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 .
Information Disclosure Statement
The information disclosure statement filed 09 December 2024 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because Foreign Patent Number 5 (WO 2015110002 A1) is not attached. It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 12/09/2024 is acknowledged.
Applicant’s election without traverse of the substitutions P65R, H16A, and D84S in the reply filed on 12/09/2024 is acknowledged.
Claims 12, 15, 19, 21-26, 32, 42, and 54 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/09/2024.
All claims withdrawn are comprising unelected amino acid substitutions.
Claim Status
Claims 3-4, 6-10, 13-14, 16-17, 20, 28-29, 31, 33-35, 37, 39, 41, 43-44, 47-49, 51-53, 56, 59-61, 63, 65, 67, 69, 75-76, 78, 83-84, 86-90, 92-94, 96-97, 99, 102, 104, and 106-125 are cancelled. Claims 1-2, 5, 11-12, 15, 18-19, 21-27, 30, 36, 38, 40, 42, 45-46, 50, 54-55, 57-58, 62, 64, 66, 68, 70, 74, 77, 79-82, 85, 91, 95, 98, 100-101, 103, and 105 as filed on 09 December 2024 are pending. Claims 12, 15, 19, 21-26, 32, 42, and 54 are withdrawn. Claims 1-2, 5, 11, 18, 27, 30, 32, 36, 38, 40, 45-46, 50, 55, 57-58, 62, 64, 66, 68, 70, 74, 77, 79-82, 85, 91, 95, 98, 100-101, 103, and 105 are under examination.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 27, 80-81, 91, 100-101, 103, and 105 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aukerman (WO 2005086798 A2) (IDS 03/15/2022 FOR 1).
Instant SEQ ID NO: 1 matches Aukerman SEQ ID NO: 2 and instant SEQ ID NO: 1 and Aukerman SEQ ID NO: 2 comprise instant SEQ ID NO: 84.
Regarding claims 1-2 and 27, Aukerman teaches the amino acid of SEQ ID NO: 2 (claim 5 in subpart b). Aukerman teaches the modification of IL-2 in substitutions of amino acids at positions H16, P65, and D84 (claim 8).
Regarding claims 80, Aukerman by teaching the substitutions encompassed by claim 1 would have the biological activity of claim 80.
Regarding claim 81, Aukerman teaches the mutated IL-2 is fused to a second protein (page 54 in lines 15-19).
Regarding claim 91, claim 91 is read to include a first polypeptide fused to a second polypeptide wherein the first polypeptide is the modified IL-2 and the second polypeptide is not a modified IL-2. , Aukerman teaches the mutated IL-2 is fused to a second protein (page 54 in lines 15-19). Aukerman further teaches the second polypeptide is a human albumin (page 54 in lines 20-21).
Regarding claim 100, Aukerman teaches a pharmaceutical composition comprising a modified IL-2 in a pharmaceutical composition with a pharmaceutically acceptable carrier (Abstract and claim 29).
Regarding claims 101 and 103, Aukerman teaches a nucleic acid encoding modified IL-2 in a host cell comprising the nucleic acid (claims 1-4).
Regarding claim 105, Aukerman teaches the method of producing the polypeptides of modified IL-2 wherein the a host cell is incubated under conditions that produce the modified IL-2 (claim 27).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 5, 11, 18, 27, 30, 45-46, 50, 79-82, 91, 100-101, 103, and 105 are rejected under 35 U.S.C. 103 as being unpatentable over Aukerman (WO 2005086798 A2) (IDS 03/15/2022 FOR 1) and Butz (WO 2016/164937 A2) (IDS 12/20/2022 FOR 1).
The teachings of Aukerman from the 102 rejections are incorporated here in full.
As Aukerman anticipates 1-2, 27, 80-81, 91, 100-101, 103, and 105 they would be obvious over Aukerman and Butz
Regarding claims 5, 11, and 18, Aukerman teaches the combination of amino acid substitutions of H16D or H16E, P65R and D84R (claim 8).
Aukermann teaches a decrease in pro-inflammatory responses with the IL-2 mutations of their invention for use in human treatment (page 8 in lines 28-31, page 12 in lines 5-15, and claim 30).
Aukerman does not teach the combination of amin acid substitutions required by claims 5, 11, and 18 or elected by applicant of H16A and D84S. Aukerman does not teach a fusion to an IgG1 Fc.
These deficiencies are filled by Butz.
Butz teaches mutated IL-2 alone and in a fusion molecule with an Fc (abstract).
Butz teaches the fusion of IL-2 fused to an IgG1-Fc domain improves half-life which reduces dosing frequency (Example 2 in pages 55-57).
Regarding claims 5, 11, and 18, Butz teaches multiple IL-2 mutations including H16A and D84S in the same mutation along with further substitutions (page 2 in par 3 and claim 1).
