DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 10, 11, 13, 21, 23-26, 29, 33, 44-47 have been canceled. Claims 1-9, 12, 14-20, 22, 27, 28, 30-32, 34-43, 48, 49 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Claims 48, 49 remain withdrawn as stated in the office action sent 7-17-25. Applicants argue they should be examined together with the rodent in claim 1 because they are also rodents. Applicants’ argument is not persuasive because they do not further limit the humanized MHC or Ig gene in the mouse of claim 9. As written, it appears that claims 48 and 49 are attempting to introduce another genetic modification on top of what is already in claim 9. The burden required to search and examine these concepts on top of what appears to be a double transgenic rat/mouse would be undue. If the concept in claim 48, 49 are an attempt to further limit the humanized Ig gene in claim 1, then much clarification is required.
Claims 15-20, 22, 27, 28, 30-32, 34, 41-43, 48, 49 remain withdrawn.
Claims 1-9, 12, 14, 35-40 remain under consideration.
Specification
The title will have to be changed to more closely reflect the claimed subject matter, i.e. ---TRANSGENIC MICE WITH HUMANIZED HLA-A2, IMMUNOGLOBLUIN HEAVY CHAIN, AND IMMUNOGLOBULIN LIGHT CHAIN GENES---. The claims are not limited to non-human animals as mentioned in the current title.
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 “Major Histocompatibility Complex (MHC) protein… …wherein the MHC protein is an MHC I or MHC II protein” in claim 1 can be written more simply as --- Major Histocompatibility Complex (MHC) I or II---.
The phrase “is a fully human MHC protein or chimeric human/rodent MHC protein, comprises a human leukocyte antigen (HLA) peptide-binding groove capable of presenting an antigenic peptide” in context of item A) of claim 1 can be written more simply as ---a fully human or chimeric human/rodent Major Histocompatibility Complex (MHC) I or II comprising a human leukocyte antigen (HLA) peptide-binding groove capable of presenting an antigen---.
The phrase “and is expressed such that the genetically modified rodent is tolerized to the MHC protein” can be written more accurately as ---wherein the genetically modified mouse or rat expresses and is tolerized to the MHC I or II---.
The concept of immunizing a rodent with a “non-rodent antigenic peptide presented in the context of the HLA peptide-binding groove” in item ii) of claim 1 does not make sense because “the HLA peptide-binding groove” is merely encoded by the germline genome of the mouse and expressed in context of the human or chimeric MHC I or II. The rodent cannot be immunized with “the” HLA peptide-binding groove expressed by the rodent. The rodent can only be immunized with an external HLA peptide-binding groove. While this HLA used for immunization may be the same or different than the one expressed in the rodent, the language used in claim 1 fails to ensure the [exogenous] HLA used for immunization is the same [endogenous] HLA expressed by the rodent.
As newly written, there is no nexus between the presence of the “human or humanized immunoglobulin (Ig) gene” and the rodent being immunized with an HLA-peptide binding groove/non-rodent antigen “such that the [ ] rodent further comprises a human or humanized Ig that a) comprises a human Ig variable domain operably linked to an IgG constant domain and b) is capable of specifically binding the pMHC complex” in claim 1. The genetic modifications associated with those structures/functions are completely missing from the claim. The breadth of any “human or humanized [Ig] gene” makes no requirement for the gene to encode a human Ig variable domain.
Claim interpretation
The concept of a “humanized” MHC or Ig gene/protein encompasses fully or partially human MHC or Ig genes/proteins.
The breadth of the nucleic acid encoding an MHC I or II comprising an antigen binding groove capable of presenting an antigenic peptide in item A) of claim 1 encompasses an MHC I or II that is just the HLA “peptide-binding groove” or any MHC I or II comprising the HLA “peptide-binding groove”. The “peptide-binding groove” can bind any self or non-self antigen. The peptide binding groove may be rodent, human, or non-human.
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 1-9, 12, 14, 35-40 remain 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
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 lacks written description for 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 drawn to:
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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.
Response to arguments
Applicants argue the examiner has failed to provide evidence to support a lack of written description (pg 18). Applicants’ discussion is not persuasive. The rejection uses references along with legal, logical, and scientifically sound reasoning.
B) The specification lacks written description for 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.
Response to arguments
Applicants’ arguments do not appear to specifically address this rejection.
