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 .
DETAILED ACTION
Claims 1-20 are pending and are under examination.
Claim Objections
Claims 4 and 5 are objected to for reciting “antigen-binding”. It appears these claims intend to recite “antigen-binding fragment thereof”.
Claim Rejections - 35 USC § 112
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.
Claim 11 is 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.
Claim 11 is indefinite in the recitation of “the amino acid sequence set forth as SEQ ID NO:11”. In this case, SEQ ID NO:11 is a nucleic acid sequence, so it is unclear what (if any) amino acid sequence is being referred to in this claim. Therefore, the scope of this limitation in the claim is unclear and cannot be determined.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-18 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Regents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The teachings of the specification and the claimed invention
The nature and scope of the claimed invention at issue is a genus of structurally and functionally diverse antigen binding proteins that bind mouse transferrin receptor which are defined by one or more CDR sequences recited in the alternative or an antigenic-fragment thereof or variant thereof that need not comprise any CDR as currently written (see claim 1). While claims 2 and 6 recite antigen binding proteins that comprise 6 CDRs, these claims continue to encompass antigenic-fragment thereof or variant thereof that need not comprise any CDR as currently written because they depend from claim 1.
The inventors disclose antigen binding protein 8D3 comprising 6 specific CDRs that bind mouse transferrin receptor (see Examples starting at page 62).
Notably, the specification does not provide evidence that antibodies with less than these 6 CDRs bind mouse transferrin receptor.
State of the Art
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single antigen. For example, Lloyd et al (Protein Engineering, Design & Selection, 22:159-168, 2009) teach that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (see, e.g., Discussion). Similarly, Edwards et al (J Mol Biol, 14;334(1):103-118, 2003), found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein with 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (see Abstract).
It is also known in the antibody art that the structure of a conventional monoclonal antibody that correlates with its function is the 6 CDRs of the antibody. For example, Gussow et al (Methods in Enzymology. 1991; 203: 99-121) teach the general methodology for making humanized antibodies; see entire document. One means for producing an antibody involves grafting the six CDRs from the light and heavy chain variable regions from a murine antibody into the framework of a human antibody. However, in general, if only two of the CDRs from either the light or heavy chain variable region were to be grafted, but not all three, the resultant antibody would not be expected to retain the specificity and functions of the parent antibody. Therefore, it is expected that all 6 CDRs need to be grafted into antibody framework regions to retain the requisite specificity and functionality of the parent antibody. Notably, as antibodies are produced by genetic recombination and affinity maturation via mutations the CDRs of one antibody with a particular function does not inform the skilled artisan as to other CDRs in antibodies that could be obtained with the same function.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, the unpredictability of single amino acid changes in an antibody is underscored by Winkler et al (J. Imm., 265:4505-4514, 2000) who teach that a single amino acid change in a CDR can result in unpredictable and substantial changes in antibody specificity; see entire document (e.g., the abstract).
Claim Analysis
The nature and scope of the claimed invention at issue is a genus of structurally and functionally diverse antigen binding domains that are defined by the antigen they bind (mouse transferrin receptor) and partial CDR structure as well as antigenic-fragments and variants thereof; see claim 1. In this case the specification does not disclose species representative of the claimed genera.
As an example to explain why the genera lack written description it is noted that merely binding mouse transferrin receptor does not adequately describe such genera of antibodies because binding an antigen does not describe the structure of an antibody that has this function. Reciting an antibody that binds to an antigen is insufficient to describe the genus of antibodies that binds to that antigen the structure of one antibody that binds an antigen will vary widely from the structure of other antibodies that bind the antigen. Furthermore, the claims recite antigenic-fragments and variants thereof and such proteins will vary widely in structure and function.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen as evidenced by Lloyd et al and Edwards et al above. Accordingly, one of skill in the art would not be able to immediately envision, recognize or predict the structure of the full scope of the antigen-binding proteins, antigenic-fragments and variants thereof encompassed by the claims and would not recognize that Applicant was in possession of the claimed invention.
Secondly, with respect to antibodies comprising partial CDRs, while the specification discloses that that the antibody with the CDR sequences of SEQ ID Nos:16-18 in the HCVR and SEQ ID Nos:20-22 in the LCVR binds mouse transferrin receptor, it does not otherwise characterize which parts or fragments of the CDR amino acid sequence are required to maintain binding. Accordingly, it is submitted that the disclosed antibody is not representative of the claimed antibodies which include variant CDR regions because one of skill in the art could not immediately envision, recognize or predict which CDR residues are required to maintain binding.
