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 2, 3, 7-9, 14, 16, 18, 22, 23 have been canceled. Claims 30, 31 have been added. Claims 1, 4-6, 10-13, 15, 17, 19-21, 24-31 are pending.
Election/Restrictions
Applicants elected Group I, claims 1, 2, 4-22, without traverse in the reply filed on 8-7-24. In the office action sent 8-27-24, a rodent with a humanized neonatal Fc receptor (FcRn) gene, a cell with a humanized FcRn gene, and a method of using the rodent with a humanized FcRn gene were examined together.
Claim 26 remains directed to an invention that is independent or distinct from the invention originally claimed because it is drawn to a method of making a genetically modified mouse expressing a humanized FcRn using the ES cells of claim 20 for reasons of record. Claim 26 remains withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
Claims 1, 4-6, 10-13, 15, 17, 19-21, 24, 25, 27-31 are under consideration as they relate to a genetically modified rodent with a humanized neonatal Fc receptor (FcRn) gene, a genetically modified rodent cell with a humanized FcRn gene, and a method of using the genetically modified rodent to screen compounds.
Applicant's arguments filed 3-20-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Interpretation
It is assumed that the metes and bounds of the phrase “neonatal Fc receptor (FcRn)” were well known in the art at the time of filing (see Wikipedia definition of FcRn).
Claim Rejections - 35 USC § 112
Written Description
The rejection of claims 13, 15, 17, 19, 20, 24, 25, 27-29 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), written description, was withdrawn.
The rejection regarding a human or humanized β2M gene comprising a replacement of a nucleic acid sequence corresponding to exons 2-4 of an endogenous mouse β2M gene with a nucleic acid sequence comprising exons 2-4 of a human β2M gene as broadly encompassed by claim 13 other than a replacement of exons 2-4 of an endogenous β2M gene with exons 2-4 of a human β2m gene was withdrawn in view of the amendment which deletes “corresponding”.
The rejection regarding a mouse cell whose genome comprises a humanized FcRn gene as broadly encompassed by claim 19 other than a mouse cell that functionally expresses the humanized FcRn protein was withdrawn in view of the amendment which requires the humanized FcRn gene encodes a functional humanized FcRn comprising the human FcRn extracellular domain and the mouse FcRn cytoplasmic domain. Applicants’ arguments filed 9-4-25 point out that not all mouse cells, e.g. ES cells, will express the humanized FcRn.
Enablement
The rejection of claims 13, 15, 17, 19, 20, 24, 25, 27-29 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), enablement, was withdrawn. The rejection regarding a human or humanized β2M gene comprising a replacement of a nucleic acid sequence corresponding to exons 2-4 of an endogenous mouse β2M gene with a nucleic acid sequence comprising exons 2-4 of a human β2M gene as broadly encompassed by claim 13 other than a replacement of exons 2-4 of an endogenous β2M gene with exons 2-4 of a human β2m gene was withdrawn in view of the amendment which deletes “corresponding”.
The rejection regarding a mouse cell whose genome comprises a humanized FcRn gene as broadly encompassed by claim 19 other than a mouse cell that functionally expresses the humanized FcRn protein was withdrawn in view of the amendment which requires the humanized FcRn gene encodes a functional humanized FcRn comprising the human FcRn extracellular domain and the mouse FcRn cytoplasmic domain. Applicants’ arguments filed 9-4-25 point out that not all mouse cells, e.g. ES cells, will express the humanized FcRn.
Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 31 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 31 refers to the mouse ES cell of claim 1, but claim 1 is drawn to a genetically modified mouse. Therefore, claim 31 does not further limit claim 1. Claim 31 should be dependent upon claim 20.
35 USC § 102
The rejection of claims 1, 4-6, 8, 10-12, 19-21, 23-25 under 35 U.S.C. 102a1 as being anticipated by Viuff (J. Controlled Release, 2016, Vol. 223, pg 22-30) was withdrawn. Viuff taught a genetically modified mouse whose genome comprises a endogenous FcRn gene comprising a replacement of an endogenous FcRn exons 3 and 4 with cDNA encoding hFcRn into exon 2 “so as to keep it under control of the mouse endogenous promoter” (pg 23, section 2.1; Fig. 1A). While the humanized FcRn gene described by Viuff comprised a replacement of endogenous FcRn exons 3 and 4 (perhaps more) with cDNA encoding hFcRn and expression of full length hFcRn, Viuff did not teach expressing a humanized FcRn comprising a human FcRn extracellular domain and a mouse FcRn cytoplasmic domain as required in claim 1.
