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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6-23-26 has been entered.
Claims 2, 5, 7, 10, 11, 13, 19, 21, 23-26, 29, 33, 38, 44-49 have been canceled. Claims 50-57 have been added. Claims 1, 3, 4, 6, 8, 9, 12, 14-18, 20, 22, 27, 28, 30-32, 34-37, 39-43, 50-57 are pending.
Election/Restrictions
Applicants elected Group I, claims 1-9, 12, 14, with traverse in the reply filed on 3-13-24. Contrary to applicant’s assertion in the response filed 3-13-24, claims 41-43 were not drawn to the claimed invention.
Claims 15-18, 20, 22, 27, 28, 30-32, 34, 41-43 remain withdrawn.
Claims 1, 3, 4, 6, 8, 9, 12, 14, 35-37, 39, 40, 50-57 are under consideration.
Specification
The title will have to be changed to more closely reflect the claimed subject matter, i.e. ---TRANSGENIC RODENTS WITH HUMANIZED HLA I, IMMUNOGLOBLUIN HEAVY CHAIN, AND IMMUNOGLOBULIN LIGHT CHAIN GENES---.
Claim objections
The preamble of claim 1 can be written more clearly as ---A genetically modified mouse or rat whose germline genome comprises:---.
The phrase “ first Major Histocompatibility Complex (MHC) class I protein, wherein the first MHC class I protein: is a” in claim 1 are redundant. Saying MHC class I protein twice in lines 5-6 is redundant. Use of “human” and “humanized” is also redundant because a mouse gene that has been made either fully or partially human is “humanized”. A “humanized” MHC I gene encompasses fully human or a chimeric human/rodent MHC class I protein. Just say ---a nucleic acid encoding a humanized Major Histocompatibility Complex (MHC) class I protein comprising α1 and α2 domains of a human leukocyte antigen (HLA) class I protein---.
Saying that the germline genome of the rodent has the genetic modification in claim 1 infers a founder animal whose germline contains the genetic modification but the majority of cells do not. The claim encompasses a rodent in which B-cells do not have the genetic modification or express humanized MHC I proteins or Igs. Since a founder animal does not express the humanized MHC I protein in a majority of cells, it is not necessarily tolerized to the humanized MHC I as claimed; immunizing the founder animal with the pMHC complex would not result in the claimed effect because the pMHC complex would be recognized as foreign and attacked. Since a founder animal does not express the humanized MHC I protein in B-cells, it is not capable of expressing a humanized Ig as claimed. Humanized MHC I expression, humanized Ig expression, and tolerization to the humanized MHC can be written more clearly as a function of the mouse instead of the nucleic acid which would make the claim more clear, i.e. ---A genetically modified rodent whose genome comprises a) a nucleic acid sequence encoding a humanized major histocompatibility complex (MHC) class I protein… …and b) a nucleic acid sequence encoding a humanized immunoglobulin (Ig), wherein the rodent expresses and is tolerized to the humanized MHC class I protein and is capable of expressing a humanized Ig…---.
The phrase “capable of presenting an antigenic peptide” in line 9 of claim 1 is redundant because the rodent has been immunized with an antigen and presents the antigen in lines 14-21.
The antigenic peptide in line 9 does not have a nexus with the non-rodent antigenic peptide in line 15.
The structure of the single chain peptide-MHC complex in claim 1 is more confusing now. The phrase “single chain” in the phrase single chain peptide-MHC complex does not make sense because peptides are always single chains, and there is nothing else to which “single chain” refers (e.g. an antibody?). Therefore, the phrase does not further limit the complex. There only appear to be two items in the complex. The first component is a non-rodent antigen. The second is an MHC I that has the same a1 and a2 domains as the humanized MHC I expressed in the rodent; it can be humanized using any species (human/bird, human/reptile, human/elephant, etc.) or fully human. The phrase “a second MHC class I protein, wherein the second MHC class I protein comprises al and a2 domains that are identical to the a1 and a2 domains of the first MHC class I protein against which the genetically modified rodent is tolerized” is not succinct. The first and second components should be linked and can be written more clearly as ---a complex comprising a non-rodent antigen presented in the context of an MHC class I protein comprising the α1 and α2 domains of the humanized MHC class I protein---. If you need to further limit the MHC class I protein in the complex, refer to it as ---the MHC class I protein in the complex” to distinguish it from the ---humanized MHC class I protein--- capable of being expressed in the rodent. If there is something more to the complex, then please explain.
It is unclear if the phrase “such that the genetically modified rodent further comprises [a]the human or humanized Ig, wherein the human or humanized Igthat (a) comprises a human Ig variable domain operably linked to an IgG constant domain and (b) is capable of specifically binding the single chain pMHC complex, and wherein the genetically modified rodent is a genetically modified rat or a genetically modified mouse” is further limiting the Ig gene in item B) or if it is a function of the rodent. If they are part of the genetic modification in item B), then put them with item B). If they are functions of the rodent, then they don’t make sense unless the entire genome and B-cells of the rodent contain the genetic modification.
Claim interpretation
The concept of a “humanized” MHC or Ig gene/protein encompasses fully or partially human MHC or Ig genes/proteins.
The human or humanized Ig gene in item B) of claim 1 encompasses any replacement of an endogenous heavy or light chain gene to create a human or humanized Ig gene. It also encompasses any targeted or random insertion of a human or humanized Ig gene anywhere in the germline genome of the mouse or rat. It also encompasses any making any insertion or deletion or substitution found in a human Ig gene anywhere in the rodent without any effect. The rodent does not necessarily have to express any portion of a human or humanized antibody.
Claim Rejections - 35 USC § 112
Written Description
Claims 1, 3, 4, 6, 8, 9, 12, 14, 35-37, 39, 40 remain and claims 50-57 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Withdrawn rejections
The rejection regarding MHC II has been withdrawn because the claims have been limited to MHC I.
The rejection regarding claim 2 has been withdrawn because the claim has been canceled.
The rejection regarding a humanized MHC and Ig genes that has been immunized with any “peptide-MHC complex” comprising a non-rodent antigenic peptide presented in the context of any “HLA peptide binding groove” in claim 1 has been withdrawn in view of the amendment.
