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 present application filed on 03/23/2023 claims priority to a U.S. provisional patent application PRO 63/323,417 filed on 03/24/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/27/23 and 04/09/2025 was filed after the mailing date of the present application filed on 03/23/2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
Instant claims 1-41 as filed on 04/08/2025 are pending and are examined under the merits herein.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-15, 18-27, 29-32, 34-39 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/094122 A1, published on 06/26/2014 (herein referred to as Uger 2014) (listed in the IDS) and in view of WO 2020/242895 A1, published on 03/12/2020 (herein referred to as Gibbs 2020). The following references are used as teaching evidences: Yang et al., 2017 (Yang D et al. Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn. MAbs. 2017 Oct;9(7):1105-1117. doi: 10.1080/19420862.2017.1359455. Epub 2017 Aug 8); Dall’Acqua et al., 2006 (Dall'Acqua WF et al. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2006 Aug 18;281(33):23514-24. doi: 10.1074/jbc.M604292200. Epub 2006 Jun 21., listed in IDS) and WO 2013/109752 A1, published on 07/27/2013 (herein referred to as Ring 2013).
Regarding instant claim 1, Uger 2014 teaches SIRPα-Fc fusion polypeptides, wherein the fusion protein comprises a modified Fc domain that has increased anti-cancer effect (Uger, page 1, Field of Invention). While Uger 2014 teaches a SIRPα-Fc fusion polypeptides but does not teach that the Fc domain of the fusion polypeptide has increased binding affinity to FcRn, Gibbs 2020 teaches mutations in the Fc domain of a SIRPα-Fc fusion polypeptide that results in an increased affinity to FcRn (page 40, paragraph 0142, “Y at position 252, T at position 254, and Eat position 256 “ and “increased FcRn binding is advantageous in making the hybrid proteins of the present invention compete more strongly with endogenous lgG for binding to FcRn”). Gibbs 2020 further teaches that the YTE mutation promotes an increased serum half-life (page 41, paragraph 0143, “designated as a "YTE mutant" exhibits a four-fold increased half-life relative to wild type versions of the same antibody”). It would have been obvious to the person of ordinary skill in the art to combine the SIRPα as taught by Uger 2014 and the modified Fc domain as taught by Gibbs 2020 to increase binding affinity to FcRn and increase half-life of the fusion polypeptide. The increased half-life of the fusion polypeptide from the YTE mutation (M252Y- S254T-T256E) as taught by Gibbs 2020 is also recited in instant claim 2. Instant claims 18 by virtue of dependency 19 and 20; instant claim 22 and by virtue of dependency 23, 24, and 25; and instant claim 38 also recite a SIRPα-Fc fusion polypeptide with the YTE mutation (M252Y- S254T-T256E) on the Fc domain which Uger 2014 and Gibbs 2020 teach.
Regarding instant claim 8, Uger 2014 teaches that the fusion polypeptide decreases the toxicity of the fusion polypeptide (page 27, paragraph 1, line 20, "single-domain SIRPαFcs would be less likely to cause RBC toxicity in vivo").
Regarding instant claim 26, Gibbs 2020 teaches that the Fc domain of the SIRPα-Fc can have any of the human isotypes, IgG1, IgG2, IgG3, and IgG4 (page 23, paragraph 0082 “lgG1, lgG2, lgG3, lgG4, lgA, lgD, lgE, lgM or fragment or combination thereof”).
