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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1,3-9,12,16-17,20, in the reply filed on 03/03/2026 is acknowledged. The traversal is on the ground(s) that the Groups are closely related and searching these groups do not substantially increase burden. This is not found persuasive because search burden is not germane to lack of unity practice. Additionally, given that the claimed product is not found to be novel, additional
The requirement is still deemed proper and is therefore made FINAL.
Claims 22,24,44,49,57,62,64,66 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 03/03/2026.
Claim Rejections - 35 USC § 112
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 1,3-9,12,16-17,20 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 genetically modified, non-human animal whose genome comprises a replacement of the portion of the endogenous TFR1 gene encoding the extracellular domain of the TFR1 protein with the corresponding human nucleic acid sequences, such that the non-human animal detectably expresses a chimeric, humanized TFR1 protein in place of the endogenous TFR1 protein on the surface of cells, does not reasonably provide enablement for the generation of a non-human animal whose genome comprises a fully human TFR1 gene, a chimeric gene using non-human sequence, or a non-human animal whose genome comprises a humanized TFR1 gene at an endogenous TFR1 locus and lacks any phenotype/expression at the cell surface. 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/or use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raises and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The nature of the invention relates to a humanized animal whereby the Transferrin Receptor Protein 1 (TFR1) is humanized at the extracellular domain. This is done to test human therapeutics that bind to the extracellular domain of human TFR1 in a non-human model system. By retaining the remaining portion of the endogenous gene, the protein can interact with normal specificity with downstream molecules while interacting with the human therapeutic with a specificity akin to human TFR1.
Claim 1 is drawn to a genetically-modified, non-human animal whose genome comprises a sequence encoding a human or chimeric TFR1 on at least one chromosome. Claim 12 is similar but limited to wherein the replacement is all or part of the extracellular domain.
Claims 1,3-9 are broad in that they embodiments that are not to replacement of the endogenous extracellular domain of TFR1 but replacement of the entire gene. Claims 1,3-9,12,16-17,20 are broad in that they encompass genomic modification without resulting expression of the protein on the cell surface.
TFR1 is a membrane bound protein that binds transferrin. Transferrin-bound TFR1 enters the cell via clathrin-dependent endocytosis. Because transferrin transports iron, this is how iron enters the cell.
The specification teaches use of the claimed animal in screening and evaluation of anti-human TFR1 antibodies in a nonhuman animal. However, the effect of an antibody on human TFR1 cannot be properly determined in a non-human wherein the signaling portions (cytoplasmic) of the protein are non-native to the model as they interact with endogenous proteins, not human proteins. In support of this concept, AL-Rafaei (Heliyon 6 (2020) e03221, 6 pages) taught that point mutation within the short 67 amino acid cytoplasmic domain impaired endocytosis (page 2, second full para). Accordingly, Iocopetta (Cell, Vol. 54, 485-489, August 12, 1988) found that deletion of cytoplasmic residues 6-41 led to a loss of association of TFR1 with clathrin coated pits and defective endocytosis (page 485-486). Rothenberger (1987, Cell, 49:, 423-431) states, “These results provide evidence that the cytoplasmic domain, or part of it, is essential for internalization of the TR…” (Abstract).
The specification discloses preparation of a targeting vector comprising as portion of exon 4 through exon19 from the human TFR1 gene to generate a chimeric protein as set forth in SEQ ID NO:9. Humanized mice were made via homologous recombination with a targeting vector in ES cells and positive clones were introduced into blastocysts (see pages 50-51). Analysis of resulting heterozygous mice showed 32.9% of B cells in the spleen were mTFR1-positive while 11.3% were hTFR1-positive. No mTFR1 was observed in F2 homozygous mice whose genome comprised the chimeric transgene.
The specification fails to disclose the structural feature or phenotype of the claimed non-human animals whose genome comprises a humanized or otherwise chimeric TFR1 gene other than the disclosed transgenic mice set forth above.
The claims encompass any species of non-human animal whose genome comprises a humanized TFR1 gene, wherein said nonhuman animal exhibits unknown and unidentified phenotype. The skilled artisan would not know how to use an animal merely comprising the recited genetic modifications. The individual gene of interest (various nucleotide sequences encoding the different human proteins), promoter, enhancer, coding or non-coding sequences present 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. The specification fails to disclose the production of the claimed humanized/chimeric TFR1 animals with a defined phenotype other than mammals with a replacement of the extracellular domain of TFR1 at the endogenous TFR1 locus such that the humanized chimeric gene is operably linked to the endogenous TFR1 regulator regions and humanized, chimeric TFR1 is expressed on the surface cells that normally express endogenous TFR1. Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to use the animals that do not exhibit such a phenotype. Furthermore, the specification fails to support a use for chimerizing the ECD of TFR1 with any species other than human.