Pending rejections
A) The specification lacks written description for any mouse/rat whose germline genome comprises a nucleotide sequence encoding a humanized MHC I and a humanized Ig gene wherein the humanized MHC I “expressed such that the genetically modified rodent is tolerized to the first MHC class I protein”; and a nucleotide sequence encoding a humanized Ig gene capable of encoding a humanized Ig other than a genetically modified mouse whose genome comprises a nucleic acid sequence encoding a humanized MHC I and a nucleic acid sequence encoding a humanized Ig gene, wherein the mouse expresses and is tolerized to the humanized MHC I protein and expresses the humanized Ig.
Claim 1 is drawn to:
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The first MHC I in claim 1 can bind any antigen. The MHC may be fully human or a chimeric human+rodent. The HLA-A can be -A1, -A2, -A3, A-24, -A30, -A68 et al. HLA-B can be -B7, -B8, -B27, -B46, -B51, -B57, -B59, et al. The HLA-C can be -C01, -C03, -C04, -C05, -C06, -C15, -C17, -C18, et al. The nucleic acid sequence encoding the MHC can replace endogenous MHC sequences or be located anywhere in the genome. The MHC coding sequence can encode a wild-type or mutant MHC protein.
Chamberlin (1998, of record) taught a mouse whose genome comprised a randomly integrated nucleic acid sequence encoding HLA I. However, Chamberlain is limited to a mouse whose genome comprised a randomly integrated nucleic acid sequence encoding HLA-B7 and random integration of a nucleic acid sequence encoding B2M. Chamberlain taught that co-expression of both HLA-B7 and B2M is essential for efficient surface expression (abstract). The claims are not so limited.
Dill (1988 of record) taught transgenic mice expressing a fragment of an HLA-Cw3 integrated randomly.
Schonbach (1996 of record) taught transgenic mice expressing a fragment of an HLA-B*3501 integrated randomly.
Pascolo (1997, of record) taught a mouse whose genome comprised a randomly integrated nucleic acid sequence encoding a chimeric MHC I; however, Pascolo is limited to a mouse whose genome comprised a randomly integrated nucleic acid sequence encoding HLA-A2.1 and randomly integrated nucleic acid sequence encoding B2M in H-2Db-/- β2m-/- double knockout mice. The claims are not so limited.
9591835, of record, taught a mouse whose genome comprised a targeted integrated nucleic acid sequence encoding a chimeric MHC I; however, ‘835 is limited to a mouse whose genome comprised a targeted integration of a nucleic acid sequence encoding HLA-B/H-2D and randomly integrated nucleic acid sequence encoding B2M in H-2Db-/- β2m-/- double knockout mice. The claims are not so limited.
Applicants describe various other mice in the response filed 11-17-25.
Saying that the germline genome of the rodent has the genetic modification in claim 1 infers a founder animal whose germline contains the genetic modification but the majority of cells do not. The claim encompasses a rodent in which B-cells do not have the genetic modification or express humanized MHC I proteins or Igs. Since a founder animal does not express the humanized MHC I protein in a majority of cells, it is not necessarily tolerized to the humanized MHC I as claimed; immunizing the founder animal with the pMHC complex would not result in the claimed effect because the pMHC complex would be recognized as foreign and attacked. Since a founder animal does not express the humanized MHC I protein in B-cells, it is not capable of expressing a humanized Ig as claimed. Humanized MHC I expression, humanized Ig expression, and tolerization to the humanized MHC can be written more clearly as a function of the mouse instead of the nucleic acid which would make the claim clearer, i.e. ---A genetically modified rodent whose genome comprises a) a nucleic acid sequence encoding a humanized major histocompatibility complex (MHC) class I protein… …and b) a nucleic acid sequence encoding a humanized immunoglobulin (Ig), wherein the rodent expresses and is tolerized to the humanized MHC class I protein and is capable of expressing a humanized Ig…---.
Applicants do not correlate the various MHC I embodiments in genetically modified mice to rats.
The structure of the single chain peptide-MHC complex in claim 1 is more confusing now. The phrase “single chain” in the phrase single chain peptide-MHC complex does not make sense because peptides are always single chains, and there is nothing else to which “single chain” refers (e.g. an antibody?). Therefore, the phrase does not further limit the complex. There only appear to be two items in the complex. The first component is a non-rodent antigen. The second is an MHC I that has the same a1 and a2 domains as the humanized MHC I expressed in the rodent; it can be humanized using any species (human/bird, human/reptile, human/elephant, etc.) or fully human. The phrase “a second MHC class I protein, wherein the second MHC class I protein comprises al and a2 domains that are identical to the a1 and a2 domains of the first MHC class I protein against which the genetically modified rodent is tolerized” is not succinct. The first and second components should be linked, e.g. ---non-rodent antigen complexed with an MHC I protein---.
It is unclear if the phrase “such that the genetically modified rodent further comprises [a]the human or humanized Ig, wherein the human or humanized Igthat (a) comprises a human Ig variable domain operably linked to an IgG constant domain and (b) is capable of specifically binding the single chain pMHC complex, and wherein the genetically modified rodent is a genetically modified rat or a genetically modified mouse” is further limiting the Ig gene in item B) or if it is a function of the rodent. If they are part of the genetic modification in item B), then put them with item B). If they are functions of the rodent, then they don’t make sense unless the entire genome and B-cells of the rodent contain the genetic modification for reasons set forth above.
Response to arguments
Applicants argue the response in OA3, Table I, establishes humanized MHC class I proteins comprising α1 and α2 domains (pg 24). Applicants’ discussion is not persuasive for reasons set forth above. Please refer to the office actions by date; they are not labeled in our system as OA1 response, OA2 response. In particular, none of the references thus far described genetically modified rats whose genomes comprise a sequence encoding a humanized MHC I randomly integrated, specifically targeted to an endogenous MHC I gene, or specifically targeted to endogenous non-MHC I genes. The genome of the mouse must contain both genetic modifications for this system to work. The mouse must be capable of expressing the humanized Ig in B-cells which can only occur in a mouse whose genome comprises the humanized Ig gene. The structure of the pMHC complex must be clarified, and interaction between the humanized MHC I and the pMHC complex must be clarified.
B) The specification lacks written description for a genetically modified mouse/rat having a humanized MHC gene, a humanized Ig gene, and an exogenous TdT gene as required in claim 4. Pg 49 discloses a number of references for mice with an exogenous TdT gene; however, upon review none of the references disclose such a mouse. 8697940 mentions TdT but does not teach a mouse or rat expressing exogenous TdT. Accordingly, the concept lacks written description.
