DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election without traverse of Group I (drawn to an engineered polypeptide), the species of L234A for additional substitution, and anti-GITR antibody comprises VH of SEQ ID NO:9 and VL of SEQ ID NO:10 in the Response filed on September 2, 2026 is acknowledged.
Upon further consideration, claim 4 (drawn to 235A) has been rejoined.
Claims 2, 5-7, 9, 10, 13, 20-44, 49, 50, 52, and 53 have been canceled.
Claims 1, 3, 4, 8, 11, 12, 14-19, 45-48, 51, and 54-56 are pending.
Claims 19, 45-48, 51, 54, and 56 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected inventions/species.
Claims 1, 3, 4, 8, 11, 12, 14-18, and 55 are currently under consideration as they read on the elected invention.
3. 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.
4. 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
5. Claims 1, 3, 4, 8, 11, 12, and 14-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lazar (WO 2016/164480, published on October 13, 2016, claims priority to April 7, 2015, reference on IDS) in view of Niwa et al. (US 2014/0120581).
Lazar teaches modified IgG antibody that binds to a cell surface receptor that is a member of receptor family in TNFR superfamily and G-protein Coupled Receptor (GPCR) family including GITR (e.g. see [0008]).
Lazar teaches a modified human IgG1 comprising an Fc variant comprising one or more amino acid substitutions selected from the group consisting of positions including E345R and E430G (e.g. see [0037]). Lazar teaches antibody that is monospecific, bispecific, or multispecific (e.g. see [0038]). Lazar teaches that the Fc region of human IgG1 can also be modified in positions L234A and L235A for reduced binding to C1q and reduced effector functions such as complement dependent cytotoxicity (e.g. see [0045] and [0264]). Lazar teaches that the antibody can be an anti-GITR antibody (e.g. see [0474]).
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Lazar teaches working examples of a humanized anti-OX40 antibody comprising a human IgG1 Fc region consisting of amino acid substitutions 345R, 430G, and 440Y and L234A, L235A, and P329G (e.g. see Examples 1 and 2 in pages 187-189).
Lazar teaches that amino acid substitutions in one or more positions selected from E435, E430, and S440 in the Fc region promote intermolecular interactions between Fc domains (e.g. see [0346] in pages 114-115). Lazar teaches the modification E345R, E430G and S440Y promotes hexamer formation of the Fc regions (e.g. see Example 1). Since hexamer contains six antibodies and each antibody is a drug, the hexamer is an antibody conjugate (six antibodies conjugated to each other via Fc). Lazar also specifically teaches combination substitutions E345K/E430G/S440Y (e.g. see [0382]), but also provide alternative substitutions in these three positions including E345K, E430G, and S440W (e.g. see [0353]). Note that there are only two suggested substitutions in position S440, namely S440W or S440Y, when combining with E345 and E430 substitutions. Lazar further teaches S228P substitution in human IgG4 (e.g. see claim 153.
Given that Lazar teaches a human IgG1 Fc variant comprises combination substitutions L234A/L235A/L329G and E345R/E430G/S440Y is beneficial in hexamer formation and reduced unwanted CDC activity and L234A/L235A as well as E345K/E430G/S440Y are the alternatives to the L234A/L235A/L329G and E435K/E430G/S440Y, respectively, an ordinary skill in the art would be able to simply substitute E345R with E345K for a human IgG1 Fc variant comprising L234A/L235A/E345K/E439G/S440Y that have the same predictable functions of reduced CDC activity and enhanced receptor clustering compared to the wildtype unmutated IgG Fc region.
The reference teachings differ from the instant invention by not describing S228P and R409K substitution and exemplifying IgG4.
Niwa et al. teach that amino acid substitutions S228P and R409K in the Fc region of IgG4 stabilizes the hinge region (e.g. see [0133]) and CH3 region (e.g. see [0130]). Niwa et al. teaches amino acid sequences of human IgG1 Fc region and human IgG4 Fc region (e.g. see Fig. 4A and 4B) and they are highly homologous to each other. Niwa et al. teach heterodimeric antibody can be IgG1 or IgG4 (e.g. see [0074], [0125], and claims 1-7.).
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to combine the teachings of Lazar and Niwa to create an human IgG4 antibody (e.g. anti-GITR antibody) comprising amino acid substitutions E345K, E430G, S440W with 234A and 235A combined with S228P and R409K. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since Lazar teach L234A/L235A/L329G and E345R/E430G/S440Y are beneficial in hexamer formation and reduced unwanted CDC activity, and Niwa specifically discloses S228P and R409K substitutions Fc region of human IgG4 promotes hinge and CH3 stability for heterodimer formation. As such, combining these mutations that are well known in art would create an IgG4 Fc variant with the functions of stable multimer formation with reduced unwanted CDC activity.
6. Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Lazar (WO 2016/164480, published on October 13, 2016, claims priority to April 7, 2015) in view of Niwa et al. (US 2014/0120581) as applied to claims 1 and 18 above, and further in view of Marasco (WO 2018/071913, reference on IDS).
The applied reference has a common inventor Wayne A. Marasco with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
The teachings of Lazar and Niwa have been discussed, supra.
The reference teachings differ from the instant invention by not teach anti-GITR antibody comprising a VH of 9 and VL of 10.
Marasco teaches an anti-GITR antibody comprising VH and VL that are 100% identical in amino acid sequences with the instantly claimed antibody (see sequence alignments below and [00080]).
SEQ ID NO:9 alignment to prior art
BFF14654
ID BFF14654 standard; protein; 118 AA.
XX
AC BFF14654;
XX
DT 31-MAY-2018 (first entry)
XX
DE Anti-GITR antibody heavy chain variable region, SEQ 1804.
XX
KW GITR protein; Glucocorticoid-induced tumor necrosis factor receptor;
KW alzheimers disease; antibody; antibody production; antibody therapy;
KW central nervous system disease; central nervous system tumor; cytostatic;
KW glioblastoma; heavy chain variable region; huntingtons chorea;
KW motor neurone disease; neurodegenerative disease; neuroprotective;
KW parkinsons disease; recombinant protein; therapeutic.
XX
OS Homo sapiens.
XX
CC PN WO2018071913-A2.
XX
CC PD 19-APR-2018.
XX
CC PF 16-OCT-2017; 2017WO-US056814.
XX
PR 14-OCT-2016; 2016US-0408271P.
XX
CC PA (DAND ) DANA FARBER CANCER INST INC.
XX
CC PI Marasco WA;
XX
DR WPI; 2018-30837C/30.
DR N-PSDB; BFF14628.
XX
CC PT New tetravalent antibody molecule useful for treating CNS-related disease
CC PT or disorder and neurodegenerative disease, comprises dimer of bispecific
CC PT single-chain variable fragment comprising first binding and second
CC PT binding site.
XX
CC PS Disclosure; SEQ ID NO 1804; 125pp; English.
XX
CC The present invention relates to a novel tetravalent antibody molecule,
CC useful for treating CNS-related disease or disorder and neurodegenerative
CC disease. The tetravalent antibody molecule is a dimer of a bispecific
CC single-chain variable fragment (scFv) comprising a first binding site for
CC a first antigen, and a second binding site for a second antigen, where
CC the two binding sites are joined together through a linker domain. The
CC invention further provides: (1) a nucleic acid construct comprising
CC nucleic acid molecules encoding a light chain variable region and a heavy
CC chain variable region of an antibody that can specifically bind to a
CC first antigen, a light chain variable region and a heavy chain variable
CC region of an antibody that can specifically bind to a second antigen, and
CC a linker domain; (2) a vector comprising the nucleic acid construct; (3)
CC a host cell comprising the vector; (4) a chimeric antigen receptor (CAR)
CC comprising an intracellular signaling domain, a transmembrane domain and
CC an extracellular domain comprising the tetravalent antibody molecule; (5)
CC a genetically engineered cell which expresses and bears the chimeric
CC antigen receptor on the cell surface membrane; (6) a method for producing
CC tetrameric bispecific antibody molecules; and (7) a method for treating a
CC disease or disorder, by administering the tetravalent antibody molecule,
CC where the disease or disorder is CNS-related disease or disorder,
CC preferably CNS cancer or neurodegenerative disease. The CNS cancer is
CC glioblastoma (GBM). The neurodegenerative disease is amyotrophic lateral
CC sclerosis, parkinson's disease, alzheimer's disease, or huntington's
CC disease. The present sequence represents an anti-glucocorticoid-induced
CC tumor necrosis factor receptor (GITR) antibody heavy chain variable
CC region, the antibody of which is used in the tetravalent antibody
CC molecule, where the tetravalent antibody molecule is used for treating
CC CNS-related disease or disorder and neurodegenerative disease.
XX
SQ Sequence 118 AA;
Query Match 100.0%; Score 611; DB 26; Length 118;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSHAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSHAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIGTADAFDIWGQGTTVTVSS 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIGTADAFDIWGQGTTVTVSS 118
SEQ ID NO:10 alignment:
RESULT 2
BFF14655
ID BFF14655 standard; protein; 110 AA.
XX
AC BFF14655;
XX
DT 31-MAY-2018 (first entry)
XX
DE Anti-GITR antibody light chain variable region, SEQ 1805.
