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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/05/2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4, 10-13, 16, 21, 26, 27, 29, 33, 34, 39, 40, 44, 45, and 56-58 are pending. Applicant amended claims 1, 4, 13, 16, and 56, cancelled claims 3 and 55, and added new claims 57-58 by amendment filed on 01/05/2026. Claims 16-17, 21, 26-27, 29-30, 39-40 and 44-45 (17 and 30 now cancelled) remain withdrawn from consideration pursuant to 37 CPR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claims. The requirement for restriction was previously made final.
Therefore, claims 1, 4, 10-13, 33-34, and 56-58 are currently under examination to which the following grounds of rejection are applicable.
Priority
The instant application is a 371 of PCT/CN2020/105529 filed on 07/29/2020, which claims foreign priority to CN 201910688648.5 filed on 07/29/2019. Thus, the earliest possible priority for the instant application is 07/29/2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/05/2026, was filed before the mailing date of the office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Maintained and modified rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claim(s) 1, 4, 10-13, 33, and 56 remain rejected and claim 58 is newly rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2018/0000056 Al, IDS, filed 3/8/2022).
Note: The rejection is modified for consideration of the amendments filed 01/05/2026.
Regarding Claims 1, 56, and 58, Amended claim 1 recites, “A genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric IL33, wherein the animal in its genome comprises from a 5’ to 3’ a 5’ untranslated region (5’ UTR), the sequence encoding the human or chimeric IL33, and a 3' untranslated region (3' UTR) wherein the 5’ UTR is directly connected to the sequence encoding the human or chimeric IL33 and the sequence encoding the human or chimeric IL33 is directly connected to the 3’ UTR, and wherein the 5’ UTR consists of 5’ UTR of an endogenous IL33 gene and the 3’ UTR of an endogenous IL33 gene.” Claim 56 recites, “The method of claim 1, wherein the animal does not comprise the 3' UTR of a human IL33 gene.” Claim 58 recites, “The animal of claim 1, wherein the sequence encoding the human or chimeric IL33 is an IL33 coding sequence.”
Wang et al. teaches a humanized non-human animal containing in its genome a sequence encoding human IL33 (Pg. 6, Paragraph 0093 and Fig 10). Wang teaches replacement of endogenous IL33 coding region with the corresponding human IL33 coding sequence at the endogenous locus while retaining endogenous flanking genomic regions. Wang further teaches alternative knock-in strategies in which endogenous regulatory elements, including endogenous 5’ and 3’ untranslated regions are retained (Pg. 17, Example 8; Fig. 10; Pg. 6, Paragraph 0104). Additionally, Wang teaches alternative knock-in strategies for other genes of interests (IL-4 and IL-4R) to be operably linked to 5’ and 3’ endogenous regulatory elements and not containing human 3’ UTRs (Pg. 4, Paragraph [0058] and [0068]).
PNG
media_image1.png
537
1066
media_image1.png
Greyscale
Specifically, they teach in Fig. 10A, “the mouse IL-33 gene (top) spanning the coding region from exon 2 starting at the ATG initiation codon through the stop codon in exon 8 is deleted and replaced by the coding region from exon 2 starting at the ATG codon through exon 8 (including the 3' untranslated region) of the human IL-33 gene (bottom). See below.
Wang teaches a retention of the endogenous mouse IL33 sequence upstream of the mouse exon-2 initiation codon, including the endogenous mouse IL33 5’ UTR and retains the endogenous mouse IL33 3’ UTR region downstream of the inserted human sequence. Therefore, in the 5-3’ direction Wang teaches the endogenous 5’ UTR – a sequence encoding human IL33 and the endogenous IL33 3’ UTR.
The human IL33 knock-in animal model presented by Wang et al. was produced using the knock-in strategy represented in Fig. 10A, and did not contain a sequence encoding human IL33 explicitly connected to a 3' untranslated region (3' UTR) of an endogenous IL33 gene at an endogenous IL33 gene locus.
