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 .
Priority
The instant application is a national stage entry under 35 U.S.C. § 371 of PCT/CN2022/095694 (filed 05/27/2022). Acknowledgement is made of Applicants’ claim for priority to foreign application CN202110595203.X (filed 05/28/2021).
Election/Restrictions
Applicant’s election with traverse of Group I in the reply filed on 03/17/2026 is acknowledged. The traversal is on the ground the IL1RAP gene of Radcliffe, et al. is endogenous to the transgenic animal. This point is well taken. The restriction has been reconsidered. The Groupings remain the same, however a new reference, Venter, et al. (US 2007/0037165) is newly relied upon. The restriction is updated as follows:
Group I, claims 1-10, 24, 28, 56-57, drawn to a genetically modified, non-human animal who genome comprises at least one chromosome comprising a sequence encoding a human or chimeric interleukin-1 receptor accessory protein (IL1RAP) (i.e., a first product).
Group II, claims 42-45, drawn to a method of making a genetically-modified, non-human animal comprising a sequence encoding a region of human IL1RAP (i.e., a first method of making said first product).
Group III, claims 60, 68, drawn to a method of determining the effectiveness of a therapeutic agent targeting IL1RAP (i.e., a first method of using said first product).
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
Groups (I-III) lack unity of invention because even though the inventions of these groups require the shared technical feature of a genetically modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric IL1RAP, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view Venter, et al. (US 2007/0037165).
Specifically, Venter, et al. teaches human disease-associated genes and corresponding proteins, including amino acid sequence SEQ ID NO: 11319 (par. 0028); as evidenced by NCBI Reference Sequence NP_002173, the amino acid sequence set forth in SEQ ID NO: 11319 encodes for IL1RAP. (Please see Office Action Appendix I for sequence alignments and percent identity.) Venter, et al. further teaches an embodiment wherein SEQ ID NO: 11319 is used to produce a transgenic mouse, wherein the sequence is introduced into said transgenic animal’s genome and integrated therein (pars. 0212-0213). This reads on the shared technical feature set forth above. Thus, unity of invention is lacking among the inventions of Groups I, II, and II a posteriori.
Therefore, Applicants’ previous election of Group I is upheld; claims 1-10, 24, 28, and 56-57 read on the elected invention and are examined on the merits herein.
Claim Interpretation
The following comments are made to establish broadest reasonable interpretation for the record.
Regarding claims 1-4, 8-9, 24, 28, 56-57: These claims recite limitations directed to a genetically-modified, non-human animal whose genome comprises a human or chimeric IL1RAP. The term chimeric, as supported by definition provided in the instant specification, is interpreted as an amino or nucleic acid sequence wherein two or more portions of the sequence are from different species, or at least one portion of the sequence does not correspond to the wildtype sequence in the animal (pg. 22; pars. 1-2).
Regarding claims 9-10: Claim 9 is directed to the sequence encoding the human or chimeric interleukin-1 receptor accessory protein (IL1RAP) of the genetically-modified, non-human animal of claim 1, further narrowing the scope by reciting the sequence encoding the human or chimeric IL1RAP comprises a part of exons 2 through 9 of the human IL1RAP nucleotide sequence; claim 10 recites wherein the part of exon 2 comprises at least 10 bp of the human IL1RAP nucleotide sequence, and the part of exon 9 comprises at least 10 bp of the human IL1RAP nucleotide sequence.
The limitation recited in claim 9 is interpreted as requiring at least a portion of exons 2 through 9 of the IL1RAP nucleotide sequence as sharing 100% sequence identity to the corresponding portions of a human IL1RAP nucleotide sequence. That is to say, if a prior art reference teaches a transgenic mouse comprising e.g., a murine IL1RAP nucleotide sequence wherein the sequence(s) encoding exons 2 through 9, or portions thereof, are replaced with sequence(s) encoding exons 2 through 9, or portions thereof, of a human IL1RAP nucleotide sequence, such a reference would be within the scope of the instant claims. Alternatively, if a prior art reference teaches a transgenic mouse wherein endogenous IL1RAP is not expressed, and instead has been modified to express only exogenous human IL1RAP, such a reference would be within the scope of the instant claims.
Table 2 of the instant Specification (pg. 14) provides guidance for the relevant portions/residues of exons 2 through 9 in reference to SEQ ID NO: 2, copied here for ease of reference:
PNG
media_image1.png
455
526
media_image1.png
Greyscale
As supported by Table 2 above, a human or chimeric IL1RAP nucleotide sequence which shares any percentage of sequence identity to each of the corresponding exon portions of SEQ ID NO: 2 above (e.g., residues 1 through 400 of SEQ ID NO: 2) reads on the limitations recited in claim 9. Further, as residues 1 through 367 of SEQ ID NO: 2 comprises the first 16 residues of exon 9, any human or chimeric IL1RAP nucleotide sequence which shares 100% sequence identity to residues 1 through 367 of SEQ ID NO: 2 necessarily reads on the limitations of claim 9, and the limitations of claim 10.