Regarding claims 30, 45-46, 50, and 82, Butz teaches the mutated IL-2 is fused to an Fc protein (claims 6-7). Butz teaches fusion to the C-terminus of the Fc with a linker comprising GGGGS (page 56 in par 2) Butz teaches fusion comprising IgG1 Fc (abstract and sequences on page 59-60). Instant SEQ ID NO: 47 is the wild type sequence for IgG1 meaning the IgG1 of Butz would teach this sequence thus teachings claim 45.
Regarding claim 79, Butz teaches the IL-2 mutation fused to Fc forms a homodimer (Figure 6, page 56 last paragraph and page 57 in par 1).
Butz teaches the use of their IL-2 mutein fused to Fc as a method of increasing the ration of T regs to non-regulatory T cells in a human patient (claims 59, 62, and 69). Butz teaches a method comprising administering the fusion protein in the treatment of inflammatory or autoimmune diseases (claim 71).
It would have been obvious to one of ordinary skill in the art to combine the amino acid substitutions of Aukerman with the amino acid substitutions of Butz and to further substitute the second polypeptide in the fusions of Aukerman with the Fc of Butz. Aukermann and Butz both teach the use of mutated IL-2 in fusions for use in human subjects both decreasing inflammation in the subject making the combination of amino acid substitutions P65R, H16A, and D84S obvious. This is the combination required by certain claims and elected by applicant. One of ordinary skill in the art would have been motivated to substitute the second polypeptide of the fusion of Aukermann with the IgG1 Fc of Butz as Butz fusion of IL-2 fused to an IgG1-Fc domain improves half-life which reduces dosing frequency. The decreased dosing improves patient adherence as it decreases barriers to care and decreased risk of complications from administration of the fusion protein. There would have been a reasonable expectation of success as Aukermann and Butz both teach the pharmaceutical administration of mutant IL-2 to a patient population.
Claims 1, 30, 32, 36, 42, 57-58, 62, 64, 66, 68, 70, 77, 85, and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Aukerman (WO 2005086798 A2) (IDS 03/15/2022 FOR 1) and Butz (WO 2016/164937 A2) (IDS 12/20/2022 FOR 1) as applied to claims 1-2, 5, 11, 18, 27, 30, 45-46, 50, 79-82, 91, 100-101, 103, and 105 above, and further in view of Codarri (WO 2018/185043 A1) (PTO-892 Hereafter “Codarri ‘043”) and Codarri (WO 2018/184965 A1) (PTO-892 Hereafter “Codarri ‘965”).
The teachings from Aukerman and Butz from the previous art rejections are incorporated here in full.
Aukerman in view of Butz teaches a modified IL-2 for therapeutic applications that can be used in fusion proteins as explained in the previous rejections including fusions to Fc, and antibodies. Including teaching the Fc forming a homodimer.
As claims 1 and 30 are obvious over Aukermann and Butz they would be obvious over Aukermann and Butz in view of Codarri ‘043 and Codarri ‘965.
Butz further teaches the mutation of the Fc to alter the effector function with either increasing or decreasing its effector function (page 24 in par 2 and page 25 in par 2).
Aukerman in view of Butz does not teach the specific amino acid substitutions of the Fc of the claims, or the fusion of a modified IL-2 with antibodies that bind multiple targets, or the binding of PD-1.
These deficiencies are filled by Codarri ‘043 and Codarri ‘965.
Codarri ‘043 teaches an immunoconjugate comprising a bispecific antigen binding molecule that binds to PD-1 and Lag-3 (abstract and claim 1). Codarri ‘043 teaches the “knob-into-into” technology to form heterodimers in Fc regions (page 33 in lines 8-13). Codarri ‘043 further teaches the immunoconjugates can comprise linkers to further moieties including drugs (page 38 in lines 35-37). Codarri ‘043 teaches immunoconjugates include molecules such as cytotoxic agents (page 39 in lines 26-27). Codarri ‘043 further teaches immunoconjugates can comprise chemotherapeutic agents or drugs (page 84 in lines 2-5).
Regarding claims 32 and 36, Codarri ‘043 teaches the amino acid substitutions of T366W, Y449C, and S54C (page 33 in lines 17-24).
Regarding claims 42 and 85, Codarri ‘043 teaches the substitution of amino acids at positions E233, L234, and L235 (page 59 in lines 20-21) and further teaches L234A, L235A, and P329G as P329G LALA (Page 59 in line 28). Codarri ‘043 teaches P329G LALA completely abolishes Fcγ receptor binding of a human IgG1 Fc domain (page 59 in lines 28-29). Claim 85 requires only 1 of the listed modifications and the changes at E233, L234, and L235 fulfill the requirements of the claim.
Codarri ‘043 teaches the use of different dimerization recombinant products are advantageous to improve yield and purity of the bispecific antibodies making the known Fc substitutions of Codarri ‘043 a desired tool in production of bispecific molecules (page 62 in par 1).
Regarding claims 57-58, 62, and 77, mutant IL-2 polypeptide and bispecific antigen binding molecule that binds to PD-1 and TIM-3 (abstract and claim 1).
