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 .
Priority
The instant application is claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US21/64476, filing date 12/21/2021, which claims the benefit of the prior-filed United States Provisional Patent Application No. 63/129,712, filing date 12/23/2020.
Status of Application/Claims
The preliminary amendment, filed 06/20/2023, is acknowledged. Claims 11-16, 21-22, 24-25, and 30-44 are canceled. Claims 3-6, 8, 10, 20, 23, 26, and 28-29 are currently amended. Claims 45-48 are new. Claims 1-10, 17-20, 23, 26-29, and 45-48 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on 09/12/2023, 10/27/2023, 10/11/2024 and 01/16/2026 have been fully considered by the examiner.
Specification
The use of the terms Molecular Probes, Sigma-Aldrich, Capto, Cytiva, Biacore, ExpiFectamine, Thermo-Fisher, Invitrogen, Biolegend, Beckman Coulter, Accelrys, GE Healthcare, mAbSelect Sure, TimeLogic, and Informax, which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 5 is objected to because of the following informalities: Claim 5 recites “…any two of the three following substitutions: a V to A…, an N to R…, or a Q to P…”. This should be corrected to “…any two of the three following substitutions: a V to A… and/or an N to R and/or a Q to P…”. Appropriate correction is required.
Claim 47 is objected to because of the following informalities: Claim 47 recites “…the IL-2 mutein of any one of claim 17.” This should be corrected to “…the IL-2 mutein of claim 17.” Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 is dependent upon claim 2 and requires the D19N substitution. Claim 3 further recites “…wherein the first polypeptide further comprises an E to S substitution at position 67…”. However, claim 2 already recites that the polypeptide comprises D19N and E67S substitutions. Thus, claim 3 fails to further limit claim 2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Viney and Higginson-Scott – US20180340014A1 (herein referred to as Viney; effective filing date: 05/24/2017, publication date 11/29/2018); and, further in view of Li, et al. – US20220235109A1 (herein referred to as Li; effective filing date: 06/14/2019); and, as evidenced by UniProt. P60568 IL2_HUMAN. 07/21/1986. p.8 (herein referred to as UniProt-IL2).
Viney teaches therapeutic compounds and methods for site-specific local and targeted immune privilege for treatment of conditions including rejection of transplanted tissue and autoimmune disorders; and, teaches that the compounds include bi-specific molecules and antibodies that can comprise targeting moieties and effector binding/modulating moieties (p.1, [0002-0009]; p.4, [0054]). Viney teaches that the therapeutic compound can be a fusion protein (p.7, [0099]) and teaches specific embodiments wherein the effector binding/modulating moiety is an IL-2 mutein polypeptide (p.3, [0037]). Viney further teaches that the fusion protein contains a targeting moiety that is a full-length antibody or fragment thereof, including VHH molecule, soluble VH domain, scFv, Fab domain, or Fc fragment (p.8 –9, [0110-0115]). Viney also teaches nucleic acids encoding the therapeutic proteins (p.7, [0099]).
[AltContent: textbox (UniProt P60568 IL-2 Human sequence: Shows N-terminal Alanine at position 21, which is position 1 of the mature protein (signal sequence = 1-20)
[img-media_image1.png] )][AltContent: textbox (Instant SEQ ID NO: 3 vs Viney SEQ ID NO: 34
[img-media_image2.png])]Viney teaches SEQ ID NO: 34 which encodes for a mature IL-2 mutein amino acid sequence that overlaps at 98.7% wherein the only differences are that instant SEQ ID NO: 3 comprises a threonine/T to alanine/A mutation at position 2 and an aspartic acid/D to asparagine/N mutation at position 19 (p.26, sequence Table). These positions/mutations correspond to instant SEQ ID NO: 3 comprising T3A and D20N substitutions based on WT IL-2 numbering, as evidenced by UniProt-IL2 (alignment and WT sequence below).
Viney additionally teaches IL-2 muteins wherein the alanine at position 1 is deleted; and, wherein the protein comprises one or more substitutions including the T3A substitution (p.21, [0223-0224]). Further, Viney teaches that the D20 position can further comprise a substitution at the D20 position (which corresponds to the D19 position of the instant application) that can be D20A, D20E, D20H, D20I, D20Y, D20F, D20G, D20T, or D20W (p.21, [0223]).
