DETAILED ACTION
Applicant’s amendment and response filed on 12/24/25 has been entered. Claims 152-153 have been canceled, and new claim 171 has been added. Claims 146, 148-150, 154-159, 161, and 166-171 are therefore currently pending and under examination in this application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Objections
The objection to claims 146, 148-150, 152-159, 161, and 166-170 because of the grammatical informalities is withdrawn in view of the cancellation of or amendments to the claims.
Double Patenting
The rejection of claims 146, 148-150, 155, 161, 166-168, and 170 on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,439,132, hereafter referred to as the ‘132 patent, is withdrawn in view of applicant’s submission of a terminal disclaimer on 12/24/25. The terminal disclaimer filed on 12/24/25 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,439,132 has been reviewed and is accepted. The terminal disclaimer has been recorded.
The rejection of claims 156-159 and 169 on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,439,132, hereafter referred to as the ‘132 patent, in view of U.S. Patent 9,565,841 (2017), hereafter referred to as Wang et al., and U.S. Patent Application Publication 2007/0197441 (8/23/07), hereafter referred to as Rixon et al., is withdrawn in view of applicant’s submission of a terminal disclaimer on 12/24/25. The terminal disclaimer filed on 12/24/25 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,439,132 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Claim Rejections - 35 USC § 112
Amended and new claims 146, 148-150, 154-159, 169, and 171 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement, is maintained. It is noted that the previous rejection of claims 161, 166-168, and 170 has been withdrawn view of applicant’s amendments to these claims. Note as well that claims 152-153, previously rejected, have been canceled. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The following scope of enablement still applies: the specification, while being enabling for a genetically modified mouse wherein the genome of the mouse comprises a replacement of a part of exon 1, exon 2 AND a part of exon 3 of the endogenous IL-17A gene, with a part of exon 1, exon 2 and a part of exon 3 of a human IL- 17A gene which encodes a human IL-17A protein, wherein the sequence encoding the human IL-17A protein is operably linked to an endogenous IL-17A regulatory element at the endogenous IL-17A gene locus, wherein the mouse expresses the human IL-17A protein, and an anti-human IL-17A antibody can specifically binds to the human IL-17A protein and inhibit the human IL-17A/mouse IL-17R signaling pathway, does not reasonably provide enablement for making or using any genetically modified mouse wherein a sequence comprising a part of exon 1, exon 2 and a part of exon 3 of a human IL- 17A gene which encodes a human IL-17A protein replaces a part of exon 1, exon 2 OR a part of exon 3 of the endogenous IL-17A gene, wherein the sequence encoding the human IL-17A protein is operably linked to an endogenous IL-17A regulatory element at the endogenous IL-17A gene locus, wherein the mouse expresses the human IL-17A protein, and an wherein anti-human IL-17A antibody can specifically binds to the human IL-17A protein and inhibit the human IL-17A/mouse IL-17R signaling pathway. 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 or use the invention commensurate in scope with these claims.
In regards to claims 159 and 169, which recites methods of making the mouse of either claim 146 or claim 161 respectively, the following scope of enablement is identified in view of applicant’s amendments to the claims. The specification, while providing an enabling disclosure for making a genetically modified mouse wherein the genome of the mouse comprises a replacement of a part of exon 1, exon 2 AND a part of exon 3 of the endogenous IL-17A gene, with a part of exon 1, exon 2 and a part of exon 3 of a human IL- 17A gene which encodes a human IL-17A protein, wherein the sequence encoding the human IL-17A protein is operably linked to an endogenous IL-17A regulatory element at the endogenous IL-17A gene locus, wherein the mouse expresses the human IL-17A protein, and an anti-human IL-17A antibody can specifically binds to the human IL-17A protein and inhibit the human IL-17A/mouse IL-17R signaling pathway comprising the steps of (a) replacing in a fertilized mouse egg or a mouse embryonic stem cell, at an endogenous IL-17A gene locus, a part of exon 1, exon 2, and a part of exon 3 of endogenous IL-17A gene with a part of exon 1, exon 2 and a part of exon 3 of a human IL-17A gene; (b) transplanting the fertilized mouse egg of step (a) into a female mouse or transplanting the mouse embryonic stem cell of step (a) into a mouse blastocyst, which is then transferred into a female mouse; and (c) obtaining a genetically-modified mouse, does not reasonably provide enablement for making or using any genetically modified mouse wherein a sequence comprising a part of exon 1, exon 2 and a part of exon 3 of a human IL- 17A gene which encodes a human IL-17A protein replaces a part of exon 1, exon 2 OR a part of exon 3 of the endogenous IL-17A gene, wherein the sequence encoding the human IL-17A protein is operably linked to an endogenous IL-17A regulatory element at the endogenous IL-17A gene locus, wherein the mouse expresses the human IL-17A protein, and an wherein anti-human IL-17A antibody can specifically binds to the human IL-17A protein and inhibit the human IL-17A/mouse IL-17R signaling pathway, wherein the replacement takes place in any one or more cells in the mouse, and/or where any egg or embryonic stem cell or blastocyst of any species is used to make the transgenic mouse. 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 the invention commensurate in scope with these claims.