Regarding claims 64, 66, 68, and 70, Codarri ‘043 teaches single-domain antibodies include VHH (page 25 in lines 4-6 and page 21 in lines 25-30). Codarri ‘043 antigen-binding fragments that comprise a VH and a VL (Figure 1). Codarri ‘043 teaches the use of anti-PD1 antibodies that are humanized (page 8 in lines 1-4). Codarri ‘043 teaches single-chain Fab (claim 32).
Codarri ‘043 teaches the use of their bispecific antibodies comprising Fc mutations in the treatment of cancer (claims 48-50).
Codarri ‘965 teaches immunoconjugates comprising IL-2 with bispecific antibodies including mutant immunoconjugates (Title, abstract). Codarri ‘965 teaches the use of mutated IL-2 to modulate its effects to reduce its toxicity and/or increase its efficacy (page 4 in lines 1-2). Codarri ‘965 further teaches IL-2 immunotherapy may be improved by targeting IL-2 tumors with immunoconjugates that bind to antigens expressed on the tumors (page 4 in lines 24-28).
Codarri ‘965 teaches the use of mutated IL-2 in its immunoconjugates (claim 1).
Codarri ‘965 teaches the Fc of its bispecific immunoconjugates comprises mutations to the Fc including T366W (claim 18), S354C (claim 19), L234, L235, and P3229 (claims 25-26) including the P329G LALA taught by Codarri ‘043.
Codarri ‘965 teaches the use of this immunoconjugate in the treatment of multiple diseases including cancer (claims 37-39).
It would have been obvious to one of ordinary skill in the art at the time the application was filed to substitute the Fc and antigen binding domains linked to a mutant IL-2 taught by Aukerman in view of Butz with the modified Fc and antigen binding of PD-1 and Tim-3 or PD-1 and Lag-3 of Codarri ‘043 and Codarri ‘965 to produce an immunoconjugate comprising a mutant IL-2 of claim 1, 2 antigen-binding domains, and a modified Fc. Aukermann teaches IL-2 can be used in fusion proteins for the treatment of cancer. Aukerman, Butz, and Codarri ‘965 all teach the use of IL-2 in therapeutics with Aukerman teaching IL-2 can be used in the treatment of cancer and to reduce inflammation in human subjects. Codarri ’043, and Codarri ‘965 teach the use of immunoconjugates in the treatment of cancer and that their altered Fc domains provide advantages in yield and purity when producing multispecific immunotherapeutic. One of ordinary skill in the art would have been motivated to combine the known therapeutic of mutant IL-2 of Aukermann with the immunoconjugates taught by Codarri ’043, and Codarri ‘965 as those in the art knew IL-2 therapy may be improved by targeting IL-2 tumors with immunoconjugates that bind to antigens expressed on the tumors. The combination improves IL-2 delivery. The prior art of Aukermann, Butz, and Codarri ‘965 are to fusions comprising mutant IL-2 in the treatment of cancer making their combination obvious. The combination of Aukermann, Butz, and Codarri ‘965 with Codarri ’043 is obvious as Codarri ’043, and Codarri ‘965 are both teaching immunoconjugates for the treatment of cancer and Codarri ‘965 is teaching a bispecific immunoconjugate can use mutated IL-2 in the treatment of cancer. There would have been a reasonable expectation of success as IL-2 for use in immunoconjugates is well known in the art as shown by Codarri ‘965 and Butz.
Claims 1, 30, 38, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Aukerman (WO 2005086798 A2) (IDS 03/15/2022 FOR 1) and Butz (WO 2016/164937 A2) (IDS 12/20/2022 FOR 1) as applied to claims 1-2, 5, 11, 18, 27, 30, 45-46, 50, 79-82, 91, 100-101, 103, and 105 above, and further in view of Codarri (WO 2018/185043 A1) (PTO-892 Hereafter “Codarri ‘043”) and Codarri (WO 2018/184965 A1) (PTO-892 Hereafter “Codarri ‘965”), and Igawa (EP 2857420 A1) (PTO-892).
The teachings from Aukerman and Butz from the previous art rejections are incorporated here in full.
Aukerman in view of Butz teaches a modified IL-2 for therapeutic applications that can be used in fusion proteins as explained in the previous rejections including fusions to Fc, and antibodies. Including teaching the Fc forming a homodimer.
As claims 1 and 30 are obvious over Aukermann and Butz they would be obvious over Aukermann and Butz in view of Codarri ‘043 and Codarri ‘965.
Butz further teaches the mutation of the Fc to alter the effector function with either increasing or decreasing its effector function (page 24 in par 2 and page 25 in par 2).
Aukermann does not teach the amino acid substitutions of M252Y and M428V in the Fc region.
These deficiencies are filled by Codarri ‘043, Codarri ‘965, and Igawa.
The teachings of Codarri ‘043 and Codarri ‘965 from the other art rejections are incorporated here in full.