Viney does not teach IL-2 muteins wherein the D20 position specifically comprises a D20N substitution (which corresponds to the D19N position of instant SEQ ID NO: 3 in the sequence shown above).
Li teaches IL-2 variants for treatment of cancer and autoimmune and inflammatory disorders, including infectious disease (title; abstract), including muteins that comprise the D20N substitution. Li teaches that this mutation is an IL-2Rβ/γc-disrupting IL-2 variant substitution with reduced binding to IL-2Rα for overall potency attenuation (Example 9, p.32, [0256-0257]; Fig.13A). Li also teaches that D20 engages in an extensive network of hydrogen bonds to receptor subunit side chains at the IL-2Rβ interface.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Viney with the teachings of Li by modifying the IL-2 mutein of Viney SEQ ID NO: 34 to include the T3A substitution (also taught by Viney) because the combination of prior art elements taught by Viney results in a predictable result of producing an IL-2 mutein that comprises the T3A mutation and Viney teaches that muteins comprising this mutation can be used in the treatment of immune disorders. It would have also been obvious to further combine the teachings of Viney with the teachings of Li by modifying Viney’s SEQ ID NO: 34 that comprises the T3A substitutions (taught by Viney) to further comprise an additional D20N substitution (taught by Li) because the combination of prior art elements results in a predictable result of arriving at the instantly claimed invention of an IL-2 mutein encoded by instant SEQ ID NO: 3. One would be motivated to do so because Li teaches that the D20N mutation results in attenuated immune receptor activation and Viney and Li teaches the use of IL-2 muteins in attenuating receptor activation for the treatment of immune disorders. One of ordinary skill in the art would have a reasonable expectation of success because Li teaches that the D20N mutation modulates receptor subunit activity.
Claims 1, 7, 23, 26-29 are rejected under 35 U.S.C. 103 as being unpatentable over Viney and Li, as applied to claim 7 above; and, further in view of Denis-Mize, et al. – US20060251617A1 (herein referred to as Denis-Mize; effective filing date: 02/15/2005; publication date: 11/09/2006); and, as evidenced by UniProt-IL2.
The combination of Viney and Li teaches an IL-2 mutein that comprises T3A and D20N substitutions (i.e., instant SEQ ID NO: 3) as applied to claim 7 above.
Viney additionally teaches the use of IL-2 muteins in methods of treating immune diseases that include rheumatoid arthritis, Crohn’s disease, psoriasis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, ankylosing spondylitis, type I diabetes, Sjogren’s syndrome, ulcerative colitis, neuromyelitis optica, celiac disease, scleroderma, arteritis, atopic dermatitis, alopecia areata, graft versus host disease (GVHD), autoimmune hepatitis, primary sclerosing cholangitis (p.32, [0277], Tables 2-3; p.33, [0278]). Viney additionally teaches nucleic acids encoding therapeutic molecules comprising modulating moieties, including IL-2 muteins (p.7, [0099]); and, vectors and host cells for methods of making (i.e., producing) the therapeutic compounds that comprise culturing a cell comprising a vector for expressing nucleotides encoding the polypeptides (p.43, [0404]; p.57, embodiments 302-306, [0456-0459]).
Regarding instant claim 1: Viney additionally teaches SEQ ID NO: 6 which encodes for the mature IL-2 amino acid sequence (p.21, [0220]), which overlaps with instant IL-2 SEQ ID NO: 1 at 99.3% and with instant SEQ ID NO: 2 at 98.7%; wherein the only differences are that instant SEQ ID NOs: 1 and 2 each comprises a serine at position 124, and instant SEQ ID NO: 2 comprises the additional T2A mutation (see sequence alignments below). The C124S mutation of instant SEQ ID NOs: 1 and 2 correspond to position 125 of the full mature protein; and, the T2A mutation of instant SEQ ID NO: 2 corresponds to position 3 of the full mature protein (instant SEQ ID NOs: 1 and 2 do not comprise the N-terminal “A/alanine” of the WT protein, as evidenced UniProt, see WT sequence above). Thus, instant SEQ ID NOs: 1 and 2 each comprise a C125S mutation based on WT IL-2 numbering; and instant SEQ ID NO: 2 comprises an additional T3A mutation based on WT IL-2 numbering. Viney teaches IL-2 muteins wherein the alanine at position 1 is deleted and wherein the protein comprises one or more additional substitutions including the T3A substitution, as described for instant SEQ ID NO: 3 above/instant claim 7. Viney also teaches SEQ ID NO: 34, as discussed above, which harbors a C125S mutation, and Viney teaches IL-2 muteins that comprise C125S for immune disorder treatment (see sequence Table p.26, SEQ ID NOs: 21-41, for example; p.21 -- 23, [0223-0231]).
