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 .
Claims Status
Claims 1, 4-5, 28, 60, and 100 are amended.
Claims 14-19 and 26-27 are cancelled.
Claims 1, 3-5, 28, 60, 100-101, 104, 107, and 110 are pending and are examined on the merits.
Rejections withdrawn
Claims 14-19 and 26-27 are cancelled, rendering all previous rejections moot.
Rejection of claims 28 and 60 under 35 U.S.C. §112(b) are withdrawn with Applicant amendment of the claims.
Rejection of claims 1, 3-5, 28, 60, 100-101, 104, 107, and 110 under 35 U.S.C. §112(a) are withdrawn with Applicant amendment of the claims.
Rejection of claims 1, 3-5, 100, 104, 107, and 110 under 35 U.S.C. §102 are withdrawn with Applicant amendment of claims necessitating new rejections.
Rejection of claims 28, 60, and 101 are withdrawn with Applicant amendment of claims necessitating new rejections.
New Rejections Necessitated by Claims Amendments
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3-5, 28, 60, 100-101, 104, 107, and 110 are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. 2017 (WO 2017/205014 A1; PTO-892), and further in view of Harms et al. 2013 (U.S. Patent No. 9,458,245B2, Priority to March 6, 2013; hereinafter Harms).
Regarding instant claims 1, 3-5, and 100, Yan teaches compositions (e.g. vectors, host cells, nucleic acids, etc.) for expressing a mixture of at least two antibodies from a single cell wherein heavy chain (HC) Fc domains of at least one of the antibodies comprises partner-directing mutations (i.e. an “antibody chain assembly promoter”) favoring specific HC-HC pairing and disfavoring heterodimerization with an unmodified Fc domain (Pg. 36-37; Abstract; Fig. 1). Yan further teaches that examples of an “alteration that disfavors heterodimers” include substitutions of charged residues or steric protuberances/knobs, and that such substitutions can be made at “domain interface residues” or contacting residues within the human IgG CH3-CH3 interface (Pg. 37-38, § “alteration that disfavors heterodimers”; Table 4). Yan also teaches at least one antibody in the mixture comprises a pair of mutations, wherein the mutations comprise K409E on the first heavy chain and D399K on the second heavy chain (Fig. 12).
Regarding instant claims 104 and 107, Yan teaches that nucleic acids encoding the mixture of antibodies can be carried on a viral vector or encased in liposomes, which in turn can be administered to a patient or directly to a tumor in the patient in order to treat a disease (pg. 66, lines 3-11; Pg. 68, lines 1-13). Regarding instant claim 107, administering a viral vector or liposome containing the nucleic acids encoding for the mixture of antibodies would inherently result in “expressing” the antibodies “in an organ or tissue” in the subject.
Regarding instant claim 110, Yan teaches mixtures of antibodies can be produced by a host cell in vitro via a method comprising “introducing DNA encoding the mixtures of antibodies described herein into host cells, culturing the host cells, and recovering the mixture of antibodies from the cell mass or culture medium” (Pg. 50, § “Mixtures of Antibodies and Methods of Producing Them”).
However, Yan does not teach the particular substitutions within the claimed assembly promoter pairs “PP3”, wherein the HC-A and the antibody HC-B comprise HC-HC-PP3: S354C, T366W on HC-A; and Y349C, T366S, L358A, Y407V on HC-B according to EU numbering of the CH3 domain.
The deficiency is resolved by Harms.
