumor cells and delivery of the IL7 mutant to PD1 expressing immune subsets, especially tumor reactive T cells (CD8+/PD1+/T cell Factor 1+ T cell populations) (p 3). The specification further teaches that the mutant IL7 comprises at least one amino acid substitution that reduces affinity of the mutant IL7 polypeptide to the IL7Rα and/or IL2Rγ subunits and that the mutant IL7 polypeptide comprises no more than 12 amino acid mutations compared to wild-type human IL7 sequence of SEQ ID NO: 52 (p 30 and 34). In addition to the significant breadth of mutant IL7 polypeptides, the immunoconjugates comprise an antibody that binds PD1, which in Fig 1A-E and working example 1, comprises a Fab fragment and through the heavy chain of the anti-PD1 Fab is connected to a Fc domain, and a linker to conjugate the IL7 mutant in a variety of locations and formats. The working examples of the specification teaches the PD1-IL7wt (i.e., wild type IL7), 31 PD1-IL7v immunoconjugates having a single mutation in the IL7 polypeptide (i.e., VAR1-31 comprising E13A, E13K, V15A, V15K, V18A, V18K, D21A, D21K, Q22A, Q22K, D25A, D25K, D74A, D74K, L77A, L77K, K81A, K81E, E84A, G85K, G85E, I88K, Q136A, Q136K, K139A, K139E, N143K, M147A, T72A, T93A, S118A, respectively, of which the species in bold are not listed in independent claim 5), two PD1-IL7v immunoconjugates having a double mutation in the IL7 polypeptide (i.e., VAR18/20 comprising K81E/G85K and VAR18/21 comprising K81E/G85E), and one PD1-IL7v immunoconjugate having a triple mutation in the IL7 peptide (i.e., VAR32 comprising T72A, T93A, and S118A). Of the 35 structures taught, only nine variants of the PD1-IL7 were selected as candidates having possible reduced affinity to the IL7 receptor (i.e., Examples 2-4) and only PD-IL7-VAR18 and PD-IL7-VAR21 compared to the wt PD1-IL7 immunoconjugate were tested in vivo (i.e., Example 5). Although this example supports making 34 PD1-IL7 mutant immunoconjugates having specific IL7 mutations and PD1-IL7v construct format, each immunoconjugate required significant screening, to determine which PD1-IL7 mutants could be used in making an immunoconjugate with reduced IL7Rα affinity, while not fully ablating IL7Rα affinity. Therefore, it is unclear whether the same effect could be observed with alternate mutations at said positions (i.e., K81E or G85E); whether similar results could be observed with alternate substitutions at the other 14 positions and combinations thereof; or whether alternate PD1 antibodies or immunoconjugate formats would be as effective. In this instance, there is no disclosure regarding making the immunoconjugate constructs comprising infinite mutations of the IL7 peptide and essentially any anti-PD1 antibody.
State of prior art and level of predictability in the art:
Furthermore, the literature teaches that there are several amino acid positions which are involved in IL7 and IL7Rα binding and that an antibody is defined by six nondegenerate CDRs. Specifically, McElroy, et al., teach that the interface between IL7 and IL7Rα comprise hydrophobic interactions, van der Waals interactions, and intermolecular H bonds and that the residues in helices A and C of IL7 contact residues in the six loop regions connecting the ß sheets of the IL7Rα domains (Structure, 2009, 17, 54-65, included in IDS, see Fig 3A-C, p57, col 2, IL-7/IL7Rα interface section). In Fig 3C, McElroy teach that the buried surface area of positions K10, Q11, S14, V15, L16, V18, S19, Q22, S71, A72, D74, L77, H78, L80, K81, E84, G85, I88, and L89 in helices A or C of IL7, dominate the contact interfaces of IL7 with IL7Rα (i.e., bolded positions are claimed in the instant application). Though it is expected that modification of any of the bolded amino acid positions would affect the IL7/IL7Rα binding interface it is unclear whether any amino acid substitutions at positions E13, D21, D25, Q136, K139, N143, and/or M147 would significantly impact binding and whether any of the 19 other naturally occurring amino acid substitution would effectively result in reduced binding affinity without significant screening. Furthermore, it should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that six nondegenerate CDRs are necessary to make an antibody that specifically binds in this instance PD1.