Response to arguments
Applicants argue the response in OA3, Table I, provides evidence (pg 25). Applicants’ discussion is not persuasive. Please refer to the office actions by date; they are not labeled in our system as OA1 response, OA2 response.
Applicants point to WO 2017210586. Applicants’ argument is not persuasive. The disclosure is limited to a genetically modified mouse whose genome comprises a nucleic acid sequence encoding human TdT (US Patent 10980221). It does not teach a genetically modified mouse/rat having a humanized MHC gene, a humanized Ig gene, and an exogenous TdT gene as required in claim 4. It does not teach only the germline genome of the mouse has the genetic modification as broadly encompassed by claim 4.
C) The specification lacks written description for a genetically modified mouse/rat having a humanized MHC gene, a humanized Ig gene, and a humanized β2 microglobulin (β2m) gene as required in claim 6 other than the mouse of US Patent 9615550. The claim encompasses any modified β2m gene expressing any portion of any human β2m gene. The specification mentions such mice were known in the art and points to 9615550 but does not teach how to make any other mouse with human/humanized β2 microglobulin. In addition, ‘550 is limited to a replacement of an endogenous nucleic acid sequence comprising exons 2, 3, and 4 of an endogenous β2m gene with a nucleic acid sequence comprising exons 2, 3, and 4 of a human β2m gene, wherein the nucleic acid sequence comprising exons 2, 3, and 4 of a human β2m gene is operably linked to an endogenous β2m promoter. Claim 1 of ‘550 is limited to a mouse whose genome comprises at an endogenous H-2K locus a nucleotide sequence encoding a chimeric human/mouse HLA-A/H-2K polypeptide, wherein the nucleotide sequence is in operable linkage with an endogenous mouse regulatory element and is operably linked to a MHC class I leader encoding sequence, wherein the nucleotide sequence comprises from 5' to 3' (i) a first nucleic acid sequence that encodes the .alpha.1, .alpha.2 and .alpha.3 domains of the human HLA-A polypeptide, which first nucleic acid sequence replaces a sequence encoding the .alpha.1, .alpha.2, and .alpha.3 domains of the mouse H-2K polypeptide at the mouse H-2K locus and (ii) a second nucleic acid sequence that encodes the transmembrane and cytoplasmic domains of the mouse H-2K polypeptide, wherein the mouse expresses, on the surface of nucleated cells, from the endogenous H-2K locus the chimeric human/mouse HLA-A/H-2K polypeptide that comprises the .alpha.1, .alpha.2 and .alpha.3 domains of the human HLA-A polypeptide and the transmembrane and cytoplasmic domains of the mouse H-2K polypeptide. The specification is limited to the replacement in Fig. 1C which is the modification in ‘550. The specification does not correlate the mouse and rat β2m genes. The specification does not teach how to express full length human β2m. The specification does not correlate the structure/function in claim 1 of ‘550 to any other structure/function in a mouse. The specification does not teach the protocols or reagents to recapitulate the structure/function in claim 1 of ‘550 in rats. Accordingly, the concept lacks written description other than the limited embodiment above. Claim 6 (and claim 1) should be limited to a mouse with a replacement of an endogenous nucleic acid sequence comprising exons 2, 3, and 4 of an endogenous β2m gene with a nucleic acid sequence comprising exons 2, 3, and 4 of a human β2m gene, wherein the nucleic acid sequence comprising exons 2, 3, and 4 of a human β2m gene is operably linked to an endogenous β2m promoter.
Claims 37 and 50-57 have been included because the specification does not teach any genetic modification at an endogenous β2 microglobulin locus other than the one set forth above.
Response to arguments
Applicants argue the response in OA3, Table I, provides evidence (pg 25-26). Applicants’ discussion is not persuasive. Please refer to the office actions by date; they are not labeled in our system as OA1 response, OA2 response.
Applicants point to 9615550. Applicants’ argument is not persuasive. The disclosure is limited to a genetically modified mouse whose genome comprises a nucleic acid sequence encoding humanized β2m. It does not teach a genetically modified mouse/rat having a humanized MHC gene, a humanized Ig gene, and an exogenous β2m gene as required in claim 6. It does not teach only the germline genome of the mouse has the genetic modification as broadly encompassed by claim 6.
D) The specification lacks written description for any HLA-1 in an endogenous ROSA26 gene as broadly encompassed by claim 39. Fig. 2 (described on pg 11, para 27) is limited to a mouse with a ROSA26 gene modified as shown:
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However, the specification does not provide the protocols or reagents required to do so. The specification does not correlate the β2m-HLA-A2 fusion protein in Fig. 2 to any other HLA molecule. The specification does not correlate the transgene for homologous recombination in mice to rats. Accordingly, the concept lacks written description.
Response to arguments
Applicants argue the response in OA3, Table I, provides evidence (pg 26-27). Applicants’ discussion is not persuasive. Please refer to the office actions by date; they are not labeled in our system as OA1 response, OA2 response.
Applicants point to Casola who taught expressing miRNA from the ROSA26 gene. Applicants’ argument is not persuasive. Casola is limited to a genetically modified mouse whose genome comprises a nucleic acid sequence encoding genetically modified Rosa26 gene in which the endogenous Rosa26 coding sequence is replaced with an exogenous coding sequence and operably linked to an endogenous Rosa26 promoter; the mouse expresses the exogenous coding sequence. Casola does not teach a genetically modified mouse/rat having a humanized MHC gene, a humanized Ig gene, and an exogenous humanized MHC I coding sequence in an endogenous Rosa26 gene as required in claim 39. It does not teach only the germline genome of the mouse has the Rosa26 genetic modification as broadly encompassed by claim 39.
New rejection
E) The specification lacks written description for a rodent whose germline genome comprises a sequence encoding a humanized MHC I comprising HLA I α1 and α2 domains and administering any peptide-MHC I complex as broadly encompassed by claim 1 other than those described by 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); and White (J. Immunol. 162: 2671-2676, 1999). The claims encompass administering just a peptide complexed with an MHC I protein. However, the specification, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White are limited to administering a pMHC I complex linked to a human β2m protein (see Materials and Methods for each). Applicants do not correlate administering a pMCH I complex comprising HLA I α1 and α2 domains bound to a human β2m to administering a pMCH I complex comprising HLA I α1 and α2 domains in the absence of the human β2m. Accordingly, the concept of doing so without it lacks written description.