However, Wang further teaches a general endogenous-locus humanization strategy in which an endogenous rodent sequence encoding a rodent protein is replaced with a human sequence encoding the corresponding human protein. The humanized gene remains associated with the endogenous 5’ and/or 3’ regulatory sequences at the endogenous locus (Pg. 4, Paragraph 0058, 0064 and 0066-0067). Wang teaches the use of endogenous locus and endogenous regulatory elements is desirable to avoid potential overexpression or under expression of the humanized protein (Pg. 7, Paragraph 0127). Wang also teaches a targeting construct may contain a removable selection cassette, indicating inclusion of such intervening cassette sequence is not required for the humanized allele (Pg. 10, Paragraph 0152).
It view of these teachings, it would have been prima facie obvious to one of ordinary skill in the art at the time of the instant application to use teachings within the same reference and modify Wang’s IL33 targeting construct by terminating the inserted human IL33 sequence at the human IL33 stop codon, rather than extending the inserted sequence through the human UTR. This modification would implement the expressly taught strategy of replacing the endogenous protein-encoding sequence with the corresponding human sequence while retaining the endogenous flanking regulatory regions to arrive at a sequence in the 5’ to 3’ direction that would be as follows: the endogenous 5’ UTR – a sequence encoding human IL33 and the endogenous IL33 3’ UTR.
One would have been motivated to apply this strategy because Wang teaches preservation of endogenous regulatory control is desirable to avoid over or under expression of the protein of interest.
There would have been reasonable expectation of success as Wang already teaches these strategies to successfully produce knock-in models. Moreover, the manipulation of previously identified sequences encoding the human or chimeric IL33 and insertion of a new or modified gene sequence at a specific location to generate a transgenic mouse is within the ordinary level of skill in the art of molecular biology.
PNG
media_image2.png
553
802
media_image2.png
Greyscale
Regarding Claim 4, Wang et al. teaches the human IL-33 gene is NM_0334393.3, which encodes a protein of NP_254274.1 (NP _24274.1 is identical to SEQ ID NO: 8 of the present application) (Pg. 17, Paragraph 0217, Example 8).See alignment below of SEQ ID NO: 8 aligned to NP_254274.1.
Regarding Claims 10-13, Wang et al. teaches the animal of claim 1, and specifically teaches a humanized mouse (for claim 10-11), wherein the endogenous IL33 mouse gene is replaced with a humanized IL33 gene (Pg. 17, Example 8). Further Wang et al. teaches the humanized mouse as expressing the humanized IL-33 (for claim 13) and not expressing endogenous IL33 gene (for claim 12) (Pg. 11, Paragraph 0166).
Regarding Claim 33, Wang et al. teaches “a triply humanized nonhuman animal is used herein to evaluate candidate compounds, wherein the triply humanized animal is a triply humanized mouse that expresses a human IL-4 protein, a humanized IL-4Ra protein which includes the ectodomain of a human IL-4Ra protein linked to the transmembrane and cytoplasmic domains of a mouse IL-4Ra protein, and a human IL-33 protein, wherein the mouse does not express mouse IL-4, mouse IL-4Ra or mouse IL-33.” (Pg. 11, Paragraph 0166).
Response to Applicants’ Arguments as they apply to the rejection of claim(s) 1, 4, 10-13, 33, 56 and 58 under 35 U.S.C. 103 as being unpatentable over Wang et al.
At pages 1-3 of the remarks filed on 01/05/2026, Applicants essentially argue that the rejection of claims be withdrawn as Wang fails to teach or suggest claim 1 as amended.
PNG
media_image3.png
480
793
media_image3.png
Greyscale
Applicants’ arguments have been considered, but have not been found persuasive. On Pg. 2-3 of the remarks, applicant supplies the following teachings from Wang provided below for ease of reference:
PNG
media_image4.png
577
818
media_image4.png
Greyscale
In response to applicant’s argument, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, while Figs. 10A-C do not fully anticipate the limitations of newly amended claim 1, the claims are rejected as being obvious under U.S.C. 103. As discussed in the 103 rejection of claim 1 above, it would have been prima facie obvious to one of ordinary skill in the art at the time of the instant application to use teachings within the same reference and modify Wang’s IL33 targeting construct by terminating the inserted human IL33 sequence at the human IL33 stop codon, rather than extending the inserted sequence through the human UTR. This modification would implement the expressly taught strategy of replacing the endogenous protein-encoding sequence with the corresponding human sequence while retaining the endogenous flanking regulatory regions to arrive at a sequence in the 5’ to 3’ direction that would be as follows: the endogenous 5’ UTR – a sequence encoding human IL33 and the endogenous IL33 3’ UTR of an endogenous IL33 gene at an endogenous IL33 gene locus.