Once again, the specification does not characterize species representative of the claimed genus as it does not characterize which CDR amino acids of the disclosed antibody are required to maintain binding. Notably, the claims do not require all 6 CDRs of a parent antibody and as the specification does not fully characterize which CDR residues can be varied or which parts of can be replaced to retain binding function, the disclosed antibody species is not representative of the genus of claimed antibodies. Accordingly, one of skill in the art would not be able to immediately envision, recognize or predict the structure of antibodies comprising less than all 6 of the recited CDRs in the proper context of heavy and light chain frameworks which would have the function of binding to mouse transferrin receptor and would not recognize that Applicant was in possession of the claimed invention.
Although the skilled artisan could potentially screen for “antibodies” as encompassed by the claims, it is duly noted that the written description provision of 35 U.S.C § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it.
The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the “written description” inquiry, whatever is now claimed.
Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (CAFC 1991). See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993); Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (CAFC 1991); University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1892 (CAFC 2004).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed structure(s) of the genus of “antibodies” and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Given the lack of particularity with which the antibodies are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize or distinguish at least most of the members of the claimed genera, to which the claims are directed; and therefore the specification would not reasonably convey to the skilled artisan that Applicant had possession of the claimed invention at the time the application was filed.
Accordingly, it is suggested this rejection could be obviated by amending the claims to recite:
An antigen-binding protein that specifically binds to murine transferrin receptor comprising: (i) an HCVR that comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 16, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 17, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:18; and (ii) an LCVR that comprises an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:20, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:21, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:22.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6 are rejected under 35 U.S.C. 102(a)(1) 35 U.S.C. 102(a)(1) as being anticipated by Hanzatian et al (WO2014/089209 A2).
Regarding claims 1-5, Hanzatian et al discloses a Fab or scFv antibodies that bind to mouse transferrin receptor comprising SEQ ID NO:56 and 57 which are 100% identical to instant SEQ ID Nos:15 and 19, which comprise the CDR sequence of claim 1 (see pages 30, 49 and 89 and alignments).
RESULT 1
BBH47449
(NOTE: this sequence has 25 duplicates in the database searched.
See complete list at the end of this report)
ID BBH47449 standard; protein; 118 AA.
XX
AC BBH47449;
XX
DT 31-JUL-2014 (first entry)
XX
DE Anti-TfR antibody heavy chain variable region (VH-TfR), SEQ 56.
XX
KW TfR protein; alzheimers disease; analgesic; antibody;
KW antibody production; antibody therapy; antidepressant; antiparkinsonian;
KW blood-brain barrier; brain disease; brain tumor; cerebroprotective;
KW diagnostic test; drug delivery; genetic-disease-gen.;
KW heavy chain variable region; huntingtons chorea; immunoassay;
KW major depressive disorder; metastatic brain cancer;
KW neurodegenerative disease; neuroleptic; neurological disease;
KW neuroprotective; nootropic; pain; parkinsons disease;
KW prophylactic to disease; protein detection; protein quantitation;
KW psychiatric disorder; psychiatric-gen.; schizophrenia; stroke;
KW therapeutic; vasotropic.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Region 26..35
FT /label= CDR1
FT Region 50..67
FT /label= CDR2
FT Region 99..107
FT /label= CDR3
XX
CC PN WO2014089209-A2.
XX
CC PD 12-JUN-2014.
XX
CC PF 04-DEC-2013; 2013WO-US073114.
XX
PR 04-DEC-2012; 2012US-0733252P.
PR 15-MAR-2013; 2013US-0792163P.
XX
CC PA (ABBO ) ABBVIE INC.
XX
CC PI Hanzatian DK, Ghayur T, Sterman AJS, Goodearl A, Harris MC;
XX
DR WPI; 2014-L33889/42.
XX
CC PT New blood-brain barrier penetrating dual variable domain (DVD) binding
CC PT protein that specifically binds to antigen expressed on brain vascular
CC PT epithelium of subject, for treating disease or disorder, e.g.
CC PT neurological disorder.
XX
CC PS Claim 18; SEQ ID NO 56; 145pp; English.
XX
CC The present invention relates to a novel blood-brain barrier (BBB)
CC penetrating dual variable domain (DVD) binding protein that specifically
CC binds to an antigen expressed on brain vascular epithelium of a subject
CC and facilitates uptake of a composition into the brain of the subject.