C) The specification lacks written description for any of the modifications as broadly encompassed by claim 2 for reasons set forth above.
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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.
Accordingly, the concepts lack written description.
Response to arguments
Applicants do not appear to address this rejection.
D) 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 do not appear to address this rejection.
E) 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.
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 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 do not appear to address this rejection.
New rejection
G) the specification lacks written description for 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. Accordingly, the concept lacks written description as broadly claimed.
Enablement
Claims 1-9, 12, 14, 35-40 remain 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.
Indefiniteness
Claims 1-9, 12, 14, 35-40 remain 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.
Withdrawn rejections
The rejection regarding the metes and bounds of a “classical HLA” molecule in claim 2 has been withdrawn because the term “classical” has been deleted.
The rejection of claim 6 regarding the phrase “the rodent is tolerized to the human or humanized β2 microglobulin” has been withdrawn in view of the amendment.
Pending rejections
A) Claim 2 remains rejected regarding the metes and bounds of “unrearranged [ ] Ig heavy chain variable region” for reasons of record. It is unclear whether an Ig variable “region” refers to a “gene segment” or the Ig “gene” as a whole. It is unclear whether the term “unrearranged” applies only to the human Ig heavy chain gene segments or if it applies to the humanized Ig heavy chain gene. It is unclear whether the phrase is limited to Ig heavy chain gene segments that remain in the same genomic order and without genomic modification. It is unclear whether the phrase encompasses any Ig heavy chain gene segments that maintain their recombination signal sequences (RSSs) before recombination (pg 20, para 45). Accordingly, those of skill would not be able to determine when they were infringing on the claim.
Response to arguments
Applicants argue the claim uses the term according to its plain and ordinary meaning as discussed in paragraph 39. Applicants’ argument is not persuasive because para 39 discusses “variable region loci” which is not what is claimed, because the metes and bounds of “loci” are unclear, and because use of “loci” in combination with “variable region” makes it even more confusing. Paragraph 39 just says “unrearranged” “variable region loci” are capable of rearranging to encode a variable domain. Applicants response fails to address whether the phrase is limited to Ig heavy chain gene segments that remain in the same genomic order and without genomic modification or whether the phrase encompasses any Ig heavy chain gene segments that maintain their recombination signal sequences (RSSs) before recombination (pg 20, para 45). Applicants point to para 45, 52, and paragraph 10 of the Declaration, none of which define when variable “regions” are “unrearranged” or whether they are gene segments or something else.
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.
Claim Rejections - 35 USC § 103
Withdrawn rejections
The rejection of claims 1, 3, 5, 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) has been withdrawn. The combined teachings of Chamberlain and Mendez taught a mouse comprising a humanized MHC gene and a humanized Ig gene, wherein the mouse expresses humanized MHC and Ig genes. The combined teachings of Chamberlain and Mendez did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claim 3 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) as applied to claims 1, 3, 5, 8, 12, 14, 35, 36 and further in view of MacDonald (8697940) has been withdrawn. The combined teachings of Chamberlain, Mendez and MacDonald taught a mouse comprising a humanized MHC gene, a humanized Ig gene, and a human ADAM6 gene, wherein the mouse expresses humanized MHC and Ig and ADAM6. The combined teachings of Chamberlain and Mendez and MacDonald did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claim 4 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) as applied to claims 1, 3, 5, 8, 12, 14, 35, 36 and further in view of WO 2017210586 has been withdrawn. The combined teachings of Chamberlain, Mendez, and WO 2017210586 taught a mouse comprising a humanized MHC gene and a humanized Ig gene and a TdT gene, wherein the mouse expresses humanized MHC, humanized Ig, and TdT. The combined teachings of Chamberlain and Mendez and WO 2017210586 did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claims 6, 37 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) as applied to claims 1, 3, 5, 8, 12, 14, 35, 36 and further in view of 9615550 has been withdrawn. The combined teachings of Chamberlain, Mendez, and 9615550 taught a mouse comprising a humanized MHC gene and a humanized Ig gene and a humanized β2m gene, wherein the mouse expresses humanized MHC, humanized Ig, and humanized β2m. The combined teachings of Chamberlain and Mendez and 9615550 did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
