DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/12/2026 has been entered.
Applicant’s amendments to the claims and arguments filed on February 12, 2026 have been received. Claims 1, 3-5, 12, 16 have been amended, while claims 2, 6-11, 13-14, 17-19, 22, 24, 26-41, 43, 45-62 have been canceled. Claims 63-64 are newly added. Claims 1, 3-5, 12, 15-16, 20-21, 23, 25, 42, 44, 63 and 64 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-9, 12, 15, 16, 20, 38, and 39 (group 1) in the reply filed on March 14, 2025 was acknowledged.
Claims 21, 23, 25, 42 and 44 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 14, 2025.
Priority
This application is a 371 of PCT/CN2020/113618 filed on 09/04/2020, which claims priority from foreign applications 201910842697.X filed on 09/06/2019 and 202010049072.0 filed on 01/16/2020 in China.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Claims 1, 3-5, 12, 15, 16, 20, 63 and 64 are under consideration.
Allowable Subject Matter
The following claim is drafted by the examiner and considered to distinguish patentably over the art of record in this application, claim 1 is presented to applicant for consideration:
A transgenic mouse whose genome comprises a nucleic acid sequence encoding a chimeric tumor necrosis factor receptor 2 (TNFR2) protein at an endogenous TNFR2 gene locus, wherein the chimeric TNFR2 comprises a human TNFR2 extracellular region, an endogenous transmembrane region and an endogenous cytoplasmic region, wherein the chimeric TNFR2 comprises the amino acid sequence of SEQ ID NO: 9, and the nucleic acid sequence encoding the chimeric TNFR2 is operably linked to an endogenous regulatory element at the endogenous TNFR2 locus, wherein the mouse expresses the chimeric TNFR2 and does not express endogenous TNFR2, wherein an anti-human TNFR2 antibody can bind to the expressed chimeric TNFR2.
New-Claim Rejections - 35 USC § 112-scope of enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-5, 12, 15, 16, 20, 63 and 64 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A transgenic mouse whose genome comprises a nucleic acid sequence encoding chimeric tumor necrosis factor receptor 2 (TNFR2) protein comprising the amino acid sequence of SEQ ID NO: 9 operably linked to an endogenous regulatory element at the endogenous TNFR2 locus, and wherein said mouse expresses the humanized TNFR2 and does not express an endogenous mouse TNFR2 protein, and wherein an anti-human TNFR2 antibody can bind to the expressed chimeric TNFR2,
does not reasonably provide enablement for any other nonhuman animal, inserting human TNFR2 at any other locus, human or chimeric TNGR2 under control of any other regulatory sequence or a nonhuman animal without any phenotype, a nonhuman animal that has a humanized or chimeric TNFR2 extracellular region comprises a sequence that is at least 70% identical to extracellular region of human TNGR2 showing contemplated biological activity or a nonhuman animal whose genome comprises both endogenous TNFR2 and human TNFR2 operably linked to endogenous regulatory sequence at the endogenous locus or a chimeric nonhuman animal without any phenotype or said animal further comprising any other human /chimeric protein.
does not reasonably provide enablement for mouse in its genome comprises exon 1, any other portion of exon 2. Any other portion of exon 6, and exons 7-10 of a mouse TNFR2 gene; and any portion of exon 2, exons 3-5, and any portion of exon 6 of a human TNFR2 gene showing contemplated biological activity of an anti-human TNFR2 antibody can bind to the expressed chimeric TNFR2, or a mouse whose genome comprises the chimeric TNFR2 comprising an amino acid sequence that is at least 70% identical to SEQ ID NO: 4 (human TNFR2) or chimeric TNFR2 comprises an amino acid sequence that is at least 70% identical to amino acids 33-259 of SEQ ID NO: 4 (human extracellular domain of TNFR2) or SEQ ID NO: 9 (humanized TNFR2) or showing contemplated biological activity.
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 use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention & Breadth of the claims:
The claim are directed to a mouse whose genome comprises at least one chromosome comprising a sequence encoding a chimeric tumor necrosis factor receptor 2 (TNFR2) operably linked to an endogenous regulatory element at the endogenous TNFR2 gene locus in the at least one chromosome, wherein a sequence encoding any region of an endogenous TNFR2 is replaced with any sequence encoding any corresponding region of human TNFR2, wherein the mouse in its genome comprises exon 1, any portion of exon 2. any portion of exon 6, and exons 7-10 of a mouse TNFR2 gene; and any portion of exon 2, exons 3-5, and any portion of exon 6 of a human TNFR2 gene and wherein an anti-human TNFR2 antibody can bind to the expressed chimeric TNFR2. Dependent claims limit the chimeric TNFR2 comprises a human or humanized extracellular region or wherein the chimeric TNFR2 comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 4 or 70% identical to SEQ ID NO: 9 or at least 70% identical to amino acids 33-259 of SEQ ID NO: 4.