CC The DVD binding protein comprising first and second polypeptide chains,
CC where the first polypeptide chain comprises a first VD1-(X1)n-VD2-C-
CC (X2)n, where VD1 is a first heavy chain variable domain, VD2 is a second
CC heavy chain variable domain, C is a heavy chain constant domain, X1 is a
CC first linker, X2 is an crystallizable fragment (Fc) region, and the
CC second polypeptide chain comprises a second VD1 -(X1)n-VD2-C-(X2)n, where
CC VD1 is a first light chain variable domain, VD2 is a second light chain
CC variable domain, C is a light chain constant domain, X1 is a second
CC linker, X2 does not comprise an Fc region. The present invention also
CC provides: (1) a monospecific binding protein (antibody) comprising a
CC heavy polypeptide chain and a light polypeptide; (2) a bispecific binding
CC protein (antibody) comprising the heavy polypeptide chain and the light
CC polypeptide chain; (3) a binding protein conjugate comprising the binding
CC protein, the binding protein conjugate further comprising an agent, where
CC the agent is an immunoadhension molecule, a diagnostic agent, an imaging
CC agent, a therapeutic agent, or a cytotoxic agent; (4) an isolated nucleic
CC acid sequence encoding the binding protein; (5) a vector comprising the
CC nucleic acid sequence (4); (6) a host cell comprising the vector of (5);
CC (7) a method of producing the binding protein, or a method for generating
CC a binding protein capable of binding two antigens; (8) a pharmaceutical
CC composition comprising the binding protein and a pharmaceutically
CC acceptable carrier; (9) a method for determining the presence of at least
CC one antigen or its fragment in a test sample by an immunoassay; (10) a
CC method for determining the amount or concentration of the antigen or its
CC fragment in the test sample by an immunoassay; (11) a kit for assaying
CC the test sample for the presence, amount, or concentration of an antigen
CC or its fragment; (12) a humanized antibody that specifically binds
CC transferrin receptor (TfR); and (13) a humanized antibody that
CC specifically binds human insulin receptor (HIR). The DVD binding protein
CC can also be used for diagnosing, preventing or treating a disease or a
CC disorder in a subject by administering the DVD binding protein, where the
CC disease or disorder includes brain disorder (e.g., autoimmune or
CC inflammatory disease of the brain, infectious disorder of the brain,
CC neurological disorder, neurodegenerative disorder, brain cancer, or brain
CC metastasis), Huntington's chorea, Parkinson's disease, Alzheimer's
CC disease, stroke, mental disorders, depression, schizophrenia, acute and
CC chronic pain. The present sequence is an Anti-TfR antibody heavy chain
CC variable region (VH-TfR), which can be in the BBB penetrating DVD binding
CC protein of the invention for diagnosing, preventing or treating the above
CC mentioned disease or disorder.
XX
SQ Sequence 118 AA;
Query Match 100.0%; Score 623; Length 118;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY 60
Qy 61 ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSS 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSS 118
RESULT 2
BBH47450
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
ID BBH47450 standard; protein; 108 AA.
XX
AC BBH47450;
XX
DT 31-JUL-2014 (first entry)
XX
DE Anti-TfR antibody light chain variable region (VL-TfR), SEQ 57.
XX
KW TfR protein; alzheimers disease; analgesic; antibody;
KW antibody production; antibody therapy; antidepressant; antiparkinsonian;
KW blood-brain barrier; brain disease; brain tumor; cerebroprotective;
KW diagnostic test; drug delivery; genetic-disease-gen.; huntingtons chorea;
KW immunoassay; light chain variable region; major depressive disorder;
KW metastatic brain cancer; neurodegenerative disease; neuroleptic;
KW neurological disease; neuroprotective; nootropic; pain;
KW parkinsons disease; prophylactic to disease; protein detection;
KW protein quantitation; psychiatric disorder; psychiatric-gen.;
KW schizophrenia; stroke; therapeutic; vasotropic.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Region 24..34
FT /label= CDR1
FT Region 50..56
FT /label= CDR2
FT Region 89..97
FT /label= CDR3
XX
CC PN WO2014089209-A2.
XX
CC PD 12-JUN-2014.
XX
CC PF 04-DEC-2013; 2013WO-US073114.
XX
PR 04-DEC-2012; 2012US-0733252P.
PR 15-MAR-2013; 2013US-0792163P.