Instant claims 3, 4, 5, 6, 7, 9, 12, 13, 14, and 15, , recite functional features of the SIRPα-Fc fusion polypeptide that contains the YTE mutation (M252Y- S254T-T256E) on the Fc domain which Uger 2014 and Gibbs 2020 teach. As evidentiary reference, Yang et al., 2017 further teaches the YTE mutation on the Fc domain can lead to increased serum clearance time as recited in instant claim 3, a lower therapeutic dosage as recited in instant claim 6 and dosing frequency as recited in instant claim 7 and increase endocytosis and degradation of the CD47 protein as recited in instant claim 13 and 14 (page 1105, column 2, paragraph 1, “This allows the antigen-free antibody to be recycled back to the cell surface by neonatal Fc receptor (FcRn), while the dissociated antigen is trafficked to the lysosome for degradation. By repeating this cycle of antigen binding in plasma and dissociating in endosomes, the half-life of pH-dependent antibodies is extended, leading to increased target exposure and greater antigen clearance, thus enabling lower therapeutic dosage or dosing frequency” and page 1109, column 1, paragraph 1, “Clearance of YTE variants was equal to or up to 5 times slower than their respective WT variants). Yang et al., 2017 discloses that the dose reduction may be beneficial for greater patient compliance and treatment cost-effectiveness (page 1105, column 2, line 1 and page 1114, column 1, paragraph 2 “can effectively neutralize targets with high baseline concentration or rapid turnover in vivo at doses that are amenable for once monthly subcutaneous dosing, thereby increasing doing convenience for patients”).
Regarding instant claim 4, 12, and 15, Uger 2014 teaches the SIRPα fusion polypeptide wherein the modified Fc domain improves binding affinity of the fusion polypeptide to a CD47 protein and increases interaction of the fusion polypeptide with a cell expressing a CD47 protein (page 25, line 3-4, “fusion proteins showed very similar binding profiles, producing nearly identical affinity binding (Kd) values (2.3-2.4 nM)” and page 23, line 28, “For the direct binding assay, CD47+ human Jurkat cells were incubated with the various concentrations (as indicated) of hSIRPαFc proteins on ice for 1 hour” and page 24, line 5-6, “in the direct binding assay, TTI-616 bound with 10-fold higher affinity than TTI-602 (EC50 values: 13.4 nM versus 139 nM)”). Uger 2014 teaches the CD47 protein is human or mouse (page 2, paragraph 6, line 35, "binding of SIRPα fusions designated TTI-602 and TTI-616 to human CD47 using a direct binding assay") as recited in claim 15.
While Uger 2014 does not teach the modified Fc domain improves the binding affinity to the CD47 protein or interaction with cell expression of CD47, the applicant’s specification and instant claims 19, 20, 23, 24, 25, and 38 which are also dependent on instant claim 1, teach the M252Y-S254T-T256E (YTE mutation) (Specification, page 13, paragraph 0062-0063) can result from the Fc domain effects as recited in the instant claims 4 and 12 (see specifications paragraphs 0080-0081). As such, Gibbs 2020 teach the mutation YTE as described above and it would have been obvious to the person of ordinary skill in the art to expect a fusion polypeptide with the same properties when incorporating the mutations as listed and described above. See MPEP § 2112.2 "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Regarding instant claim 5, Uger 2014 teaches the binding of the SIRPα fusion polypeptide to human erythrocytes is lower than other CD45 antibodies (page 28, paragraph 3, line 27, “As shown in Figure 7B, all four antibodies bound human RBCs at dramatically higher levels than SIRPαFc”). Per applicant’s disclosure, the Ec50 value measured is the amount of construct bound to red blood cells in vitro (page 30, paragraph 0119, “The Ec50 value measured for the two constructs was the amount of construct bound to red blood cells in vitro. As shown in FIGS. 3, at half-maximal binding of Construct 67, which contains the YTE mutation, was equal or lower than that of Construct 50.”) As such, the Ec50 values here are interpreted as the half maximal binding of the fusion polypeptide to the red blood cell or erythrocyte as specified in the disclosure.