Codarri ‘965 as previously stated teaches an immunoconjugate comprising a bispecific antigen binding molecule and a mutant IL-2 wherein the Fc has been altered to for dimerization.
Regarding claim 38 and 40, Igawa teaches multispecific molecules that dimerize for the purpose of therapeutic applications (abstract). Igawa teaches the substitutions M252Y and M428V in Table 2-7 in row F251 and teaches H435K or H435R in table 2-23 in rows F954 and F960.
It would have been obvious to one of ordinary skill in the art to substitute the dimerized Fc of the immunoconjugate taught by Aukermann in view of Butz, Codarri ‘043 and Codarri ‘965 with a dimerized Fc taught by Igawa. Codarri ‘965 and Igawa both teach T cell binding multispecific molecules with dimerized Fc created with amino acid substitutions making their substitution obvious. There would have been a reasonable expectation of success as T cell targeting multispecific molecules with dimerized Fc domains are analogous art and Codarri ‘043, Codarri ‘965, and Igawa like most art teaching the knob in hole methods teach the amino acid alterations in the Fc as art equivalents.
Claims 1, 81, 95, and 98 are rejected under 35 U.S.C. 103 as being unpatentable over Aukerman (WO 2005086798 A2) (IDS 03/15/2022 FOR 1), Butz (WO 2016/164937 A2) (IDS 12/20/2022 FOR 1), Codarri (WO 2018/185043 A1) (PTO-892 Hereafter “Codarri ‘043”), Codarri (WO 2018/184965 A1) (PTO-892 Hereafter “Codarri ‘965”), and Brinkmann and Kontermann. MABS 9(2):182-212. (2017) (PTO-892).
The teachings of Aukerman from the 102 rejections are incorporated here in full.
As Aukerman anticipates claims 1 and 81 They would be obvious over Aukerman in view of Butz, Codarri ’043, Codarri ‘965, and Brinkmann.
Aukermann does not teach the configuration of the first and second polypeptides required by claim 95. Aukermann does not teach the first antigen-binding domain binding PD-1 and the second binding domain binding LAG3.
There deficiencies are filled by of Butz, Codarri ’043, Codarri ‘965, and Brinkmann.
The teachings of Butz, Codarri ’043, and Codarri ‘965 are incorporated here in full.
Codarri ‘965 teaches the first antigen binding domain fused to the N-terminus of the Fc region and the second polypeptide comprising the second-antigen binding domain and an Fc region (claim 22 and Figure 1). These are for a bispecific that binds PD-1 and Tim-3 (claim 1 and Figure 1).
Codarri ’043 teaches a bispecific domain comprising a first binding domain that binds PD-1 and is fused to the N-terminus of the Fc and a second antigen binding domain that binds LAG3 fused to an Fc region in Figure 1.
Brinkmann teaches zybodies which include peptides fused to the N or C terminus of heavy or light chains (Figure 2 and 196 col 2 in par 4). Brinkmann teaches multiple configurations of bispecific antibodies comprising IgG structures, multiple binding domains, including dimerization alterations to Fc domains for the use in therapeutics (abstract). Brinkmann teaches these configurations provide guidance for improved stability, solubility, and other parameters that confer drug properties (abstract).
It would have been obvious at the time the application was filed to substitute the general configuration of an immunoconjugate comprising mutant IL-2 and bispecific antibodies taught by Aukermann in view of Butz, Codarri ’043, and Codarri ‘965 and the specific configurations taught by Brinkmann. Aukermann in view of Butz, Codarri ’043, and Codarri ‘965 teach the use of IL-2 in fusion molecules for therapeutic applications. One of skill in the art would have been motivated to look at the known configurations of Brinkmann to produce a molecule that binds targets of interest in the treatment of cancer and have configurations known to be useful as therapeutics that maintain binding ability. There would have been a reasonable expectation of success as the configurations of Codarri ’043 and Codarri ‘965 are similar to those taught by Brinkmann and Brinkmann is providing a variety of known configurations for therapeutic applications.
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, 27, 32, 36, 38, 40, 45-46, 55, 57-58, 62, 66, 68, 70, 74, 77, 79-82, 85, 91, 95, 98, 100-101, 103, and 105 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 14-16, 30, 32, 43, 56-58, 65, 69, 76, 80-81, 84, 86-87, 89-90, 93, 95-96, 100, 108-110, 113, 117-118, 120, 129, 132, 142-144, 148, 153-154, 158, 163-164, 166, 168, 170, and 176-177 of copending Application No. 18002613 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-2, and 27, the reference application recites modified IL-2 comprising the substitutions of H16A, P65R, and D84 (claims 1, 3, 6, 43, and 69).
Regarding claim 30, the reference application recites the polypeptide comprises an Fc region wherein the IL-2 is fused to the C-terminus of the Fc region via a linker (claims 93 and 113).
Regarding claims 32, 36, 38,40, and 42, the reference application recites Fc substitutions including T366W, H435R, Y349C, M252Y, and a combination of L234A, L235A, and P329G (claims 96 and 110).