For the reasons discussed above, it would have required undue experimentation for one skilled in the art before the effective filing date of the claimed invention to practice over the full scope of the invention claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the working examples provided and scarcity of guidance in the specification, the level of skilled artisan which is high, and the unpredictable nature of the art.
Claim Rejections - 35 USC § 112
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.
Claims 1, 3-9,12,16,17 and 20 are 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 1 is indefinite with regard to what is encompassed by “endogenous TFR1 locus”. Typically a gene locus is considered to be a “chromosomal address” or location where a gene is located. However, the specification offers that a locus can be a portion of a gene. For example, page 3, lines 10-11 infer that the locus can be the extracellular region of TFR1. TFR1 is a protein but even if considered to be referring to the tfr1 gene, the region of the gene encoding the extracellular portion of the TFR1 protein is considered to be a locus given this recitation in the specification. The specification. At page 13, para 3 states that the TFR1 gene locus has 19 exons. Page 36, last para states, “. In some embodiments, the endogenous TFR1 locus is exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, exon 9, exon 10, exon 11, exon 12, exon 13, exon 14, exon 15, exon 16, exon 17, exon 18, and/or exon 19 of mouse TFR1.” Thus it is not clear if the locus includes introns or bordering sequence such as regulatory elements. Dependent claims 3-9,12,16,17 and 20 are also rejected as they fail to clarify what is encompassed by the term “locus”.
Claim 4 is unclear as it encompasses an animal comprising a human sequence encoding an amino acid identical to the sequence set forth in SEQ ID NO:9. SEQ ID NO:9 is a chimeric sequence and cannot be identical to the sequence of human TFR1.
Claim 5 is unclear as it recites the sequence is at least identical. It is not clear how a sequence can be more than identical.
Claim 16 is unclear as it recites the sequence is at least identical. It is not clear how a sequence can be more than identical.
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 17 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 17 depends from claim 16. Claim 16 requires the extracellular domain be identical to the extracellular region of human TFR1. Claim 17, however, requires only 200 contiguous amino acids if the extracellular domain. Thus, claim 17 falls outside the scope 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 § 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.
Claim(s) 1,6-9,12 and 20 is/are rejected under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by US10,143,187 (to Dennis; IDS).
Claim 1 is drawn to a genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a chimeric TFR1 wherein the sequence encoding the chimeric TFR1 is operably linked to an endogenous regulatory element at the endogenous TFR1 locus in the at least one chromosome.
Dennis teaches a transgenic mouse (rodent, claim 6-7) whose genome comprises a chimeric Tfr1 gene comprising a sequence encoding the human apical domain in place of the corresponding mouse sequence (encoding the mouse apical domain; see Example 1, paragraph 80). This constitutes replacing a part of the extracellular region as recited in claim 12. Replacement of this domain leads to a gene that remains operably linked to endogenous regulatory elements. Homozygous mice do not express endogenous TFR1 and express the genetically modified gene in at least one cell (claims 8-9). Dennis teaches the mice can also be heterozygous (see col. 3; claim 20).
Claim(s) 1,6-9,12 and 20 is/are rejected under 35 U.S.C. 102(a)(1) and 102 (a)(2) as being anticipated by Yu (2014, IDS).
Claim 1 is drawn to a genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human TFR1 wherein the sequence encoding the chimeric TFR1 is operably linked to an endogenous regulatory element at the endogenous TFR1 locus in the at least one chromosome.
Yu teaches a human TfR knock-in mouse model (rodent, claim 6-7) whose genome comprises a human Tfr1 cDNA inserted following exon 1 of the mouse Tfr1 gene. This places the cDNA in operable linkage with the endogenous regulatory sequences. This constitutes replacing a part of the extracellular region as recited in claim 12. Replacement of this domain leads to a gene that remains operably linked to endogenous regulatory elements. Homozygous mice do not express endogenous TFR1 and express the genetically modified gene in at least one cell (claims 8-9). Yu teaches the mice can also be hemizygous or homozygous (claim 20).
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.
Claim(s) 1 and 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yu (2014, IDS) in view of GenBank: AAH01188.1 (NIH National Library of Medicine. 10/04/2003, TFRC protein [Homo sapiens] - Protein - NCBI, accessed 03/13/2026).
Yu meets the limitations of claim 1 as set froth above. Yu does not teach the sequence of the TFR1 protein encoded by their cDNA. However, the sequence of human Tfr1 protein was available well before filing and use of this sequence would lead to one with 100% identity to amino acids 89-760 of the human protein (see alignment below).
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Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached on M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632