The applicant argues that claim 146 has been amended to recite a transgenic mouse, and further amended to recite, “wherein the sequence encoding the human IL-17A protein comprises a part of exon 1, exon 2, and a part of exon 3 of human IL-17A gene, wherein the mouse expresses the human IL-17A protein, and an anti-human IL-17A antibody can specifically bind to the human IL-17A protein and inhibit the IL-17A/IL-17R signaling pathway, wherein at least a part of exon 1, exon 2, or exon 3 of the endogenous IL-17A gene is replaced by the sequence”. The applicant argues that the disclosure of the specification provides sufficient enablement to make and use the mouse now recite in the amended claims without undue experimentation. In particular, the applicant points to Example 1 in which a mouse is made which has a replacement of a part of exon 1, exon 2, and a part of exon 3 of the endogenous IL-17A gene with a sequence comprising a part of exon 1, exon 2, and a part of exon 3 of the human IL-17A gene.
In response, while claim 161 has been amended to reflect the identified scope of enablement, which corresponds to the mouse described in Example 1, where the transgenic mouse has a replacement of a part of exon 1, exon 2, and a part of exon 3 of the endogenous IL-17A gene with a sequence comprising a part of exon 1, exon 2, and a part of exon 3 of the human IL-17A gene, claim 146 recites where the transgenic mouse has a replacement of a part of exon 1, exon 2, or a part of exon 3 of the endogenous IL-17A gene with a sequence comprising a part of exon 1, exon 2, and a part of exon 3 of the human IL-17A gene. The limitation in mended claim 146, where the transgenic mouse has a replacement of “a part of exon 1, exon 2, or a part of exon 3” of the endogenous IL-17A gene with a sequence comprising a part of exon 1, exon 2, and a part of exon 3 of the human IL-17A gene reads on the replacement of only a part, any part, of the endogenous exon 1, OR only exon 2, OR only a part, any part, of exon 3 of the IL-17A gene with the human sequence. Since the claim also requires that the human IL-17A sequence is operably linked an endogenous IL-17A regulatory element at an endogenous IL-17A gene locus, it appears that the claims thus read broadly on a variety of chimeric proteins which may include portions of the endogenous IL-17A protein sequence, such as amino acid sequence encoding a part of the endogenous exon 1, OR amino acid sequence encoded by endogenous exon 2, OR amino acid sequence encoded by a part of endogenous exon 3, OR amino acid sequence encoded by endogenous exons 2 and a part of exon 1. The claim as amended thus continue to read broadly on transgenic mice which express chimeric IL-17A protein comprising the human IL-17A coding sequence fused to part or all of the endogenous mouse IL-17A protein. Furthermore, the method of making the mouse of claim 146 recited in claim 159 does not produce the mouse of claim 146 as claimed. As noted in the new rejection of claim 159 under 35 U.S.C. 112(b)- see below, claim 159 comprises only a single step of “replacing in at least one cell of the mouse, at an endogenous IL-17A gene locus, a sequence encoding a region of an endogenous IL-17A with a sequence encoding a corresponding region of human IL-17A”. The method recited in claim 159 as written is confusing as it does not make actually make the mouse set forth in claim 146. The mouse of claim 146 has a specific structure which is present in the genome of the mouse, i.e. in every nucleated cell of the mouse. The method of claim 159 recites that the replacement can be in “at least one” cell of the mouse, which conflicts with the requirements of claim 146. Likewise, the recitation that a sequence encoding “a region of an endogenous IL-17A” is replaced with a sequence encoding a corresponding “region” of human IL-17A, is substantially broader than the specific replacement now required in amended claim 146. Claim 159 thus appears to read on a method of making a genus of transgenic mice which is substantially broader than the specific mice recited in claim 146. In regards to amended claim 169, which is a method of making the mouse of claim 161, it is noted that while claim has been amended to limit the animal to a mouse, step (a) more broadly recites the modification of a fertilized egg or embryonic stem cell from any species, which when transferred to a female mouse to produce a transgenic mouse with the genomic structure recited in claim 161. As the egg or embryonic stem cell, or the blastocyst comprising the embryonic stem cell, are not limited to mouse, they read on any species of fertilized egg, embryonic stem cell, or blastocyst from any species including invertebrates, insects, amphibians, fish, birds, and mammals.