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) has been withdrawn. The combined teachings of Woods and Mendez taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding an HLA II and a human Ig gene. They did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claim 3 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) as applied to claims 1, 3, 7, 8, 12, 14, 35, 38 and further in view of MacDonald (8697940) has been withdrawn. The combined teachings of Woods, Mendez, MacDonald taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding an HLA II and a human Ig gene. They did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claim 4 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) as applied to claims 1, 3, 7, 8, 12, 14, 35, 38 and further in view of WO 2017210586 has been withdrawn. The combined teachings of Woods, Mendez, and ‘586 taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding an HLA II and a human Ig gene. They did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claims 6, 37 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) as applied to claims 1, 3, 7, 8, 12, 14, 35, 38 and further in view of 9615550 has been withdrawn. The combined teachings of Woods, Mendez, ‘550 taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding an HLA II and a human Ig gene. They did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
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) has been withdrawn. The combined teachings of ‘835 and Mendez taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding an HLA I and a human Ig gene. They did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claim 3 under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156) as applied to claims 1, 3, 5, 9, 12, 14, 35, 36 and further in view of MacDonald (8697940) has been withdrawn. The combined teachings of ‘835, Mendez, and MacDonald taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding an HLA I and a human Ig gene. They did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claim 4 under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156) as applied to claims 1, 3, 5, 9, 12, 14, 35, 36 and further in view of WO 2017210586 has been withdrawn. The combined teachings of ‘835, Mendez, and ‘586 taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding an HLA I and a human Ig gene. They did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
The rejection of claims 6, 37 under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156) as applied to claims 1, 3, 5, 9, 12, 14, 35, 36 and further in view of 9615550 has been withdrawn. The combined teachings of ‘835, Mendez, and Spanier taught a genetic modified mouse whose genome comprises a nucleic acid sequence encoding an HLA I and a human Ig gene. They did not teach administering a composition comprising a non-rodent antigen presented in a peptide-binding groove of an MHC molecule as newly required in claim 1.
Pending rejections
A) Claims 1, 3, 5, 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) and Spanier (Nature Communications, 2016, Vol. 7, Article 11804, pg 1-11).
Chamberlain 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 (pg 7690, paragraph bridging col. 1-2; paragraph bridging pg 7690-7691). The teachings of Chamberlain are equivalent to item A) of claim 1 and a rodent that expresses an MHC comprising the HLA peptide-binding groove in item i) of 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 non-rodent antigen to the mouse and determining whether an antibody that specifically binds the antigen in context of an MHC complex is formed in the mouse.
However, Spanier administered a non-rodent antigen to a genetically modified mouse and determining whether an antibody that specifically binds the antigen in context of an MHC II complex is formed in the mouse (abstract; materials and methods).
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 HLA and Ig genes as described by Chamberlain and Mendez and using it to administer and antigen and determine whether it produced antibodies against an antigen:MHC complex as described by Spanier. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make human antibodies against an antigen in an in vivo model of humans.
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 5 has been included because it limits the MHC to an MHC I molecule and because Chamberlain taught an HLA-I that is an MHC I molecule.
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 the claims are not obvious for reasons cited on pg 45. Applicants’ arguments are not persuasive because they are not specific to the combined teachings of Chamberlain, Mendez, and Spanier. All of the limitations are taught. Motivational statements have been provided. Applicants infer Spanier teaches away on pg 47 and cite “pp. 31-31 of the OA2/AA response and paragraph 22 of the Badithe Declaration” – none of which are persuasive because Spanier explicitly administered p:MHC complexes to mice for tolerance research.
Applicants infer “unexpected results” on pg 47 and cite “pp. 33-35 of the OA2/AA response and paragraph 23-24 of the Badithe Declaration” – none of which are persuasive because the analysis fails to begin with what was expected based on these references, fails to take into account secondary considerations, and fails to compare what was expected with applicants’ results. Most importantly, para 8 of the declaration is limited to mice having being tolerant to the humanized proteins expressed in the mice; however, the concept was well-known, i.e. genetically modified mice that express humanized proteins at the time of gestation are tolerized to those proteins. The argument also appears to rely on the mice having the ability to discern antigens in a “self” MHC complex, but the claims make no requirement that the MHC in the pMHC complex is expressed in the mouse or is tolerized by the mouse.