XX
CC PA (ABBO ) ABBVIE INC.
XX
CC PI Hanzatian DK, Ghayur T, Sterman AJS, Goodearl A, Harris MC;
XX
DR WPI; 2014-L33889/42.
XX
CC PT New blood-brain barrier penetrating dual variable domain (DVD) binding
CC PT protein that specifically binds to antigen expressed on brain vascular
CC PT epithelium of subject, for treating disease or disorder, e.g.
CC PT neurological disorder.
XX
CC PS Claim 20; SEQ ID NO 57; 145pp; English.
XX
CC The present invention relates to a novel blood-brain barrier (BBB)
CC penetrating dual variable domain (DVD) binding protein that specifically
CC binds to an antigen expressed on brain vascular epithelium of a subject
CC and facilitates uptake of a composition into the brain of the subject.
CC The DVD binding protein comprising first and second polypeptide chains,
CC where the first polypeptide chain comprises a first VD1-(X1)n-VD2-C-
CC (X2)n, where VD1 is a first heavy chain variable domain, VD2 is a second
CC heavy chain variable domain, C is a heavy chain constant domain, X1 is a
CC first linker, X2 is an crystallizable fragment (Fc) region, and the
CC second polypeptide chain comprises a second VD1 -(X1)n-VD2-C-(X2)n, where
CC VD1 is a first light chain variable domain, VD2 is a second light chain
CC variable domain, C is a light chain constant domain, X1 is a second
CC linker, X2 does not comprise an Fc region. The present invention also
CC provides: (1) a monospecific binding protein (antibody) comprising a
CC heavy polypeptide chain and a light polypeptide; (2) a bispecific binding
CC protein (antibody) comprising the heavy polypeptide chain and the light
CC polypeptide chain; (3) a binding protein conjugate comprising the binding
CC protein, the binding protein conjugate further comprising an agent, where
CC the agent is an immunoadhension molecule, a diagnostic agent, an imaging
CC agent, a therapeutic agent, or a cytotoxic agent; (4) an isolated nucleic
CC acid sequence encoding the binding protein; (5) a vector comprising the
CC nucleic acid sequence (4); (6) a host cell comprising the vector of (5);
CC (7) a method of producing the binding protein, or a method for generating
CC a binding protein capable of binding two antigens; (8) a pharmaceutical
CC composition comprising the binding protein and a pharmaceutically
CC acceptable carrier; (9) a method for determining the presence of at least
CC one antigen or its fragment in a test sample by an immunoassay; (10) a
CC method for determining the amount or concentration of the antigen or its
CC fragment in the test sample by an immunoassay; (11) a kit for assaying
CC the test sample for the presence, amount, or concentration of an antigen
CC or its fragment; (12) a humanized antibody that specifically binds
CC transferrin receptor (TfR); and (13) a humanized antibody that
CC specifically binds human insulin receptor (HIR). The DVD binding protein
CC can also be used for diagnosing, preventing or treating a disease or a
CC disorder in a subject by administering the DVD binding protein, where the
CC disease or disorder includes brain disorder (e.g., autoimmune or
CC inflammatory disease of the brain, infectious disorder of the brain,
CC neurological disorder, neurodegenerative disorder, brain cancer, or brain
CC metastasis), Huntington's chorea, Parkinson's disease, Alzheimer's
CC disease, stroke, mental disorders, depression, schizophrenia, acute and
CC chronic pain. The present sequence is an Anti-TfR antibody light chain
CC variable region (VL-TfR), which can be in the BBB penetrating DVD binding
CC protein of the invention for diagnosing, preventing or treating the above
CC mentioned disease or disorder.
XX
SQ Sequence 108 AA;
Query Match 100.0%; Score 558; Length 108;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPS 60
Qy 61 RFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK 107
With respect to claim 6, Hanzatian et al discloses scFv antibodies can be formed by linking VL and VH regions with a linker comprising the amino acid sequence of GGGGSGGGGSGGGGS, which when linking SEQ ID Nos: 56 and 57 gives the instant SEQ ID NO:23 of claim 6.
Claims 1-3 and 7-8 are rejected under 35 U.S.C. 102(a)(1) 35 U.S.C. 102(a)(1) as being anticipated by Pardridge et al (WO2006/088503 A1, IDS).
Regarding claims 1-3 and 7, Pardridge et al discloses a fusion protein comprising the antibody 8D3 that binds mouse transferrin receptor and which comprises the instant sequences (see instant specification) and the hydrolase, beta-gal (see Figures and Examples).
