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 .
Detailed Action
This action is in response to the papers filed August 21, 2026.
Election/Restrictions
Applicant’s reply filed 08/21/2026 to the Requirement for Restriction/Election mailed 06/26/2026 is acknowledged.
Applicant elected without traverse Group 1, claims 1-15, 19-20 and 24, drawn to humanized non-human animal genome, a non-human animal cell comprising thereof, a non-human animal comprising thereof, a non-human animal tissue comprising thereof, a composition comprising thereof, and a non-human animal model of coronavirus infection comprising thereof.
Claims 16-18 and 25 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Amendments
Applicant’s amendment to the claims filed 08/21/2026 is acknowledged.
Claims 21-23 and 26 have been cancelled.
Claims 1-20 and 24-25 are pending.
Claims 16-18 and 25 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-15, 19-20 and 24 are under examination.
Priority
The instant application 18/721,743 was filed on 06/19/2024. This application is a national stage of international application PCT/US22/81833 filed 12/16/2022, claiming priority based on U.S. Provisional Patent Application No. 63/291,502 filed 12/20/2021
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/03/2025 and 08/21/2026 have been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, or by applicant in an information disclosure statement (IDS), they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
37 CFR 1.52 and 1.58 require all papers, other than drawings, that are submitted on paper or by facsimile transmission, and are to become a part of the permanent United States Patent and Trademark Office records in the file of a patent application or reexamination or supplemental examination proceeding, must be (i) plainly and legibly written either by a typewriter or machine printer in permanent dark ink or its equivalent and (ii) presented in a form having sufficient clarity and contrast between the paper and the writing thereon to permit the direct reproduction of readily legible copies in any number by use of photographic, electrostatic, photo-offset, and microfilming processes and electronic capture by use of digital imaging and optical character recognition. In this case, the Table 11 on page 82 fails to comply with one or more of these requirements. Applicant should amend the Table to remove the shading/background color from each cell in the Table. Tables in the body of the specification should be presented in black-and-white only and without grayscale shading.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 19 recites a non-human animal, non-human animal cell or non-human animal genome made according to the method of claim 16. As instructed by MPEP 608.01(n), when a first claim directed to a product is dependent upon a second claim directed to a method of making the product, the first claim would not be a proper dependent claim if the product can be made by a method other than that recited in the second claim because the first claim does not necessarily require the limitations of the second claim. In this case, the product of claim 19 can be made by a materially-different method of making the product than that recited by claim 16. For example, the non-human animal genome of claim 19 can be made by genetically-modifying cells cultured in vitro. Therefore, claim 19 is improper dependent for failing to include all the limitations of the claim upon which it depends, i.e., the method steps of claim 16.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 1-15, 19-20 and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
The claims are directed to product, which is a statutory category of invention. However, the claims are directed to a product of nature, which is a judicial exception.
In particular, the claims recite a non-human animal, non-human animal cell or non-human animal genome comprising (1) a humanized ACE2 gene encoding a recombinant ACE2 protein and (2) a humanized TMPRSS gene encoding a recombinant TMPRSS protein. The recombinant ACE2 and TMPRSS proteins are described as comprising (a) the endogenous signal, transmembrane and cytoplasmic domains of and (b) an extracellular domain “substantially identical” to the extracellular domain of their homologous human counterpart.
Accordingly, the claims recite recombinant ACE2 and TMPRSS proteins at least modified by having an extracellular domain “substantially identical” to the extracellular domain of their homologous human counterpart. However, the recombinant ACE2 and TMPRSS proteins broadly read on their naturally-occurring counterparts because the endogenous extracellular domains of ACE2 and TMPRSS proteins are “substantially identical” to the human extracellular domains of ACE2 and TMPRSS proteins.
For example, the extracellular domains of mouse and human ACE2 proteins share 84.1% identity. See, Figure 3. See also, alignment between amino acids 20-740 of SEQ ID NO: 2 (mouse) and amino acids 20-740 of SEQ ID NO: 4 (human). For example, the extracellular domains of mouse and human TMPRSS2 proteins share 82.3% identity. See, Figure 16. See also, alignment between amino acids 104-490 of SEQ ID NO: 69 (mouse) and amino acids 105-492 of SEQ ID NO: 71 (human).
For these reasons, given the broad scope of the claims, the recombinant ACE2 and TMPRSS proteins broadly read on their naturally-occurring counterparts, and the claimed non-human animal, non-human animal cell and non-human animal genome broadly encompasses naturally-occurring non-human animals, non-human animal cells and non-human animal genomes.
The claims do not recite additional elements that integrate the judicial exception into a practical application because the additional elements, considered individually or in combination, do not confer markedly different characteristics to the judicial exception as compared to its naturally occurring counterpart.