XX
KW GITR protein; Glucocorticoid-induced tumor necrosis factor receptor;
KW alzheimers disease; antibody; antibody production; antibody therapy;
KW central nervous system disease; central nervous system tumor; cytostatic;
KW glioblastoma; huntingtons chorea; light chain variable region;
KW motor neurone disease; neurodegenerative disease; neuroprotective;
KW parkinsons disease; recombinant protein; therapeutic.
XX
OS Homo sapiens.
XX
CC PN WO2018071913-A2.
XX
CC PD 19-APR-2018.
XX
CC PF 16-OCT-2017; 2017WO-US056814.
XX
PR 14-OCT-2016; 2016US-0408271P.
XX
CC PA (DAND ) DANA FARBER CANCER INST INC.
XX
CC PI Marasco WA;
XX
DR WPI; 2018-30837C/30.
DR N-PSDB; BFF14629.
XX
CC PT New tetravalent antibody molecule useful for treating CNS-related disease
CC PT or disorder and neurodegenerative disease, comprises dimer of bispecific
CC PT single-chain variable fragment comprising first binding and second
CC PT binding site.
XX
CC PS Disclosure; SEQ ID NO 1805; 125pp; English.
XX
CC The present invention relates to a novel tetravalent antibody molecule,
CC useful for treating CNS-related disease or disorder and neurodegenerative
CC disease. The tetravalent antibody molecule is a dimer of a bispecific
CC single-chain variable fragment (scFv) comprising a first binding site for
CC a first antigen, and a second binding site for a second antigen, where
CC the two binding sites are joined together through a linker domain. The
CC invention further provides: (1) a nucleic acid construct comprising
CC nucleic acid molecules encoding a light chain variable region and a heavy
CC chain variable region of an antibody that can specifically bind to a
CC first antigen, a light chain variable region and a heavy chain variable
CC region of an antibody that can specifically bind to a second antigen, and
CC a linker domain; (2) a vector comprising the nucleic acid construct; (3)
CC a host cell comprising the vector; (4) a chimeric antigen receptor (CAR)
CC comprising an intracellular signaling domain, a transmembrane domain and
CC an extracellular domain comprising the tetravalent antibody molecule; (5)
CC a genetically engineered cell which expresses and bears the chimeric
CC antigen receptor on the cell surface membrane; (6) a method for producing
CC tetrameric bispecific antibody molecules; and (7) a method for treating a
CC disease or disorder, by administering the tetravalent antibody molecule,
CC where the disease or disorder is CNS-related disease or disorder,
CC preferably CNS cancer or neurodegenerative disease. The CNS cancer is
CC glioblastoma (GBM). The neurodegenerative disease is amyotrophic lateral
CC sclerosis, parkinson's disease, alzheimer's disease, or huntington's
CC disease. The present sequence represents an anti-glucocorticoid-induced
CC tumor necrosis factor receptor (GITR) antibody light chain variable
CC region, the antibody of which is used in the tetravalent antibody
CC molecule, where the tetravalent antibody molecule is used for treating
CC CNS-related disease or disorder and neurodegenerative disease.
XX
SQ Sequence 110 AA;
Query Match 100.0%; Score 588; DB 26; Length 110;
Best Local Similarity 100.0%;
Matches 110; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QSALTQPPSVSGTPGQRVTISCSGGVPNIGSNPVNWYLHRPGTAPKLLIYNSNQWPSGVP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QSALTQPPSVSGTPGQRVTISCSGGVPNIGSNPVNWYLHRPGTAPKLLIYNSNQWPSGVP 60
Qy 61 DRFSGSRSGTSASLAISGLQSEDEADYYCAAWDDSLDGLVFGGGTKLTVL 110
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DRFSGSRSGTSASLAISGLQSEDEADYYCAAWDDSLDGLVFGGGTKLTVL 110
The teachings of Lazar and Niwa have been discussed above.
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to combined the teachings of the references to produce a human anti-GITR IgG1 antibody with mutations in L234A/L235A for reduced effector functions such as CDC activity and E435K/E430G/S440W and S238P/R409K to promote multimer formations. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since Marasco teaches tetramer anti-GITR antibody and anti-PD-L1 antibody are useful for treating CNS cancer such as glioblastoma (e.g. see [000259] and claims 36) and Lazar and Niwa teaches that modifications in the Fc region of either IgG1 or IgG4 in the positions described above could promote multimer formation and altered effector functions. As such, combining the teachings of the reference for an anti-GITR antibody with modifications in the Fc region would be well within the skill of an ordinary skill in the art.
7. No claim is allowed.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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