Regarding claims 45-46, reference application SEQ ID NO: 47 matches instant SEQ ID NO: 47. Instant SEQ ID NO: 47 is the wild type sequence for IgG1 meaning the IgG1 of the reference application would recite claim 45.
Regarding claims 55, 57-58, 62, 74, and 77, the reference application recites the polypeptide comprising one or more antigen binding domains including those that binds CD4+ or CD8+ T-cell, and PD-1 and LAG3 (claims 118 and 120).
Regarding claim 66, 68, and 70, the reference application recites binding domains of VHH, or VH and VL, or scFv (claim 129). The reference application recites the antigen binding domains bind PD-1 and LAG-3 (claim 120).
Regarding claim 80, the reference application recites the modified IL-2 binds to IL-2R with at least 2-fold lower affinity (claim 143).
Regarding claim 81, , the reference application recites first polypeptide and second polypeptide wherein the first polypeptide is the one of claim 1 (claim 144).
Regarding claim 81, Instant SEQ ID NO: 47 is the wild type sequence for IgG1 meaning the IgG1 of the reference application would recite claim 45. Instant SEQ ID NO: 87 matches SEQ ID NO: 87 of the reference application.
Regarding claim 85, the reference application recites Fc substitutions including T366W, H435R, Y349C, M252Y, and a combination of L234A, L235A, and P329G (claims 96 and 110).
Regarding claim 91, the reference application recites the second polypeptide does not comprise a modified IL-2 (claims 154 and 158).
Regarding claim 95, the reference application recites the first polypeptide comprises a first antigen binding domain, an Fc region and a modified IL-2 wherein the binding domain is fused to the N-terminus of the Fc and the IL-2 is fused to the C-terminus of the Fc and the second polypeptide comprising a second antigen binding domain fused to an Fc domain but does not comprise a modified IL-2 (claim 158)
Regarding claim 98, the reference application recites the antigen binding domains bind PD-1 and LAG-3 (claim 120).
Regarding claim 100, the reference application recites a pharmaceutical composition comprising a pharmaceutically acceptable carrier (claim 163).
Regarding claims 101 and 103, the reference application recites an isolated host cell comprising a nucleic acid encoding the polypeptide (claims 166 and 164).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 11, 18, 30, 46, 50, 55, and 64 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 14-16, 30, 32, 43, 56-58, 65, 69, 76, 80-81, 84, 86-87, 89-90, 93, 95-96, 100, 108-110, 113, 117-118, 120, 129, 132, 142-144, 148, 153-154, 158, 163-164, 166, 168, 170, and 176-177 of copending Application No. 18002613 (reference application) in view of Aukerman (WO 2005086798 A2) (IDS 03/15/2022 FOR 1), Butz (WO 2016/164937 A2) (IDS 12/20/2022 FOR 1), and Codarri (WO 2018/185043 A1) (PTO-892 Hereafter “Codarri ‘043”)
The recitations of the reference application from the previous double patenting rejection are incorporated here in full.
As claims 1, 30, 46, and 55 were recited by application they would also be rejected further in view of Aukermann, Butz, and Codarri ‘043.
The reference application does not recite the IL-2 amino acid substitution of D84S, the glycine or glycine and serine amino acids, or the human or humanized binding domain.
These deficiencies are filled by Aukermann, Butz, and Codarri ‘043.
The teachings of Aukermann, Butz, and Codarri ‘043 from the previous art rejections are incorporated here in full.
It would have been obvious to one of ordinary skill in the art to substitute the general recitations of the D84, linker, and antigen binding domains with the specifics of a D84S substitution taught by Aukermann, glycine-serine linker taught by Butz and the humanized binding domain taught by Codarri ‘043. The reference application already recites amino acid substitutions at D84 and Aukermann provides the amino acid substitution of D84S for use in combination with the substitutions recited by the reference application making the substitution obvious. The substitution of the general linker recited by the reference application with the linker taught by Butz that works with modified IL-2 in an immunoconjugate as taught by Butz, and to further substitute the general antigen binding domains of anti-PD-1 and anti-LAG3 with humanized PD-1 and humanized Lag-3 taught by Codarri ‘043 as both are PD-1 and LAG-3 binding domains in an immunoconjugate for treatment of humans. There would have been a reasonable expectation of success as the reference application, Aukermann, Butz, and Codarri ‘043 all teach treatment of human subjects.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5, 11, 18, 27, 32, 36, 38, 40, 45-46, 55, 57-58, 62, 66, 74, 77, 79-82, 85, 91, 100-101, 103, and 105 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6, 9, 12, 14-15, 17-20, 26, 56-61, 63, 66-72, 74, and 78 of copending Application No. 18578137 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-2, 5, 11, 18, and 27, the reference application recites modified IL-2 comprising the substitutions of H16A, P65R, and D84S (claims 1-2).