Quantity of experimentation needed to make or use the invention based on the disclosure:
Thus, one skilled in the art would be unable to make an immunoconjugate comprising i) a mutant IL7 comprising at least one amino acid substitution (i.e., 19 alternate naturally occurring amino acids) at 16 different positions of wild type IL7 (i.e., SEQ ID NO: 52) and ii) essentially any antibody that binds to PD1. Therefore, the implementation of the invention in view of the breadth of variables (i.e., IL7 mutants, anti-PD1 antibodies, alternate constructs), level of predictability in the art, and lack of support in the working examples, would require undue experimentation for one of ordinary skill in the art to make and/or use the instantly claimed invention.
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 5-6, 8-10, and 14-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 11,401,331 (included in IDS), herein referred to as “’331” in view of US 2018/0326010 (Hoffmann-La Roche Inc., et al., 15NOV2018), herein referred to as “‘010,” Morello, et al., (J for ImmunoTherapy of Cancer, 2019, 7, 137, “P256”, included in IDS), herein referred to as “Morello,” and McElroy, et al., (Structure, 2009, 17, 54-65, included in IDS), herein referred to as “McElroy.”
The issued claims of the ‘331 patent recite: A fusion molecule (i.e., immunoconjugate or immunocytokine) comprising an anti-PDL1 antibody or antigen-binding fragment thereof fused through a peptide linker to a peptide comprising the amino acid sequence of SEQ ID NO: 9 (i.e., claim 1, wherein SEQ ID NO: 9 has 99.3% identity to SEQ ID NO: 52 of the instant application and comprises a W142A substitution, see OA.APPENDIX). A method of treating a cancer in a patient in need thereof, comprising administering to the patient the fusion molecule of claim 1 (i.e., claim 6)
However, they do not claim: an amino acid substitution in IL7 at K81 or G85, or an anti-PD1 antibody which may comprise SEQ ID NOs: 1, 2, 7, 3, 4, 5, and 6 or 14 and 15, or wherein the antibody comprises an Fc domain composed of a first and second subunit, or wherein the Fc domain comprises specific substitutions, or wherein the linker peptide comprises the amino acid sequence of SEQ ID NO: 21.
Nevertheless, ‘010 teaches an anti-PD1/IL2 immunoconjugate, wherein the PD1 antibody comprises SEQ ID NOs: 24 and 25 (i.e., 100% query match to fusion of SEQ ID NOs: 1, 2, 7, and 3, and fusion of SEQ ID NOs: 4, 5, and 6, respectively or SEQ ID NOs: 14 and 15, respectively, of the instant application, see OA.APPENDIX), wherein the IL2 (i.e., cytokine) is a variant having reduced affinity for the IL2R to reduce the adverse effect of vascular leak syndrome, and wherein the N terminal of mutant IL2 is linked via SEQ ID NO: 21 (i.e., (GGGGS)3) to the C terminal of the Fc region (see entire document, specifically see ¶0029, ¶0011-0012, ¶0027, and Fig 1). ‘010 further teaches that an immunoconjugate comprising an anti-PD1 conjugate showed significantly superior anti-tumor efficacy in vivo as compared to a similar anti-PDL1 immunoconjugate (¶0022 and Example 3). The Fc domain comprises a modification promoting the association of the first and second subunit of the domain, inclusive of T366W, Y407, S354C, Y349C, L234A, L235A, and P329G (¶0027-0028).
Additionally, Morello teach a bifunctional anti-PD1/IL7 fusion protein which potentiates effector function of exhausted T cell and disarms Treg suppressive activity (see entire document). Furthermore, Morello teach that despite the clinical success of anti-PD(L)1 therapies, most patients remain unresponsive or fail to develop a durable response; however, by fusing an IL7 cytokine to the Fc portion of an anti-PD1 antibody, the IL7 cytokine synergizes with anti-PD1 to enhance TCR mediated signaling (Background and Results section). Although, IL7R expression on T cells decrease over repeated antigen stimulation, Morello teach that the IL7 efficiently activated partially and fully exhausted human T cells and maintain their proliferation capacity (Results section). Furthermore, Morello teach that the anti-PD1/IL7 fusion protein reactivates tumor infiltrating T cells (TILs) that are resistant to PD1 therapy (results section).