Claim Rejections - 35 USC § 103
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.
Claims 1-10, 12-18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Hanzatian et al (WO2014/089209 A2) and Baik et al (WO2019157224 A1, IDS).
Hanzatian et al discloses a Fab or scFv antibodies that bind to mouse transferrin receptor comprising SEQ ID NO:56 and 57 which are 100% identical to instant SEQ ID Nos:15 and 19, which comprise the CDR sequence of claim 1 (see pages 30, 49 and 89 and alignments).
RESULT 1
BBH47449
(NOTE: this sequence has 25 duplicates in the database searched.
See complete list at the end of this report)
ID BBH47449 standard; protein; 118 AA.
XX
AC BBH47449;
XX
DT 31-JUL-2014 (first entry)
XX
DE Anti-TfR antibody heavy chain variable region (VH-TfR), SEQ 56.
XX
KW TfR protein; alzheimers disease; analgesic; antibody;
KW antibody production; antibody therapy; antidepressant; antiparkinsonian;
KW blood-brain barrier; brain disease; brain tumor; cerebroprotective;
KW diagnostic test; drug delivery; genetic-disease-gen.;
KW heavy chain variable region; huntingtons chorea; immunoassay;
KW major depressive disorder; metastatic brain cancer;
KW neurodegenerative disease; neuroleptic; neurological disease;
KW neuroprotective; nootropic; pain; parkinsons disease;
KW prophylactic to disease; protein detection; protein quantitation;
KW psychiatric disorder; psychiatric-gen.; schizophrenia; stroke;
KW therapeutic; vasotropic.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Region 26..35
FT /label= CDR1
FT Region 50..67
FT /label= CDR2
FT Region 99..107
FT /label= CDR3
XX
CC PN WO2014089209-A2.
XX
CC PD 12-JUN-2014.
XX
CC PF 04-DEC-2013; 2013WO-US073114.
XX
PR 04-DEC-2012; 2012US-0733252P.
PR 15-MAR-2013; 2013US-0792163P.
XX
CC PA (ABBO ) ABBVIE INC.
XX
CC PI Hanzatian DK, Ghayur T, Sterman AJS, Goodearl A, Harris MC;
XX
DR WPI; 2014-L33889/42.
XX
CC PT New blood-brain barrier penetrating dual variable domain (DVD) binding
CC PT protein that specifically binds to antigen expressed on brain vascular
CC PT epithelium of subject, for treating disease or disorder, e.g.
CC PT neurological disorder.
XX
CC PS Claim 18; SEQ ID NO 56; 145pp; English.
XX
CC The present invention relates to a novel blood-brain barrier (BBB)
CC penetrating dual variable domain (DVD) binding protein that specifically
CC binds to an antigen expressed on brain vascular epithelium of a subject
CC and facilitates uptake of a composition into the brain of the subject.
CC The DVD binding protein comprising first and second polypeptide chains,
CC where the first polypeptide chain comprises a first VD1-(X1)n-VD2-C-
CC (X2)n, where VD1 is a first heavy chain variable domain, VD2 is a second
CC heavy chain variable domain, C is a heavy chain constant domain, X1 is a
CC first linker, X2 is an crystallizable fragment (Fc) region, and the
CC second polypeptide chain comprises a second VD1 -(X1)n-VD2-C-(X2)n, where
CC VD1 is a first light chain variable domain, VD2 is a second light chain
CC variable domain, C is a light chain constant domain, X1 is a second
CC linker, X2 does not comprise an Fc region. The present invention also
CC provides: (1) a monospecific binding protein (antibody) comprising a
CC heavy polypeptide chain and a light polypeptide; (2) a bispecific binding
CC protein (antibody) comprising the heavy polypeptide chain and the light
CC polypeptide chain; (3) a binding protein conjugate comprising the binding
CC protein, the binding protein conjugate further comprising an agent, where
CC the agent is an immunoadhension molecule, a diagnostic agent, an imaging
CC agent, a therapeutic agent, or a cytotoxic agent; (4) an isolated nucleic
CC acid sequence encoding the binding protein; (5) a vector comprising the
CC nucleic acid sequence (4); (6) a host cell comprising the vector of (5);
CC (7) a method of producing the binding protein, or a method for generating
CC a binding protein capable of binding two antigens; (8) a pharmaceutical
CC composition comprising the binding protein and a pharmaceutically
CC acceptable carrier; (9) a method for determining the presence of at least
CC one antigen or its fragment in a test sample by an immunoassay; (10) a
CC method for determining the amount or concentration of the antigen or its
CC fragment in the test sample by an immunoassay; (11) a kit for assaying
CC the test sample for the presence, amount, or concentration of an antigen
CC or its fragment; (12) a humanized antibody that specifically binds
CC transferrin receptor (TfR); and (13) a humanized antibody that
CC specifically binds human insulin receptor (HIR). The DVD binding protein
CC can also be used for diagnosing, preventing or treating a disease or a
CC disorder in a subject by administering the DVD binding protein, where the
CC disease or disorder includes brain disorder (e.g., autoimmune or
CC inflammatory disease of the brain, infectious disorder of the brain,
CC neurological disorder, neurodegenerative disorder, brain cancer, or brain
CC metastasis), Huntington's chorea, Parkinson's disease, Alzheimer's
CC disease, stroke, mental disorders, depression, schizophrenia, acute and
CC chronic pain. The present sequence is an Anti-TfR antibody heavy chain
CC variable region (VH-TfR), which can be in the BBB penetrating DVD binding
CC protein of the invention for diagnosing, preventing or treating the above
CC mentioned disease or disorder.