Even though Uger 2014 does not teach the modified Fc domain reduces the EC50 of a SIRPα fusion polypeptide, the applicant’s specification and instant claims 19, 20, 23, 24, 25, and 38 which are also dependent on instant claim 1 teach M252Y-S254T-T256E (YTE mutation) (Specification, page 13, paragraph 0062-0063) can result from the Fc domain effects as recited in the instant claim 5 (see Specification, paragraph 0075). As such, Gibbs 2020 teach the fusion polypeptide with the SIRPα domain and a modified Fc domain with the mutation YTE as described above and it would have been obvious to the person of ordinary skill in the art to expect a fusion polypeptide with the same properties when incorporating the mutations as listed and described above. See MPEP § 2112.2 "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Regarding instant claim 9, Gibbs 2020 discloses that the YTE mutation in the fusion polypeptide reduce ADCC function (page 40, paragraph 0142, "Also numerous mutations are known for reducing any of ADCC, ADP or CMC."). As evidentiary teaching, Dall’Acqua et al., 2006 discloses YTE mutations in the Fc domain reduces ADCC (page 23523, column 2, “YTE significantly reduced the binding of MEDI-522 to human FcγRIIIA (F158 allotype) as well as its ADCC activity”).
Fc domain modifications on the fusion polypeptide that have increased effector functions
Regarding instant claims 10, 11, and 23, Gibbs 2020 teaches the mutations on the Fc domain include combinations of G236A, S239D and I322E as recited in instant claim 23 (page 41, paragraph 0114, “Fc domain of the antibody comprises DEA modifications (i.e., S239D, I332E and G236A by EU numbering) in the Fc region”). Gibbs further teaches that these modifications increase effector activity such as antibody-dependent cellular phagocytosis as recited in instant claims 10 and 11 (page 41, paragraph 0114 and page, 8, paragraph 0040). See MPEP § 2112.2 "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Fc domain sequences
Regarding instant claims 22, 23, 24, 25, and 30, Uger 2014 teaches the SEQ ID NO: 6 which encodes for the IgG1 Fc domain (page 7, paragraph “human IgG1 designated P01857, and in a specific embodiment has the amino acid sequence that incorporates the lower hinge-CH2-CH3 region thereof i.e., SEQ ID NO: 2”).
Regarding instant claims 18, 19, 20, and 30, Uger 2014 teaches SEQ ID NO: 8 which corresponds to an IgG4 Fc domain with the S228P mutation (page 7, paragraph 2-3, “IgG4 Fc, the Fc incorporates at least the S228P mutation, and has the amino acid sequence set out below and referenced herein as SEQ ID NO: 24:”) and SEQ ID NO: 7 which corresponds to a wild type IgG4 Fc domain (page 6, paragraph 5-6, line 32-36, “Fc region is based on the amino acid sequence of a human IgG4 set out as P01861 in UniProtKB/Swiss-Prot, residues 99-327, and has the amino acid sequence shown below and referenced herein as SEQ ID No: 23”).
Regarding instant claims 21, 31, 30, and 38, Uger 2014 teaches SEQ ID NO: 9 encodes for a modified IgG4 Fc domain containing the S228P mutation (page 7, paragraph 2-3, “SEQ ID NO: 24”) but Uger 2014 does not teach the mutation M252Y, S254T, T256E in SEQ ID NO: 9 and as recited in claim 38. Gibbs 2020 teaches the YTE mutation in the Fc domain to increase half-life of the fusion polypeptide as described above.
Regarding instant claim 37, Uger 2014 teaches the nucleotide sequence corresponding to the fusion polypeptide (page 8, line 18-21, SEQ ID NO: 6; and page 17, paragraph 4, line 19, "Accordingly, the present invention also provides polynucleotides, including DNA and RNA, which upon expression yield a secretable form of the single chain polypeptides that make up the present fusion proteins.").