[AltContent: textbox (Instant SEQ ID NO: 2 vs Viney SEQ ID NO: 6
[img-media_image3.png])][AltContent: textbox (Instant SEQ ID NO: 1 vs Viney SEQ ID NO: 6
[img-media_image4.png])] Regarding instant claim 7 SEQ ID NO: 5: Instant SEQ ID NO: 5 differs from Viney’s SEQ ID NO: 34 in that instant SEQ ID NO: 5 encodes for an IL-2 mutein that harbors the following mutations according to WT mature full-length IL-2 numbering: T3A, D20N, and P33R (see alignment below). As discussed above, the combination of Viney/Li teaches IL-2 muteins that harbor T3A and D20N mutations.
[AltContent: textbox (Instant SEQ ID NO: 5 vs Viney SEQ ID NO: 34
[img-media_image4.png])]The combination of Viney and Li does not teach an IL-2 mutein comprising the amino acid sequence as set forth in SEQ ID NO: 1 or 2 that comprises an additional P33R mutation (i.e., P34R based on WT numbering; instant claim 1); or, an IL-2 mutein of instant SEQ ID NO: 5 which contains the additional P33R mutation (i.e., P34R based on WT numbering; instant claim 7).
The P33R mutation recited in instant claim 1 corresponds to mature WT position P34R (as evidenced by UniProt-IL2, see sequence above).
Denis-Mize teaches the use of IL-2 therapy for treatment of lymphomas (i.e., cancer/inflammatory disease; title; abstract). Denis-Mize additionally teaches IL-2 muteins wherein the mutein comprises a C125S mutation as well as an additional mutation that can be P34R; and, teaches that the C125S and P34R mutations are expected to provide for reduced toxicity (p.9, [0090]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Viney and Li with the teachings of Denis-Mize by modifying an IL-2 T3A/D20N/C125S mutein taught by the combination of Viney/Li to additionally comprise a P34R substitution in order to arrive at the instantly claimed invention, because the combination of prior art elements taught by Viney, Li, and Denis-Mize results in a predictable result of arriving at an IL-2 mutein that comprises the T3A, D10N, C125S, and P34R mutations. One of ordinary skill in the art would be motivated to do so because Denis-Mize teaches that the C125S and P34R mutations result in reduced toxicity. One of ordinary skill in the art would have a reasonable expectation of success because Viney and Li teach the use of IL-2 muteins for treatment of immune disease and Deniz-Mize teaches the use of IL-2 muteins in treatment of lymphoma (a cancer/immune disease).
Claims 17-19 and 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Viney and Li; further in view of Brack, et al. – US20190100587A1 (herein referred to as Brack; effective filing date: 09/24/2018; publication date: 04/04/2019); and further in view of Barnes and Gray. Bioinformatics for geneticists. John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England. 2003, p.1-411 (herein referred to as Barnes); and, as evidenced by UniProt. P0DOX5 IGG1_HUMAN. 07/18/2018. p.6 (herein referred to as UniProt-IGG1).
Viney teaches the use of IL-2 muteins (as described above), and additionally teaches the use of the IL-2 muteins in pharmaceutical compositions with a pharmaceutically acceptable carrier (p.43, [0417]). As stated above for claim 7, Viney also teaches nucleic acids encoding therapeutic molecules comprising modulating moieties, including IL-2 muteins (p.7, [0099]); and, vectors and host cells for methods of making (i.e., producing) the therapeutic compounds that comprise culturing a cell comprising a vector for expressing nucleotides encoding the polypeptides (p.43, [0404]; p.57, embodiments 302-306, [0456-0459]). Viney, as described above, teaches production of the IL-2 muteins for treatment of various immune diseases and disorders (p.32, [0277], Tables 2-3; p.33, [0278]).