Enablement
Claims 1, 3, 4, 6, 8, 9, 12, 14, 35-37, 39, 40 remain and claims 50-57 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for genetically modified mouse whose genome comprises:
a) a replacement of a nucleic acid sequence encoding α1, α2 and α3 domains of an endogenous H-2K with a nucleic acid sequence encoding α1, α2 and α3 domains of human HLA-A2, wherein the nucleic acid sequence encoding α1, α2 and α3 domains of human HLA-A2 is operably linked to: i) a nucleic acid sequence encoding a transmembrane and cytoplasmic domain of the H-2K; ii) an endogenous H-2K promoter; and iii) a nucleic acid sequence encoding a human HLA-A2 leader or an endogenous H-2K leader;
b) a replacement of an endogenous nucleic acid sequence encoding exons 2, 3, and 4 of an endogenous β2 microglobulin gene with a nucleic acid sequence encoding exons 2, 3, and 4 of a human β2 microglobulin gene, wherein the nucleic acid sequence encoding exons 2, 3, and 4 of the human β2 microglobulin gene is operably linked to an endogenous β2 microglobulin promoter;
c) and [“replacement” claim language from allowed patents],
wherein said mouse expresses a functional chimeric H-2K/HLA-A2 protein and humanized β2 microglobulin, and B-cells of the mouse are capable of expressing a humanized antibody.
does not reasonably provide enablement for the claims as broadly written. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Withdrawn rejections
Various genetically modified mice and rats with humanized Ig genes were known in the art at the time of filing as required in item B).
The rejection regarding any human or humanized Ig light chain gene as broadly encompassed by claim 1 has been withdrawn.
The rejection regarding a mouse/rat of claim 1 without having humanized HLA-A2/H-2K, Ig heavy chain, Ig light chain, and β2m genes has been withdrawn.
The rejection regarding a mouse/rat that is tolerized to the human/humanized MHC I and capable of generating a specific B-cell response against a peptide-MHC (pMHC) complex as encompassed by claims 1 or 6 has been withdrawn.
The rejection regarding a Ig heavy or light chain “locus” in claim 15 and 29 has been withdrawn in view of the amendment.
The rejection regarding a humanized antibody that contains a humanized variable domain as required in item b) i) of claim 1 has been withdrawn.
Pending rejections
A) The specification does not enable making/using any mouse/rat with any nucleotide sequence encoding a humanized MHC I comprising any peptide-binding groove as broadly encompassed by item A) of claim 1 other than a genetically modified mouse whose genome comprises a nucleic acid sequence encoding a humanized MHC I, wherein the mouse or rat expresses a humanized MHC I protein and is tolerized to the humanized MHC I protein.
Claim 1 is summarized above.
The MHC I comprising the groove in claim 1 can bind any antigen. The MHC may be fully human or a chimeric human+rat/mouse. The HLA-A can be -A1, -A2, -A3, A-24, -A30, -A68 et al. HLA-B can be -B7, -B8, -B27, -B46, -B51, -B57, -B59, et al. The HLA-C can be -C01, -C03, -C04, -C05, -C06, -C15, -C17, -C18, et al. The HLA peptide binding groove is limited to human. The nucleic acid sequence encoding the MHC can replace endogenous MHC sequences or be located anywhere in the genome. The MHC coding sequence can encode a wild-type or mutant MHC protein. The MHC can be just the peptide binding groove, an MHC fragment comprising the peptide binding groove, or a full length MHC comprising the peptide binding groove.
Chamberlin (1998, of record) taught a mouse whose genome comprised a randomly integrated nucleic acid sequence encoding HLA I. However, Chamberlain is limited to a mouse whose genome comprised a randomly integrated nucleic acid sequence encoding HLA-B7 and random integration of a nucleic acid sequence encoding B2M. Chamberlain taught that co-expression of both HLA-B7 and B2M is essential for efficient surface expression (abstract). The claims are not so limited.
Dill (1988 of record) taught transgenic mice expressing a fragment of an HLA-Cw3 integrated randomly.
Schonbach (1996 of record) taught transgenic mice expressing a fragment of an HLA-B*3501 integrated randomly.
Pascolo (1997, of record) taught a mouse whose genome comprised a randomly integrated nucleic acid sequence encoding a chimeric MHC I; however, Pascolo is limited to a mouse whose genome comprised a randomly integrated nucleic acid sequence encoding HLA-A2.1 and randomly integrated nucleic acid sequence encoding B2M in H-2Db-/- β2m-/- double knockout mice. The claims are not so limited.
9591835, of record, taught a mouse whose genome comprised a targeted integrated nucleic acid sequence encoding a chimeric MHC I; however, ‘835 is limited to a mouse whose genome comprised a targeted integration of a nucleic acid sequence encoding HLA-B/H-2D and randomly integrated nucleic acid sequence encoding B2M in H-2Db-/- β2m-/- double knockout mice. The claims are not so limited.
Applicants describe various other mice in the response filed 11-17-25.
Applicants do not correlate the various MHC I embodiments in genetically modified mice to rats.
The specification does not correlate a fully or partial human MHC I protein to a mouse/rat MHC I protein comprising JUST an HLA peptide binding groove as broadly claimed.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use any mouse/rat with any nucleotide sequence encoding a humanized MHC I comprising any peptide-binding groove as broadly encompassed by item A) of claim 1 other than a genetically modified mouse whose genome comprises a nucleic acid sequence encoding a humanized MHC I, wherein the mouse or rat expresses a humanized MHC I protein and is tolerized to the humanized MHC I protein.
Response to arguments
Applicants argue the examiner has failed to provide evidence to support a lack of enablement (pg 18). Applicants’ discussion is not persuasive. The rejection uses references along with legal, logical, and scientifically sound reasoning.
B) The specification does not enable making/using any mouse/rat with any nucleotide sequence encoding a humanized MHC II comprising any peptide-binding groove as broadly encompassed by item A) of claim 1 other than a genetically modified mouse whose genome comprises a nucleic acid sequence encoding a humanized MHC II, wherein the mouse or rat expresses a humanized MHC II protein and is tolerized to the humanized MHC II protein. The MHC II comprising the groove in claim 1 can bind any antigen. The MHC II may be fully human or a chimeric human+rat/mouse.
Woods (1994) taught a mouse whose genome comprised a random integration of a nucleic acid sequence encoding HLA-DRB1*0401 and expression of a full length HLA-DRB1*0401 along with endogenous MHC molecules. The claims are not so limited. The other references are similarly limited, but the claims are not.