As set forth in the rejection of record, the specification, while generally teaching insertion of a human IL-17A coding sequence into non-human IL-17A gene locus operatively linked to the endogenous Il-17A 5’ sequence or to an endogenous IL-17A regulatory sequence in the genome of a mouse, only provides detailed guidance for the complete replacement of the mouse endogenous IL-17A coding sequence comprising genomic exons and introns of the mouse with genomic coding sequence comprising human IL-17A exons and introns. In particular, the specification discloses the replacement of part of exon 1, exon 2 AND a part of exon 3 of the endogenous IL-17A gene, with a part of exon 1, exon 2 and a part of exon 3 of a human IL- 17A gene, and even more specifically where the endogenous sequence replaced and the replacing human sequence both comprise sequence from the start codon through the stop codon of each gene. The specification does disclose other types of insertions, including where a chimeric IL-17A gene is produced; however, the specification provides no detail guidance for sequence or functional properties of any chimeric IL-17A protein, or teach that a human IL-17A sequence fused with part of all of IL-17A sequence from a different species including the mouse would be capable of being expressed, fold into a functional protein, or be capable of recognition and binding by an anti-human IL-17A antibody in a mouse. Further, in terms of making a mouse as claimed, the specification only provides detailed guidance for making transgenic mouse with a genomic replacement endogenous IL-17A sequence by genetically modifying either a fertilized mouse egg, or mouse embryonic stem cell, transplanting the fertilized mouse egg of step (a) into a female mouse or transplanting the mouse embryonic stem cell of step (a) into a mouse blastocyst, which is then transferred into a female mouse; and (c) obtaining a genetically-modified mouse. The specification does not teach methods of modifying the genome, i.e. the genetic chromosomal sequence present in every nucleated cell in the mouse, which do not involve the use of a fertilized mouse egg or a mouse embryonic stem cell. The specification does not disclose direct genomic modification of the genome of a mouse in vivo, nor does the specification disclose making a mouse using a fertilized egg, or embryonic stem cell, or a blastocyst from a species other than a mouse.