As discussed above, the limitation of an extracellular domain “substantially identical” to the extracellular domain of the homologous human counterpart does not confer markedly different characteristics because the endogenous extracellular domains of ACE2 and TMPRSS proteins are “substantially identical” to the human extracellular domains of ACE2 and TMPRSS proteins.
Thus, the claims are directed to non-patent eligible subject matter.
Dependent claims are included in the basis of the rejection because they do not correct the deficiencies of the claim upon which they depend. For example, the ACE2 and TMPRSS genes are naturally under the control of their respective, endogenous promoters (claim 7), the product-by-process limitations (claim 18) are not found to necessarily confer markedly different characteristics, and the addition of a coronavirus broadly reads on a naturally-occurring infection (claim 24).
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, 6-15, 19-20 and 24 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2023/0080265 A1 to Lai et al., claiming priority based on U.S. Provisional Application No. 63/237,445 filed 08/26/2021.
Lai discloses a genetically modified non-human animal, such as a mouse or rodent, that expresses human transgenes encoding ACE2 (hACE2) and human TMPRRS2 (hTMPRRS2) under control of the mouse promoter and the genetically modified non-human animals do not express native (endogenous) ACE2 and/or TMPRRS2. See, Abstract.
The human transgenes encoding hACE2 and hTMPRRS2 are inserted at the orthologous genomic loci, such that expression of the human transgenes is regulated by the endogenous promoter and expression of the endogenous gene is disrupted. See, Figure 2, and paragraphs 10-13 and 84-85.
One or both chromosomes of the non-human animal are genetically modified to comprise the human transgenes. See, paragraphs 14-15.
The non-human animals include rodents, such as rat or murine (mouse). See, paragraph 42.
The genetically modified non-human animals are generated by a process comprising genetically modifying embryonic stem (ES) cells to express hACE2 and/or hTMPRRS2. See, paragraphs 104, 144, 191 and 236.
The non-human animals serve as models for a SARS-like disease, such as a SARS-CoV-2 infection or COVID-19. See, paragraph 83.
For written support, see Figure 2, paragraphs 8-13, 40, 78, 81-83, 86, 97, 163, and 194, and claims 14-20 of the provisional application.
For these reasons, claims 1, 6-15, 19-20 and 24 are anticipated by Lai.
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.
Claims 2-5 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0080265 A1 to Lai et al., claiming priority based on U.S. Provisional Application No. 63/237,445 filed 08/26/2021, as applied to claims 1, 6-15, 19-20 and 24 above; in view of US Patent No. 10,070,631 B2 to Purcell et al.
Regarding dependent claims 3-4, Lai discloses replacing the complete endogenous TMPRSS gene sequence with its non-human animal counterpart. Lai does not teach or fairly suggest replacing only the endogenous TMPRSS gene sequence encoding the extracellular domain with its human counterpart, as instantly claimed in dependent claims 3-4.
Purcell is relevant prior art for teaching genetically modified rodents, such as mice and rats, comprising a humanization of at least one endogenous rodent TMPRSS gene, such as an endogenous rodent TMPRSS2, TMPRSS4 or TMPRSS11D gene. See, Abstract.
The humanized TMPRSS gene encodes a humanized TMPRSS protein comprising an ectodomain (extracellular domain) substantially identical to or identical to the ectodomain of a human TMPRSS protein, and a cytoplasmic and transmembrane portion that is identical to the cytoplasmic and transmembrane portion of an endogenous rodent TMPRSS protein, wherein the humanized TMPRSS gene is under control of the native promoter of the endogenous rodent TMPRSS gene. The genetically modified rodents are useful models for viral infections. See, col. 2-6.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Lai such that only the endogenous TMPRSS gene sequence encoding the extracellular domain is replaced with its human counterpart, as found in Purcell, with a reasonable expectation of success because humanization of only the ectodomain permits interaction with and/or entry of human viruses into the non-human animal model while retaining the native intracellular signaling and downstream function of the humanized protein.
Regarding dependent claims 2 and 5, Lai discloses replacing the complete endogenous ACE2 gene sequence with its non-human animal counterpart. Lai does not teach or fairly suggest replacing only the endogenous ACE2 gene sequence encoding the extracellular domain with its human counterpart, as instantly claimed in dependent claims 2 and 5.
As discussed above, Purcell discloses a humanization strategy for TMPRSS genes, wherein only the endogenous TMPRSS gene sequence encoding the extracellular domain with its human counterpart. Accordingly, prior to the effective filing date of the instantly claimed invention, one of ordinary skill in the art would have recognized that (i) replacement of the complete endogenous protein coding sequence with its human counterpart and (ii) replacement of only the endogenous ectodomain with its human counterpart are two alternative strategies of generating humanized non-human animal models for viral infection.