Furthermore, McElroy teach the structural features of the human IL7/IL7Rα complex, which plays fundamental roles in the ECM remodeling, development, and homeostasis of T and B cells, and that IL7 is being tested to spark T cell development and expansion in recovering cancer patients (see entire document, see p 54, col 1, introduction section). McElroy further teach that a W142 substitution in the IL7 causes defective folding of the helix D and/or complete unfolding of IL7 resulting in the decreased affinity for IL7Rα and signaling (Fig 2B and p56, col 2, ¶2). In addition, McElroy teach that the interface between IL7 and IL7Rα comprise hydrophobic interactions, van der Waals interactions, and intermolecular H bonds and that the residues in helices A and C of IL7 contact residues in the six loop regions connecting the ß sheets of the IL7Rα domains (Fig 3A-C, p57, col 2, IL-7/IL7Rα interface section). In Fig 3C, the buried surface area of K10, Q11, S14, V15, L16, V18, S19, Q22, S71, A72, D74, L77, H78, L80, K81, E84, G85, I88, and L89 in helices A or C of IL7, support that these positions dominate the contact interfaces of IL7 with IL7Rα. Thus, it is expected by modifying one or more of said positions by amino acid substitution that IL7/IL7Rα would be affected similar to the case of a substitution of W142.
It would have been obvious to artisans to modify the issued products of a fusion molecule comprising an anti-PDL1 antibody or antigen-binding fragment thereof fused through a peptide linker to a mutant IL7 polypeptide of SEQ ID NO: 9 as claimed by the ‘331 patent to include a specific anti-PD1 antibody and IL7 mutant to form an anti-PD1/IL7 immunoconjugate, as taught by ‘010, Morello, and McElroy. This is because ‘010 teach that an anti-PD1 immunoconjugate (i.e., comprising SEQ ID NOs: 24 and 25 which are 100% query match to fusion of SEQ ID NOs: 1, 2, 7, and 3, and fusion of SEQ ID NOs: 4, 5, and 6, respectively or SEQ ID NOs: 14 and 15, respectively, of the instant application) is significantly more effective than an analogous anti-PDL1 immunoconjugate and that by reducing binding efficacy of the cytokine to its receptor provides reduced side effects such as VLS. The synergizing effect of an anti-PD1 antibody fused with an IL7 peptide to enhance TCR mediated signaling is further taught by Morello and the efficacy of alternate substitutions in the IL7 polypeptide such as K81 or G85 for reducing cytokine-receptor binding affinity is taught by McElroy. One would have been motivated to do so, given the direction by the ‘331 patent that the fusion molecule (i.e., fusion protein, immunoconjugate, or immunocytokine) could be used in a method of effectively treating a cancer by administration of a fusion molecule; comprising a blockade of the PD1/PDL1 pathway and a mutant IL7 peptide which has reduced binding affinity with its receptor. There would have been a reasonable expectation of success, given the knowledge that by modifying the fusion molecule (i.e., fusion protein, immunoconjugate, or immunocytokine) comprising an anti-PDL1 antibody and a mutant IL7 polypeptide taught by the ‘331 patent with an alternate PD1/PDL1 blockade, such as the more effective anti-PD1 antibody and a mutant IL7 polypeptide comprising alternate mutations/substitutions for reduced cytokine/receptor binding affinity, would lead to a synergizing effect which could be used to enhance TCR mediated signaling for stimulating effector and exhausted T cells while disarming Tregs suppressive functions, as taught by ‘010, Morello, and McElroy.
Provisional NSDP
Claims 5, 9-10, 14-18, 20-22, and 40-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of co-pending Application No. 18/634666; herein referred to as the “reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the immunoconjugate of claim 1 of the reference application anticipates the immunoconjugate of claim 1 of the instant application. Specifically, both immunoconjugates comprise i) a mutant IL7 peptide and ii) an anti-PD1 antibody, wherein the mutant peptide comprises an amino acid substitution at the position of G85 of human IL7 (see OA.APPENDIX).