Claim Rejections - 35 USC § 103
Withdrawn rejections
The rejection of claims 1, 4-6, 10-12, 19-21, 24, 25 under 35 U.S.C. 103 as being unpatentable over Viuff (J. Controlled Release, 2016, Vol. 223, pg 22-30) in view of Proetzel (Methods, 2014, Vol. 65, pg 148-153) was withdrawn. Viuff taught a genetically modified mouse whose genome comprises a humanized FcRn gene comprising replacement of a portion of endogenous FcRn exon 2 with cDNA encoding hFcRn “so as to keep it under control of the mouse endogenous promoter” (pg 23, section 2.1; Fig. 1A). Exons 1, part of exon 2, and exons 3-7 of the endogenous FcRn gene remain intact (Fig. 1A). Viuff did not teach expressing a humanized FcRn comprising a human FcRn extracellular domain and a mouse FcRn cytoplasmic domain as required in claim 1. Contrary to the office action sent 7-7-25, Viuff did not reference or contemplate replacing portions of an endogenous mouse FcRn gene with its human counterpart (pg 23, col. 1, 1st partial paragraph). While Viuff cites Proetzel (reference 17), Proetzel is limited to knocking out an endogenous FcRn gene and a randomly inserting its human counterpart. The combined teachings of Viuff and Proetzel did not teach replacing a sequence encoding endogenous FcRn extracellular domain with a sequence encoding a human FcRn extracellular domain as required in claim 1 or 19.
The rejection of claims 13, 15, 17, 27-29 under 35 U.S.C. 103 as being unpatentable over Viuff (J. Controlled Release, 2016, Vol. 223, pg 22-30) in view of Proetzel (Methods, 2014, Vol. 65, pg 148-153) as applied to claims 1, 4-6, 10-12, 19-21, 24, 25 and further in view of 20130111617 and 20130185819 was withdrawn for reasons set forth above.
Pending rejection
A) Claims 1, 4-6, 10-13, 15, 17, 19-21, 24, 25, 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Viuff (J. Controlled Release, 2016, Vol. 223, pg 22-30) in view of Macdonald (20200375159), Murphy (20230232795; 17967510), Macdonald (20200375160; 16991283), Macdonald (2013011617), Guo (20130185819), Proetzel (Methods, 2014, Vol. 65, pg 148-153).
Viuff taught a genetically modified mouse whose genome comprises a humanized FcRn gene comprising replacement of a portion of endogenous FcRn exon 2 with cDNA encoding hFcRn “so as to keep it under control of the mouse endogenous promoter” (pg 23, section 2.1; Fig. 1A). Exons 1, part of exon 2, and exons 3-7 of the endogenous FcRn gene remain intact (Fig. 1A).
Viuff did not replace a nucleic acid sequence encoding an endogenous FcRn extracellular domain with a nucleic acid sequence encoding a human FcRn extracellular domain or expressing a humanized FcRn comprising a human FcRn extracellular domain and a mouse FcRn cytoplasmic domain in the mouse as required in claim 1.
However, it was well known to replace just an endogenous nucleic acid sequence encoding an extracellular domain of a protein with a sequence encoding a human extracellular domain and expressing a humanized protein comprising the human extracellular domain and the endogenous cytoplasmic domain (see claims of Macdonald, Murphy, Macdonald, Macdonald, Guo). Macdonald taught doing so in MHC molecules, Murphy taught doing so in FcγRI molecule, Macdonald (‘159) taught doing so in MCH molecules, Macdonald (‘617) taught doing so in β macroglobulin (2βm) molecules (pg 12-16; para 108-131), Guo taught doing so in 2βm (pg 56, para 210). The sequence of human and mouse cytoplasmic and extracellular coding sequences of 2βm were well known as shown by Macdonald and Guo.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a genetically modified mouse whose genome comprises a humanized FcRn gene as described by Viuff with a replacement of a sequence encoding an endogenous extracellular domain with a sequence encoding a human extracellular domain leaving the endogenous cytoplasmic domain intact as described by Macdonald, Macdonald, Murphy, and Macdonald. Those of ordinary skill in the art at the time of filing would have been motivated to replace just the extracellular domain to have the human functional extracellular domain tested in vivo while leaving the endogenous cytoplasmic domain intact for cell stability, i.e. the mouse portion of the chimeric FcRn remains intact with cytoplasmic mouse cellular machinery responsible for trafficking, membrane retention, recycling, and degradation required for basic expression. The cytoplasmic domain contains motifs that interact with intracellular proteins involved in ER export, endocytosis, recycling, ubiquitination, cytoskeletal anchoring. If the chimeric FcRn in claim 1 were expressed in human cells, the same motifs in the mouse cytoplasmic domain would bind less efficiently to the corresponding human proteins, leading to reduced surface stability. Therefore, those of skill would want to maintain the mouse cytoplasmic and transmembrane domains to ensure expression stability in mouse cells. The humanized FcRn protein obtained by combining the teachings of Viuff, Macdonald, Macdonald, Murphy, and Macdonald results in expression of an FcRn that has a human extracellular domain and a mouse cytoplasmic domain as required in claim 1.