SIRPα sequences
Uger 2014 and Gibbs 2020 teach a SIRPα-Fc fusion polypeptide with a modified Fc domain. Furthermore, Uger 2014 teaches the SEQ ID NO: 1 which encodes for the wild type SIRPα D1 domain and is recited in instant claims 27, 28, 30, and 40 (page 5, line 9-10, SEQ ID NO: 22) and SEQ ID NO: 2 which encodes for the mutated SIRPα D1 domain (the CV1 variant) recited in instant claim 29 and 31 (page 19, Table 1, “TTI-724, hSIRPα V2, 1 domain (118 aa) CV1 mutations"). As evidentiary reference, Ring 2013 teaches that the SEQ ID NO: 2 in the instant application is the high affinity SIRPα D1 CV1 variant (page 32, paragraph 00134, “the CV1 sequence” of “SEQ ID NO: 10:”).
Regarding instant claim 39, Uger 2014 and Gibbs 2020 teach the SIRPα-Fc fusion polypeptide as described above, comprising the SIRPα domain and modified Fc domain comprising one or more amino acid modifications relative to wild-type Fc domain, wherein the wild-type Fc domain is a human IgG4 Fc domain, and wherein the one or more amino acid modifications decrease effector functions relative to the wild type Fc domain.
Methods of using SIRPα-Fc fusion polypeptide
Regarding instant claim 32, Uger 2014 teaches a method of treating a disease comprising administering a fusion polypeptide to the subject, wherein the fusion polypeptide comprises: (i) a SIRPα domain and (ii) the modified IgG1 or IgG4 Fc domain (page 2, paragraph 4, line 23, "the method comprising administering to the subject an amount of the SIRPαFc fusion protein effective to inhibit the growth and/or proliferation of the disease cells).
Regarding instant claim 34, Uger 2014 teaches the fusion polypeptide is administered subcutaneously (page 10, paragraph 4, line 30 "The SIRPα Fc fusion protein may be administered to the subject through any of the routes established for protein delivery, in particular intravenous, intradermal and subcutaneous injection").
Regarding instant claim 35 and 36, Uger 2014 teaches a method of increasing phagocytosis by macrophages comprising contacting a population of macrophages with the fusion polypeptide of claim 1 (page 25, paragraph 2, line 30 "TTI-621 and TTI-622 exhibit similar pro-phagocytosis activity, whereas TTI-616 is clearly weaker (this is particularly evident at the 10nM dose). This indicates either a wild type IgG4 or IgG1 Fc region is required for maximal SIRPαFc-triggered tumor cell killing by macrophages" and see Figure 6 showing higher phagocytic index levels of the fusion polypeptides compared to wild-type and control) and that the macrophage is a human macrophage (page 3, paragraph 3, line 25 “The AML-2 cells and macrophages were then co-cultured for 2 hours, and the macrophages were stained with wheat germ agglutinin Alexa Fluor® 555 conjugate and analyzed by confocal microscopy”).
Claims 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Uger 2014 and Gibbs 2020 as applied to claim 1 above and further in view of Yang et al., 2018 (Yang C et al. Engineering of Fc Fragments with Optimized Physicochemical Properties Implying Improvement of Clinical Potentials for Fc-Based Therapeutics. Front Immunol. 2018 Jan 8;8:1860. doi: 10.3389/fimmu.2017.01860).
While Uger 2014 and Gibbs 2020 teach the SIRPα-Fc YTE fusion polypeptide as described above, they do not teach that the SIRPα-Fc YTE fusion polypeptide has reduced aggregation and improved purification from the Fc modification. Yang et al., 2018 teaches strategies on engineering Fc fragments to improve stability and aggregation resistance of Fc fusion proteins that contain the “YTE” mutation (page 7, column 2, paragraph 1, “To compensate the decreased physiochemical properties, several mutants were designed with different combinations of mutations with the strategies including substitution of charged residues (e.g., E) by uncharged residues (e.g., Q)”). Yang et al., 2018 also teaches the importance of stability of the fusion polypeptide which can affect protein aggregation and purification (page 3, column 2, paragraph 2, “For example, aggregation may lead to not only loss of activity but also immune response, and negatively impact on many production processes including expression, purification, and formulation” and “In many cases, increased stability can also lead to less aggregation propensity”). It would have been obvious to the person of ordinary skill in the art to add mutation strategies taught by Yang et al., 2018 to prevent loss of immune responses and slow down production processes from the YTE mutation as taught by Gibbs 2020.