Additionally, SEQ ID NO: 8 shares 100% identity to residues 1 through 350 of SEQ ID NO: 2 (i.e., exons 2 through 8) and 96% identity to residues 351 through 400 of SEQ ID NO: 2 (i.e., exon 9); please see pg. 4 of Office Action Appendix I. Therefore, as claim 9 requires the IL1RAP sequence to comprise only a part of exons 2 through 9, any human or chimeric IL1RAP nucleotide sequence which shares 100% sequence identity to SEQ ID NO: 8 necessarily reads on the limitations recited in the instant claims.
Regarding claim 28: This claim is directed to the genetically-modified, non-human animal of claim 24, reciting the limitation wherein one or more cells expresses a chimeric IL1RAP having one or more humanized extracellular regions, transmembrane regions, and cytoplasmic regions. The term humanized, as supported by the instant specification, is interpreted as an amino or nucleic acid sequence wherein at least a portion of the sequence is from the human sequence (pg. 22; pars. 3-4).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-6, and 8-10 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Venter, et al. (US 2007/0037165), as evidenced by National Center for Biotechnology Information (NCBI Reference Sequence NP_002173).
Venter, et al. teaches variant protein sequences and methods of use for the same (Abstract).
Regarding claims 1, 3-6, 8-10: Venter, et al. teaches human disease-associated genes and corresponding proteins, including amino acid sequence SEQ ID NO: 11319 (par. 0028); as evidenced by its 100% shared identity to NCBI Reference Sequence NP_002173, the amino acid sequence set forth in SEQ ID NO: 11319 encodes for IL1RAP. Additionally, SEQ ID NO: 11319 shares 98.6% sequence identity with SEQ ID NO: 8, and 100% sequence identity with residues 1 to 367 and 21 to 367 of SEQ ID NO: 2. Please see Office Action Appendix I for sequence alignments (pgs. 5-6) and percent identity (pg. 6).
Venter, et al. further teaches an embodiment wherein SEQ ID NO: 11319 is used to produce a transgenic mouse, wherein the sequence is introduced into mouse’s genome and integrated therein (pars. 0212-0213). This anticipates:
the genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric interleukin-1 receptor accessory protein (IL1RAP) limitation recited in claim 1;
the wherein the human or chimeric IL1RAP comprises a sequence encoding an amino acid sequence that is at least 70% identical to SEQ ID NO: 8 limitation recited in claim 3;
the wherein the human or chimeric IL1RAP comprises an amino acid sequence that is at least 70% identical to amino acids 1-367 of SEQ ID NO: 2 or amino acids 21-367 of SEQ ID NO: 2 limitations recited in claim 4;
the wherein the animal is a rodent limitation recited in claim 5;
the wherein the animal is a mouse limitation recited in claim 6;
the wherein the animal has one or more cells expressing human or chimeric IL1RAP limitation recited in claim 8;
the wherein the sequence encoding the human or chimeric IL1RAP comprises a part of exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8 and a part of exon 9 of the human IL1RAP nucleotide sequence limitations recited in claim 9; and
the wherein the part of exon 2 comprises at least 10 bp of the human IL1RAP nucleotide sequence, and the part of exon 9 comprises at least 10 bp of the human IL1RAP nucleotide sequence limitations recited in claim 10.
Claims 1-2, 5-8, 24, 28, and 56 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Yang and Gu (WO 2020/154348).
Yang and Gu (hereinafter Yang) teaches microglial or myeloid expressed Alzheimer's disease associated gene reporter constructs, cell lines and transgenic animals and their use (Abstract).
Regarding claims 1, 5-8: Yang teaches a germline-transmitted genome-engineered animal, e.g., transgenic animal (pg. 4; par. 8), comprising a transgene which encodes a human microglial or myeloid expressed Alzheimer's disease associated (ME-AD) gene (pg. 38; par. 5). In an embodiment, an entire human ME-AD gene is added to a mouse cell to make human ME-AD transgenic mice; these mice are bred to obtain a mouse that expresses only human ME-AD protein (pg. 39; par. 1). Yang teaches an embodiment wherein the ME-AD gene is IL1RAP (pg. 4; par. 3). This anticipates:
the genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric interleukin-1 receptor accessory protein (IL1RAP) limitation recited in claim 1;
the wherein the animal is a rodent limitation recited in claim 5;
the wherein the animal is a mouse limitation recited in claim 6;
the wherein the animal does not express endogenous IL1RAP as compared to that of an animal without genetic modification limitation recited in claim 7; and
the wherein the animal has one or more cells expressing human or chimeric IL1RAP limitation recited in claim 8.