Viuff successfully expressed a humanized FcRn gene (pg 23, section 2.1; Fig. 1A), and Macdonald, Murphy, Macdonald, Macdonald, Guo successfully did so in MHC molecules, FcγRI molecules, and 2βm. The combined teachings of Viuff, Macdonald, Murphy, Macdonald, Macdonald, Guo handily provide a reasonable expectation of successfully humanizing just the extracellular domain of a FcRn gene and successfully expressing a chimeric FcRn in which just the extracellular domain is humanized in a genetically modified mouse as required in claim 1.
Viuff did not teach expressing a humanized FcRn comprising a human FcRn extracellular domain, a human FcRn transmembrane domain, and a mouse FcRn cytoplasmic domain as required in claim 4. However, it was well known to replace an endogenous nucleic acid sequence encoding the extracellular and transmembrane domains of a protein with a sequence encoding human extracellular and transmembrane domains and expressing a humanized protein comprising the human extracellular and transmembrane domains and the endogenous cytoplasmic domain (see claims of each). Macdonald taught doing so in MHC molecules, Murphy taught doing so in FcγRI molecule, Macdonald (‘159) taught doing so in MCH molecules, Macdonald (‘617) taught doing so in β macroglobulin molecules (pg 12-16; para 108-131). The sequence of human and mouse transmembrane coding sequences of FcRn were well known as shown by Viuff and Proetzel. Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a genetically modified mouse whose genome comprises a humanized FcRn gene with a replacement of a sequence encoding endogenous FcRn extracellular and transmembrane domains with a sequence encoding human FcRn extracellular and transmembrane domains leaving the endogenous FcRn cytoplasmic domain intact. Those of ordinary skill in the art at the time of filing would have been motivated to replace just the extracellular and transmembrane domains to have the human functional extracellular and transmembrane domains tested in vivo while leaving the endogenous cytoplasmic domain intact for cell stability for reasons set forth above.
The humanized FcRn gene obtained by combined teachings of Viuff and Proetzel contains a exons all endogenous mouse exons as claimed despite the fact that human exons 3-7 are intervening between exons 2 and 3 (Fig. 1A). This is equivalent to claim 5 and 6.
The humanized FcRn gene obtained by combined teachings of Viuff and Proetzel contains a exons all endogenous mouse exons as claimed despite the fact that human exons 3-7 are intervening between exons 2 and 3 (Fig. 1A). This is equivalent to claim 10.
The mice were homozygous for the humanized gene (pg 23, col. 1, last 3 lines; Fig. 1C caption) as required in claim 11.
The mice do not express endogenous FcRn as required in claim 12 because the FcRn gene has been humanized.
Viuff did not teach expressing a humanized β2m in the mouse as required in claim 13. However, the specification acknowledges it was well-known to do so as described by 20130111617 and 20130185819 (pg 56, para 210). Claims 27-47 of ‘617 and claims 12-16, 23-27 of ‘819 discuss various replacement to obtain the humanized β2M genes that are the same as those set forth in claims 13, 15, 17. Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a genetically modified mouse whose genome comprises a humanized FcRn gene as described by the combined teachings of Viuff, Macdonald, Murphy, Macdonald, Macdonald, Guo with a replacement of a sequence encoding an endogenous β2M with a sequence encoding a human β2M as described by Macdonald and Guo. Those of ordinary skill in the art at the time of filing would have been motivated to humanize the β2M gene because β2M interacts with the FcRn protein, thereby making the mouse more “humanized”.
Claims 15 and 27 have been included because ‘617 and ‘819 taught replacing all or part of the endogenous β2m gene or exons 2-4 of an endogenous β2m gene with exons 2-4 of a human β2m gene.
None of the scenarios described in ‘617 or ‘819 result in expression of a function endogenous mouse β2m which is equivalent to claims 17 and 28.
Viuff taught mouse ES cells as encompassed by claim 19.
Viuff taught mouse ES cells as required in claim 20.
Viuff administered antibodies to the mouse and tested “pharmacokinetic properties” (pg 25, section 2.9) and tested recovery (pg 25, section 2.9) as required in claim 21.
The humanized FcRn gene contains a exons all endogenous mouse exons as claimed despite the fact that human exons 3-7 are intervening between exons 2 and 3 (Fig. 1A). This is equivalent to claim 24.
The mice and all of their cells were homozygous (pg 23, col. 1, last 3 lines; Fig. 1C caption) as required in claim 25.
Claim 29 has been included because 20130111617 and 20130185819 taught the β2M modification was homozygous (Examples).