Regarding instant claims 28 and 60, Harms teaches tandem Fc antibodies (“TFcAs) which comprise one or at least two binding sites that specifically bind to one or more cell surface receptors, wherein the binding sites are connected through a TFc comprising a first Fc region and a second Fc region wherein the first and the second Fc regions are linked through a TFc linker to form a contiguous polypeptide and dimerize to form an Fc dimer (page 1, Abstract), wherein either or both of the first CH3 domain and the second CH3 domain of a TFc may comprise 1) an Association Enhancing Modification, or “AEM”, wherein one or more amino acid modifications enhance or stabilize the binding between the first and second Fc regions; and/or 2) a “DiS” modification wherein a cysteine is added as an insertion or replacement in which the cysteine forms a disulfide bond with a cysteine in the other Fc region (page 152, column 4, last paragraph – page 153, column, 5, line 5). Furthermore, Harms teaches exemplary combinations of AEMs and DiSs that are made in the CH3 domains to favor the association of CH3 domains or Fc regions as disclosed in Tables 5 and 6, wherein the “AEM1+DiS1” pair,
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comprise a Y349C/T366S/L368A/Y407V in one of the CH3 domains and a S354C/T366W in the other CH3 domain comprising the amino acid sequence SEQ ID NOs:76 and 80, which are identical to the instantly claimed amino acid sequences instant SEQ ID NOs:105 and 104, respectively, comprising the instantly claimed HC-HC-PP3 promoter pair (sequence alignment shown below; page 182, Table 6).
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Regarding instant claim 101, Harms teaches kits comprising one or more TFcAs, wherein the kits may include a label indicating the intended use of the contents of the kit and optionally including instructions for use of the kit in treating a disease associated with a target of TFcA-dependent signaling (page 196, column 91, third paragraph). Finally, regarding instant claim 110, Harms discloses nucleic acid molecules comprising at least one coding sequence, said at least one coding sequence encoding a heavy chain or a light chain of a TFcA. Also provided are vectors comprising one or more nucleic acid molecules encoding the TFcA. Further provided are cells, e.g., host cells or isolated cells, comprising one or more vectors and/or nucleic acid molecules encoding the TFcA. A cell may comprise a nucleic acid molecule encoding the heavy chain of a TFcA and a nucleic acid molecule encoding the light chain of the TFcA (page 156, column 11, third paragraph).
Regarding instant claims 1, 3-5, 28, 60, and 100, it would have been obvious for a person having ordinary skill in the art at the time of filing to substitute the paired K409E and D399K fc mutations taught by Yan with the paired S354C/T366W and Y349C/T366S/L368A/Y407V Fc mutations of Harms to arrive at a composition for expressing a mixture of antibodies wherein one of said antibodies comprises a HC-HC assembly promoter pair identical to instantly claimed “PP3”. The skilled artisan would have been motivated to employ the Fc mutations taught by Harms owing to their enhanced or stabilized binding between the first and second Fc regions. This is obvious because, Yan teaches compositions for expressing a mixture of at least two antibodies from a single cell wherein heavy chain (HC) Fc domains of at least one of the antibodies comprises partner-directing mutations (i.e. an “antibody chain assembly promoter”) favoring specific HC-HC pairing and disfavoring heterodimerization with an unmodified Fc domain, wherein at least one antibody in the mixture comprises a pair of mutations, wherein the mutations comprise K409E on the first heavy chain and D399K on the second heavy chain, and Harms teaches compositions comprising TFcAs wherein the binding sites are connected through a TFc comprising a first Fc region and a second Fc region, wherein the first and the second Fc regions comprise the Y349C/T366S/L368A/Y407V and S354C/T366W Fc mutations in the CH3 domains comprising the amino acid sequence SEQ ID NOs:76 and 80, which are identical to the instantly claimed amino acid sequences instant SEQ ID NOs:105 and 104, respectively, of the HC-HC-PP3 promoter pair. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant composition for expression of at least two antibodies in a cell comprising nucleic acid sequence A comprising at least one coding sequence encoding at least one antibody HC-A, and nucleic acid sequence B comprising at least one coding sequence encoding at least one antibody HC-B, wherein the at least one coding sequence of nucleic acid sequence A and/or B encodes at least one antibody chain assembly promoter, wherein the antibody HC-A and HC-B comprise the HC-HC-assembly promoter pair HC-HC-PP3.