Ito (1996, of record) taught a mouse whose genome comprised a random or targeted integration of a nucleic acid sequence encoding a chimeric MHC II comprising HLA-DRA-1Eα or HLA-DRB1*0401-IEβ expression of the chimeric MHC-II molecule. The claims are not so limited.
8847005 taught a mouse whose genome comprised a targeted integration of a nucleic acid sequence encoding HLA-DP, -DQ, or -DR into a mouse MHC II gene (claim 1) and expression of a chimeric mouse/human MHC-II molecule. The claims are not so limited.
The specification is limited to humanizing a mouse H2-E gene with sequences encoding α and β chains of a human HLA-DR2 (Fig. 1B).
Applicants describe various other mice in the response filed 11-17-25.
Applicants do not correlate the various MHC I embodiments in genetically modified mice to rats.
The specification does not correlate a fully or partial human MHC I protein to a mouse/rat MHC I protein comprising JUST an HLA peptide binding groove as broadly claimed.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use any mouse/rat with any nucleotide sequence encoding a humanized MHC II comprising any peptide-binding groove as broadly encompassed by item A) of claim 1 other than a genetically modified mouse whose genome comprises a nucleic acid sequence encoding a humanized MHC II, wherein the mouse or rat expresses a humanized MHC II protein and is tolerized to the humanized MHC II protein
Response to arguments
Applicants’ arguments do not appear to specifically address this rejection.
C) The specification does not enable making/using any of the modifications as broadly encompassed by claim 2 for reasons set forth above.
The humanized Ig heavy chain genes of a) i)-vi) cannot be found in the specification or the art at the time of filing. In particular, the “common” humanized Ig heavy chain genes of a) iii), the “histidine modified unrearranged” Ig heavy chain V regions of a) iv), the Ig heavy chain only of a) v) and the hybrid Ig chain in a) vi) cannot be found in the specification or the art at the time of filing.
The humanized Ig light chain genes of b) i)-v) cannot be found in the specification or the art at the time of filing. In particular, the “common” humanized Ig light chain genes of b) ii), the restricted unrearranged Ig light chain of b) iii), the “histidine modified unrearranged” Ig light chain V regions of b) iv), and the “histidine modified rearranged” Ig heavy chain only of b) v) cannot be found in the specification or the art at the time of filing.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use any mouse/rat in claim 2.
Response to arguments
Applicants do not appear to address this rejection.
D) The specification does not enable making/using a genetically modified mouse/rat having a humanized MHC gene, a humanized Ig gene, and an exogenous TdT gene as required in claim 4. Pg 49 discloses a number of references for mice with an exogenous TdT gene; however, upon review none of the references disclose such a mouse. 8697940 mentions TdT but does not teach a mouse or rat expressing exogenous TdT. Accordingly, the concept lacks written description. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use a mouse/rat having the structure in claim 4.
Response to arguments
Applicants do not appear to address this rejection.
E) The specification does not enable making/using a genetically modified mouse/rat having a humanized MHC gene, a humanized Ig gene, and a humanized β2 microglobulin (β2m) gene as required in claim 6 other than the mouse of US Patent 9615550. The claim encompasses any modified β2m gene expressing any portion of any human β2m gene. The specification mentions such mice were known in the art and points to 9615550 but does not teach how to make any other mouse with human/humanized β2 microglobulin. In addition, ‘550 is limited to a replacement of an endogenous nucleic acid sequence comprising exons 2, 3, and 4 of an endogenous β2m gene with a nucleic acid sequence comprising exons 2, 3, and 4 of a human β2m gene, wherein the nucleic acid sequence comprising exons 2, 3, and 4 of a human β2m gene is operably linked to an endogenous β2m promoter. Claim 1 of ‘550 is limited to a mouse whose genome comprises at an endogenous H-2K locus a nucleotide sequence encoding a chimeric human/mouse HLA-A/H-2K polypeptide, wherein the nucleotide sequence is in operable linkage with an endogenous mouse regulatory element and is operably linked to a MHC class I leader encoding sequence, wherein the nucleotide sequence comprises from 5' to 3' (i) a first nucleic acid sequence that encodes the .alpha.1, .alpha.2 and .alpha.3 domains of the human HLA-A polypeptide, which first nucleic acid sequence replaces a sequence encoding the .alpha.1, .alpha.2, and .alpha.3 domains of the mouse H-2K polypeptide at the mouse H-2K locus and (ii) a second nucleic acid sequence that encodes the transmembrane and cytoplasmic domains of the mouse H-2K polypeptide, wherein the mouse expresses, on the surface of nucleated cells, from the endogenous H-2K locus the chimeric human/mouse HLA-A/H-2K polypeptide that comprises the .alpha.1, .alpha.2 and .alpha.3 domains of the human HLA-A polypeptide and the transmembrane and cytoplasmic domains of the mouse H-2K polypeptide. The specification is limited to the replacement in Fig. 1C which is the modification in ‘550. The specification does not correlate the mouse and rat β2m genes. The specification does not teach how to express full length human β2m. The specification does not correlate the structure/function in claim 1 of ‘550 to any other structure/function in a mouse. The specification does not teach the protocols or reagents to recapitulate the structure/function in claim 1 of ‘550 in rats. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use a mouse/rat having the structure in claim 6. Claim 6 (and claim 1) should be limited to a mouse with a replacement of an endogenous nucleic acid sequence comprising exons 2, 3, and 4 of an endogenous β2m gene with a nucleic acid sequence comprising exons 2, 3, and 4 of a human β2m gene, wherein the nucleic acid sequence comprising exons 2, 3, and 4 of a human β2m gene is operably linked to an endogenous β2m promoter.
Claim 37 has been included because the specification does not teach any genetic modification at an endogenous β2 microglobulin locus other than the one set forth above.
Response to arguments
Applicants do not appear to address this rejection.
F) The specification does not enable making/using any HLA-1 in an endogenous ROSA26 gene as broadly encompassed by claim 39. Fig. 2 (described on pg 11, para 27) is limited to a mouse with a ROSA26 gene modified as shown:
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However, the specification does not provide the protocols or reagents required to do so. The specification does not correlate the β2m-HLA-A2 fusion protein in Fig. 2 to any other HLA molecule. The specification does not correlate the transgene for homologous recombination in mice to rats. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use a mouse/rat having the structure in claim 39.