The co-pending claims of the reference application recite:
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In this instance, because the anti-PD1/IL7 mutant immunoconjugate of the reference application is a species of the anti-PD1/IL7 mutant immunoconjugate of the instant application, there is no clear difference in the scope between the products of the instant and reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 5-6, 8-10, 14-18, 20-22, and 40-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of co-pending Application No. 18/634660; herein referred to as “’660.” Although the claims at issue are not identical, they are not patentably distinct from each other because the immunoconjugate of claims 8-26 comprising a mutant IL7 polypeptide comprising an amino acid substitution of G85 of human IL7 set forth in SEQ ID NO: 28 (i.e., 100% query match to SEQ ID NO: 52 of the instant application, see OA.APPENDIX) of claim 1, an anti-PD1 antibody comprising SEQ ID NOs: 1-7 of claim 10, and a Fc domain of claim 12 of the ‘660 reference application is an obvious variant of the immunoconjugate comprising a mutant IL7 polypeptide and an anti-PD1 antibody of claims 5-6, 8-10, 14-22, and 40-41 of the instant application.
The co-pending claims of the reference application recite:
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In this instance, because the immunoconjugate of the ‘660 reference application comprises an anti-PD1 antibody and IL7 mutant polypeptide, which comprise the same sequences of the instant application, there is no clear difference in the scope between the products of the instant and ‘660 reference applications. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the ’660 reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 5, 10, 18, and 40-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15, 17, 20-21, and 23-29 of co-pending Application No. 19/092753; herein referred to as the “’753.” Although the claims at issue are not identical, they are not patentably distinct from each other because the immunoconjugate of claims 4-5 and 8 comprising a mutant IL7 polypeptide comprising the amino acid substitutions of E13K and G85E of human IL7 set forth in SEQ ID NO: 64 (i.e., 100% query match to SEQ ID NO: 52 of the instant application, see OA.APPENDIX) of claim 1 of the ‘753 reference application is an obvious variant of the immunoconjugate comprising a mutant IL7 polypeptide of claims 5, 10, 18, and 40-41 of the instant application.
The co-pending claims of the reference application recite:
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In this instance, because the immunoconjugate comprising the E13K and G85E substitutions of the human IL7 polypeptide and an antibody that binds to PD1 which are fused of claims 1, 4-5, and 8 of the ‘753 reference application is a species of the immunoconjugate comprising a mutant IL7 peptide comprising at least one amino acid substitution in the position selected from E13,…G85, of human IL7 and an antibody that binds PD1 of the instant application, there is no clear difference in the scope between the products of the instant application and the ‘753 reference application. In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the ‘753 reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 102
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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 5, 10, and 18-21 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0071889 A1 (Poirier, et al., PCT/EP2019/085791 effectively filed 17DEC2019, herein referred to as “’889.”
‘889 teaches a bifunctional molecule comprising an anti-PD1 and mutant IL7 (i.e., an immunostimulatory cytokine member of the IL2 superfamily, which plays an important role in immune responses mediated by B and T cells) (see entire document, specifically see abstract, Fig 31, ¶0038, and ¶0012). Specifically, ‘889 teaches an anti-PD1 antibody comprising a VH/VL that binds PD1, a Fc domain comprising the LALA mutation, a peptide linker comprising (GGGGS)3, and a mutant IL7 peptide comprising a K81R amino acid substitution to human IL7 (i.e., SEQ ID NO: 66 is 100% query match to SEQ ID NO: 52 having a substitution at position K81 of the instant application, see OA.APPENDIX) (¶0015-0020, 0046, 0044, 0038, and 0409). Furthermore, ‘889 teaches that multiple mechanisms have been described to explain the differential efficacy to CPI therapy, such as 1) impaired formation of memory T cells, 2) impaired T cell infiltration, 3) insufficient generation of tumor specific T cells, 4) inadequate function of T cells, and 5) immunosuppressive microenvironment induced by regulatory T cells, which may be overcome by combining in this instance an anti-PD1 and IL7 mutant which is able to stimulate T cell infiltration, sustain T cell effector capacity, and promote a long-lasting memory T cell response without stimulation of Tregs (¶0011).
Therefore, the prior art anticipates the invention as presently claimed.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 6, 8-9, 14-17, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0071889 A1 (Poirier, et al., PCT/EP2019/085791 effectively filed 17DEC2019, herein referred to as “’889” as applied to claims 5, 10, and 18-21 and in further view of in view of US 2018/0326010 (Hoffmann-La Roche Inc., et al., 15NOV2018), herein referred to as “‘010.”
The teachings of ‘889 are summarized above.