Claims 28 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Uger 2014 (cited previously) and Gibbs 2020 (cited previously) as applied to claim 1 above, and further in view of Ring 2013 (cited previously) and Hatherley et al., 2014 (Hatherley D et al. Polymorphisms in the human inhibitory signal-regulatory protein α do not affect binding to its ligand CD47. J Biol Chem. 2014 Apr 4;289(14):10024-8. doi: 10.1074/jbc.M114.550558. Epub 2014 Feb 18).
While Uger 2014 and Gibbs 2020 teach the SIRPα-Fc fusion polypeptide with the modified Fc domain and the CV1 variant of SIRPα as described above, Uger 2014 and Gibbs 2020 not teach the amino acid substitutions of SIRPα domain as recited in instant claims 28 and 40. Ring 2013 teaches amino acid substitutions in the SIRPα domain V6I, V27I, I31F, E47V, K53R, E54Q, H56P, S66T, V29I as recited in the instant claims 28 and 40 (page 49, Figure 1C, and see Figure 1 of the office action). Ring further discloses that dissociation constants Kd as low as 34.0 μM and decay half-lives (t ½) as long as 44 minutes of the mutant SIRPα compared to 0.3-0.5 μM Kd and 1 .8 seconds (t ½) for wild-type SIRPα (page 32, paragraph 00133).
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Figure 1. Table of AA substitutions in SIRPα domain (Ring 2013, page 49, Figure 1C)
It would have been obvious to the person of ordinary skill in the art to incorporate the amino acid substitutions in the SIRPα domain to increase affinity to CD47 and half-life of the fusion polypeptide as taught by Ring 2013.
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Figure 2. Sequence alignment of variants of SIRPα based on structural alignment of v1 and v2 (Hatherley et al., 2014, page 10025, Figure 1).
Further, Uger 2014 and Gibbs 2020 do not teach mutations S14L, S20T, I22T, H24R, A45G, E70N, and S77R as recited in instant claim 28 and 40. These mutations are drawn to the polymorphisms of the SIRPα variants as taught by Hatherley et al., 2014 (page 10025, figure 1 showing the residues that differ between variant 1 and 2 (blue and green)). Hatherley et al. teaches that the amino acid residues have similar binding affinity because they are surface exposed and distant from binding site and that they may have been selected for other purposes such as evasion of pathogens (page 10024, column 1, abstract). It would have been obvious to the person of ordinary skill in the art to include variants of SIRPα to increase breath of coverage of the SIRPα variants as taught by Hatherley et al., 2014.
Claims 33 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Uger 2014 (cited previously) and Gibbs 2020 (cited previously) as applied to claims 32 and 1 above and further in view of Kojima et al., 2016 (Kojima Y, et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature. 2016 Aug 4;536(7614):86-90. doi: 10.1038/nature18935. Epub 2016 Jul 20; listed in IDS).
While Uger 2014 and Gibbs 2020 teach the SIRPα-Fc fusion polypeptide as described in claim 1 and method of treating a disease as described in claim 32, Uger 2014 and Gibbs do not teach that the disease is cardiovascular disease as recited in instant claims 33 and 41.
Kojima et al., 2016 discloses CD47 expression is implicated in atherosclerosis and cancer (page 4, paragraph 4, "The finding that CD47 expression is pathologically upregulated in both cancer and cardiovascular disease suggests a commonality between these two conditions") and suggests a mechanism of inhibiting the SIRPα-CD47 signaling as a therapeutic target (page 41, Figure 4h, right figure illustrating the inhibition (red) of the SIRPα-CD47 signaling to reduce cardiovascular disease).
It would have been obvious to the person of ordinary skill in the art to use the link between CD47 expression and cardiovascular disease as taught by Kojima et al., 2016 to develop SIRPα therapeutics studied in cancer to inhibit CD47 and treat cardiovascular disease.