Regarding claim 2: Following the above discussion, Yang teaches an embodiment wherein the construct comprising the IL1RAP gene comprises a genomic regulatory element of the gene (pg. 4; par. 2). Further disclosed is an embodiment wherein IL1RAP is integrated into the genome of the mouse and replaces the homologous genomic segment in the mouse genome (pg. 5; par. 6). This anticipates the wherein the sequence encoding the human or chimeric IL1RAP is operably linked to an endogenous regulatory element at the endogenous IL1RAP gene locus in the at least one chromosome limitation recited in claim 2.
Regarding claim 24: Following the above discussion, Yang teaches an embodiment wherein the transgene is inserted into the endogenous genomic region through gene targeting (pg. 70; par. 4); this anticipates the genetically-modified, non-human animal, wherein the genome of the animal comprises an insertion of a sequence encoding a human or a chimeric IL1RAP at an endogenous IL1RAP gene locus limitation of claim 24.
Regarding claim 28: Following the above discussion, Yang teaches an embodiment wherein the human IL1RAP gene is under the control of the endogenous promoter (pg. 39; par. 4). As the promoter is the only murine component in this embodiment, this anticipates the wherein the animal has one or more cells expressing a chimeric IL1RAP having one or more humanized extracellular regions, transmembrane regions, and cytoplasmic regions, wherein one or more of the humanized extracellular regions comprise a sequence that is at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% identical to the corresponding extracellular region of human IL1RAP limitations recited in claim 28.
Regarding claim 56: Following the above discussion, Yang teaches an embodiment wherein the animal contains a transgene encoding more than one human ME-AD gene (pg. 37, par. 2; pg. 38; par. 5). This anticipates the wherein the animal further comprises a sequence encoding an additional human or chimeric protein limitation recited in claim 56.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10, 24, 28, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Yang and Gu (WO 2020/154348) in view of Venter, et al. (US 2007/0037165), as evidenced by National Center for Biotechnology Information (NCBI Reference Sequence NP_002173).
The teachings of Yang are set forth above; claims 1-2, 5-8, 24, 28, and 56 are anticipated by the same.
The teachings of Venter, et al. are set forth above.
Regarding claims 3-4, 9-10: Following the above discussion, Yang does not teach the sequence limitations recited in the instant claims.
However, Venter, et al. teaches human disease-associated genes and corresponding proteins, including amino acid sequence SEQ ID NO: 11319 (par. 0028); as evidenced by its 100% shared identity to NCBI Reference Sequence NP_002173, the amino acid sequence set forth in SEQ ID NO: 11319 encodes for IL1RAP. Additionally, SEQ ID NO: 11319 shares 98.6% sequence identity with SEQ ID NO: 8, and 100% sequence identity with residues 1 to 367 and 21 to 367 of SEQ ID NO: 2. Please see Office Action Appendix I for sequence alignments (pgs. 5-6) and percent identity (pg. 6). This reads on:
the wherein the human IL1RAP comprises a sequence encoding an amino acid sequence that is at least 70% identical to SEQ ID NO: 8 limitation recited in claim 3;
the wherein the human IL1RAP comprises an amino acid sequence that is at least 70% identical to amino acids 1-367 of SEQ ID NO: 2 or amino acids 21-367 of SEQ ID NO: 2 limitations recited in claim 4;
the wherein the sequence encoding the human IL1RAP comprises a part of exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8 and a part of exon 9 of the human IL1RAP nucleotide sequence limitations recited in claim 9; and
the wherein the part of exon 2 comprises at least 10 bp of the human IL1RAP nucleotide sequence, and the part of exon 9 comprises at least 10 bp of the human IL1RAP nucleotide sequence limitations recited in claim 10.
It would have been prima facie obvious to a person having ordinary skill in the art to have used the sequence set forth in SEQ ID NO: 11319 of Venter, et al. to generate the transgenic IL1RAP mouse of Yang. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; the skilled artisan would have been motivated to do so as it would have been obvious to use a known sequence. Further, as Venter, et al. teaches an embodiment wherein SEQ ID NO: 11319 is used to produce a transgenic mouse (pars. 0212-0213), one would have a reasonable expectation of success.
This renders obvious the limitations of claims 3-4 and 9-10.
Claims 1-2, 5-8, 24, 28, and 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Yang and Gu (WO 2020/154348) in view of Weinstein, et al. (US 2012/0192298), Lehman and Stairs (Cancer Growth Metastasis. 2015), and Gramatzki, et al. (Oncol Lett. 2016).