Response to arguments
Applicants argue the references do not teach all the limitations of the claims. Applicants’ argument is not persuasive for reasons set forth in the rejection above. All limitations are covered by the combination of references. Each reference need not teach all limitations. Applicants have not pointed to one specific limitation that is missing from the combined teachings of Viuff, Macdonald (20200375159), Murphy (20230232795; 17967510), Macdonald (20200375160; 16991283), Macdonald (2013011617), Guo, and Proetzel.
Applicants argue the references do not provide motivation for mice or mouse cells with the humanized FcRn gene. Applicants’ argument is not persuasive. Those of ordinary skill in the art at the time of filing would have been motivated to replace just the extracellular domain to have the human functional extracellular domain tested in vivo while leaving the endogenous cytoplasmic domain intact for cell stability, i.e. the mouse portion of the chimeric FcRn remains intact with cytoplasmic mouse cellular machinery responsible for trafficking, membrane retention, recycling, and degradation required for basic expression. The cytoplasmic domain contains motifs that interact with intracellular proteins involved in ER export, endocytosis, recycling, ubiquitination, cytoskeletal anchoring. If the chimeric FcRn in claim 1 were expressed in human cells, the same motifs in the mouse cytoplasmic domain would bind less efficiently to the corresponding human proteins, leading to reduced surface stability. Therefore, those of skill would want to maintain the mouse cytoplasmic and transmembrane domains to ensure expression stability in mouse cells.
The concept of replacing just the extracellular domain of a mouse receptor with a human extracellular domain was well-known and was handily performed in a number of proteins that were successfully expressed in genetically modified mice.
Applicants argue Zhu (2019) contradicts motivation for using a human extracellular domain because “the design of a humanization strategy is far from routine”. This appears to be a “lack of reasonable expectation of success” argument. Applicants’ argument and Zhu are not persuasive. First, Zhu was filed after the effective filing date and cannot be used to establish what was expected. Second, the statement cited by applicants in Zhu refers to Table 2 (pg 3) which refers to whole gene humanization and large gene cluster humanization. Third, and most importantly in this case, Viuff successfully expressed a humanized FcRn gene (pg 23, section 2.1; Fig. 1A), and Macdonald, Murphy, Macdonald, Macdonald, Guo successfully did so in MHC molecules, FcγRI molecules, and 2βm. The combined teachings of Viuff, Macdonald, Murphy, Macdonald, Macdonald, Guo handily provide a reasonable expectation of successfully humanizing just the extracellular domain of a FcRn gene and successfully expressing a chimeric FcRn in which just the extracellular domain is humanized in a genetically modified mouse as required in claim 1.
Applicants’ discussion on pg 10 is noted, but it is limited to the limitation of mouse FcRn exons 1 and 2 in claim 6. Applicants point out hFcRn cDNA was inserted into exon 2 of the mouse FcRn gene but then somehow leaps to a conclusion that “since there is a deletion in the exon 2 coding sequence, the mouse of Viuff does not comprise endogenous exons 1-2”. Applicants’ argument is not persuasive. Viuff makes no statement about deleting exon 2; inserting hFcRn cDNA into exon 2 does not delete exon 2 – it merely is an insertion. Viuff left exon 1 intact, so exon 1 is still there.
Applicants argue the mice have beneficial characteristics, e.g. faster antibody clearance than wild-type mice and reduced levels of mouse IgG in the blood. Applicants’ argument is not persuasive. If this is an “unexpected results” argument, such an argument must begin with what was expected, it must take secondary considerations into account, and it must compare applicants’ results to what was expected.
Double Patenting
The claims are patentably distinct from the claims allowed in US Patent 11576984 (parent application 16363774) because the claims of ‘984 are drawn to a method of using a patentably distinct rodent, i.e. a genetically modified mouse whose genome comprises a replacement of an endogenous nucleic acid sequence encoding immunoglobulin G2a (IgG2a) heavy chain constant domain 1 (CH1), hinge (H), heavy chain constant domain 2 (CH2), and heavy constant domain 1 (CH3) with nucleic acids encoding human IgG1 CH1, H, CH2, and CH3 domains, wherein the mouse functionally expresses IgG antibodies comprising the human IgG1 CH1, H, CH2, and CH3 domains, has decreased mouse-anti-human antibody response to human IgG1 antibodies compared to a mouse that does not functionally express IgG antibodies comprising the human IgG1 CH1, H, CH2, and CH3 domains, and has a disease symptom; and
(b) determining the therapeutic effect of the human IgG1 antibody on the disease symptom.
The art at the time of filing did not reasonably teach or suggest the amino acid sequence of SEQ ID NO: 16 as required in claims 30 and 31.
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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
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