One would have been motivated to apply this strategy because Wang teaches preservation of endogenous regulatory control is desirable to avoid over or under expression of the protein of interest.
There would have been reasonable expectation of success as Wang already teaches these strategies to successfully produce knock-in models. Moreover, the manipulation of previously identified sequences encoding the human or chimeric IL33 and insertion of a new or modified gene sequence at a specific location to generate a transgenic mouse is within the ordinary level of skill in the art of molecular biology.
Claim 34 remains rejected under 35 U.S.C. 103 as being unpatentable over by Wang et al. (US 2018/0000056 Al, IDS, filed 3/8/2022) as newly applied to claims 1 and 33 above in view of Shen et. al (US 11,279,948 B2).
With regard to instant claims 1 and 33 above, Wang et al., renders obvious the claimed animal, as iterated above in the 103 rejection, the content of which is incorporated herein, in its entirety.
Wang et al. does not teach a humanized animal engineered to express TNF Receptor Super Family Member 4 (OX40) within their humanized IL33 mouse model.
Shen et al. cures the deficiencies of Wang et al., as they teach a non-human animal genetically modified to express a human or chimeric OX40 (Abstract). Specifically, Shen et al. teaches “…methods for making a genetically-modified, non-human animal, including: replacing in at least one cell of the animal, at an endogenous OX40 gene locus, a sequence encoding a region of an endogenous OX40 with a sequence encoding a corresponding region of human OX40. In some embodiments, the sequence encoding the corresponding region of human OX40 comprises exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, and/or exon 7 of a human OX40 gene. In some embodiments, the sequence encoding the corresponding region of OX40 comprises exon 2 to exon 4 of a human OX40 gene, and/or a part of exon 1 and/or exon 5 of a human OX40 gene. In some embodiments, the sequence encoding the corresponding region of human OX40 encodes amino acids 35-197 of SEQ ID NO: 28. In some embodiments, the region is located within the extracellular region of OX40. In some embodiments, the animal is a mouse, and the sequence encoding the region of the endogenous OX40 locus is Exon 1 to Exon 5 of mouse OX40 gene.” (Pg. 25, Column 3, 1st Paragraph).
It would have been obvious for one of ordinary skill in the art at the time of the invention to have modified the animal model taught by Wang et al., which includes animals engineered to express multiple human proteins, to alternatively express a humanized OX40 gene as taught by Shen et al. to develop an animal model suited for antibody screening of the respective human protein targets. One would have been also motivated to include the OX40 gene to produce an animal that would allow for the study of the single or multi-targeting of human OX40 and IL-33 to further characterize their roles in the immune system or specific pathologies.
There would have been reasonable expectations of success in the inclusion of OX40 within the humanized animals as both Wang and Shen teach successful development of genetically modified mice with the goal of developing models for antibody/drug targeting and for study related to pathological conditions.
Response to Applicants’ Arguments as they apply to the rejection of claim(s) 34 under 35 U.S.C. 103
At pages 5 of the remarks, Applicants argue that the rejection of claims be withdrawn as “Shen is related to genetically modified non-human animals that express a human or chimeric OX40, and methods of use thereof (see abstract of Shen). Shen does not teach or suggest methods of making genetically modified non-human animals that express a human or chimeric IL33. Thus, Shen fails to cure the deficiencies of Wang as described above.”
In response to applicant's argument that Shen is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, It would have been obvious for one of ordinary skill in the art at the time of the invention to have modified the animal model taught by Wang et al., which includes animals engineered to express multiple human proteins, to alternatively express a humanized OX40 gene as taught by Shen et al. to develop an animal model suited for antibody screening of the respective human protein targets. One would have been also motivated to include the OX40 gene to produce an animal that would allow for the study of the single or multi-targeting of human OX40 and IL-33 to further characterize their roles in the immune system or specific pathologies.