Applicants’ discussion of “long-felt” need on pg 47 (citing “pp. 37-38 of the OA2/AA response and paragraph 7, 24 of the Badithe Declaration”) is not persuasive because the claims are obvious and the discussion is not specific to the combination of references.
B) Claims 1, 3, 7, 8, 12, 14, 35, 38 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) and Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11).
Claim 1 merely requires the mouse is capable of making an antibody against a non-rodent antigen in context of an MHC molecule; it does not require administering the non-rodent antigen to the mouse, determining whether the mouse makes antibodies against an antigen:MHC complex, or using the mouse in such an assay. This rejection has been added to point out that administering an antigen to a mouse and determining whether it makes antibodies to an antigen:MHC complex were well-know and was an obvious way to use cross-bred mice.
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 peptide-binding groove 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 non-rodent antigen to the mouse and determining whether an antibody that specifically binds the antigen in context of an MHC complex is formed in the mouse.
However, Spanier administered a non-rodent antigen to a genetically modified mouse and determining whether an antibody that specifically binds the antigen in context of an MHC II complex is formed in the mouse (abstract; materials and methods).
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 HLA II and Ig genes as described by Woods and Mendez and using it to administer and antigen and determine whether it produced antibodies against an antigen:MHC complex as described by Spanier. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make human antibodies against an antigen in an in vivo model of humans.
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 the claims are not obvious for reasons cited on pg 45. Applicants’ arguments are not persuasive because they are not specific to the combined teachings of Woods, Mendez, and Spanier. All of the limitations are taught. Motivational statements have been provided. Applicants infer Spanier teaches away on pg 47 and cite “pp. 31-31 of the OA2/AA response and paragraph 22 of the Badithe Declaration” – none of which are persuasive because Spanier explicitly administered p:MHC complexes to mice for tolerance research.
Applicants infer “unexpected results” on pg 47 and cite “pp. 33-35 of the OA2/AA response and paragraph 23-24 of the Badithe Declaration” – none of which are persuasive because the analysis fails to begin with what was expected based on these references, fails to take into account secondary considerations, and fails to compare what was expected with applicants’ results. Most importantly, para 8 of the declaration is limited to mice having being tolerant to the humanized proteins expressed in the mice; however, the concept was well-known, i.e. genetically modified mice that express humanized proteins at the time of gestation are tolerized to those proteins. The argument also appears to rely on the mice having the ability to discern antigens in a “self” MHC complex, but the claims make no requirement that the MHC in the pMHC complex is expressed in the mouse or is tolerized by the mouse.
Applicants’ discussion of “long-felt” need on pg 47 (citing “pp. 37-38 of the OA2/AA response and paragraph 7, 24 of the Badithe Declaration”) is not persuasive because the claims are obvious and the discussion is not specific to the combination of references.
C) Claims 1, 3, 5, 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) and Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11).
‘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 peptide-binding groove in item i) 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 non-rodent antigen to the mouse and determining whether an antibody that specifically binds the antigen in context of an MHC complex is formed in the mouse.
However, Spanier administered a non-rodent antigen to a genetically modified mouse and determining whether an antibody that specifically binds the antigen in context of an MHC complex is formed in the mouse (abstract; materials and methods).
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 HLA and Ig genes as described by ‘835 and Mendez and using it to administer and antigen and determine whether it produced antibodies against an antigen:MHC complex as described by Spanier. Those of ordinary skill in the art at the time of filing would have been motivated to do so to make human antibodies against an antigen in an in vivo model of humans.
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 5 has been included because it limits the MHC to an MHC I molecule and because ‘835 taught an HLA-I that is an MHC I molecule.
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 the claims are not obvious for reasons cited on pg 45. Applicants’ arguments are not persuasive because they are not specific to the combined teachings of ‘835, Mendez, and Spanier. All of the limitations are taught. Motivational statements have been provided. Applicants infer Spanier teaches away on pg 47 and cite “pp. 31-31 of the OA2/AA response and paragraph 22 of the Badithe Declaration” – none of which are persuasive because Spanier explicitly administered p:MHC complexes to mice for tolerance research.