Instant claims 17-19 and 45-49 require an IL-2 mutein comprising a first and second polypeptide that each comprise the amino acid sequence set forth in SEQ ID NO: 47, which encodes for fusion constructs that comprise Fc IgG1 antibody fragments. That is, the fusion construct of SEQ ID NO: 47 encodes for IgG1 Fc SEQ ID NO: 13 – linker SEQ ID NO: 16 – IL-2 mutein SEQ ID NO: 3 (i.e., fusion construct SEQ ID NO: 47 = SEQ ID NOs: 13/16/3, see alignment below).
The combination of Viney/Li teaches the IL-2 mutein fragment of instant SEQ ID NO: 3, as described for instant claim 7 above.
Viney additionally teaches that the linker for the fusion protein encoding the therapeutic compound can comprise a glycine/serine linker of repeating GGGGS, including specifically a GGGGSGGGGS (instant SEQ ID NO: 16; p.49, [0452], embodiment 89 O-X).
[AltContent: textbox (Instant SEQ ID NO: 47 vs Instant SEQ ID NOs: 13/16/3 fusion
[img-media_image5.png])][AltContent: textbox (Instant SEQ ID NO: 13 vs UniProt-IGG1 P0DOX5
[img-media_image6.png])]Instant SEQ ID NO: 13 encodes for the Fc domain of human IgG1 except that instant SEQ ID NO: 13 comprises L234A, L235A, and D265S substitutions, as evidenced by UniProt-IGG1 (see alignment below; L234A and L235A, dashed box; D265S, solid box):
As mentioned above in the rejection for claim 7, Viney teaches fusion constructs wherein the IL-2 mutein is conjugated to an antibody or fragment thereof that can be a VHH molecule, soluble VH domain, scFv, Fab domain, or Fc fragment (p.8 –9, [0110-0115]). Viney also teaches examples of IL-2 muteins that are N-terminally or C-terminally conjugated to Fc domains (p.3 — 4, [0037-0043]); wherein the construct can be a bispecific antibody format; and, wherein the Fc domain comprises the human IgG1 Fc domain. Viney further teaches that the Fc domain can comprise “LALA” mutations L234A and L235A to ablate FcγR interactions (p.8, [0114]; p.62, [0491]; p.63, [0498]; p64, [0504]; p.64, [0506]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Viney and Li by producing an Fc – linker – IL-2 mutein fusion construct by conjugating the IL-2 mutein (taught by the combination of Viney/Li) to the human IgG1 Fc domain (taught by Viney) using a GS linker sequence of GGGGSGGGGS (also taught by Viney), and to modify the Fc polypeptide sequences to contain “LALA” mutations, to arrive at a fusion protein wherein the IL-2 mutein is conjugated to the C-terminus of a modified IgG1 Fc domain, because the combination of prior art elements results in a predictable result of producing an Fc – linker – IL-2 mutein fusion construct that arrives at the instantly claimed invention of a sequence comprised of instant SEQ ID NOs: 13/16/3 except for a D265S substitution (see below). One of ordinary skill would be motivated to do so because Viney teaches pharmaceutical compositions of fusion Fc-IL-2 proteins for the treatment of immune related disease and because Viney teaches that “LALA” mutations reduce effector function by ablating FcγR interactions. One would have a reasonable expectation of success because Viney teaches the amino acid positions of the “LALA” mutations.
The combination of Viney and Li do not teach an Fc – Linker – IL-2 mutein fusion construct wherein the Fc is a human IgG1 Fc domain comprises an additional D265S substitution.
Brack teaches IgG1 Fc mutants with ablated effector function, including Fc molecules with reduced binding to FcγRs (title; abstract). Brack also teaches that the D265 was determined to decrease affinity to FcγRs when alanine/A was substituted at this position (p.2, [0013]).
Barnes teaches the nature of mutations and the properties of amino acids in a variety of different protein contexts to provide for anticipating or interpreting the effect that a particular amino acid change will have on protein structure and function (p.292, para.2). Barnes teaches that alanine/A and serine/S are small/“tiny” amino acids (p.297, Fig.14.3); and, teaches that alanine/A can be substituted by other small amino acids such as serine/S (p.300, section 14.5.1.1; Fig.14.3).
It would have been prima facie obvious for one of ordinary skill in the art to further combine the teachings of Viney/Li with the teachings of Brack by modifying the Fc/IL-2 fusion construct (taught by the combination of Viney/Li) that comprises an Fc domain harboring LALA mutations (as taught by Viney) to additionally comprise a D265A mutation (taught by Brack), in order to arrive at the instantly claimed invention of an IL-2 mutein harboring fusion polypeptides encoded by instant SEQ ID NO: 47 harboring a mutation at the D265 position, because the combination of prior art elements results in a predictable result of producing a fusion protein of instant SEQ ID NOs: 13/16/3 with a D265 substitution that encodes for a modified Fc/IL-2 fusion construct wherein the Fc mutations facilitate heterodimerization (taught by Viney) and reduced effector function (taught by Brack). One of ordinary skill in the art would have a reasonable expectation of success and would be motivated to do so because Brack teaches that a mutation at the D265 position to alanine/A reduces affinity to FcγRs. It would have further been obvious to modify the D265A mutation to be a D265S mutation by substituting the alanine/A for a serine/S (as taught by Barnes), to arrive at the instantly claimed invention, because this would be a simple substitution of one known small amino acid for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Barnes teaches that alanine/A can be substituted with serine/S.
Claims 2-7, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Viney and Li; further in view of Denis-Mize; and, further in view of Barnes.
The combination of Viney/Li teaches the aforementioned IL-2 muteins that comprise T3A (instant T2A), D20N, and C125S (instant C124S).
Viney also teaches IL-2 muteins additionally comprising V69A, N71R, and Q74P substitutions for the purpose of treating immune disease (p.23, [0231]). Thus, the combination of Viney/Li also teaches IL-2 muteins comprising the following mutations: T3A, D20N, V69A, N71R, Q74P, and C125S.
The combination of Viney/Li/Denis-Mize additionally teaches the P34R mutation, as described for claims 1 and 7 above. Thus, the combination of Viney/Li/Denise-Mize teaches IL-2 muteins that comprise the following mutations: T3A (instant T2A), D20N (instant D19N), P34R (instant P33R), V69A (instant V68A), N71R (instant N70R), Q74P (instant Q73P) , and C125S (instant C124S) substitutions.
Instant claim 2 and instant claim 7 SEQ ID NOs: 4 and 6-12 additionally require an additional E68S (instant E67S) substitution.
In addition to the D20N mutation, Li further teaches IL-2 variants wherein the IL-2 mutein comprises a substitution at position E68 that can be E68A, E68F, E68H, E68L, or E68P (p.15, Table 2). Li teaches that these mutations disrupt CD25/IL-2Rα receptor subunit interaction in the IL-2 receptor to promote selectivity toward IL-2Rβγ activation (p.15, [0144]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Viney/Li/Denis-Mize with additional teachings of Li by modifying an IL-2 mutein that comprises T3A, D20N, and C125S mutations as well as V69A and/or Q74P and/or N71R substitutions (as taught by Viney) as well as the P34R mutation (as taught by Denis-Mize) to also comprise an amino acid substitution at the E68 position (instant SEQ ID NOs: 4 and 6-12 position E67), in order to arrive at an IL-2 mutein of the instantly claimed invention, because the combination of prior art elements results in the predictable result of producing an IL-2 mutein with mutations that disrupt IL-2Rα interactions (taught by Li) and reduce toxicity of IL-2 (taught by Denis-Mize). One of ordinary skill would be motivated to do so because Viney teaches the use of IL-2 muteins in pharmaceutical compositions for the treatment of immune disease and Viney, Li, and Denis-Mize teach IL-2 muteins for the purpose of treating immune diseases.
The combination of Viney/Li/Denis-Mize does not teach that the E68 mutation is specifically E68S (instant E67S).
Barnes teaches the nature of mutations and the properties of amino acids in a variety of different protein contexts to provide for anticipating or interpreting the effect that a particular amino acid change will have on protein structure and function (p.292, para.2). Barnes teaches that alanine/A and serine/S are small/“tiny” amino acids (p.297, Fig.14.3); and, teaches that alanine/A can be substituted by other small amino acids such as serine/S (p.300, section 14.5.1.1; Fig.14.3).
It would have been prima facie obvious for one of ordinary skill before the effective filing date to further combine the teachings of Viney/Li/Denis-Mize and the teachings of Barnes by modifying the IL-2 mutein comprising an E68 mutation to specifically comprise an E68S substitution (i.e., instant “E67S” substitution), in order to arrive at the instantly claimed invention of an IL-2 mutein encoded by any of amino acid SEQ ID NOs: 4 or 6-12, because the combination of prior art elements results in a predictable result of producing an IL-2 mutein harboring an E68S substitution. One of ordinary skill would be motivated to do so because Li teaches that introducing an E68 mutation provides for disruption of IL2Rα interactions and promotes selective activation of the dimeric βγ receptor. It would have further been obvious to modify the E68 mutation to be an E68S mutation by substituting the alanine/A modification (taught by Li) to a serine/S modification (taught by Barnes), to arrive at the instantly claimed invention, because this would be a simple substitution of one known element for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Li teaches that the E68 position can be mutated to small (i.e., alanine/A or proline/P), aromatic (i.e., phenylalanine/F), aliphatic (i.e., leucine/L) and positively-charged (i.e., histidine/H) amino acids and produce the same effect, and Barnes teaches that serine/S is comparable to alanine/A and proline/P small amino acids.
Claims 8-10, 17-19, and 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Viney, Li, Denis-Mize; further in view of Brack; and, further in view of Barnes.
The combination of Viney/Li/Denise-Mize/Barnes teaches an IL-2 mutein that comprises the following IL-2 mutations, as applied to instant claim 2 above: T3A, D20N, P34R, E68S, V69A, N70R, Q74P, and C125S.
The combination of Viney/Li/Brack/Barnes teaches IL-2 muteins that are conjugated to human IgG1 Fc to produce an Fc – linker – IL-2 mutein fusion construct wherein the Fc domain comprises “LALA” and D265S substitutions for heterodimerization and ablation of effector function, as applied to instant claim 17, SEQ ID NO: 13 (Fc domain), and SEQ ID NO: 47 (fusion construct) above.
Neither the combination of Viney/Li/Denise-Mize/Barnes nor the combination of Viney/Li/Brack/Barnes teaches an Fc – linker – IL-2 mutein fusion construct encoded by any of instant SEQ ID NOs 45-46 and 48-54, which each comprise IL-2 muteins encoded by the following corresponding instant amino acid SEQ ID NOs, as evidenced by applicant specification (p.102-104, sequence Table): SEQ ID NO: 8 (fusion SEQ ID NO: 45); SEQ ID NO: 7 (fusion SEQ ID NO: 46); SEQ ID NO: 4 (fusion SEQ ID NO: 48), SEQ ID NO: 5 (fusion SEQ ID NO: 49), SEQ ID NO: 6 (fusion SEQ ID NO: 50), SEQ ID NO: 9 (fusion SEQ ID NO: 51); SEQ ID NO: 10 (fusion SEQ ID NO: 52); SEQ ID NO: 11 (fusion SEQ ID NO: 53); and, SEQ ID NO: 12 (fusion SEQ ID NO: 54) (instant claim 17-19 and 45-48); and, neither the combination of Viney/Li/Denise-Mize/Barnes nor the combination of Viney/Li/Brack/Barnes teaches Fc constructs encoded by any of instant SEQ ID NOs: 14-15 and 17-18 (instant claim 8-10).
Regarding instant claims 17-19 and 45-48: The combination of Viney/Li teaches the IL-2 muteins, that comprise the following substitutions, as applied to claims 1, 2, and 17 above: T3A (instant T2A), D20N (instant D19N), V69A (instant V68A), N71R (instant N70R), Q74P (instant Q73P), and C125S (instant C124S). The combination of Viney/Li/Denis-Mize teaches the substitution of P34R (instant P33R), as applied to claims 1 and 17 above. The combination of Viney/Li/Denis-Mize/Barnes further teaches the substitution of E68S (instant E67S), as applied to instant claims 2 and 17 above. The combination of Viney/Li/Brack/Barnes teaches Fc/IL-2 mutein fusion constructs wherein the Fc domain is encoded by a human IgG1 Fc comprising “LALA” and D265S substitutions (i.e., Fc domain encoded by instant SEQ ID NO: 13).