Regarding claim 30, the reference application recites the polypeptide comprises an Fc region wherein the IL-2 is fused to the C-terminus of the Fc region via a linker (claims 17 and 26).
Regarding claims 32, 36, 38,40, 42, and 79, the reference application recites Fc substitutions including T366W, H435R, Y349C, M252Y, and a combination of L234A, L235A, and P329G (claim 15) by reciting the SEQ ID NO: 32-70 and 112-122 as those claims comprise these substitutions. These substitutions would form a homodimer as required by claim 79.
Regarding claims 45-46, reference application SEQ ID NO: 47 matches instant SEQ ID NO: 27. Instant SEQ ID NO: 47 is the wild type sequence for IgG1 meaning the IgG1 of the reference application would recite claim 45.
Regarding claims 55, 57-58, 62, 74, and 77, the reference application recites the polypeptide comprising one or more antigen binding domains including those that binds CD4+ or CD8+ T-cell, and PD-1 and LAG3 (claims 1-2 and 20).
Regarding claim 66, and 70, the reference application recites binding domains of VHH (claim 1). The reference application recites the antigen binding domains bind PD-1 and LAG-3 (claim 20).
Regarding claim 80, the reference application recites the substitutions encompassed by claim 1 would have the biological activity of claim 80.
Regarding claim 81, the reference application recites a complex comprising the first polypeptide of claim 1 and a second polypeptide (claims 1-2 and 26).
Regarding claim 82, the reference application recites an Fc IgG1 as previously described.
Regarding claim 85, the reference application recites Fc substitutions including T366W, H435R, Y349C, M252Y, and a combination of L234A, L235A, and P329G (claim 15) by reciting the SEQ ID NO: 32-70 and 112-122 as those claims comprise these substitutions.
Regarding claim 91, the reference application recites a method of administration that comprises a pharmaceutical composition of claim 1 and a second polypeptide including antibodies that are not a modified IL-2 (claims 69-72).
Regarding claim 100, the reference application recites a pharmaceutical composition comprising an acceptable carrier (claim 56).
Regarding claims 101 and 103, the reference application recites a host cell comprising a vector comprising a nucleic acid encoding the polypeptide of claim 1 (claims 57-59).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 30, 55, 68, 70, 81, 95, and 98 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6, 9, 12, 14-15, 17-20, 26, 56-61, 63, 66-72, 74, and 78 of copending Application No. 18578137 (reference application) in view of Codarri (WO 2018/184965 A1) (PTO-892 Hereafter “Codarri ‘965”), and Brinkmann and Kontermann. MABS 9(2):182-212. (2017) (PTO-892).
The recitations of the reference application from the previous double patenting rejection are incorporated here in full.
As claims 1, 30, and 55 were recited by application they would also be rejected further in view of Aukermann, Butz, and Codarri ‘043. Regarding claim 98, the reference application recites the binding to PD-1 and LAG-3 as previously described.
The reference application does not recite the binding domains as VH and VL or scFv and does not recite the configuration as recited by claim 95.
These deficiencies are filled by Codarri ‘043 and Brinkmann.
The teachings of Codarri ‘043 and Brinkmann from the previous art rejections are incorporated here in full.
It would have been obvious to one of ordinary skill in the art to substitute VHH antigen binding domains and general configuration of the reference application with the VH and VL and scFv binding domains of Codarri ‘043 and the configurations of Brinkmann. The reference application and Codarri ‘043 are both reciting immunoconjugates comprising binding domains to PD-1 and LAG-3 for use in the treatment of human subjects. This substitution would be of art recognized equivalents that Codarri ‘043 teaches can be used in polypeptides of the same nature and is further supported by Brinkmann teaching the many configurations and varying binding domains are useful as therapeutics that provide binding ability and effective therapeutics.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5, 11, 18, 27, 32, 36, 38, 40, 45-46, 55, 57-58, 62, 64, 66, 74, 77, 79-82, 85, 91, 95, 98, 100-101, 103, and 105 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6, 15-16, 18, 20, 29-30, 32, 34-37, 55, 67-71, 73, 75, 77, 79, 81, 83-84, 97-98, and 102 of copending Application No. 18685666 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-2, 5, 11, 18, and 27, the reference application recites modified IL-2 comprising the substitutions of H16A, P65R, and D84 (claims 1-2).
Regarding claim 30, the reference application recites the polypeptide comprises an Fc region wherein the IL-2 is fused to the C-terminus of the Fc region (claims 32).
Regarding claims 32, 36, 38,40, and 42, the reference application recites Fc substitutions including T366W, H435R, Y349C, M252Y, and a combination of L234A, L235A, and P329G (claims 96 and 110).
Regarding claims 45-46, reference application SEQ ID NO: 47 matches instant SEQ ID NO: 53. Instant SEQ ID NO: 47 is the wild type sequence for IgG1 meaning the IgG1 of the reference application would recite claim 45. by reciting the SEQ ID NO: 44 and 53-89 as those claims comprise these substitutions. These substitutions would form a homodimer as required by claim 79.