XX
SQ Sequence 118 AA;
Query Match 100.0%; Score 623; Length 118;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGNSLTLSCVASGFTFSNYGMHWIRQAPKKGLEWIAMIYYDSSKMNY 60
Qy 61 ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSS 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADTVKGRFTISRDNSKNTLYLEMNSLRSEDTAMYYCAVPTSHYVVDVWGQGVSVTVSS 118
RESULT 2
BBH47450
(NOTE: this sequence has 3 duplicates in the database searched.
See complete list at the end of this report)
ID BBH47450 standard; protein; 108 AA.
XX
AC BBH47450;
XX
DT 31-JUL-2014 (first entry)
XX
DE Anti-TfR antibody light chain variable region (VL-TfR), SEQ 57.
XX
KW TfR protein; alzheimers disease; analgesic; antibody;
KW antibody production; antibody therapy; antidepressant; antiparkinsonian;
KW blood-brain barrier; brain disease; brain tumor; cerebroprotective;
KW diagnostic test; drug delivery; genetic-disease-gen.; huntingtons chorea;
KW immunoassay; light chain variable region; major depressive disorder;
KW metastatic brain cancer; neurodegenerative disease; neuroleptic;
KW neurological disease; neuroprotective; nootropic; pain;
KW parkinsons disease; prophylactic to disease; protein detection;
KW protein quantitation; psychiatric disorder; psychiatric-gen.;
KW schizophrenia; stroke; therapeutic; vasotropic.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Region 24..34
FT /label= CDR1
FT Region 50..56
FT /label= CDR2
FT Region 89..97
FT /label= CDR3
XX
CC PN WO2014089209-A2.
XX
CC PD 12-JUN-2014.
XX
CC PF 04-DEC-2013; 2013WO-US073114.
XX
PR 04-DEC-2012; 2012US-0733252P.
PR 15-MAR-2013; 2013US-0792163P.
XX
CC PA (ABBO ) ABBVIE INC.
XX
CC PI Hanzatian DK, Ghayur T, Sterman AJS, Goodearl A, Harris MC;
XX
DR WPI; 2014-L33889/42.
XX
CC PT New blood-brain barrier penetrating dual variable domain (DVD) binding
CC PT protein that specifically binds to antigen expressed on brain vascular
CC PT epithelium of subject, for treating disease or disorder, e.g.
CC PT neurological disorder.
XX
CC PS Claim 20; SEQ ID NO 57; 145pp; English.
XX
CC The present invention relates to a novel blood-brain barrier (BBB)
CC penetrating dual variable domain (DVD) binding protein that specifically
CC binds to an antigen expressed on brain vascular epithelium of a subject
CC and facilitates uptake of a composition into the brain of the subject.