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.
Claim 1-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 3, 4, 7, 9, 10, 11, 12, 14, 16, 18, 21, 22, 24, 31, 37, 45, and 48 of copending Application No. 18/849,291 filed on 09/20/2024 in view of Uger 2014 (cited previously); Gibbs 2020 (cited previously); and Dall’Acqua et al., 2006 (cited previously). The examiner notes that although currently the instant application does not have inventor or assignee in common with the co-pending application, the instant application claims priority to provisional 63/323432 filed on 03/24/2022 which names common inventors (Jens-Peter VOLKMER, Recklinghausen, GERMANY from instant application and Jie LIU, Palo Alto, CA, UNITED STATES and Irving L. WEISSMAN, Stanford, CA, UNITED STATES for the copending application) and assignee (Bitterroot Bio, Inc., Palo Alto, CA, of the instant application and The Board of Trustees of the Leland Stanford Junior University, Stanford, CA of the copending application), and therefore the rejection is proper. Examiner requests clarification as to the inventorship of the material that is common and obvious between the claim sets.
Regarding instant claims 1-31, 38, 39, and 40, App’291 claims 1, 2, 3, 7, 9, 10, 11, 12, 14, and 16 recite a SIRPα fusion polypeptide comprising a SIRPα domain and a modified Fc domain.
Regarding instant claims 27, 28, 29, 30, 31, and 40, App’291 claim 4 recites the multivalent SIRPα fusion polypeptide of claim 1, wherein one or more SIRPα domains comprise the amino acid SEQ ID NO: 1 or SEQ ID NO:2 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, optionally wherein one or more SIRPα domains comprise one or more of the following mutations relative to SEQ ID NO: 1:V61, S14L, S20T, 122T, H24R, V271, 131F, A45G, E47V, K53R, E54Q, H56P, S66T, E70N, S77R, V921, and/or a duplication of the D100 residue.
Regarding instant claims 26, App’291 claim 18 recites the multivalent SIRPα fusion polypeptide of claim 1, wherein the Fc domain is a human IgG1, IgG2, IgG3, or IgG4 Fc region or comprises at least one mutation relative to a wild-type human IgG1, IgG2, IgG3, or IgG4 Fc region.
However, App’291 claims do not recite specific amino acid mutations in the Fc domains of the SIRPα-Fc fusion polypeptide as recited in instant claims 19, 20, 22, 23, 24, 25, and 38.
Regarding instant claims 19, 20, 22, 24, 25 and 38, Gibbs 2020 teaches the mutations in the Fc domain of the SIRPα-Fc fusion polypeptide (page 41, paragraph 0143, “M428L and N434S ("LS") substitutions can increase the pharmacokinetic half-life of the multi-specific antigen binding molecule”, “CD3-targeting heavy chain and the HIV antigen-targeting heavy chain comprise T250Q and M428L (EU numbering) mutation”, “the Fc region comprise H433K and N434F”) and further teaches M252Y, S254T, T256E amino acid substitutions or the YTE mutation (page 41, paragraph 0143, “methionine to tyrosine substitution at position 254 (M252Y) a serine to threonine substitution at position 254 (S254T), and a threonine to glutamic acid substitution at position 256 (T256E)” and “This type of mutant, designated as a "YTE mutant" exhibits a four-fold increased half-life relative to wildtype versions of the same antibody”). Gibbs 2020 teaches that the amino acid substitutions can promote an increased serum half-life of the anti-binding molecule (page 41, paragraph 0143, “promote an increased serum half-life of the anti- binding molecule”). It would have been obvious to the person of ordinary skill in the art to include amino acid modifications as taught by Gibbs 2020 that would improve the half-life of the fusion polypeptide.