Response to arguments
Applicants do not appear to address this rejection.
New rejection
G) the specification does not enable making/using any mouse/rat with any humanized MHC and Ig genes that has been immunized with any “peptide-MHC complex” comprising a non-rodent antigenic peptide presented in the context of any “HLA peptide binding groove” as newly required in claim 1. The specification contemplates pMHC complexes throughout the specification (e.g. pg 80, para 172). However, all of the complexes must be soluble and have a β2m to function in binding humanized Igs expressed by the mouse/rat (pg 82, para 175-177; pg 84, 4,478,82; 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez et al. J. Exp. Med. 181: 493-502, 1995; Madden et al. Cell 70: 1035-1048, 1992; Matsumura et al., Science 257: 927- 934, 1992; Mage et al., Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992; Toshitani et al, Proc. Nat'l Acad. Sci. 93: 236-240, 1996; Chung et al, J. Immunol. 163:3699-3708, 1999; Uger and Barber, J. Immunol. 160: 1598-1605, 1998; Uger et al., J. Immunol. 162, pp. 6024-6028, 1999; White et al., J. Immunol. 162: 2671-2676, 1999). It also appears that the MHC molecule used in the pMHC complex must match the MHC molecule that has been humanized in mouse/rat (pg 105, para 248, “Mice are immunized with a peptide-MHC (pMHC) complex of interest that comprises a peptide that is antigenic to the mice and the human or humanized MHC against which the mouse is tolerized”) which is missing from the claim. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use the mouse/rat as broadly claimed.
New rejection
E) The specification does not enable a rodent whose germline genome comprises a sequence encoding a humanized MHC I comprising HLA I α1 and α2 domains and administering any peptide-MHC I complex as broadly encompassed by claim 1 other than those described by 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); and White (J. Immunol. 162: 2671-2676, 1999). The claims encompass administering just a peptide complexed with an MHC I protein. However, the specification, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White are limited to administering a pMHC I complex linked to a human β2m protein (see Materials and Methods for each). Applicants do not correlate administering a pMCH I complex comprising HLA I α1 and α2 domains bound to a human β2m to administering a pMCH I complex comprising HLA I α1 and α2 domains in the absence of the human β2m. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to do so without the hβm2.
Indefiniteness
The rejection of claim 2 has been withdrawn because the claim has been canceled.
Double Patenting
The rejection of claims 1-9, 12, 14, 35-40 on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent Application No. 17113485 was withdrawn because the claims of ‘485 are limited to a mouse or rat with a humanized Ig gene and do not contemplate a humanized MHC gene as required in claim 1.
8,895,020; U.S. Patent No 8,992,937; Hansen et al. (2010) Trends Immunol. 31:363-69; Truscott et al. (2007) J. Immunol. 178:6280-89; Mitaksov et al. (2007) Chem Biol 14:909-22
Claim Rejections - 35 USC § 103
Withdrawn rejections
The rejection of claims 1, 3, 8, 12, 14, 35, 36 under 35 U.S.C. 103 as being unpatentable over Chamberlain (PNAS, 1988, Vol. 85, pg 7690) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156) and Spanier (Nature Communications, 2016, Vol. 7, Article 11804, pg 1-11) has been withdrawn because Spanier is limited to administering a peptide-MHCII complex while the claims are limited to administering a peptide-MHCI complex.
The rejection of claims 1, 3, 7, 8, 12, 14, 35, 38 under 35 U.S.C. 103 as being unpatentable over Woods (J. Exp. Med., 1994, Vol. 180, pg 173-181) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156) and Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11) has been withdrawn because Spanier is limited to administering a peptide-MHCII complex while the claims are limited to administering a peptide-MHCI complex.
The rejection of claims 1, 3, 5, 9, 12, 14, 35, 36 under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156) and Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11) has been withdrawn because Spanier is limited to administering a peptide-MHCII complex while the claims are limited to administering a peptide-MHCI complex.
Pending rejections
A) Claims 1, 3, 8, 12, 14, 35, 36 remain rejected under 35 U.S.C. 103 as being unpatentable over Chamberlain (PNAS, 1988, Vol. 85, pg 7690) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999).
Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11) has been removed because Spanier is limited to administering a peptide-MHCII complex while the claims are limited to administering a peptide-MHCI complex.
Chamberlain taught a genetic modified mouse whose genome comprises a HLA I comprising α1 and α2 domains and functionally expressing the HLA I capable of binding a non-mouse antigen (pg 7690, paragraph bridging col. 1-2; paragraph bridging pg 7690-7691). The HLA I coding sequence in Chamberlain is the humanized MHC I sequence in claim 1. Expression of the HLA I in Chamberlain is expression of the MHC I capable of binding an antigen in claim 1.
Chamberlain did not teach the genome of the mouse contained a nucleic acid sequence encoding a human Ig gene as required in item B) of claim 1.
However, Mendez taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding a human Ig gene that functionally expresses the Ig that is capable of binding a non-mouse antigen (pg 146, abstract; pg 147, col. 1, last paragraph). The teachings of Mendez are equivalent to item B) of claim 1 and a rodent that expresses an Ig comprising a human variable domain operably linked to an IgG constant domain that is capable of specifically binding a non-rodent antigen” in item ii) of claim 1.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene as described by Chamberlain and crossing it with the mouse with a humanized Ig gene described by Mendez. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition and expression of human HLA-I and human antibodies. The combined teachings of Chamberlain and Mendez are equivalent to a rodent that expresses an Ig comprising a human variable domain operably linked to an IgG constant domain that is capable of specifically binding a non-rodent antigen in the HLA peptide-binding groove” in item ii) of claim 1 because each protein is human and functionally expressed in the teachings of Chamberlain and Mendez, respectively.
The combined teachings of Chamberlain and Mendez did not teach administering a pMHC complex to the mouse as required in claim 1.
However, administering a pMHC I complex to a mouse was well known as described by ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White who administered a pMHC complex to a mouse (see Materials and Methods for each; Applicants acknowledge this on pg 84, para 180).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with humanized MHC and Ig genes as described by Chamberlain and Mendez followed by administering a pMHC complex to the mouse as described by ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White. Those of ordinary skill in the art at the time of filing would have been motivated to do so to for tolerization research and the interaction of humanized antibodies created by the mice with the pMHC complex.