However, they do not teach: wherein the anti-PD1 antibody may comprise SEQ ID NOs: 1, 2, 7, 3, 4, 5, and 6 or 14 and 15, or wherein the antibody comprises an Fc domain which may comprise T366W, Y407, S354C, Y349C, or L234A, L235A, and P329G.
Nevertheless, ‘010 teaches an anti-PD1/IL2 immunoconjugate, wherein the PD1 antibody comprises SEQ ID NOs: 24 and 25 (i.e., 100% query match to fusion of SEQ ID NOs: 1, 2, 7, and 3, and fusion of SEQ ID NOs: 4, 5, and 6, respectively or SEQ ID NOs: 14 and 15, respectively, of the instant application, see OA.APPENDIX), wherein the IL2 (i.e., cytokine) is a variant having reduced affinity for the IL2R to reduce the adverse effect of vascular leak syndrome, and wherein the N terminal of mutant IL2 is linked via SEQ ID NO: 21 (i.e., (GGGGS)3) to the C terminal of the Fc region for the treatment of cancer (see entire document, specifically see ¶0029, ¶0011-0012, ¶0027, Fig 1, and ¶0034). The Fc domain comprises a modification promoting the association of the first and second subunit of the domain, inclusive of mutations that promote the association of the first and second subunit of the Fc domain (i.e., T366W, Y407, S354C, Y349C) and/or mutations that reduce binding to a Fc receptor and/or reduce effector function (i.e., L234A, L235A, and P329G) (¶0027-0028). The anti-PD1 antibodies that bind to PD1 are known in the art (e.g., PCT/EP2016/073248) (¶0018).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the bifunctional molecule comprising an anti-PD1 antibody and mutant human IL7 comprising a K81 substitution disclosed by ‘889 by utilizing a specific anti-PD1 antibody comprising a Fc domain comprising specific mutations within an immunoconjugate disclosed by ‘010 because the immunoconjugate construct of ‘010 was able to effectively in a synergistic model treat cancer wherein the Fc domain had improved subunit association, reduced binding to a Fc receptor and/or reduced effector function. One would have been motivated to do so, given the teachings of ‘889 that combining in this instance an anti-PD1 antibody and IL7 mutant which is able to stimulate T cell infiltration, sustain T cell effector capacity, and promote a long-lasting memory T cell response without stimulation of Tregs effectively overcomes CPI resistant cancers. There would have been a reasonable expectation of success, given the knowledge that an immunoconjugate construct comprising an anti-PD1 antibody that is well-studied and a mutated cytokine lead to a method of synergistically treating cancer, as taught by ‘010.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Claims 5-6, 8-10, and 14-22 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0352405 A1 (Fang, et al., 21NOV2019), herein referred to as “’405” and in view of US 2018/0326010 (Hoffmann-La Roche Inc., et al., 15NOV2018), herein referred to as “‘010,” Morello, et al., (J for ImmunoTherapy of Cancer, 2019, 7, 137, “P256”), herein referred to as “Morello,” and McElroy, et al., (Structure, 2009, 17, 54-65), herein referred to as “McElroy.”
‘405 teaches a fusion comprising an anti-PDL1 linked to an IL7 polypeptide, wherein improved results could be achieved with mutant IL7 proteins having reduced activities (see entire document, specifically see abstract, Fig 1, and ¶0006).
However, they do not teach: an amino acid substitution in IL7 at K81 or G85, or an anti-PD1 antibody which may comprise SEQ ID NOs: 1, 2, 7, 3, 4, 5, and 6 or 14 and 15, or wherein the antibody comprises an Fc domain composed of a first and second subunit, or wherein the Fc domain comprises specific substitutions, or wherein the linker peptide comprises the amino acid sequence of SEQ ID NO: 21.
Nevertheless, ‘010 teaches an anti-PD1/IL2 immunoconjugate, wherein the PD1 antibody comprises SEQ ID NOs: 24 and 25 (i.e., 100% query match to fusion of SEQ ID NOs: 1, 2, 7, and 3, and fusion of SEQ ID NOs: 4, 5, and 6, respectively or SEQ ID NOs: 14 and 15, respectively, of the instant application, see OA.APPENDIX), wherein the IL2 (i.e., cytokine) is a variant having reduced affinity for the IL2R to reduce the adverse effect of vascular leak syndrome, and wherein the N terminal of mutant IL2 is linked via SEQ ID NO: 21 (i.e., (GGGGS)3) to the C terminal of the Fc region (see entire document, specifically see ¶0029, ¶0011-0012, ¶0027, and Fig 1). ‘010 further teaches that an immunoconjugate comprising an anti-PD1 conjugate showed significantly superior anti-tumor efficacy in vivo as compared to a similar anti-PDL1 immunoconjugate (¶0022 and Example 3). The Fc domain comprises a modification promoting the association of the first and second subunit of the domain, inclusive of T366W, Y407, S354C, Y349C, L234A, L235A, and P329G (¶0027-0028).