Applicants infer “unexpected results” on pg 47 and cite “pp. 33-35 of the OA2/AA response and paragraph 23-24 of the Badithe Declaration” – none of which are persuasive because the analysis fails to begin with what was expected based on these references, fails to take into account secondary considerations, and fails to compare what was expected with applicants’ results. Most importantly, para 8 of the declaration is limited to mice having being tolerant to the humanized proteins expressed in the mice; however, the concept was well-known, i.e. genetically modified mice that express humanized proteins at the time of gestation are tolerized to those proteins. The argument also appears to rely on the mice having the ability to discern antigens in a “self” MHC complex, but the claims make no requirement that the MHC in the pMHC complex is expressed in the mouse or is tolerized by the mouse.
Applicants’ discussion of “long-felt” need on pg 47 (citing “pp. 37-38 of the OA2/AA response and paragraph 7, 24 of the Badithe Declaration”) is not persuasive because the claims are obvious and the discussion is not specific to the combination of references.
New rejections
D) Claims 1, 3, 5, 8, 12, 14, 35, 36 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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).
Chamberlain 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 (pg 7690, paragraph bridging col. 1-2; paragraph bridging pg 7690-7691). The teachings of Chamberlain are equivalent to item A) of claim 1 and a rodent that expresses an MHC comprising the HLA peptide-binding groove in item i) of 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 complex to a mouse was well known as described by Spanier who administered a non-rodent antigen to a genetically modified mouse and determining whether an antibody that specifically binds the antigen in context of an MHC complex is formed in the mouse (abstract; materials and methods). ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White also 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 Spanier, ‘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 5 has been included because it limits the MHC to an MHC I molecule and because Chamberlain taught an HLA-I that is an MHC I molecule.
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.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
E) Claim 3 is 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, Spanier, ‘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, Spanier, ‘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, Spanier, ‘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.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
F) Claim 4 is 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, Spanier, ‘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, Spanier, ‘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, Spanier, ‘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).
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
G) Claims 6, 37 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, Spanier, ‘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, Spanier, ‘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, 961550 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, Spanier, ‘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.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
H) Claims 1, 3, 7, 8, 12, 14, 35, 38 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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).
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 peptide-binding groove 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 Spanier who administered a non-rodent antigen to a genetically modified mouse and determining whether an antibody that specifically binds the antigen in context of an MHC complex is formed in the mouse (abstract; materials and methods). ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White also 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 Woods and Mendez followed by administering a pMHC complex to the mouse as described by Spanier, ‘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).
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
I) Claim 3 is 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, Spanier, ‘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, Spanier, ‘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, Spanier, ‘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.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
J) Claim 4 is 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, Spanier, ‘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, Spanier, ‘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, Spanier, ‘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).
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
K) Claims 6, 37 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, Spanier, ‘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, Spanier, ‘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, 961550 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, Spanier, ‘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.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
L) Claims 1, 3, 5, 9, 12, 14, 35, 36 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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).
‘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 peptide-binding groove in item i) 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 Spanier who administered a non-rodent antigen to a genetically modified mouse and determining whether an antibody that specifically binds the antigen in context of an MHC complex is formed in the mouse (abstract; materials and methods). ‘146; ‘020; ‘937; WO 96/04314; Mottez; Madden; Matsumura; Mage; Toshitani; Chung; Uger 1998; Uger 1999; and White also 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 the combined teachings of ‘835 and Mendez followed by administering a pMHC complex to the mouse as described by Spanier, ‘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 5 has been included because it limits the MHC to an MHC I molecule and because ‘835 taught an HLA-I that is an MHC I molecule.
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).
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
M) Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, 9, 12, 14, 35, 36 and further in view of MacDonald (8697940).
The combined teachings of ‘835, Mendez, Spanier, ‘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, Spanier, ‘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, Spanier, ‘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.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
N) Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over 9591835 in view of Mendez (Nature Genetics, 1997, Vol. 15, pg 146-156), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, 9, 12, 14, 35, 36 and further in view of WO 2017210586.
The combined teachings of ‘835, Mendez, Spanier, ‘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, Spanier, ‘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, Spanier, ‘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).
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
O) Claims 6, 37 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), Spanier (Nature Comm., 2016, Vol. 7, Article 11804, pg 1-11), 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, 9, 12, 14, 35, 36 and further in view of 9615550.
The combined teachings of ‘835, Mendez, Spanier, ‘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, Spanier, ‘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, 961550 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, Spanier, ‘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.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638