CC The DVD binding protein comprising first and second polypeptide chains,
CC where the first polypeptide chain comprises a first VD1-(X1)n-VD2-C-
CC (X2)n, where VD1 is a first heavy chain variable domain, VD2 is a second
CC heavy chain variable domain, C is a heavy chain constant domain, X1 is a
CC first linker, X2 is an crystallizable fragment (Fc) region, and the
CC second polypeptide chain comprises a second VD1 -(X1)n-VD2-C-(X2)n, where
CC VD1 is a first light chain variable domain, VD2 is a second light chain
CC variable domain, C is a light chain constant domain, X1 is a second
CC linker, X2 does not comprise an Fc region. The present invention also
CC provides: (1) a monospecific binding protein (antibody) comprising a
CC heavy polypeptide chain and a light polypeptide; (2) a bispecific binding
CC protein (antibody) comprising the heavy polypeptide chain and the light
CC polypeptide chain; (3) a binding protein conjugate comprising the binding
CC protein, the binding protein conjugate further comprising an agent, where
CC the agent is an immunoadhension molecule, a diagnostic agent, an imaging
CC agent, a therapeutic agent, or a cytotoxic agent; (4) an isolated nucleic
CC acid sequence encoding the binding protein; (5) a vector comprising the
CC nucleic acid sequence (4); (6) a host cell comprising the vector of (5);
CC (7) a method of producing the binding protein, or a method for generating
CC a binding protein capable of binding two antigens; (8) a pharmaceutical
CC composition comprising the binding protein and a pharmaceutically
CC acceptable carrier; (9) a method for determining the presence of at least
CC one antigen or its fragment in a test sample by an immunoassay; (10) a
CC method for determining the amount or concentration of the antigen or its
CC fragment in the test sample by an immunoassay; (11) a kit for assaying
CC the test sample for the presence, amount, or concentration of an antigen
CC or its fragment; (12) a humanized antibody that specifically binds
CC transferrin receptor (TfR); and (13) a humanized antibody that
CC specifically binds human insulin receptor (HIR). The DVD binding protein
CC can also be used for diagnosing, preventing or treating a disease or a
CC disorder in a subject by administering the DVD binding protein, where the
CC disease or disorder includes brain disorder (e.g., autoimmune or
CC inflammatory disease of the brain, infectious disorder of the brain,
CC neurological disorder, neurodegenerative disorder, brain cancer, or brain
CC metastasis), Huntington's chorea, Parkinson's disease, Alzheimer's
CC disease, stroke, mental disorders, depression, schizophrenia, acute and
CC chronic pain. The present sequence is an Anti-TfR antibody light chain
CC variable region (VL-TfR), which can be in the BBB penetrating DVD binding
CC protein of the invention for diagnosing, preventing or treating the above
CC mentioned disease or disorder.
XX
SQ Sequence 108 AA;
Query Match 100.0%; Score 558; Length 108;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPASLSASLEEIVTITCQASQDIGNWLAWYQQKPGKSPQLLIYGATSLADGVPS 60
Qy 61 RFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSRSGTQFSLKISRVQVEDIGIYYCLQAYNTPWTFGGGTKLELK 107
Hanzatian et al discloses scFv antibodies can be formed by linking VL and VH regions with a linker comprising the amino acid sequence of GGGGSGGGGSGGGGS, which when linking SEQ ID Nos: 56 and 57 gives the instant SEQ ID NO:23 of claim 6. Hanzatian et al teach that such antibodies are useful for crossing the blood-brain barrier (BBB).
Baik et al discloses the targeted delivery of the therapeutic protein to CNS tissue (e.g. brain) is employed by use of anti-transferrin receptor (see pages 18 and 19). Baik et al discloses that such an antibody can be fused to the hydrolase enzyme GAA to reduce stored glycogen in CNS tissue (see page 18). Baik et al discloses delivering the antibody-hydrolase enzyme GAA fusion to the mouse in a viral vector or gene therapy vector to the liver of the mouse wherein the vector further comprises a liver specific promoter or neuronal specific promoter (see pages 42-43, 50 and 77).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to make a fusion protein comprising the mouse transferrin receptor antibodies of Hanzatian et al fused to GAA and administer that fusion protein or gene therapy or viral vectors encoding the fusion protein wherein the vector further comprises a liver specific promoter or neuronal specific promoter to mice because that construct would be expected to deliver the GAA to the brain of the mouse as suggested by Baik et al which would have the advantage of reducing stored glycogen in CNS tissue.
One would have reasonably expected that such constructs could be made and delivered to the CNS of the mouse because mouse transferrin receptor antibodies were known to cross the BBB and methods of making such constructs were known.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references.
Conclusion
No claims are allowed. Claim 19 is objected to for depending from a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is (571) 272-9935. The examiner works a flexible schedule.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
August 13, 2025