Additionally, Morello teach a bifunctional anti-PD1/IL7 fusion protein which potentiates effector function of exhausted T cell and disarms Treg suppressive activity (see entire document). Furthermore, Morello teach that despite the clinical success of anti-PD(L)1 therapies, most patients remain unresponsive or fail to develop a durable response; however, by fusing an IL7 cytokine to the Fc portion of an anti-PD1 antibody, the IL7 cytokine synergizes with anti-PD1 to enhance TCR mediated signaling (Background and Results section). Although, IL7R expression on T cells decrease over repeated antigen stimulation, Morello teach that the IL7 efficiently activated partially and fully exhausted human T cells and maintain their proliferation capacity (Results section). Furthermore, Morello teach that the anti-PD1/IL7 fusion protein reactivates tumor infiltrating T cells (TILs) that are resistant to PD1 therapy (results section).
Furthermore, McElroy teach the structural features of the human IL7/IL7Rα complex, which plays fundamental roles in the ECM remodeling, development, and homeostasis of T and B cells, and that IL7 is being tested to spark T cell development and expansion in recovering cancer patients (see entire document, see p 54, col 1, introduction section). McElroy further teach that a W142 substitution in the IL7 causes defective folding of the helix D and/or complete unfolding of IL7 resulting in the decreased affinity for IL7Rα and signaling (Fig 2B and p56, col 2, ¶2). In addition, McElroy teach that the interface between IL7 and IL7Rα comprise hydrophobic interactions, van der Waals interactions, and intermolecular H bonds and that the residues in helices A and C of IL7 contact residues in the six loop regions connecting the ß sheets of the IL7Rα domains (Fig 3A-C, p57, col 2, IL-7/IL7Rα interface section). In Fig 3C, the buried surface area of K10, Q11, S14, V15, L16, V18, S19, Q22, S71, A72, D74, L77, H78, L80, K81, E84, G85, I88, and L89 in helices A or C of IL7, support that these positions dominate the contact interfaces of IL7 with IL7Rα. Thus, it is expected by modifying one or more of said positions by amino acid substitution that IL7/IL7Rα would be affected similar to the case of a substitution of W142.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the fusion protein comprising an anti-PDL1 and mutant IL7 polypeptide disclosed by ‘405 by utilizing an anti-PD1 antibody and alternate mutations of the IL7 polypeptide disclosed by ‘010, Morello, and McElroy. This is because ‘010 teach that an anti-PD1 immunoconjugate (i.e., comprising SEQ ID NOs: 24 and 25 which are 100% query match to fusion of SEQ ID NOs: 1, 2, 7, and 3, and fusion of SEQ ID NOs: 4, 5, and 6, respectively or SEQ ID NOs: 14 and 15, respectively, of the instant application) is significantly more effective than an analogous anti-PDL1 immunoconjugate. The synergizing effect of an anti-PD1 antibody fused with an IL7 peptide to enhance TCR mediated signaling is further taught by Morello and the efficacy of alternate substitutions in the IL7 polypeptide such as K81 or G85 for reducing cytokine-receptor binding affinity is taught by McElroy. One would have been motivated to do so, given the teachings of ‘405 that utilization of a mutant IL7 with reduced binding affinity for IL7Rα resulted in better efficacy; given the teachings of ‘010 that an immunocytokine or immunoconjugate comprising an anti-PD1 antibody and a mutant cytokine was able to more effectively treat cancer compared to an analogous anti-PDL1 antibody and mutant cytokine; and given the teachings of McElroy that specific amino acids such as K81 and E85 are involved in the surface binding of IL7 and IL7Rα. There would have been a reasonable expectation of success, given the knowledge that a bifunctional anti-PD1/IL7 fusion protein potentiates effector function of exhausted T cell and disarms Treg suppressive activity, as taught by Morello.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641