Turning to the working examples, the examples disclose the generation of a single transgenic mouse in which about 2.9kb (2898bp) of genomic sequence containing the start codon to the stop codon of mouse IL-17A was replaced with corresponding 2861bp of human IL-17A genomic sequence (52186432-52189292 of NC_000006.12) from the start ATG in exon 1 to the TAA step codon in exon 3 such that the human sequence was operably linked to the mouse 5’ regulatory sequence, including promoter and enhancer(s). The working examples disclose the genetic modification was make in a mouse embryonic stem cell which was then transplanted into a mouse blastocyst and then transferred to the oviduct of a female mouse resulting in the birth of a transgenic mouse with a germline genomic modification at the endogenous IL-17A gene locus. The working examples demonstrate that human IL-17A was produced in these mice, that the human IL-17A was functional in the mice, and that anti-human IL-17A antibody was capable of interfering with human IL-17A/mouse IL-17RA signaling in the mice. The working examples also describe the generation of a human IL-17RA mouse with a similar replacement of the endogenous mouse IL-17RA gene with the human IL-17RA genomic sequence, and discuss breeding the human IL-17A and IL-17RA mice to generate double transgenic knock-in mice. However, the working examples do not show that the human IL-17RA was functional in the mouse. Thus, of the breadth of genetically modified mice whose genome encodes and is capable of expressing various chimeric human/mouse IL-17A protein encompassed by the claims, the specification and working examples only provide sufficient guidance for making and using a single genetically modified mouse wherein the genome of the mouse comprises a replacement of a part of exon 1, exon 2 AND a part of exon 3 of the endogenous IL-17A gene, with a part of exon 1, exon 2 and a part of exon 3 of a human IL- 17A gene, wherein the sequence encoding the human IL-17A protein is operably linked to an endogenous IL-17A regulatory element at the endogenous IL-17A gene locus, wherein the mouse expresses the human IL-17A protein, and an anti-human IL-17A antibody can specifically binds to the human IL-17A protein and inhibit the human IL-17A/mouse IL-17R signaling pathway.
Turning to the state of prior art at the time of filing, it is noted that IL-17A or IL-17A like sequences had been identified in a number of invertebrate and vertebrate species. Huang et al. for example, compared the sequence and putative functional domains in IL-17A proteins in a large number of invertebrates and vertebrates including humans (Huang et al. (2015) PloS ONE, Vol. 10(7), e0132802.doi.1371/journal.pone.0132802, pages 1-15). Huang teaches that the amino acid sequence similarities of the IL-17 proteins were rather low between the species, that the length and putative domain numbers of IL-17 proteins varied greatly, suggesting broadened or reduced functions, and that some IL-17 proteins contain incomplete IL-17 domains, and/or some motifs were lost in certain species (Huang et al., page 12). Huang et al. also teaches that as a whole there are significant different between invertebrate IL-17A and vertebrate IL-17A, where there is a third disulfide bond for the cystine knot fold in invertebrate IL-17 proteins, suggesting that they may possess the canonical disulfides of the cystine knot, which belongs to the canonical cystine knot fold superfamily, with members such as the NGF subfamily, and that unlike almost all vertebrate IL-17 proteins, which contain a predicted signal peptide, a significant proportion of those of invertebrates IL-17 proteins have no predicted signal peptide suggesting that the invertebrate IL-17 proteins without a predicted signal peptide may perform a different function from that of their vertebrate counterparts (Huang et al., page 12). Thus, due to art-recognized sequence and structural domain dissimilarity between various species of IL-17A, the skilled artisan at the time of filing would not have predicted that human IL-17A would be able to functionally replace the IL-17A of any animal species, vertebrate or invertebrate. It is further noted at the time of filing, the prior art does not teach that replacement of mouse genes, or the genes of other animal species, with a human gene sequence, particularly where the regulatory elements are endogenous and not human or heterologous promoters and enhancers, was considered routine or predictable. Zhu et al. (Exhibit A) that, “relatively few examples of full genomic humanization of mouse genes-i.e. the replacement of the entire coding region, including introns, with the human sequence” were known in the prior art at the time of filing and that negative effects on expression of the human protein in these mice were observed (Zhu et al. (2019) Nat. Commun., Vol. 10(1), 1-13, of record, previously submitted as Exhibit A). Applicant’s Zhou Declaration concurs with this analysis of the state of the prior art. The Zhou Declaration provide evidence that the inventors tried and failed in two separate attempts to achieve functional expression of two different human proteins in fully humanized mice. In particular, the Zhou Declaration states;
The development of humanized animals is unpredictable for a new target protein. For example, in an effort to obtain humanized mice expressing a fully human alkaline phosphatase, we replaced, in situ, the entire mouse ALPG gene with human ALPG gene (from start codon to stop codon). However, the resulting mouse did not express any human alkaline phosphatase. Later studies revealed that the ALPG humanization led to improper RNA splicing. As another example, in order to obtain humanized mice expressing a fully human protein S, we replaced, in situ, the entire mouse PROS1 gene with the human PROS1 gene (from start codon to stop codon). However, the resulting mouse expressed only trace amounts of human protein S. These results clearly show that … the development of humanized animals for a new target protein is not predictable (Zhou Declaration paragraph 7). It is also noted that for all of the reported methods of making knock-in mice in the prior art and in the Zhou Declaration, mouse embryonic stem cells were used to produce the transgenic mice. The state of the art at the time of filing does not teach or provide any expectation of success that a fertilized egg, embryonic stem cell, or blastocyst from any species other than mouse could be used to generate a transgenic mouse. Thus, while the prior art does teach technical methods for replacement of a mouse gene with a human gene using a mouse embryonic stem cell at the time of filing, the art the time of filing and the evidence of record show that functional expression of a human gene in a knock-in was not considered routine or predictable.