Regarding instant claim 23, Gibbs 2020 teaches the mutations include combinations of G236A, S239D and I322E (page 41, paragraph 0114, “In some embodiments, the Fc region or Fc domain of the antibody comprises DEAL modifications (i.e., S239D, I332E, G236A and A330L”). Gibbs further teaches that the modifications increase effector activity such as antibody-dependent cellular phagocytosis (page 41, paragraph 0114 and page, 8, paragraph 0040). It would have been obvious to the person of ordinary skill in the art to include amino acid substitutions in the Fc domain that enhance effector function in the fusion polypeptide as taught by Gibbs 2020 and Uger 2014.
Regarding instant claims 18, 21, 22, 27, 29, 30, 31, and 40, App’291 claim 21, recites the multivalent SIRPα fusion polypeptide of claim 1, wherein he SIRPα domain comprises either of SEQ ID NOS: 1 or 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the Fc domain comprises any of SEQ ID NOS:6-8, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.
Regarding instant claim 27, 28, 30, and 40, App’291 claim 24 recites the multivalent SIRPα fusion polypeptides of claim 1, comprising any of SEQ ID NOS: 10-18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto (24). SEQ ID NO: 10 and 16 are 91.7% query match to instant SEQ ID NO: 1 as recited in instant claims 27, 28, 30, and 40.
Regarding instant claims 3, 6, 7, 10, 11, 16, and 17, App’291 claim 31 recites the multivalent SIRPα fusion polypeptide of claim 1, wherein the multivalent SIRPα fusion polypeptide exhibits a slower blood clearance; is effective at a lower dose in a subject, is effective at a lower dosage frequency, provides increased phagocytosis in a phagocytosis assay, is associated with comparable red blood cell in vitro agglutination, or exhibits comparable expression purity.
However, App’291 does not recite the modified Fc domain in the fusion polypeptide increases FcRn binding affinity and increases half-life of the fusion polypeptide as recited in instant claim 1 and 2. As described above, Gibbs 2020 teach that YTE mutations in the Fc domain of the fusion polypeptide increase binding affinity to FcRn and extend the half-life of the fusion polypeptide (Gibbs 2020, page 41, paragraph 0143). It would have been obvious to the person of ordinary skill in the art to combine the YTE mutation of Gibbs 2020 in the Fc domain to extend the half-live of the fusion polypeptide.
Regarding instant claims 9, 13, and 14, App’291 claim 21 does not recite the modified Fc domain in the fusion polypeptide increases endocytosis and degradation of the CD47 protein. Yang et al., 2017 further teaches the Fc modification YTE increases binding affinity to FcRn which in turn increase endocytosis and degradation of the CD47 protein as recited in instant claim 13 and 14 (page 1105, column 2, paragraph 1, “This allows the antigen-free antibody to be recycled back to the cell surface by neonatal Fc receptor (FcRn), while the dissociated antigen is trafficked to the lysosome for degradation” and page 1109, column 1, paragraph 1, “Clearance of YTE variants was equal to or up to 5 times slower than their respective WT variants). Yang et al., 2017 discloses that the dose reduction may be beneficial for greater patient compliance and treatment cost-effectiveness (page 1105, column 2, line 1 and page 1114, column 1, paragraph 2 “can effectively neutralize targets with high baseline concentration or rapid turnover in vivo at doses that are amenable for once monthly subcutaneous dosing, thereby increasing doing convenience for patients”). And in further view of Yang et al., 2018, Dall’Acqua et al., 2006 discloses YTE mutations in the Fc domain reduces ADCC (page 23523, column 2, “YTE significantly reduced the binding of MEDI-522 to human FcγRIIIA (F158 allotype) as well as its ADCC activity”) as recited in instant claim 9.
It would have been obvious to the person of ordinary skill in the art to modify the Fc domain of the fusion polypeptide with YTE mutation to increase half-life, increase endocytosis and degradation of CD47 protein which improves greater patient compliance and treatment cost-effectiveness taught by Yang et al., 2017 and that the expect that the YTE mutation in the Fc domain decreases the ADCC as taught by Dall’Acqua et al., 2006.