Regarding claims 55, 57-58, 62, 64, 74 and 77, the reference application recites the polypeptide comprising one or more antigen binding domains including those that binds CD4+ or CD8+ T-cell, and NKG2D and NKp46 (claims 32 and 69). The reference application recites the binding domain is humanized (claim 15).
Regarding claim 66, the reference application recites binding domains of VHH (claim 15).
Regarding claim 80, the reference application by reciting the substitutions of the modified IL-2 of claim 1 recites the change in binding affinity.
Regarding claim 81, the reference application recites first polypeptide and second polypeptide wherein the first polypeptide is the one of claim 1 (claims 1 and 35).
Regarding claim 82, the reference application recites IgG1 as previously described.
Regarding claim 85, the reference application recites Fc substitutions including T366W, H435R, Y349C, M252Y, and a combination of L234A, L235A, and P329G (claims 30 and 69) by reciting the SEQ ID NO: 44 and 53-89 as those claims comprise these substitutions.
Regarding claim 91, the reference application recites the second polypeptide does not comprise a modified IL-2 (claims 35 and 67-68).
Regarding claim 95, the reference application recites the first polypeptide comprises a first antigen binding domain, an Fc region and a modified IL-2 wherein the binding domain is fused to the N-terminus of the Fc and the IL-2 is fused to the C-terminus of the Fc and the second polypeptide comprising a second antigen binding domain fused to an Fc domain but does not comprise a modified IL-2 (claims 35 and 69).
Regarding claim 98, the reference application recites the antigen binding domains bind NKG2D and NKp46 (claims 32 and 69).
Regarding claim 100, the reference application recites a pharmaceutical composition comprising a pharmaceutically acceptable carrier (claim 70).
Regarding claims 101 and 103, the reference application recites an isolated host cell comprising a nucleic acid encoding the polypeptide (claims 71 and 73).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 30, 46, 50, 55, 68, and 70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 14-16, 30, 32, 43, 56-58, 65, 69, 76, 80-81, 84, 86-87, 89-90, 93, 95-96, 100, 108-110, 113, 117-118, 120, 129, 132, 142-144, 148, 153-154, 158, 163-164, 166, 168, 170, and 176-177 of copending Application No. 18002613 (reference application) in view of Codarri (WO 2018/185043 A1) (PTO-892 Hereafter “Codarri ‘043”) and Codarri (WO 2018/184965 A1) (PTO-892 Hereafter “Codarri ‘965”)
The recitations of the reference application from the previous double patenting rejection are incorporated here in full.
As claims 1, 30, 46, and 55 were recited by application they would also be rejected further in view of Codarri ‘043 and Codarri ‘965.
The reference application does not recite a linker comprising glycine and serine, or antigen binding domains comprising a VH and VL domain, or an scFv.
These deficiencies are filled by Codarri ‘043 and Codarri ‘965.
The teachings of Codarri ‘043 and Codarri ‘965 from the previous art rejections are incorporated here in full.
Regarding claim 50, Codarri ‘043 teaches a series of peptide linkers comprising glycine and serine (page 34 in lines 13-25) and further teaches the use of linkers in Figure 1.
Codarri ‘965 teaches joining IL-2 and other components of an immunoconjugate by peptides linkers (page 29 in lines 4-12).
It would have been obvious to one of ordinary skill in the art to substitute the linkers and antigen binding domains of the immunoconjugate of the reference application with the glycine-serine linker and ScFv immunoconjugates of Codarri ‘043 and Codarri ‘965 to have a modified IL-2 fused by glycine-serine linker in an immunoconjugate that comprises ScFv antigen binding domains. Codarri ‘043 and Codarri ‘965 both teach immunoconjugates that bind T cells as the reference application recites and provides well known art equivalent antigen binding domain molecules that Codarri ‘043 and Codarri ‘965 teach can be used in therapeutic applications. Codarri ‘965 teaches peptide linkers for use in immunoconjugates and Codarri ‘043 teaches the glycine-serine linkers of the instant claim as peptide linkers for use in immunoconjugates that bind T cells. One of ordinary skill in the art would immediately envisage the reference application immunoconjugates would comprise linkers and Codarri ‘043 and Codarri ‘965 teach peptide linkers that work in art equivalent immunoconjugates making the use of Codarri ‘043 linkers obvious in the reference application.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 5, 11, 18, 27, 32, 36, 38, 40, 45-46, 55, 57-58, 62, 64, 66, 68, 70, 74, 77, 79-82, 85, 91, 95, 98, 100-101, 103, and 105 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-80 of copending Application No. 18726350 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-2, 5, 11, 18, and 27, the reference application recites modified IL-2 comprising the substitutions of H16A, P65R, and D84S (claims 1-2 and 4).
Regarding claim 30, the reference application recites the polypeptide comprises an Fc region wherein the IL-2 is fused to the C-terminus of the Fc region (claims 16).