Therefore, absent a secondary consideration, it would have been prima facie obvious to one of ordinary skill in the art to further modify the invention of Lai such that only the endogenous ACE2 gene sequence encoding the extracellular domain is replaced with its human counterpart, in view of the teachings of the prior art, with a reasonable expectation of success because humanization of only the ectodomain permits interaction with and/or entry of human viruses into the non-human animal model while retaining the native intracellular signaling and downstream function of the humanized protein.
For these reasons, claims 2-5 would have been prima facie obvious over the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-15, 19-20 and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12,702,122 B2; in view of US 2023/0080265 A1 to Lai et al.; and US Patent No. 10,070,631 B2 to Purcell et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over reference claims.
The reference claims recite a rodent comprising a genetically modified endogenous ACE2 locus encoding a recombinant ACE2 protein comprising the signal sequence of the endogenous ACE2 protein, the extracellular domain of a human ACE2 protein, the transmembrane domain of the endogenous ACE2 protein and the cytoplasmic domain of the endogenous ACE2 protein, wherein the rodent expresses the recombinant protein.
The reference claims do not recite that the rodent further comprises a humanized TMPRSS gene.
The teachings of Lai have been provided above and are hereby incorporated by reference.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by further including a humanized TMPRSS gene, as found in Lai, with a reasonable expectation of success because TMPRSS proteins participate in SARS-CoV-2 infection, and thus humanizing TMPRSS genes would improve the non-human animal model as a model for SARS-CoV-2 infection.
Regarding dependent claims 2 and 5, the reference claims and Lai combined do not teach replacing only the endogenous TMPRSS gene sequence encoding the extracellular domain with its human counterpart, as instantly claimed in dependent claims 2 and 5.
The teachings of Purcell have been provided above and are hereby incorporated by reference.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims and Lai combined such that only the endogenous TMPRSS gene sequence encoding the extracellular domain is replaced with its human counterpart, as found in Purcell, with a reasonable expectation of success because humanization of only the ectodomain permits interaction with and/or entry of human viruses into the non-human animal model while retaining the native intracellular signaling and downstream function of the humanized protein.
For these reasons, the instant claims are unpatentable over the reference claims and secondary references.
Claims 1-15, 19-20 and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Patent Application No. 19/727,418 (reference to claim listing filed 07/02/2026); in view of US 2023/0080265 A1 to Lai et al.; and US Patent No. 10,070,631 B2 to Purcell et al. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over reference claims.
The reference claims recite a rodent comprising a genetically modified endogenous ACE2 locus encoding a recombinant ACE2 protein comprising the signal sequence of the endogenous ACE2 protein, the extracellular domain of a human ACE2 protein, the transmembrane domain of the endogenous ACE2 protein and the cytoplasmic domain of the endogenous ACE2 protein, wherein the rodent expresses the recombinant protein.
The reference claims do not recite that the rodent further comprises a humanized TMPRSS gene.
The teachings of Lai have been provided above and are hereby incorporated by reference.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims by further including a humanized TMPRSS gene, as found in Lai, with a reasonable expectation of success because TMPRSS proteins participate in SARS-CoV-2 infection, and thus humanizing TMPRSS genes would improve the non-human animal model as a model for SARS-CoV-2 infection.
Regarding dependent claims 2 and 5, the reference claims and Lai combined do not teach replacing only the endogenous TMPRSS gene sequence encoding the extracellular domain with its human counterpart, as instantly claimed in dependent claims 2 and 5.
The teachings of Purcell have been provided above and are hereby incorporated by reference.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the reference claims and Lai combined such that only the endogenous TMPRSS gene sequence encoding the extracellular domain is replaced with its human counterpart, as found in Purcell, with a reasonable expectation of success because humanization of only the ectodomain permits interaction with and/or entry of human viruses into the non-human animal model while retaining the native intracellular signaling and downstream function of the humanized protein.
For these reasons, the instant claims are unpatentable over the reference claims and secondary references.
Sequence Alignments
Alignment between amino acids 20-740 of SEQ ID NO: 2 (mouse) and amino acids 20-740 of SEQ ID NO: 4 (human).
PNG
media_image1.png
778
561
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Greyscale
Alignment between amino acids 104-490 of SEQ ID NO: 69 (mouse) and amino acids 105-492 of SEQ ID NO: 71 (human).
PNG
media_image2.png
472
555
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Greyscale
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D Schultz can be reached at (571)272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631
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