Claim Rejections - 35 USC § 112(b)
Claim 58 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 58 recites “wherein the sequence encoding the human or chimeric IL33 is an IL33 coding sequence.”. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the presence instance, claim 58 recites the broad limitation “is an IL33 coding sequence”, and the claim also recites “ the sequence encoding the human or chimeric IL33” which is the narrower statement of the range/limitation.
New rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112(a)
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.
Claim 57 is newly 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.
Claim 57 recites, The animal of claim 1, wherein the sequence encoding the human or chimeric IL33 comprises a portion of exon 2, intron 2, exon 3, intron 3, exon 4, intron 4, exon 5, intron 5, exon 6, intron 6, exon 7, intron 7, and a portion of exon 8 of a human IL33 gene, wherein the portion of exon 8 comprises less than 300 nucleotides.
Nature of the Invention
The instant claims are drawn to a genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric IL33, wherein the sequence encoding the human or chimeric IL33 comprises a portion of exon 2, intron 2, exon 3, intron 3, exon 4, intron 4, exon 5, intron 5, exon 6, intron 6, exon 7, intron 7, and a portion of exon 8 of a human IL33 gene, wherein the portion of exon 8 comprises less than 300 nucleotides.
Specification Disclosure
The specification provides an exemplary definition of a portion as “at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nucleotides, e.g., contiguous or non-contiguous nucleotides)” (Pg. 17, 4th full paragraph). The specification expressly describes the genomic donor fragment by its endpoints and coordinates, from which the full claim 57 structure does broadly encompass.
Table 1. identifies human exon boundaries and the example 1 donor region as positions 79-891, with exon 8 beginning at position 691. From this it can be assumed the exon 8 portion is 201 nucleotides. In fact, at page 9 of the remarks filed on 01/05/2026, the applicant is on record as stating that a first sequence corresponding to positions 691-891 ofNM_033439.3 (SEQ ID NO: 3) is the portion of human IL33 exon 8 (with a total length of 201 nucleotides).
The instant disclosure does not describe alternative truncation locations, selection of alternative truncation size other the ~201nt portion, biological rational for specifically truncating below 300nt, whether any and all truncations would retain the biological function as described. The instant disclosure fails to provide sufficient support pertaining to a human or chimeric IL33 sequence containing a portion of exon 2 and a portion of exon 8 (with exon 8 comprising less than 300 nucleotides) that retain the cited functionality of encoding for a functional IL33. The specification does not provide sufficient support to identify which nucleotides and how many nucleotides can be removed from the IL33 human or chimeric sequences that would be encompassed by the structural limitations of claim 57 and still be able to produce a functional IL33 protein as claimed. The instant specification does not provide a sufficient representative sampling of structures that contain as few as 1 nucleotide from the claimed exon portions.
Guidance Provided by the Art
PNG
media_image5.png
662
931
media_image5.png
Greyscale
The UTR regions were well known in the art at the time of the instant application to have multiple biological functions. Tian et al. (Tian, B., Nat Rev Mol Cell Biol, 2017) described that UTR regions have multiple biological roles including through the modulation of mRNA stability, translation, nuclear export and cellular localization, and even through effects on the localization of the encoded protein (Fig 1a, provided below).
Tian further describes that different lengths of 3’ UTR produce different regulatory outcomes (Pg. 18-19, APA in 3’ UTRs). Therefore, a person having ordinary skill in the art would not have considered arbitrary truncation points within a terminal exons to be interchangeable. Thus, there is not structure/ function correlation for the claimed portions of exon 8 comprises less than 300 nucleotides.
Taken together, the prior art provides clear evidence the integrity of the length of terminal exons are obviously critical and any full variation or fragment (portion) of said sequence characterized by deletions alter the ability of the of molecule to perform its normal biological function.
Conclusion
Considering the large variation in the genus encompassed by the instant claims, the singular species described in the specification, and the lack of predictability provided by the specification and art for the full scope of the claimed genus, it is reasonable to conclude that applicant did not possess the invention as claimed at the time of filing.
Conclusion
Claims 1, 4, 10-13, 33-34 and 56-58 are rejected. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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, Maria G. Leavitt can be reached on (571) 272-1085. 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.
/KODYE LEE ABBOTT/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights