Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s preliminary amendments and remarks, filed 06/30/2023, are acknowledged.
Claims 1-57 are canceled.
Claims 58-69 are new.
Claims 58-69 are pending.
As such, claims 58-69 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos. 62/408,655 and 62/416,087, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The present claims are drawn to compositions comprising a human IL-15 variant comprising the amino acid substitutions D30N and E64Q, wherein said human IL-15 variant is at least 95% identical to SEQ ID NO: 2 and variant Fc domains comprising amino acid substitutions T366S/L368A/Y407V and T366W. Provisional applications 62/408,655 and 62/416,087 fail to disclose of the instantly claimed human IL-15 variant nor the variant Fc domains. Accordingly, claims 58-69 are not entitled to the benefit of these prior applications. However, Examiner acknowledges that provisional applications 62/443,465 and 62/477,926, filed on 01/06/2017 and 03/28/2017, respectively, do disclose of the instantly claimed human IL-15 variant and the variant Fc domains. Therefore, the instant claims have a priority date of 01/06/2017.
If Applicant disagrees with the examiner’s factual determination above, Applicant should provide evidence as to where the relevant features were disclosed in the earlier-filed application. This could be accomplished, for example, by pointing to specific pages or figures within the provisional application that disclose the now-claimed invention.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/21/2023 and 09/10/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: Compositions Containing a Human IL-15 Variant.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
The disclosure is objected to because of the following informalities:
[0070]: “CD16=negative” should read “CD16-negative”.
[0072]: The sentence should end in a period (.).
[00473]: “HiTrapQ” should read “HiTrap Q”.
[00485]: “53A-53Cdepict” should read “53A-53C depict”.
Appropriate correction is required.
The use of the term Octet, Luminex, TWEEN™, PLURONICS™, HiTrap, Thermo Fisher Scientific, LabChip, GXII Touch, eFluor, Superdex™, Agilent, PerkinElmer, R&D Systems, Bio-Rad, and SYPRO, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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 Interpretation
Claims 60-62 and 67-69 recite the transitional phrase “contains”, the scope of which is not defined by the specification. As such, according to MPEP 2111.03(I), the term will be interpreted as an open-ended transitional term, similar to the transitional phrase “comprising”. For example, the structure recited in the claims can comprise additional, unrecited elements.
Claims 63 and 64 recite “domain linker”. Examiner acknowledges that the specification indicates a “domain linker” is a linker used to link any two domains (see [00342]).
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.
Claims 60-62 and 67-69 are 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. Claims 60-62 and 67-69 are drawn to said human IL-15 variant contain[ing] 1, 2, or 3 additional amino acid substitutions. The language “additional amino acid substitutions” broadens the claims because the addition of amino acid substitutions gives more variability than the 95% recited in claims 58 and 63.
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 § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 58-69 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.
Claims 58 and 63 recite “amino acid substitutions D30N and E64Q” and “at least 95% identical to SEQ ID NO: 2”. It is unclear if the amino acid substitutions are encompassed within the “at least 95%”, or if the amino acid substitutions are in combination with the 95% variability. As such, claims 58 and 63, and their dependent claims are rejected.
Claims 60-62 and 67-69 recite “additional amino acid substitutions”. It is unclear if the additional substitutions are in addition to the 95% variability, or if the additional substitutions are included in the 95% variability.
The term “reduces” in claim 65 is a relative term which renders the claim indefinite. The term “reduces” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claims nor the specification provide a definition for one to understand what the terms encompass or what is considered to be reducing without a standard value to compare; thus, one would not be apprised of the scope of the invention.
Additionally, the term “ablation variant” in claim 65 is a relative term which renders the claim indefinite. The term “ablation variant” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While the specification discloses that Figure 3 and Figure 5 depicts useful ablation variants that ablate FcγR binding (see [0018] and [0108]), Applicant is reminded that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Lastly, claim 65 contains the trademark/trade name Biacore. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a binding assay and, accordingly, the identification/description is indefinite.
As such, claim 65 is rejected.
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.
10,550,185 B2
Claims 58 and 60-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 10-13 of U.S. Patent No. 10,550,185 B2 (patent date: 02/04/2020). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58 and 60-62, the ‘185 patent is drawn to a bispecific heterodimeric protein comprising: a) a fusion protein comprising a first protein domain, a second protein domain, and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said second protein domain using a first domain linker, wherein said second protein domain is covalently attached to the N-terminus of said first Fc domain using a second domain linker, and wherein said first protein domain comprises a human IL-15Rα(sushi) protein and said second protein domain comprises a variant of a human IL-15 protein of SEQ ID NO: 2 comprising amino acid substitutions selected from the group consisting of (i) N4D/N65D, (ii) D30N/N65D, and (iii) D30N/E64Q/N65D; and b) an antibody fusion protein comprising a PD-1 antigen binding domain (ABD) and a second Fc domain, wherein said PD-1 antigen binding domain is covalently attached to the N-terminus of said second Fc domain, and said PD-1 antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment; wherein said first and said second Fc domains are variants of a human IgG1 Fc domain and have a set of amino acid substitutions selected from the group consisting of (i) S267K/L368D/K370S : S267K/S364K/E357Q; (ii) S364K/E357Q : L368D/K370S; (iii) L368D/K370S : S364K; (iv) L368E/K370S : S364K; (v) T411E/K360E/Q362E : D401K; (vi) L368D/K370S : S364K/E357Q. and (vii) K370S : S364K/E357Q, according to EU numbering (see claims 1, 10, and 12). SEQ ID NO: 2 of the ‘185 patent shares 100% identity to instant SEQ ID NO: 2.
Additionally, the ‘185 patent is drawn to the bispecific heterodimeric protein, wherein said variant IL-15 protein and said IL-15Rα protein have a set of amino acid substitutions selected from the group consisting of (i) E87C:D96/P97/C98; (ii) E87C:D96/C97/A98; (iii) V49C:S40C; (iv) L52C:S40C; (v) E89C:K34C; (vi) Q48C:G38C; (vii) E53C:L42C; (viii) C42S:A37C, and (ix) L45C:A37C, respectively (see claims 11 and 13).
As such, the ‘185 patent anticipates the present invention.
10,550,185 B2 and Atwell
Claims 58, 60-65, and 67-69 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 10-13 of U.S. Patent No. 10,550,185 B2 (patent date: 02/04/2020) in view of Atwell et al (J. Mol. Biol. (1997) 270, 26-35). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58, 60-63, 65, and 67-69, the ‘185 patent is drawn to a bispecific heterodimeric protein comprising: a) a fusion protein comprising a first protein domain, a second protein domain, and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said second protein domain using a first domain linker, wherein said second protein domain is covalently attached to the N-terminus of said first Fc domain using a second domain linker, and wherein said first protein domain comprises a human IL-15Rα(sushi) protein and said second protein domain comprises a variant of a human IL-15 protein of SEQ ID NO: 2 comprising amino acid substitutions selected from the group consisting of (i) N4D/N65D, (ii) D30N/N65D, and (iii) D30N/E64Q/N65D; and b) an antibody fusion protein comprising a PD-1 antigen binding domain (ABD) and a second Fc domain, wherein said PD-1 antigen binding domain is covalently attached to the N-terminus of said second Fc domain, and said PD-1 antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment; wherein said first and said second Fc domains are variants of a human IgG1 Fc domain and have a set of amino acid substitutions selected from the group consisting of (i) S267K/L368D/K370S : S267K/S364K/E357Q; (ii) S364K/E357Q : L368D/K370S; (iii) L368D/K370S : S364K; (iv) L368E/K370S : S364K; (v) T411E/K360E/Q362E : D401K; (vi) L368D/K370S : S364K/E357Q. and (vii) K370S : S364K/E357Q, according to EU numbering (see claims 1, 10, and 12). SEQ ID NO: 2 of the ‘185 patent shares 100% identity to instant SEQ ID NO: 2.
Additionally, the ‘185 patent is drawn to the bispecific heterodimeric protein, wherein said variant IL-15 protein and said IL-15Rα protein have a set of amino acid substitutions selected from the group consisting of (i) E87C:D96/P97/C98; (ii) E87C:D96/C97/A98; (iii) V49C:S40C; (iv) L52C:S40C; (v) E89C:K34C; (vi) Q48C:G38C; (vii) E53C:L42C; (viii) C42S:A37C, and (ix) L45C:A37C, respectively (see claims 11 and 13).
The difference between the instant claims and the ‘185 claims is that the instant claims recite a composition comprising two variant Fc domains wherein one domain comprises the amino acid substitutions T366S/L368A/Y407V and the other domain comprises the amino acid substitution T366W (see instant claim 63). However, Atwell et al disclose of stable heterodimers from remodeling the domain interface of a homodimer using a phage display library (see Title). Atwell et al disclose that such knob-into-hole mutations promotes heterodimerization and enhances the formation of diabodies (see pg. 27, left column). Specifically, Atwell disclose of the heterodimer T366W-T366S:L368A:Y407V which is more stable than the heterodimer T366W-Y407A (see Table 1 and Fig. 3; pg. 29, left column).
As such, it would have been obvious to combine the teachings of the ‘185 patent and Atwell et al to develop the claimed invention. One would be motivated to do so as Atwell et al disclose that these specific knob-into-hole mutations developed a more stable heterodimer compared to other species at these amino acid positions. As such, one would have a reasonable expectation that modifying the Fc domains of a composition to comprise the mutations T366W-T366S:L368A:Y407V would increase the stability of the composition.
11,084,863 B2
Claims 58-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 12-13 of U.S. Patent No. 11,084,863 B2 (patent date: 08/10/2021). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58-62, the ‘863 patent is drawn to a bifunctional heterodimeric protein comprising: a) an IL-15/IL-15Rα fusion protein comprising a human IL-15Rα protein having the amino acid sequence of SEQ ID NO:4, a human IL-15 variant protein having the amino acid sequence of SEQ ID NO:2 and comprising one or more amino acid substitutions, and a first Fc domain, wherein said human IL-15Rα protein is covalently attached to the N-terminus of said human IL-15 variant protein using a first domain linker and said human IL-15 variant protein is covalently attached to the N-terminus of said first Fc domain using a second domain linker, or wherein said human IL-15 variant protein is covalently attached to the N-terminus of said human IL-15Rα protein using a first domain linker and said human IL-15Rα protein is covalently attached to the N-terminus of said first Fc domain using a second domain linker; and b) an antigen binding domain monomer comprising a heavy chain comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a variable heavy chain and CH2-CH3 is a second Fc domain, and a light chain comprising a variable light chain (VL) and a light constant domain (CL), wherein said first and said second Fc domains are variants of a human IgG1 Fc domain and have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S : S267K/S364K/E357Q; S364K/E357Q : L368D/K370S; L368D/K370S S364K; L368E/K370S : S364K; T411E/K360E/Q362E : D401K; L368D/K370S : S364K/E357L and K370S : S364K/E357Q, according to EU numbering, and wherein said antigen binding domain monomer binds human CD8 (see claim 1). SEQ ID NO: 2 of the ‘863 patent shares 100% identity with instant SEQ ID NO: 2.
The ‘863 patent is drawn to the bifunctional heterodimeric protein according to claim 1, wherein said human IL-15 variant protein has one or more amino acid substitutions selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, and Q108E (see claim 5).
The ‘863 patent is drawn to the bifunctional heterodimeric protein according to claim 1, wherein said human IL-15 variant protein comprises the amino acid substitutions N4D/N65D or D30N/E64Q/N65D (see claim 6).
The difference between the instant claims and the ‘863 patent is that the ‘863 claims are also drawn to a method of using the claimed bifunctional heterodimeric protein (see claim 13). However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
As such, the ‘863 patent anticipates the present invention.
11,084,863 B2 and Atwell
Claims 58-69 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 12-13 of U.S. Patent No. 11,084,863 B2 (patent date: 08/10/2021) in view of Atwell et al (J. Mol. Biol. (1997) 270, 26-35). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58-69, the ‘863 patent is drawn to a bifunctional heterodimeric protein comprising: a) an IL-15/IL-15Rα fusion protein comprising a human IL-15Rα protein having the amino acid sequence of SEQ ID NO:4, a human IL-15 variant protein having the amino acid sequence of SEQ ID NO:2 and comprising one or more amino acid substitutions, and a first Fc domain, wherein said human IL-15Rα protein is covalently attached to the N-terminus of said human IL-15 variant protein using a first domain linker and said human IL-15 variant protein is covalently attached to the N-terminus of said first Fc domain using a second domain linker, or wherein said human IL-15 variant protein is covalently attached to the N-terminus of said human IL-15Rα protein using a first domain linker and said human IL-15Rα protein is covalently attached to the N-terminus of said first Fc domain using a second domain linker; and b) an antigen binding domain monomer comprising a heavy chain comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a variable heavy chain and CH2-CH3 is a second Fc domain, and a light chain comprising a variable light chain (VL) and a light constant domain (CL), wherein said first and said second Fc domains are variants of a human IgG1 Fc domain and have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S : S267K/S364K/E357Q; S364K/E357Q : L368D/K370S; L368D/K370S S364K; L368E/K370S : S364K; T411E/K360E/Q362E : D401K; L368D/K370S : S364K/E357L and K370S : S364K/E357Q, according to EU numbering, and wherein said antigen binding domain monomer binds human CD8 (see claim 1). SEQ ID NO: 2 of the ‘863 patent shares 100% identity with instant SEQ ID NO: 2.
The ‘863 patent is drawn to the bifunctional heterodimeric protein according to claim 1, wherein said human IL-15 variant protein has one or more amino acid substitutions selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, and Q108E (see claim 5).
The ‘863 patent is drawn to the bifunctional heterodimeric protein according to claim 1, wherein said human IL-15 variant protein comprises the amino acid substitutions N4D/N65D or D30N/E64Q/N65D (see claim 6).
The difference between the instant claims and the ‘863 patent is that the ‘863 claims are also drawn to a method of using the claimed bifunctional heterodimeric protein (see claim 13), and the instant claims recite a composition comprising two variant Fc domains wherein one domain comprises the amino acid substitutions T366S/L368A/Y407V and the other domain comprises the amino acid substitution T366W (see instant claim 63). However, with respect to the method of using claim, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
Additionally, with respect to the variant Fc domain substitutions recited in instant claim 63, Atwell et al disclose of stable heterodimers from remodeling the domain interface of a homodimer using a phage display library (see Title). Atwell et al disclose that such knob-into-hole mutations promotes heterodimerization and enhances the formation of diabodies (see pg. 27, left column). Specifically, Atwell disclose of the heterodimer T366W-T366S:L368A:Y407V which is more stable than the heterodimer T366W-Y407A (see Table 1 and Fig. 3; pg. 29, left column).
As such, it would have been obvious to combine the teachings of the ‘683 patent and Atwell et al to develop the claimed invention. One would be motivated to do so as Atwell et al disclose that these specific knob-into-hole mutations developed a more stable heterodimer compared to other species at these amino acid positions. As such, one would have a reasonable expectation that modifying the Fc domains of a composition to comprise the mutations T366W-T366S:L368A:Y407V would increase the stability of the composition.
11,377,477 B2
Claims 58-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,377,477 B2 (patent date: 07/05/2022). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58 and 60-62, the ‘477 patent is drawn to a PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein comprising: a) a first monomer comprising, from N- to C-terminal: i) a IL-15Rα sushi domain protein; ii) a first domain linker; iii) an IL-15 protein; and iv) a first variant Fc domain; and b) a second monomer comprising a heavy chain comprising VH-CH1-hinge-CH2- CH3, wherein said CH2-CH3 is a second variant Fc domain; c) a third monomer comprising a light chain comprising VL-CL; wherein said VH and VL domains form an antigen binding domain that binds to human PD-1 and does not compete for said human PD-I with nivolumab and/or pembrolizumab; wherein said VH domain has at least 95% amino acid sequence identity with SEQ ID NO:5 and said VL domain has at least 95% amino acid sequence identity with SEQ ID NO:6, wherein said first variant Fc domain and said second variant Fc domain are each a variant of a human IgG Fc domain (see claim 1).
The ‘477 patent is drawn to the PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1 wherein said IL-15 protein is a variant human IL-15 protein comprising amino acid substitution(s) selected from the group of D30N/E64Q/N65D; D30N/N65D; N1D; N4D; D8N; D30N; D61N; E64Q; N65D; Q108E; N1D/N4D/D8N; N1D/N4D/N65D; N1D/D30N; N1D/D61N; N1D/D61N/E64Q/Q108E; N1D/E64Q; N1D/N65D; N1D/Q108E; N4D; N4D/D30N; N4D/D61N; N4D/D61N/N65D; N4D/D61N/E64Q/Q108E; N4D/E64Q; N4D/N65D; D8N/D61N; D8N/E64Q; D30N/E64Q; D30N/Q180E; D61N/E64Q/N65D; E64Q; E64Q/N65D; E64Q/Q108E; and N65D/Q108E (see claim 5).
The ‘477 patent is drawn to the PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1, wherein said IL-15 protein is a variant human IL-15 protein comprising amino acid substitution(s) selected from the group of N4D/N65D; D30N; D30N/E64Q; D30N/N65D; and D30N/E64Q/N65D (see claim 6).
While the ‘477 patent does not disclose of the sequence of the variant human IL-15, it is inherent that the human IL-15 of the ‘477 patent comprises instant SEQ ID NO: 2 as the ‘477 patent discloses the variant human IL-15 comprises overlapping substitutions such as N1, D30N, and E64Q (see MPEP 2112). As such, the ‘477 patent anticipates the present invention.
11,377,477 B2 and Atwell
Claims 58-69 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,377,477 B2 (patent date: 07/05/2022) in view of Atwell et al (J. Mol. Biol. (1997) 270, 26-35). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58 and 60-62, the ‘477 patent is drawn to a PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein comprising: a) a first monomer comprising, from N- to C-terminal: i) a IL-15Rα sushi domain protein; ii) a first domain linker; iii) an IL-15 protein; and iv) a first variant Fc domain; and b) a second monomer comprising a heavy chain comprising VH-CH1-hinge-CH2- CH3, wherein said CH2-CH3 is a second variant Fc domain; c) a third monomer comprising a light chain comprising VL-CL; wherein said VH and VL domains form an antigen binding domain that binds to human PD-1 and does not compete for said human PD-I with nivolumab and/or pembrolizumab; wherein said VH domain has at least 95% amino acid sequence identity with SEQ ID NO:5 and said VL domain has at least 95% amino acid sequence identity with SEQ ID NO:6, wherein said first variant Fc domain and said second variant Fc domain are each a variant of a human IgG Fc domain (see claim 1).
The ‘477 patent is drawn to the PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1 wherein said IL-15 protein is a variant human IL-15 protein comprising amino acid substitution(s) selected from the group of D30N/E64Q/N65D; D30N/N65D; N1D; N4D; D8N; D30N; D61N; E64Q; N65D; Q108E; N1D/N4D/D8N; N1D/N4D/N65D; N1D/D30N; N1D/D61N; N1D/D61N/E64Q/Q108E; N1D/E64Q; N1D/N65D; N1D/Q108E; N4D; N4D/D30N; N4D/D61N; N4D/D61N/N65D; N4D/D61N/E64Q/Q108E; N4D/E64Q; N4D/N65D; D8N/D61N; D8N/E64Q; D30N/E64Q; D30N/Q180E; D61N/E64Q/N65D; E64Q; E64Q/N65D; E64Q/Q108E; and N65D/Q108E (see claim 5).
The ‘477 patent is drawn to the PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1, wherein said IL-15 protein is a variant human IL-15 protein comprising amino acid substitution(s) selected from the group of N4D/N65D; D30N; D30N/E64Q; D30N/N65D; and D30N/E64Q/N65D (see claim 6).
While the ‘477 patent does not disclose of the sequence of the variant human IL-15, it is inherent that the human IL-15 of the ‘477 patent comprises instant SEQ ID NO: 2 as the ‘477 patent discloses the variant human IL-15 comprises overlapping substitutions such as N1, D30N, and E64Q (see MPEP 2112).
The difference between the instant claims and the ‘477 patent is that the instant claims recite a composition comprising two variant Fc domains wherein one domain comprises the amino acid substitutions T366S/L368A/Y407V and the other domain comprises the amino acid substitution T366W (see instant claim 63). However, Atwell et al disclose of stable heterodimers from remodeling the domain interface of a homodimer using a phage display library (see Title). Atwell et al disclose that such knob-into-hole mutations promotes heterodimerization and enhances the formation of diabodies (see pg. 27, left column). Specifically, Atwell disclose of the heterodimer T366W-T366S:L368A:Y407V which is more stable than the heterodimer T366W-Y407A (see Table 1 and Fig. 3; pg. 29, left column).
As such, it would have been obvious to combine the teachings of the ‘477 patent and Atwell et al to develop the claimed invention. One would be motivated to do so as Atwell et al disclose that these specific knob-into-hole mutations developed a more stable heterodimer compared to other species at these amino acid positions. As such, one would have a reasonable expectation that modifying the Fc domains of a composition to comprise the mutations T366W-T366S:L368A:Y407V would increase the stability of the composition.
11,524,991 B2
Claims 58 and 60-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 13-17 of U.S. Patent No. 11,524,991 B2 (patent date: 12/13/2022). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58 and 60-62, the ‘991 patent is drawn to a PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein comprising: a) a first monomer comprising, from N- to C-terminal: i) an IL-15 receptor alpha (IL-15Rα) sushi domain; ii) a first domain linker, iii) a variant IL-15 domain, and iv) a second domain linker, and v) a first variant human IgG1 Fc domain comprising CH2-CH3; and b) a second monomer comprising, from N- to C-terminal: a heavy chain comprising VH-CH1-hinge-CH2-CH3, wherein said CH2-CH3 is a second human IgG1 variant Fc domain; and c) a light chain comprising VL-CL; wherein said VH and VL form an antigen binding domain that binds human PD-1 and have sequences selected from the pairs consisting of 1C11[PD-1]_H3L3 from XENP22553(SEQ ID NOS:186-187), 1C11[PD-1]_H3.234_L3.144 from XENP25806 (SEQ ID NOS:578-579), 1C11[PD-1]_H3.240_L3.148 from XENP25812 (SEQ ID NO:584), 1C11[PD- 1]_H3.241_L3.148 from XENP25813 (SEQ ID NO:585), 1C1 [PD-1]_H3.241_L3.92 from XENP25819 (SEQ ID NO:591), 1C11[PD-1]_H3.303_L3.152 from XENP26940 (SEQ ID NOS:642 and 1103), 1C11[PD-1]_H3.329_L3.220 from XENP28026 (SEQ ID NOS:708 and 1169), and 1C11[PD-1]_H3.328_L3.152 from XENP28652 (SEQ ID NOS:719 and 1180); and wherein said first variant and said second variant human IgG1 Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S :S267K/LS364K/E357Q; S364K/E357Q : L368D/K370S; L368D/K370S : S364K; L368E/K370S : S364K; T411E/K360E/Q362E : D401K; L368D/K370S : S364K/E357L; L368D/K370S :S364K/E357Q; and K370S : S364K/E357Q, respectively and according to EU numbering (see claim 1).
The ‘991 patent is drawn to the heterodimeric Fc fusion protein according to claim 1, wherein said variant IL-15 domain comprises the amino acid sequence of SEQ ID NO:2 (see claim 5). SEQ ID NO: 2 of the ‘991 patent shares 100% identity with instant SEQ ID NO: 2.
The ‘991 patent is drawn to the heterodimeric Fc fusion protein according to claim 1 wherein said variant IL-15 domain comprises the amino acid sequence of SEQ ID NO:2 and amino acid substitutions selected from the group consisting of N4D/N65D, D30N/N65D, and D30N/E64Q/N65D (see claim 6).
The difference between the instant claims and the ‘991 patent is that the ‘991 claims are also drawn to a method of using the claimed bifunctional heterodimeric protein (see claims 13-16). However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
As such, the ‘991 patent anticipates the present invention.
11,524,991 B2 and Atwell
Claims 58, 60-65, and 67-69 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 13-17 of U.S. Patent No. 11,524,991 B2 (patent date: 12/13/2022) in view of Atwell et al (J. Mol. Biol. (1997) 270, 26-35). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58, 60-65, and 67-69, the ‘991 patent is drawn to a PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein comprising: a) a first monomer comprising, from N- to C-terminal: i) an IL-15 receptor alpha (IL-15Rα) sushi domain; ii) a first domain linker, iii) a variant IL-15 domain, and iv) a second domain linker, and v) a first variant human IgG1 Fc domain comprising CH2-CH3; and b) a second monomer comprising, from N- to C-terminal: a heavy chain comprising VH-CH1-hinge-CH2-CH3, wherein said CH2-CH3 is a second human IgG1 variant Fc domain; and c) a light chain comprising VL-CL; wherein said VH and VL form an antigen binding domain that binds human PD-1 and have sequences selected from the pairs consisting of 1C11[PD-1]_H3L3 from XENP22553(SEQ ID NOS:186-187), 1C11[PD-1]_H3.234_L3.144 from XENP25806 (SEQ ID NOS:578-579), 1C11[PD-1]_H3.240_L3.148 from XENP25812 (SEQ ID NO:584), 1C11[PD- 1]_H3.241_L3.148 from XENP25813 (SEQ ID NO:585), 1C1 [PD-1]_H3.241_L3.92 from XENP25819 (SEQ ID NO:591), 1C11[PD-1]_H3.303_L3.152 from XENP26940 (SEQ ID NOS:642 and 1103), 1C11[PD-1]_H3.329_L3.220 from XENP28026 (SEQ ID NOS:708 and 1169), and 1C11[PD-1]_H3.328_L3.152 from XENP28652 (SEQ ID NOS:719 and 1180); and wherein said first variant and said second variant human IgG1 Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S :S267K/LS364K/E357Q; S364K/E357Q : L368D/K370S; L368D/K370S : S364K; L368E/K370S : S364K; T411E/K360E/Q362E : D401K; L368D/K370S : S364K/E357L; L368D/K370S :S364K/E357Q; and K370S : S364K/E357Q, respectively and according to EU numbering (see claim 1).
The ‘991 patent is drawn to the heterodimeric Fc fusion protein according to claim 1, wherein said variant IL-15 domain comprises the amino acid sequence of SEQ ID NO:2 (see claim 5). SEQ ID NO: 2 of the ‘991 patent shares 100% identity with instant SEQ ID NO: 2.
The ‘991 patent is drawn to the heterodimeric Fc fusion protein according to claim 1 wherein said variant IL-15 domain comprises the amino acid sequence of SEQ ID NO:2 and amino acid substitutions selected from the group consisting of N4D/N65D, D30N/N65D, and D30N/E64Q/N65D (see claim 6).
The difference between the instant claims and the ‘991 patent is that the ‘991 claims are also drawn to a method of using the claimed bifunctional heterodimeric protein (see claims 13-16) ), and the instant claims recite a composition comprising two variant Fc domains wherein one domain comprises the amino acid substitutions T366S/L368A/Y407V and the other domain comprises the amino acid substitution T366W (see instant claim 63). However, with respect to the method of using claim, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
Additionally, with respect to the variant Fc domain substitutions recited in instant claim 63, Atwell et al disclose of stable heterodimers from remodeling the domain interface of a homodimer using a phage display library (see Title). Atwell et al disclose that such knob-into-hole mutations promotes heterodimerization and enhances the formation of diabodies (see pg. 27, left column). Specifically, Atwell disclose of the heterodimer T366W-T366S:L368A:Y407V which is more stable than the heterodimer T366W-Y407A (see Table 1 and Fig. 3; pg. 29, left column).
As such, it would have been obvious to combine the teachings of the ‘991 patent and Atwell et al to develop the claimed invention. One would be motivated to do so as Atwell et al disclose that these specific knob-into-hole mutations developed a more stable heterodimer compared to other species at these amino acid positions. As such, one would have a reasonable expectation that modifying the Fc domains of a composition to comprise the mutations T366W-T366S:L368A:Y407V would increase the stability of the composition.
11,584,794 B2
Claims 58 and 60-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 8-9 of U.S. Patent No. 11,584,794 B2 (patent date: 02/21/2023). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58 and 60-61, the ‘794 patent is drawn to a bispecific heterodimeric protein comprising: a) a fusion protein comprising a first protein domain, a second protein domain, and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said second protein domain using a first domain linker, wherein said second protein domain is covalently attached to the N-terminus of said first Fc domain using a second domain linker, and wherein said first protein domain comprises a human IL-15Rα protein and said second protein domain comprises a variant of a human IL-15 protein of SEQ ID NO:2 comprising amino acid substitutions selected from the group consisting of (i) N4D/N65D, (ii) D30N/N65D, and (iii) D30N/E64Q/N65D; and b) an antibody fusion protein comprising a PD-1 antigen binding domain (ABD) and a second Fc domain, wherein said PD-1 antigen binding domain is covalently attached to the N-terminus of said second Fc domain, and said PD-1 antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment (see claims 1-2 and 8-9). SEQ ID NO: 2 of the ‘794 patent shares 100% identity with instant SEQ ID NO: 2.
As such, the ‘794 patent anticipates the present invention.
11,584,794 B2 and Atwell
Claims 58, 60-61, 63-64, and 67-68 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 8-9 of U.S. Patent No. 11,584,794 B2 (patent date: 02/21/2023) in view of Atwell et al (J. Mol. Biol. (1997) 270, 26-35). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58, 60-61, 63-64, and 67-68, the ‘794 patent is drawn to a bispecific heterodimeric protein comprising: a) a fusion protein comprising a first protein domain, a second protein domain, and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said second protein domain using a first domain linker, wherein said second protein domain is covalently attached to the N-terminus of said first Fc domain using a second domain linker, and wherein said first protein domain comprises a human IL-15Rα protein and said second protein domain comprises a variant of a human IL-15 protein of SEQ ID NO:2 comprising amino acid substitutions selected from the group consisting of (i) N4D/N65D, (ii) D30N/N65D, and (iii) D30N/E64Q/N65D; and b) an antibody fusion protein comprising a PD-1 antigen binding domain (ABD) and a second Fc domain, wherein said PD-1 antigen binding domain is covalently attached to the N-terminus of said second Fc domain, and said PD-1 antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment (see claims 1-2 and 8-9). SEQ ID NO: 2 of the ‘794 patent shares 100% identity with instant SEQ ID NO: 2.
The difference between the instant claims and the ‘794 claims is that the instant claims recite a composition comprising two variant Fc domains wherein one domain comprises the amino acid substitutions T366S/L368A/Y407V and the other domain comprises the amino acid substitution T366W (see instant claim 63). However, Atwell et al disclose of stable heterodimers from remodeling the domain interface of a homodimer using a phage display library (see Title). Atwell et al disclose that such knob-into-hole mutations promotes heterodimerization and enhances the formation of diabodies (see pg. 27, left column). Specifically, Atwell disclose of the heterodimer T366W-T366S:L368A:Y407V which is more stable than the heterodimer T366W-Y407A (see Table 1 and Fig. 3; pg. 29, left column).
As such, it would have been obvious to combine the teachings of the ‘794 patent and Atwell et al to develop the claimed invention. One would be motivated to do so as Atwell et al disclose that these specific knob-into-hole mutations developed a more stable heterodimer compared to other species at these amino acid positions. As such, one would have a reasonable expectation that modifying the Fc domains of a composition to comprise the mutations T366W-T366S:L368A:Y407V would increase the stability of the composition.
11,618,776 B2
Claims 58-62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11,618,776 B2 (patent date: 04/04/2023). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 58-62, the ‘776 patent is drawn to a targeted heterodimeric protein comprising: a) a first monomer comprising, from N-to C-terminal: i) a human IL-15Rα(sushi) domain; ii) a first domain linker; iii) a variant of human IL-15 comprising the amino acid sequence of SEQ ID NO:2 and one or more amino acid substitutions selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, and Q108E; iv) a second domain linker; and v) a first variant Fc domain; and b) a second monomer comprising, from N-to C-terminal: i) a NKG2D antigen binding domain (ABD); and ii) a second variant Fc domain, wherein said first Fc domain and said second Fc domain have a set of amino acid substitutions selected from the group consisting of: (i)S267K/L368D/K370S:S267K/S364K/E357Q; (ii) S364K/E357Q : L368D/K370S; (iii) L368D/K370S: S364K, (iv) L368E/K370S : S364K, (v) T411E/E360E/Q362E : D401K: (vi) L368D/K370S:S364K/E357Q, and (vii) K370S:S364K/E357Q, according to EU numbering; and wherein said NKG2D ABD comprises a variable heavy and light domain pair selected from the group consisting of MS[NKG2D]_H0L0 (variable domain of SEQ ID NO: 931 and variable domain of SEQ ID NO: 932), KYK-1.0[NKG2D]_H1L1(SEQ ID NO: 1042 and SEQ ID NO: 1043), KYK-2.0[NKG2D]_H0L0 (SEQ ID NO: 1044 and 1045), 1D7B4[NKG2D]_H1L1(SEQ ID NO: 1040 and SEQ ID NO: 1041), 6E5A7[NKG2D]_H0L0(SEQ ID NO: 1048 and SEQ ID NO: 1049), 6H7E7[NKG2D]_H0L0 (SEQ ID NO: 1050 and SEQ ID NO: 1051), 1 1B2D10[NKG2D] H0L0 (SEQ ID NO: 1046 and SEQ ID NO: 1047), 16F31 [NKG2D] H1L1(SEQ ID NO: 1054 and SEQ ID NO: 1055), mAb A[NKG2D]_HIL1(SEQ ID NO: 1060 and SEQ ID NO: 1062), mAb A[NKG2D]_H1L2 (SEQ ID NO: 1060 and SEQ ID NO: 1063), mAb A[NKG2D] H2L1 (SEQ ID NO: 1061 and SEQ ID NO: 1062), mAb A[NKG2D] H2L2 (SEQ ID NO: 1061 and SEQ ID NO: 1063), mAb B[NKG2D]H1L1(SEQ ID NO: 1064 and SEQ ID NO: 1067), mAb B[NKG2D]_H1L1.1(SEQ ID NO: 1064 and SEQ ID NO: 1068), mAb B[NKG2D] H1L2 (SEQ ID NO: 1064 and SEQ ID NO: 1069), mAb B[NKG2D] H2L1 (SEQ ID NO: 1065 and SEQ ID NO: 1067), mAb B[NKG2D]_H2LI.1(SEQ ID NO: 1065 and SEQ ID NO: 1068), mAb B[NKG2D]_H2L2(SEQID NO: 1065 and SEQ ID NO: 1069), mAb B[NKG2D]_H3L1 (SEQ ID NO: 1066 and SEQ ID NO: 1067), mAb B[NKG2D]_H3LI.1 (SEQ ID NO: 1066 and SEQ D NO: 1068), mAb B[NKG2D] H3L2 (SEQID NO: 1066 and SEQ ID NO: 1069), mAb C[NKG2D]HL1(SEQ ID NO: 1070 and SEQ ID NO: 1072), mAb C[NKG2D]_H1L2 (SEQ ID NO: 1070 and SEQ ID NO: 1073), mAb C[NKG2D]_H2L1(SEQ ID NO: 1071 and SEQ ID NO: 1072), mAb C[NKG2D] H2L2 (SEQID NO: 1071 and SEQ ID NO: 1073), mAb D[NKG2D] H1L1(SEQ ID NO: 1056 and SEQ ID NO: 1057), and mAb E[NKG2D]_H1L1(SEQ ID NO: 1052 and SEQ ID NO: 1053) (see claim 1). SEQ ID NO: 2 of the ‘776 patent shares 100% identity with instant SEQ ID NO: 2.
The ‘776 patent is drawn to the targeted heterodimeric protein of claim 1, wherein said variant of human IL-15 has amino acid substitutions selected from the group consisting of N4D/N65D, D30N/N65D, D30N/E64Q/N65D, N1D, N4D, D8N, D30N, D61N, E64Q, N65D, Q108E, N1D/D61N, N1D/E64Q, N4D, D61N, N4D/E64Q, D8N/D61N, D8N/E64Q, D61N/E64Q, E64Q/Q108E, N1D/N4D/D8N, D61N/E64Q/N65Q, N1D/D61N/E64Q/Q108E, N4D/D61N/E64Q/Q108E, N1D/N65D, D30N/Q108E, N65D/Q108E, E64Q/N65D, N1D/N4D/N65D, and N4D/D61N/N65D (see claim 2).
The ‘776 patent is drawn to the targeted heterodimeric protein of claim 1, where