Claim 3 has been included because the mouse of Chamberlain inherently MUST have a functional endogenous ADAM6 gene because it has not been genetically modified.
Claim 8 has been included because Chamberlain used a full length human MHC I coding sequence.
Claim 12 has been included because Chamberlain made a homozygous using heterozygous mice (Materials and Methods).
Claim 14 has been included because Chamberlain made a mouse.
Claim 35 has been included because the mouse of Chamberlain inherently MUST have a functional endogenous ADAM6 gene because the endogenous ADAM6 gene has not been genetically modified.
Claim 36 has been included because Chamberlain taught expressing HLA-B7.
Response to arguments
Applicants argue Spanier does not arrive at the claimed subject matter, there is no motivation to combine with Spanier, and no reasonable expectation of success with Spanier (pg 32, 33, 34). Applicants’ argument is not persuasive because Spanier has been removed.
B) Claim 3 remains rejected under 35 U.S.C. 103 as being unpatentable over Chamberlain (PNAS, 1988, Vol. 85, pg 7690) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 5, 8, 12, 14, 35, 36 and further in view of MacDonald (8697940).
The combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed human ADAM6 as required in claim 3.
However, MacDonald taught a genetically modified mouse expressed human ADAM6 (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of MacDonald. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies, and human ADAM6.
Response to arguments
Applicants do not specifically address this rejection.
C) Claim 4 remains rejected under 35 U.S.C. 103 as being unpatentable over Chamberlain (PNAS, 1988, Vol. 85, pg 7690) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 5, 8, 12, 14, 35, 36 and further in view of WO 2017210586.
The combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed TdT as required in claim 4.
However, WO 2017210586 taught a genetically modified mouse expressed TdT (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of WO 2017210586. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies with increased expression of TdT leading to increased V(D)J recombination (para 24-25 of WO 2017210586).
Response to arguments
Applicants do not specifically address this rejection.
D) Claims 6, 37 remain and claims 50-57 are rejected under 35 U.S.C. 103 as being unpatentable over Chamberlain (PNAS, 1988, Vol. 85, pg 7690) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 5, 8, 12, 14, 35, 36 and further in view of 9615550.
The combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed human β2m as required in claim 6.
However, 9615550 taught a genetically modified mouse expressed human β2m (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of Chamberlain, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of 9615550. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies, and human β2m (col. 6-7).
Claim 37 has been included because ‘550 taught the human β2m was at an endogenous β2m gene.
Claims 50-57 have been included because the β2m limitations were taught by 9615550.
Response to arguments
Applicants do not specifically address this rejection.
E) Claims 1, 3, 7, 8, 12, 14, 35, 38 remain rejected under 35 U.S.C. 103 as being unpatentable over Woods (J. Exp. Med., 1994, Vol. 180, pg 173-181) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999).
Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11) has been removed because Spanier is limited to administering a peptide-MHCII complex while the claims are limited to administering a peptide-MHCI complex.
Woods taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding a human leukocyte antigen (HLA II) that functionally expresses the HLA that is capable of binding a non-mouse antigen (pg 174, paragraph bridging col. 1-2; paragraph bridging pg 175-176). The teachings of Woods are equivalent to item A) of claim 1 and a rodent that expresses an MHC comprising the HLA α1 and α2 domains in item i) of claim 1.
Woods did not teach the genome of the mouse contained a nucleic acid sequence encoding a human Ig gene as required in item B) of claim 1.
However, Mendez taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding a human Ig gene that functionally expresses the Ig that is capable of binding a non-mouse antigen (pg 146, abstract; pg 147, col. 1, last paragraph). The teachings of Mendez are equivalent to item B) of claim 1 and a rodent that expresses an Ig comprising a human variable domain operably linked to an IgG constant domain that is capable of specifically binding a non-rodent antigen” in item ii) of claim 1.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA II gene as described by Woods and crossing it with the mouse with a humanized Ig gene described by Mendez. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition and expression of human HLA-II and human antibodies. The combined teachings of Woods and Mendez are equivalent to a rodent that expresses an Ig comprising a human variable domain operably linked to an IgG constant domain that is capable of specifically binding a non-rodent antigen in the HLA peptide-binding groove” in item ii) of claim 1 because each protein is human and functionally expressed in the teachings of Woods and Mendez, respectively.
The combined teachings of Woods and Mendez did not teach administering a pMHC complex to the mouse as required in claim 1.
However, administering a pMHC complex to a mouse was well known as described by ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White (see Materials and Methods for each; Applicants acknowledge this on pg 84, para 180).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with humanized MHC and Ig genes as described by Woods and Mendez followed by administering a pMHC complex to the mouse as described by ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White. Those of ordinary skill in the art at the time of filing would have been motivated to do so to for tolerization research and the interaction of humanized antibodies created by the mice with the pMHC complex.
Claim 3 has been included because the mouse of Woods inherently MUST have a functional endogenous ADAM6 gene because the endogenous ADAM6 gene has not been genetically modified.
Claim 7 has been included because Woods taught an MHC II molecule.
Claim 8 has been included because Woods taught a full length MHC II coding sequence.
Claim 12 has been included because Woods made a homozygous using heterozygous mice (Materials and Methods).
Claim 14 has been included because Woods made a mouse.
Claim 35 has been included because the mouse of Woods inherently MUST have a functional endogenous ADAM6 gene because the endogenous ADAM6 gene has not been genetically modified.
Claim 38 has been included because Woods used a HLA-DR sequence (abstract).
Response to arguments
Applicants argue Spanier does not arrive at the claimed subject matter, there is no motivation to combine with Spanier, and no reasonable expectation of success with Spanier (pg 32, 33, 34). Applicants’ argument is not persuasive because Spanier has been removed.
F) Claim 3 remains rejected under 35 U.S.C. 103 as being unpatentable over Woods (J. Exp. Med., 1994, Vol. 180, pg 173-181) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 7, 8, 12, 14, 35, 38 and further in view of MacDonald (8697940).
The combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed human ADAM6 as required in claim 3.
However, MacDonald taught a genetically modified mouse expressed human ADAM6 (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of MacDonald. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies, and human ADAM6.
Response to arguments
Applicants do not specifically address this rejection.
J) Claim 4 remains rejected under 35 U.S.C. 103 as being unpatentable over Woods (J. Exp. Med., 1994, Vol. 180, pg 173-181) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 7, 8, 12, 14, 35, 38 and further in view of WO 2017210586.
The combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed TdT as required in claim 4.
However, WO 2017210586 taught a genetically modified mouse expressed TdT (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of WO 2017210586. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies with increased expression of TdT leading to increased V(D)J recombination (para 24-25 of WO 2017210586).
Response to arguments
Applicants do not specifically address this rejection.
G) Claims 6, 37 remain and claims 50-57 are rejected under 35 U.S.C. 103 as being unpatentable over Woods (J. Exp. Med., 1994, Vol. 180, pg 173-181) in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 7, 8, 12, 14, 35, 38 and further in view of 9615550.
The combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed human β2m as required in claim 6.
However, 9615550 taught a genetically modified mouse expressed human β2m (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of Woods, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of 9615550. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies, and human β2m (col. 6-7).
Claim 37 has been included because ‘550 taught the human β2m was at an endogenous β2m gene.
Claims 50-57 have been included because the β2m limitations were taught by 9615550.
Response to arguments
Applicants do not specifically address this rejection.
H) Claims 1, 3, 9, 12, 14, 35, 36 remain rejected under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999).
Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11) has been removed because Spanier is limited to administering a peptide-MHCII complex while the claims are limited to administering a peptide-MHCI complex.
‘835 taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding a human leukocyte antigen (HLA I) that functionally expresses the HLA that is capable of binding a non-mouse antigen (claims). The teachings of ‘835 are equivalent to item A) of claim 1 and a rodent that expresses an MHC comprising the HLA α1 and α2 domains of claim 1.
‘835 did not teach the genome of the mouse contained a nucleic acid sequence encoding a human Ig gene as required in item B) of claim 1.
However, Mendez taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding a human Ig gene that functionally expresses the Ig that is capable of binding a non-mouse antigen (pg 146, abstract; pg 147, col. 1, last paragraph). The teachings of Mendez are equivalent to item B) of claim 1 and a rodent that expresses an Ig comprising a human variable domain operably linked to an IgG constant domain that is capable of specifically binding a non-rodent antigen” in item ii) of claim 1.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene as described by ‘835 and crossing it with the mouse with a humanized Ig gene described by Mendez. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition and expression of human HLA-I and human antibodies. The combined teachings of ‘835 and Mendez are equivalent to a rodent that expresses an Ig comprising a human variable domain operably linked to an IgG constant domain that is capable of specifically binding a non-rodent antigen in the HLA peptide-binding groove” in item ii) of claim 1 because each protein is human and functionally expressed in the teachings of ‘835 and Mendez, respectively.
The combined teachings of ‘835 and Mendez did not teach administering a pMHC complex to the mouse as required in claim 1.
However, administering a pMHC complex to a mouse was well known as described by ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White (see Materials and Methods for each; Applicants acknowledge this on pg 84, para 180).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with humanized MHC and Ig genes as described by the combined teachings of ‘835 and Mendez followed by administering a pMHC complex to the mouse as described by ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White. Those of ordinary skill in the art at the time of filing would have been motivated to do so to for tolerization research and the interaction of humanized antibodies created by the mice with the pMHC complex.
Claim 3 has been included because the mouse of ‘835 inherently MUST have a functional endogenous ADAM6 gene because the endogenous ADAM6 gene has not been genetically modified.
Claim 9 has been included because ‘835 used a partial human MHC I coding sequence resulting in a chimeric MHC I gene.
Claim 12 has been included because ‘835 made a homozygous using heterozygous mice (Examples).
Claim 14 has been included because ‘835 made a mouse.
Claim 35 has been included because the mouse of ‘835 inherently MUST have a functional endogenous ADAM6 gene because the endogenous ADAM6 gene has not been genetically modified.
Claim 36 has been included because the mouse of Woods expressed HLA-A (col. 19, lines 52-68).
Response to arguments
Applicants argue Spanier does not arrive at the claimed subject matter, there is no motivation to combine with Spanier, and no reasonable expectation of success with Spanier (pg 32, 33, 34). Applicants’ argument is not persuasive because Spanier has been removed.
I) Claim 3 remains rejected under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 9, 12, 14, 35, 36 and further in view of MacDonald (8697940).
The combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed human ADAM6 as required in claim 3.
However, MacDonald taught a genetically modified mouse expressed human ADAM6 (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of MacDonald. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies, and human ADAM6.
Response to arguments
Applicants do not specifically address this rejection.
J) Claim 4 remains rejected under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 9, 12, 14, 35, 36 and further in view of WO 2017210586.
The combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed TdT as required in claim 4.
However, WO 2017210586 taught a genetically modified mouse expressed TdT (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of WO 2017210586. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies with increased expression of TdT leading to increased V(D)J recombination (para 24-25 of WO 2017210586).
Response to arguments
Applicants do not specifically address this rejection.
K) Claims 6, 37 remain and claims 50-57 are rejected under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), 6,011,146; 8,895,020; 8,992,937; WO 96/04314; Mottez (J. Exp. Med. 181: 493-502, 1995); Madden (Cell 70: 1035-1048, 1992); Matsumura (Science 257: 927- 934, 1992); Mage (Proc. Natl. Acad. Sci. USA 89: 10658-10662, 1992); Toshitani (Proc. Nat'l Acad. Sci. 93: 236-240, 1996); Chung (J. Immunol. 163:3699-3708, 1999); Uger (J. Immunol. 160: 1598-1605, 1998); Uger (J. Immunol. 162, pp. 6024-6028, 1999); White (J. Immunol. 162: 2671-2676, 1999) as applied to claims 1, 3, 9, 12, 14, 35, 36 and further in view of 9615550.
The combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White taught a genetically modified mouse that expresses a human HLA-I and a human Ig protein for reasons set forth above.
The combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White did not teach the genetically modified mouse expressed human β2m as required in claim 6.
However, 9615550 taught a genetically modified mouse expressed human β2m (Examples).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a mouse with a humanized HLA I gene and a humanized Ig gene described by the combined teachings of ‘835, Mendez, ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White and crossing it with the mouse of 9615550. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make a mouse model that more-closely reflected the human condition by expressing human HLA-I, human antibodies, and human β2m (col. 6-7).
Claim 37 has been included because ‘550 taught the human β2m was at an endogenous β2m gene.
Response to arguments
Applicants do not specifically address this rejection.
Conclusion
No claim is allowed.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
Prosecution Insights