It is relevant to note that recitation of the term "region" or "portion" is broadly defines to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, to 600 nucleotides, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 to 200 amino acid residues. In some embodiments, the "region" or "portion" can be at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, signal peptide, extracellular region, transmembrane region, or cytoplasmic region. In some embodiments, a region, a portion, or the entire sequence of mouse exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, and/or exon 10 (e.g., exon 2, exon 3, exon 4, exon 5, and exon 6) are replaced by a region, a portion, or the entire sequence of the human exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, and/or exon 10 (e.g., exon 2, exon 3, exon 4, exon 5, and exon 6) sequence (see page 21 para. 2 of the specification).
Guidance of the Specification and The Existence of Working Examples:
The specification provides guidance of a transgenic mouse whose genome comprises humanized TNFR2 could be achieved by introducing into the endogenous mouse TNFR2 locus a gene sequence encoding the human TNFR2 (example 1). The specification teaches under control of a mouse TNFR2 regulatory element, a sequence about 8807 bp spanning from exon 2 (including only a part of exon 2) to exon 6 (including only a part of exon 6) of mouse TNFR2 gene was replaced with a corresponding human DNA sequence to obtain a humanized TNFR2 locus, thereby humanizing mouse TNFR2 gene (shown in FIG. 2). Figure 3 of the specification teaches the targeting strategy of the targeting vector. In this example, the conventional ES cell gene homologous recombination technique is used as an example to describe how to obtain a TNFR2 humanized mouse (see page 50). The results shows that this method can be used to construct genetically engineered TNFR2 mice and the genetic modification can be stably passed to the next generation without random insertions. The results of flow cytometry showed that the expression of mouse TNFR2 was detected in T cells, CD4+ T cells and B cells in the spleen cells of wild-type mice (FIGS. 9A, 10A, 11A,12A, 13A, 14A, 15A, and 16A). However, expression of human or humanized TNFR2 was not detected in the same cells of wild-type mice (FIGS. 9C, 10C, 11C, 12C, 13C, 14C, 15C, and 16C). In addition, expression of humanized TNFR2 was detected in homozygous cells of TNFR2 gene humanized mice (FIGS. 9D, 10D, 11D, 12D, 13D, 14D, 15D, and 16D). However, expression of mouse TNFR2 was not detected in the same cells of the TNFR2 gene humanized mice (FIGS. 9B, 10B, 11B, 12B, 13B, 14B, 15B, and 16B). After anti-mCD3 antibody stimulation, the expression of TNFR2 on the surface of immune cells in both wild-type and TNFR2 gene humanized mice increased to varying degrees. Among them, T cells and CD4+ T cells increased significantly (FIGS. 10A-10D, 12A-12D, and 14A-14D).
State of the Art & Predictability of the Art and the Amount of Experimentation Necessary:
Claims are drawn to a genetically-modified mouse whose genome comprises at least one chromosome comprising a sequence encoding a chimeric tumor necrosis factor receptor 2 (TNFR2) operably linked to an endogenous regulatory element at the endogenous TNFR2 gene locus in the at least one chromosome, wherein a sequence encoding any region of an endogenous TNFR2 is replaced with a sequence encoding any corresponding region of human TNFR2, and wherein the mouse in its genome comprises exon 1, any portion of exon 2. any portion of exon 6, and exons 7-10 of a mouse TNFR2 gene; and any portion of exon 2, exons 3-5, and a portion of exon 6 of a human TNFR2 gene. Dependent claims limit the chimeric TNFR2 comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 4 or 70% identical to 9 or 70% identical to amino acids 33-259 of SEQ ID NO: 4.