Therefore, in view of the state of the art at the time of filing which shows that few knock-in mice and even fewer fully replacement knock-in mice had been made, the art-recognized issues with expression and function following knockin of human genes in a mouse, the art recognized substantial sequence, structural, and likely functional differences between species of IL-17A, the lack of guidance for chimeric proteins comprising the coding sequence of the human IL-17A protein fused either the N-terminus or C-terminus, or both to mouse IL-17A amino acid sequence which are capable of being expressed as a functional protein and which can interact with endogenous or human IL-17RA, the limitation of the detailed description in the specification and the working examples to a single transgenic knockin mouse with a specific replacement of the mouse genomic coding sequence comprising a part of exon 1, exon 2, and a part of exon 3, with the human genomic coding sequence comprising a part of exon 1, exon 2, and part of exon 3, the lack of guidance in the specification or teachings in the prior art for using a different species of fertilized egg, embryonic stem cell, or blastocyst other than mouse to generate a transgenic mouse, and the breadth of the claims, it would have required undue experimentation to make and use the scope of the genetically modified mice as claimed.
The following new grounds of rejection have been necessitated by applicant’s amendments to the claims.
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.
Amended claim 159 is newly 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 159 depends on claim 146 which has been amended to recite a transgenic mouse “whose genome comprises a sequence encoding a human IL-17A protein, wherein the sequence encoding the human IL-17A protein is operably linked to an endogenous 5'UTR at an endogenous IL-17A gene locus, wherein the sequence encoding the human IL-17A protein comprises a part of exon 1, exon 2, and a part of exon 3 of human IL-17A gene, wherein the mouse expresses the human IL-17A protein, and an anti-human IL-17A antibody can specifically bind to the human IL-17A protein and inhibit the IL-17A/IL-17R signaling pathway, wherein at least a part of exon 1, exon 2, or exon 3 of the endogenous IL-17A gene is replaced by the sequence”. Claim 159 recites a method of making the mouse of claim 146 comprising, “replacing in at least one cell of the mouse, at an endogenous IL-17A gene locus, a sequence encoding a region of an endogenous IL-17A with a sequence encoding a corresponding region of human IL-17A”. The method recited in claim 159 is confusing as it does not make actually make the mouse set forth in claim 146. The mouse of claim 146 has a specific structure which is present in the genome of the mouse, i.e. in every nucleated cell of the mouse. The method of claim 159 recites that the replacement can be in “at least one” cell of the mouse, which conflicts with the requirements of claim 146. Likewise, the recitation that a sequence encoding “a region of an endogenous IL-17A” is replaced with a sequence encoding a corresponding “region” of human IL-17A, is substantially broader than the specific replacement now required in amended claim 146. Claim 159 thus appears to read on a method of making a genus of transgenic mice which is substantially broader than the specific mice recited in claim 146. As such, the metes and bounds of claim 159 cannot be determined.
Amended claims 161 and 166-169 are newly 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 161, as amended, lacks proper antecedent basis for “the human IL-17A protein” in line 8. Prior to this recitation, claim 161 recites “a human IL-17A gene”. It is suggested that applicant amend this first recitation of “the human IL-17A protein” to recite “a human IL-17A protein”. Claims 166-169 depend on claim 161 and thus is included in this rejection.
Allowable Subject Matter
Claim 170 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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.
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
Prosecution Insights