The teachings of Yang are set forth above; claims 1-2, 5-8, 24, 28, and 56 are anticipated by the same.
Weinstein, et al. teaches methods for creating an animal with at least one chromosomal edit (Abstract).
Lehman and Stairs (hereinafter Lehman) teaches the capabilities of genetic mouse models of cancers to recapitulate human carcinoma with single versus combinatorial genetic modifications (Abstract).
Gramatzki, et al. teaches the role of IL-33 in human gliomas (Abstract).
Regarding claim 57: It is set forth above Yang anticipates the genetically-modified, non-human animal whose genome comprises human IL1RAP and an additional human transgene (pgs. 4, 37-38). Yang does not teach the additional human or chimeric proteins recited in the instant claim.
However, Lehman teaches the relevance of genetically-engineered mouse models (GEMMs) of human cancer relies on how closely it is able to mimic the histologic, molecular, physiologic, and metastatic characteristics of the respective human cancer (pg. 1; col. 1, par. 1). The low frequency of cancer occurring in GEMMs with single gene manipulations may be related to cancer being a multistep process (pg. 1; col. 1, par. 2); e.g., no gliomagenesis in EGFRvIII mice but diffuse brain lesions in EGFRvIII/Ink4a/Arf mice, hypertrophy and hyperproliferation without glioma formation in PTEN mice but aggressive tumors in PTEN/Ink4a/Arf mice (pg. 3; Table 1). Thus, Lehman teaches GEMMs are likelier to provide meaningful data with combinatorial gene manipulations which more closely recapitulate the nuanced and rich interactions of said genes in a human cancer.
Gramatzki, et al. teaches IL-33 is expressed in human gliomas and associated with inferior survival in patients with recurrent glioblastoma (pg. 446; col. 2, par. 3). The median overall survival time of IL-33+ patients is significantly reduced compared to IL-33- patients (14 months vs. 34 months, respectively); likewise, the median post-recurrence survival time of IL-33+ patients is significantly reduced compared to IL-33- patients (4 months vs 10 months, respectively). There is a significant, positive correlation between mRNA levels of IL1RAcP (i.e., IL1RAP) and IL-33 (pg. 448, par. 1; Fig. 2D); IL1RAcP mRNA levels are significantly increased in glioblastoma patients compared to patients with grades 2 or 3 astrocytomas, as well as normal brain tissue samples (pg. 448, par. 1; Fig. 2C). However, IL-33 protein labeling indexes were not associated with progression-free survival in the glioblastoma patients; thus, IL-33 may contribute to tumor progression or antitumor activity, depending on IL-33 levels and the microenvironment (pg. 451; col. 1, par. 2). Gramatzki, et al. further teaches other members of the IL-1 family, e.g., IL-1β and IL-6, are expressed by glioma cells and modulate survival, migration, and invasion (pg. 451; col. 1, par. 1), important processes involved in cancer. Thus, Gramatzki, et al. teaches a role for both IL-33 and IL1RAP in glioblastomas, as well as the involvement of IL-1β and IL-6.
Weinstein, et al. teaches genetically-modified animals (par. 0005) comprising human exogenous sequences inserted at endogenous loci (par. 0125), wherein the sequences may encode IL-33, IL-6, and IL-1β (par. 0163).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have used the genetically-modified, non-human animal whose genome comprises human IL1RAP of Yang to generate a mouse model of glioblastoma by inserting human IL-33, IL-1β, and IL-6 sequences into the endogenous loci of the animal as taught by Weinstein, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would have been motivated to do so because, as taught by Lehman, genetically-modified animal models are useful for understanding tumorigenesis as well as offer utility for preclinical target validation and experimental therapeutic studies (pg. 1, col. 1, par. 1). In order to generate a mouse model of glioblastoma which more closely recapitulates the histologic, molecular, physiologic, and metastatic characteristics of glioblastoma, and therefore provide more meaningful data, as taught by Lehman (pg. 1; col. 1, pars. 1-2), the skilled artisan would be motivated to incorporate IL-33, IL-1β, and IL-6 into said model as these molecules play a role in glioblastoma, as taught by Gramatzki, et al (see e.g. pg. 451). Further, as Yang teaches the animal may contain more than one transgene (pg. 37; par. 2), and as Weinstein, et al. evidences generating a genetically-modified animal with human IL-33, IL-6, and IL-1β sequences is well within the purview of the skilled artisan, one would have more than a reasonable expectation of success.
This renders obvious the wherein the additional human or chimeric protein is IL6, IL33, and IL1B limitations recited in claim 57.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
Prosecution Insights