The guidance provided in the specification is limited to a coding sequence of the mouse TNFR2 gene exon part of 2 through part of exon 6 is replaced with a corresponding coding sequence of human homologous TNFR2 gene. The humanized mouse TNFR 2 gene DNA sequence (chimeric TNFR2 gene DNA) is as set forth in SEQ ID NO: 9 (see fig. 2). The art teaches “exclusion of introns, which might help to keep things simple in a humanization strategy, can potentially be disruptive. For example, when the xenobiotic sensor PXR (Pregnane X receptor) was originally humanized, some introns were excluded-it was later discovered that this caused a mis-splicing event as a result of exons 7 and 8 fusion, leading to creation of a new splice-acceptor site and variant whereby exon 5 spliced to exon 8 (see page 8, col. 1, para. 2). Further, it is not always clear how far one should extend genomic humanization in order to most faithfully recapitulate human gene expression in a mouse context. In eukaryotes, for example, it largely remains to be determined where and how transcription terminates, which may be many bp or even kb beyond the polyadenylation signal in a transcript. Transcription terminator proteins are involved in releasing mRNAs and RNA Polymerase II from each, and this is coupled to cleavage and polyadenylation of the 3ʹ end of mRNAs and associated with the effects of transcription boundary-associated RNAs, which include terminus-associated RNA. Termination can occur at different sites 3ʹ of the polyadenylation signal, and usually it is not known how far to humanize beyond the 3ʹ-UTR of a gene. Yet, these sequences can have profound effects on transcription and translation (see Zhu et al). The art further teaches genomic humanization studies have shown that phenotypes could range from relatively mild to apparently no different from wild-type mice (see page 6, col. 2, last para.).
The specification does not enable making and using a mouse with a chimeric TNFR2 gene comprising a humanized TNFR2 extracellular region and an endogenous cytoplasmic region, wherein the humanized TNFR2 extracellular region comprises a sequence that is at least 70% identical to the extracellular region of human TNFR2. The specification is limited to a mouse that expresses a humanized TNFR2 protein as set forth in SEQ ID NO: 9. The specification does not teach any variants with 70°/o or higher homology to SEQ ID NO: 4 or 9 that allow expression of TNFR2 showing contemplated biological phenotype other than 100% sequence identity to SEQ ID NO: 9. The specification does correlate any variants with at least 70% sequence homologous to amino acids 33-259 of SEQ ID NO: 4 or at least 70% of SEQ ID NO: 4 or 9 such that the desired region of the extracellular domain of TNFR2 would be humanized as required in claims. It is relevant to note that a host of species within the genus can be envisioned, the specification does not teach any variants as discussed supra. Maksimenko et al., (Acta Naturae, 2013 Vol. 5, No. 1, p. 33-46) reports that "The site at which the construct is integrated into the genome plays a crucial role in ensuring efficient transgene expression. Injected DNA is typically incorporated into the gene-poor regions, which are characterized by frequent DNA breaks. The chromatin in these regions typically exerts a negative influence on the expression of the transgene integrated nearby. In addition, several copies of the construct are typically integrated onto the same genome site, which can, in turn, lead to repression of transcription due to the formation of heterochromatin in repetitive sequences (e.g., bridging right column, p. 36 and left column, p. 37). Given the lack of guidance in the specification regarding variants of at least 70% sequence homologous to amino acids 33-259 of SEQ ID NO: 4 or at least 70% of SEQ ID NO: 4 or 9 that allow production of a humanized TNFR2 protein that is set forth in SEQ ID NO: 9 with the claimed genus of variant showing recited phenotype. The genus of variants encoding the humanized TNFR2 gene in the transgene construct, the genetic background of the transgenic animals, the form (linear or circular) of the DNA molecule, the DNA concentration, the DNA copy number, and the integration site of the transgene could determine the transgene expression in the transgenic animals and the resulting phenotype of the transgenic animals. It is emphasized that predictability of amino acid changes can be tolerated in a protein's amino acid sequence and to obtain the desired activity/utility requires a knowledge of and guidance with regard to which amino acids in the protein's sequence of extracellular protein of TNFR2, if any, are tolerant of modification and which are conserved (expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. The positions within a protein's sequence where modifications can be made with a reasonable expectation of success in obtaining a polypeptide having the desired activity/utility are limited in any protein and the result of such modifications is highly unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, eg multiple substitutions. The specification fails to disclose any other working examples of sequences as encompassed by the claims that could be used to express chimeric TNFR2 in mouse, wherein TNFR2 that is at least 70 % identical to SEQ ID NO: 4 or 9 or at least 70% of amino acid 33-259 of SEQ ID NO: 4. Further, the art teaches that “[t]he rules of the genome are not fully understood, nor are the full phenotypic consequences of creating mice with human genomic DNA” and “the design of a humanization strategy is far from routine. (Zhu, F Nature communications 10.1 (2019): 1-13, page 7, col. 2, para. 3, art of record). It is relevant to note that Zhu explicitly states that the “The phenotype of a genetic mouse model— transgenic or genomically humanized—is not always predictable, but when unexpected outcomes arise, such models can provide valuable insight from studying the mechanism of why the observed outcome is different from expectation. As an example, Zhu teaches “in larger-scale humanizing of the introns and exons of a gene, the mouse environment (chromosomal or cellular) causes unexpected phenotypes. Currently, this is unpredictable and must be assessed on a case-by-case basis, but does not preclude working with such animals. (Zhu, page 10).