It would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Viney/Li and Viney/Li/Denis-Mize/Barnes with the teachings of Viney/Brack/Barnes by modifying the Fc/IL-2 mutein construct wherein the Fc domain comprises “LALA” and D265S mutations (taught by Viney/Brack/Barnes) to comprise IL-2 muteins containing T3A, D20N, and C125 substitutions (taught by Viney/Li; instant SEQ ID NOs: 45-46 and 48-54); and, V69A, N71R, and/or Q74P substitutions (taught by Viney; instant SEQ ID NOs: 45-46, 49-54); and/or a P34R substitution (taught by Denis-Mize/Barnes; instant SEQ ID NOs: 48-50, 52, and 54); and/or an E68S substitution (taught by Li/Barnes; instant SEQ ID NOs: 45-46, 48, 50-54), to arrive at the instantly claimed IL-2 mutein/Fc fusion constructs, because the combination of prior art elements predictably results in Fc/IL-2 fusion constructs of instant SEQ ID NOs: 45-46 and 48-54. One of ordinary skill in the art would be motivated to modify the IL-2 muteins taught by Viney/Li and Viney/Li/Denis-Mize/Barnes by adding an Fc domain comprising “LALA” to L234A and L235A to receive the benefit of ablating FcγR interactions (taught by Viney) and to add a D265S mutation which also decreases affinity to FcγRs (taught by Viney/Brack/Barnes). One would have a reasonable expectation of success because Viney teaches the locations of the human IgG1 Fc “LALA” and D265 mutations.
Regarding instant claims 8-10: Claims 8-10 are dependent on instant claim 2, and the combination of Viney/Li/Denis-Mize/Barnes teaches IL-2 mutein Fc-fusion constructs wherein the IL-2 mutein comprises at least the T3A, D20N, and E68S substitutions; and, wherein the Fc domain comprises the “LALA” and D265S mutations, which is encoded by instant SEQ ID NO: 13 as discussed above.
Instant claims 8-10 recite that the first polypeptide comprises an amino acid SEQ ID NO: 14 or 15; and, instant claim 10 recites that the second polypeptide comprises an amino acid SEQ ID NO: 17 or 18. Compared to the Fc domain encoded by instant SEQ ID NO: 13 that contains the “LALA” and D265S mutations, instant SEQ ID NOs: 14 and 18 additionally harbor S134C and T146W mutations which correspond to positions S354C and T366W, respectively, of the full-length WT human IgG1 (see UniProt-IGG1 sequence above); and, compared instant SEQ ID NO: 13, instant SEQ ID NOs: 15 and 17 additionally harbor Y129C, T146S, L148A, and Y187V. These mutations correspond to positions Y349C, T366S, L368A, and Y407V of the full-length WT human IgG1, respectively.
Viney additionally teaches that the human IgG1 polypeptide can comprise additional mutations to facilitate heterodimerization of the heavy chains by introducing CH3 domain mutations T366W (i.e., a “knob” mutation) in one chain and T366S, L368A, and Y407V (i.e., “hole” mutations) in the other chain. Viney additionally teaches that heterodimerization and stabilization can be further facilitated by introducing S354C (typo noted as Viney recites “5354’ instead of “S354”) into one chain and Y349C into the other chain to allow for disulfide bonding (p.10, [0121-0123]). Thus, instant SEQ ID NOs: 14 and 18 harbor “knob” mutations; and, instant SEQ ID NOs: 15 and 17 harbor “hole” mutations.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Viney, Li, Denis-Mize, Brack, and Barnes with additional teachings of Viney by modifying the Fc domain of the Fc/IL-2 mutein fusion construct (taught by the combination of Viney/Li/Denis-Mize/Brack/Barnes) to further comprise “knob” and “hole” mutations (taught by Viney), to arrive at the instantly claimed SEQ ID NOs: 14-15 and 17-18, in order to receive the benefit that a “knob” polypeptide and “hole” polypeptide would facilitate heterodimerization and stabilization of an Fc heterodimer. One of ordinary skill in the art would have a reasonable expectation of success because Viney teaches the amino acid positions for the “knob” and “hole” mutations.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jami M Gurley whose telephone number is (571)272-0117. The examiner can normally be reached Monday - Friday, 8am - 4pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647