Regarding instant claim 101, it would have been obvious for a person having ordinary skill in the art at the time of filing to substitute the TFcAs used in the kits comprising one or more TFcAs to treat a disorder associated with a target of TFcA-dependent signaling as taught by Harms with the composition, e.g. nucleic acids, for expressing the mixture of antibodies wherein one of said antibodies comprises a HC-HC assembly promoter pair comprising S354C/T366W and Y349C/T366S/L368A/Y407V Fc mutations identical to instantly claimed promoter pair “PP3” as taught by the combined teachings of Yan and Harms. This is obvious because, Harms teaches kits comprising one or more TFcAs, wherein the kits may include a label indicating the intended use of the contents of the kit and instructions for use of the kit in treating a disorder associated with a target of TFcA-dependent signaling, and the combined teachings of Yan and Harms teach compositions for expressing a mixture of at least two antibodies from a single cell wherein HC Fc domains of at least one of the antibodies comprises an “antibody chain assembly promoter” wherein at least one antibody in the mixture comprises a pair of mutations comprising Y349C/T366S/L368A/Y407V and S354C/T366W Fc mutations in the CH3 domains which are identical to the instantly claimed HC-HC-PP3 promoter pair. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant kit comprising at least one composition of instant claim 1 and technical instructions providing information on administration and dosage of the kit components.
Regarding instant claims 104 and 107, it would have been obvious for a person having ordinary skill in the art at the time of filing to substitute the nucleic acids used in the method of treating a tumor in the patient comprising administering the nucleic acids encoding the mixture of antibodies via a viral vector as taught by Yan with the composition, e.g. nucleic acids, for expressing the mixture of antibodies wherein one of said antibodies comprises a HC-HC assembly promoter pair comprising S354C/T366W and Y349C/T366S/L368A/Y407V Fc mutations as taught by the combined teachings of Yan and Harms. This is obvious because, Yan teaches that nucleic acids encoding the mixture of antibodies can be carried on a viral vector which in turn can be administered to a patient or directly to a tumor in the patient in order to treat a disease, and the combined teachings of Yan and Harms teach compositions for expressing a mixture of at least two antibodies from a single cell wherein HC Fc domains of at least one of the antibodies comprises an “antibody chain assembly promoter” wherein at least one antibody in the mixture comprises a pair of mutations comprising Y349C/T366S/L368A/Y407V and S354C/T366W Fc mutations in the CH3 domains which are identical to the instantly claimed HC-HC-PP3 promoter pair. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating a disorder wherein the method comprises administering to a subject in need thereof a composition according to instant claim 1, thereby expressing the antibodies in an organ or tissue in the subject.
Regarding instant claim 110, it would have been obvious for a person having ordinary skill in the art at the time of filing to substitute the nucleic acid molecule encoding the TFcA in a host cell as taught by Harms with the composition, e.g. nucleic acids, for expressing the mixture of antibodies wherein one of said antibodies comprises a HC-HC assembly promoter pair comprising S354C/T366W and Y349C/T366S/L368A/Y407V Fc mutations as taught by the combined teachings of Yan and Harms to produce mixtures of antibodies in vitro. This is obvious because, Harms discloses nucleic acid molecules comprising at least one coding sequence encoding a heavy chain or a light chain of a TFcA, vectors comprising one or more said nucleic acid molecules and cells comprising one or more vectors and/or nucleic acid molecules encoding the TFcA, Yan teaches that mixtures of antibodies can be produced by a host cell in vitro via a method comprising “introducing DNA encoding the mixtures of antibodies described herein into host cells, culturing the host cells, and recovering the mixture of antibodies from the cell mass or culture medium”, and the combined teachings of Yan and Harms teach compositions for expressing a mixture of at least two antibodies from a single cell wherein HC Fc domains of at least one of the antibodies comprises an “antibody chain assembly promoter” wherein at least one antibody in the mixture comprises a pair of mutations comprising Y349C/T366S/L368A/Y407V and S354C/T366W Fc mutations in the CH3 domains which are identical to the instantly claimed HC-HC-PP3 promoter pair. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of producing at least two nucleic acid encoded antibodies, wherein the method comprises a step of applying the instant composition of instant claim 1 to allow expression of at least two assembled antibodies in a cell.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jieun Ham whose telephone number is (571)272-7779. The examiner can normally be reached Monday - Friday 7-2.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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