The specification teaches that human TNFR2 extracellular region and mouse TNFR2 region are only 57% identical (see sequence homology between mouse and human EC region of SEQ ID NO: 2 and 4 ). The specification fails to describe what portions of the extracellular region fall into this genus and it was unknown as of Applicants' effective filing date that any of these portions would have the same structural and functional properties as that encoded by part of exon 2 or a portion of amino acid residue of extracellular region of an endogenous TNFR2 (encoding at least 70% identical to amino acids 33-259 of SEQ ID NO: 4 or at least 70% identical to SEQ ID NO: 4 or 9). There is no evidence on the record of a relationship between the structures of the nucleotide sequences coding for the claimed portions and the nucleotide sequence set forth by part of exon 2 or 70% identical to the extracellular region of human TNFR2 that would provide any reliable information about the structure of DNA molecules within the genus resulting in claimed biological phenotype. The artisan cannot envision the variants recited by clams, wherein 30% of the sequence of EC region of a human TNFR2 can be varied from those results from a replacement of on the nucleic acid encoding amino acids 33-259 of SEQ ID NO: 4 in the extracellular region. Additionally, human DNA and mouse DNA have very different regulatory elements and humanizing only a portion of a mouse gene may not work possibly due to aberrant splicing (see Scheer et al Drug Metab. Dispos. 38, 1046- 1053, 2010). As discussed above there is difference between different regions of human and mouse TNFR2, a person skilled in the art would have understood that humanizing only a portion of a mouse gene would not work due to aberrant splicing. One of skill in the art cannot envision the residues outside the cell that can be varied and still bind the antihuman TNFR2 antibody. Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would have to perform undue experimentation to determine how to make/use a mouse with different variant of TNFR2 encompassing any nucleic acid sequence encoding at least 70% sequence homologous to SEQ I DNO:4, 9 or amino acids 33-259 of SEQ ID NO: 4 other than nucleic acid encoding humanized TNFR2 comprising amino acid as set forth in SEQ ID NO: 9 showing the contemplated phenotype of an anti-human TNFR2 antibody that could bind to the expressed chimeric TNFR2 to make and use the mouse, without reasonable expectation of success.
New-Claim Rejections - 35 USC § 112- necessitated by amendments
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-5, 12, 15, 16, 20, 63 and 64 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claim embraces a mouse whose genome comprises at least one chromosome comprising a sequence encoding a chimeric tumor necrosis factor receptor 2 (TNFR2) operably linked to an endogenous regulatory element at the endogenous TNFR2 gene locus in the at least one chromosome, wherein a sequence encoding any region of an endogenous TNFR2 is replaced with any sequence encoding any corresponding region of human TNFR2, wherein the mouse in its genome comprises exon 1, any portion of exon 2. any portion of exon 6, and exons 7-10 of a mouse TNFR2 gene; and any portion of exon 2, exons 3-5, and any portion of exon 6 of a human TNFR2 gene and wherein an anti-human TNFR2 antibody can bind to the expressed chimeric TNFR2. Dependent claims limit the chimeric TNFR2 comprises a human or humanized extracellular region or wherein the chimeric TNFR2 comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 4 or 70% identical to SEQ ID NO: 9 or at least 70% identical to amino acids 33-259 of SEQ ID NO: 4.
The specification defines the term "region" or "portion" to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, to 600 nucleotides, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 to 200 amino acid residues. In some embodiments, the "region" or "portion" can be at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, signal peptide, extracellular region, transmembrane region, or cytoplasmic region. In some embodiments, a region, a portion, or the entire sequence of mouse exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, and/or exon 10 (e.g., exon 2, exon 3, exon 4, exon 5, and exon 6) are replaced by a region, a portion, or the entire sequence of the human exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, and/or exon 10 (e.g., exon 2, exon 3, exon 4, exon 5, and exon 6) sequence (see page 21 para. 2 of the specification).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now darned." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
The specification has described a mouse whose genome comprises a replacement, within the endogenous TNFR2 gene, with the corresponding human TNFR2 sequence such that the extracellular domain of the chimeric gene product is human and the remainder of the gene product is mouse. Claims 1 and 12, however, encompasses replacement of a portion or variants of the extracellular region with a portion or variants of the human extracellular region, to render it “humanized” or “chimeric”, requiring only 70% identity to the human TNFR2 as set forth in SEQ ID NO: 4 or 70% identical to humanized TNFR2 as set forth in SEQ ID NO: 9.