Regarding claims 32, 36, 38,40, and 42, the reference application recites Fc substitutions including T366W, H435R, Y349C, M252Y, and a combination of L234A, L235A, and P329G in SEQ ID NO: 32-70 comprise these substitutions (claims 19 and 31-32).
Regarding claims 45-46, reference application SEQ ID NO: 32 matches instant SEQ ID NO: 47. Instant SEQ ID NO: 47 is the wild type sequence for IgG1 meaning the IgG1 of the reference application would recite claim 45.
Regarding claims 55, 57-58, 62, 64, 66, 74, and 77, the reference application recites the polypeptide comprising one or more antigen binding domains including those that binds CD4+ or CD8+ T-cell, and PD-1 and Lag-3 (claims 11-15 and 23 ) with VHH binding domains (claim 1). The reference application recites the binding domain is humanized (claim 35).
Regarding claim 80, the reference application by reciting the substitutions of the modified IL-2 of claim 1 recites the change in binding affinity.
Regarding claim 81, the reference application recites first polypeptide and second polypeptide wherein the first polypeptide is the one of claim 1 (claims 28).
Regarding claim 82, the reference application recites IgG1 as previously described.
Regarding claim 85, the reference application recites Fc substitutions including T366W, H435R, Y349C, M252Y, and a combination of L234A, L235A, and P329G in SEQ ID NO: 32-70 comprise these substitutions (claims 19 and 31-32).
Regarding claim 91, the reference application recites the second polypeptide does not comprise a modified IL-2 (claims 17).
Regarding claim 95, the reference application recites the first polypeptide comprises a first antigen binding domain, an Fc region and a modified IL-2 wherein the binding domain is fused to the N-terminus of the Fc and the IL-2 is fused to the C-terminus of the Fc and the second polypeptide comprising a second antigen binding domain fused to an Fc domain but does not comprise a modified IL-2 (claims 16, 20,and 28).
Regarding claim 98, the reference application recites the polypeptide comprising one or more antigen binding domains including those that binds CD4+ or CD8+ T-cell, and PD-1 and Lag-3 (claims 11-15 and 23).
Regarding claim 100, the reference application recites a pharmaceutical composition comprising a pharmaceutically acceptable carrier (claim 58).
Regarding claims 101 and 103, the reference application recites an isolated host cell comprising a nucleic acid encoding the polypeptide (claims 59-62).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 30, 46, 50, 55, 68, and 70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 14-16, 30, 32, 43, 56-58, 65, 69, 76, 80-81, 84, 86-87, 89-90, 93, 95-96, 100, 108-110, 113, 117-118, 120, 129, 132, 142-144, 148, 153-154, 158, 163-164, 166, 168, 170, and 176-177 of copending Application No. 18002613 (reference application) in view of Codarri (WO 2018/185043 A1) (PTO-892 Hereafter “Codarri ‘043”) and Codarri (WO 2018/184965 A1) (PTO-892 Hereafter “Codarri ‘965”)
The recitations of the reference application from the previous double patenting rejection are incorporated here in full.
As claims 1, 30, 46, and 55 were recited by application they would also be rejected further in view of Codarri ‘043 and Codarri ‘965.
The reference application does not recite a linker comprising glycine and serine, or antigen binding domains comprising a VH and VL domain, or an scFv.
These deficiencies are filled by Codarri ‘043 and Codarri ‘965.
The teachings of Codarri ‘043 and Codarri ‘965 from the previous art rejections are incorporated here in full.
Regarding claim 50, Codarri ‘043 teaches a series of peptide linkers comprising glycine and serine (page 34 in lines 13-25) and further teaches the use of linkers in Figure 1.
Codarri ‘965 teaches joining IL-2 and other components of an immunoconjugate by peptides linkers (page 29 in lines 4-12).
It would have been obvious to one of ordinary skill in the art to substitute the linkers and antigen binding domains of the immunoconjugate of the reference application with the glycine-serine linker and ScFv immunoconjugates of Codarri ‘043 and Codarri ‘965 to have a modified IL-2 fused by glycine-serine linker in an immunoconjugate that comprises ScFv antigen binding domains. Codarri ‘043 and Codarri ‘965 both teach immunoconjugates that bind T cells as the reference application recites and provides well known art equivalent antigen binding domain molecules that Codarri ‘043 and Codarri ‘965 teach can be used in therapeutic applications. Codarri ‘965 teaches peptide linkers for use in immunoconjugates and Codarri ‘043 teaches the glycine-serine linkers of the instant claim as peptide linkers for use in immunoconjugates that bind T cells. One of ordinary skill in the art would immediately envisage the reference application immunoconjugates would comprise linkers and Codarri ‘043 and Codarri ‘965 teach peptide linkers that work in art equivalent immunoconjugates making the use of Codarri ‘043 linkers obvious in the reference application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims allowable.
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/F.E./Examiner, Art Unit 1643
/Meera Natarajan/Primary Examiner, Art Unit 1643