Regarding instant claims 4, 12, and 15, App’291 does not teach the SIRPα fusion polypeptide improves the binding affinity of the CD47 protein and increases interaction of the fusion polypeptide with a cell expressing a CD47 protein. Uger 2014 teaches the SIRPα fusion polypeptide with improved binding affinity of the fusion polypeptide to a CD47 protein and increased interaction of the fusion polypeptide with a cell expressing a CD47 protein (page 25, line 3-4, “fusion proteins showed very similar binding profiles, producing nearly identical affinity binding (Kd) values (2.3-2.4 nM)” and page 23, line 28, “For the direct binding assay, CD47+ human Jurkat cells were incubated with the various concentrations (as indicated) of hSIRPαFc proteins on ice for 1 hour” and page 24, line 5-6, “in the direct binding assay, TTI-616 bound with 10-fold higher affinity than TTI-602 (EC50 values: 13.4 nM versus 139 nM)”). Uger 2014 further teaches high affinity SIRPα domains that bind with higher affinity to CD47 for optimal inhibition of the CD47/SIRPα axis and thus promote phagocytosis (page 1, line 16 and line 26). It would have been obvious to the person of ordinary skill in the art to include high affinity SIRPα domains in the fusion polypeptide to increase binding affinity to the CD47 target for optimal inhibition and phagocytosis as taught by Uger 2014.
Regarding instant claims 5 and 8, App’291 does not teach the fusion SIRPα fusion polypeptide decreases toxicity and lowers Ec50 of the fusion polypeptide. Uger 2014 teaches the SIRPα domain in the fusion polypeptide decreases the toxicity of the fusion polypeptide (page 27, paragraph 1, line 20, "single-domain SIRPαFcs would be less likely to cause RBC toxicity in vivo") which allows them to be inhibitors (page 1, line 33 “SIRPαFc fusion proteins also demonstrate negligible CD47 agonism, permitting them to act as a dedicated inhibitor of SIRPα-mediated signaling in vivo.”). It would have been obvious to the person of ordinary skill in the art to include the SIRPα domains as taught by Uger 2014 to reduce toxicity of the fusion polypeptide and act as antagonists. Further, Uger 2014 teaches a lowered Ec50 of the fusion polypeptide (Ec50 as defined in the instant application’s specification described previously) (page 28, paragraph 3, line 27, “As shown in Figure 7B, all four antibodies bound human RBCs at dramatically higher levels than SIRPαFc”). It would have been obvious to the person of ordinary skill in the art to expect reasonable lower binding to RBCs using the high affinity SIRPα domains as taught by Uger 2014 to allow better inhibitory activity as an antagonist.
Regarding instant claims 32, 33, 34, and 41, App’291 claim 37 recites a method of treating a disease or disorder in a subject in need thereof, comprising administering a multivalent SIRPα fusion polypeptide of claim 1 to the subject, wherein the disease or disorder is selected from the group consisting of a cardiovascular disease, a cancer, fibrosis, an infectious disease, a hematological disease, and a neurological disease.
However, App’291 does not recite subcutaneous administration as recited in instant claim 34. Uger 2014 teaches a subcutaneous administration of the fusion polypeptide (page 10, line 30, “fusion polypeptide may be administered to the subject through any of the routes established for protein delivery, in particular […] subcutaneous injection”). It would have been obvious to the person of ordinary skill in the art to use the administration routes that are already established for protein delivery as suggested by Uger 2014.
Regarding instant claim 35 and 36, App’291 claim 45 recites a method of inducing increased phagocytosis in macrophages comprising contacting a population of macrophages with multivalent SIRPα fusion polypeptide of claim 1.
Regarding instant claim 37, App’291 claim 48 recites a nucleotide encoding the SIRPα fusion polypeptide.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647
/JOANNE HAMA/ Supervisory Patent Examiner, Art Unit 1647