The specification has not described any portion sequences of the TNFR2 extracellular region that are within the genus as claimed that would serve the same function as a replacement of the whole. The replacement described in the specification results in a chimeric protein that has the same binding properties as fully human TNFR2. The specification has not described fragments or variants that would retain this property. The claims as amended require that anti human -TNFR2 effectively bind the expressed chimeric TNFR2. The skilled artisan cannot readily envision the genus of protein sequences that meet this functional limitation given the specification and in view of unpredictability disclosed art of record as discussed above in enablement section (see Zhu, Nature communications 10.1 (2019): 1-13 and Scheer et al Drug Metab. Dispos. 38, 1046- 1053, 2010 .
In the instant case the portions of the extracellular domain encompassed by the claims lack a written description. The specification fails to describe what portions of the extracellular region fall into this genus of humanized extracellular domains and it was unknown as of Applicants' effective filing date that any of these portions would have the same structural and functional properties as single, while extracellular domain replacement, in its entirety, taught by the specification. The claimed embodiments of portions encompassed within the genus lack a written description. There is no evidence on the record of a relationship between the structures of the nucleotide sequences coding for the claimed portions or variants with 70% sequence identity to SEQ ID NO:4 or 9 and the nucleotide sequence set forth by a replacement of the corresponding mouse sequence with sequence encoding amino acids 33-259 of SEQ ID NO: 9 (see fig. 26) that would provide any reliable information about the structure of DNA molecules within the genus. The human replacement region is also described at page 49 of the specification (see figure 2 and 6A-D). Additionally, claim 15 is drawn to a replacement of the extracellular region of an endogenous TNFR2 gene in a mouse yet also requires the resulting sequence by at least 70% identical to a human/mouse chimeric sequence (SEQ ID NO: 9). The skilled artisan cannot envision mouse where replacement of the extracellular domain of the endogenous gene with human sequence would result in sequence with 70% identity to human/mouse chimeric TNFR2 protein as set forth in sequence ID NO: 4 or 9. .
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc.. 48USPQ2d 1641,1646 (1998).
The skilled artisan cannot envision the variants recited by the claims, wherein 30% of the chimeric sequence can be varied amino acids are required to be present whereby the resulting protein would retain the biding activity of SEQ ID NO:9. One of skill in the art cannot envision the residues outside the cell that can be varied and still bind the antihuman TNFR2 antibody or the internal residues that retain signaling activity.
With the exception of the sequence referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides or polypeptides, and therefore conception is not achieved until reduction to practice has occurred regardless of the complexity or simplicity of the method of isolation. The skilled artisan cannot envision the detailed chemical structure of the encompassed nucleic acid molecules and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Bard, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In view of the above considerations one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by any member of the genus of portions of extracellular region encompassed by the claims. University of California v. Eli Lilly and Co.. 43 USPQ2d 1398,1404, 1405 held that "to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude "the inventor invented the claimed invention".
Withdrawn- Claim Rejections - 35 USC § 103
Claims 1, 3-5, 12, 15, 16 and 20 were rejected under 35 U.S.C. 103 as being unpatentable over Douni et al (J Exp Med. 1998, 188-1343-1352) as evidenced by Sheng (Frontiers in Immuno, 2018, 9, 1-9), NCBI accession no NP_001057.1 dated 2/06/2018) and Gurer (USPGPUB 20160157470, dated 6/09/2016). In view of Applicants’ amendment of base claims 1 and 12, introducing the limitation “wherein an anti-human TNFR2 antibody can bind to the expressed chimeric TNFR2, and wherein the mouse in its genome comprises exon 1, a portion of exon 2, a portion of exon 6, and exons 7-10 of a mouse TNFR2 gene; and a portion of exon 2, exons 3-5, and a portion of exon 6 of a human TNFR2 gene”, that is not taught by the combination of references, the previous rejection is rendered moot and hereby withdrawn.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Akassoglou (Proc Natl Acad Sci U S A 2003, 100, 709-714) discloses a transgenic mouse whose genome comprises human p75 TNFR cDNA (See 709). Akassoglou teaches producing a “humanized" mice that express human tmTNF in astrocytes and a physiologically regulated human p75TNFR transgene, in the absence of the endogenous (murine) p55TNFR (see abstract).
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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