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 .
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-3, 6, 8, 14, 15, 19, 24, 46, and 49 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 11576984 B2, effective filing date 03/26/2018.
US 11576984 B2 discloses, “… provided herein are rodents (e.g., rats or mice) comprising in their genome a genetically modified neonatal Fc receptor (FcRn) locus. In certain embodiment the FcRn locus comprises a nucleic acid sequence encoding an FcRn polypeptide comprising a human extracellular domain, a rodent or human transmembrane domain and rodent or human cytoplasmic domain. In certain embodiments the locus is positioned at the endogenous rodent FcRn locus.” (Background section, paragraph 11). Furthermore, “As used herein, the term “locus” refers to a location on a chromosome that contains a set of related genetic elements (e.g., genes, gene segments, regulatory elements). For example, an unrearranged immunoglobulin locus may include immunoglobulin variable region gene segments, one or more immunoglobulin constant region genes and associated regulatory elements (e.g., promoters, enhancers, switch elements, etc.) that direct V(D)J recombination and immunoglobulin expression.” (Description section paragraph 43). Therefore, they have disclosed a genetically modified mouse (claim 6) who has a chimeric FcRn receptor inserted (claim 1) at the endogenous FcRn locus and under control of the endogenous regulatory elements (claim 2 and claim 14). Therefore, the mouse will express the chimeric FcRn (claim 8 and claim 15).
They also disclose in exemplary embodiment 3 titled, “Mouse Comprising Humanized Neonatal Fc Receptor (FcRn) as an In Vivo Model for Studying Human Antibody Recycling” the following; “The mouse FcRn locus, located on mouse chromosome 7, was humanized by construction of unique targeting vectors from human and mouse bacterial artificial chromosomes (BAC) DNA using VELOCIGENE…DNA from mouse BAC RP23-19D22 (Invitrogen-Thermo Fisher) was modified by homologous recombination to delete 8.3 Kb of mouse genomic DNA encoding the extracellular portion of mouse FcRn and subsequently to insert 11.5 Kb of corresponding human FcRn sequence…” (paragraph 1083). This anticipates claim 24 as it details a method to insert human sequences into the mouse FcRn locus.
Additionally, they disclose, “To test whether the mice expressing chimeric mouse/human FcRn exhibited human antibody recycling properties similar to that of humans, three of each wild type mice and mice homozygous for the chimeric FcRn and humanized B2M described above were dosed with human IgG4 antibody subcutaneously at 1 mg/kg, and antibody drug levels in serum were measured at 6 hours, 1, 2, 3, 8, 10, 14, 22, and 30 days post injection using a Gyros immunoassay.” (paragraph 1097). This anticipates claim 46 because it is a method of determining the effectiveness of a therapeutic agent that targets the FcRn receptor. This is to say that FcRn primarily binds the Fc region of IgG.
Furthermore, they disclose, “Provided herein are methods and compositions related to the in vivo testing of therapeutic agents comprising a human Fc in genetically modified rodents (e.g., the testing of the pharmacokinetic and/or pharmacodynamic properties and dosing regimens of such therapeutic agents in genetically modified rodents)…In certain embodiments the genetically modified rodents comprise one or more Fc receptors with a human extracellular domain (e.g., a Neonatal Fc Receptor (FcRn)…” (paragraph 0051). Furthermore, “In some embodiments the one or more pharmacokinetic parameters include, but are not limited to, area under the plasma concentration versus time (AUC), in vivo recovery (IVR), clearance rate (CL), mean residence time (MRT), agent half-life (t½), and volume of distribution at steady state (Vss).” (paragraph 0228). This anticipates claim 49 as they administer a therapeutic agent comprised of a Fc (aka antibody) and measure pharmacokinetic parameters.
They go on to disclose that, “In some embodiments the amino acid sequence of the humanized FcRn encoded by the locus is SEQ ID NO: 16.” (paragraph 164). Importantly, SeqID 16 is 88.5% identical to SeqID 2 of the current application (claim 3 and claim 19).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 9-10, 13, 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over US 11576984 B2 further in view of (Mikulska JE, et al 2000), (R&D systems product data sheet, 2018), and (Chaudhury C, 2003).
US 11576984 B2 teaches, “In certain embodiments, the mouse exons encoding alpha 1, alpha 2, and alpha 3 domains (exons 3, 4, and 5, which are the first three coding exons) of the mouse FcRn gene are replaced with human exons encoding alpha 1, alpha 2, and alpha 3 domains (exons 3, 4, and 5) of the human FcRn gene.” (paragraph 0181). Furthermore, “In some embodiments, the FcRn gene comprises mouse exon 1 (non-coding exon), mouse exon 2 (comprising nucleic acid sequence encoding the signal peptide), and human exons 3-6, mouse exons 6 and 7 (encoding transmembrane and cytoplasmic domains).” (paragraph 0181). Therefore, US 11576984 B2 teaches using various combinations of human and mouse exons to create an animal that is transgenic for the FcRn receptor. However, it does not teach the specific mosaics detailed in claims 9-10, 13, 30-31.
Human FcRn sequence identity and exon/intron mapping indicates a modular protein architecture with various domains corresponding to discrete coding segments. (Mikulska JE, et al 2000). Mouse and human FcRn receptors display 69% identity in primary amino acid structure in the extracellular domain region. (R&D systems product data sheet, 2018). Human and mouse FcRn are functional analogs that mediate IgG homeostasis and maternal-fetal transmission. (Chaudhury C, 2003).
The modular genetic structure, sequence homology, and functional equivalence between human and mouse FcRn genes provides a motivation/suggestion to use exon swapping to generate chimeric coding and functional mutants for use in in-vivo model systems during drug discovery. Importantly, this method has a finite and reasonable number of possible combinations. Combined with the fact that the prior art shows multiple working combinations, it would be obvious to try different combinations of various exons. Different combinations would yield predictable results and there would be a reasonable expectation of success as well. Thus, claims 9-10, 13, 30-31 are rendered obvious.
Claims 12 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over US WO2021195574A1, effective filing date 3/27/2020 further in view of US Patent number US7358416B2, published 04/15/2008.
WO2021195574A1 discloses, “Exemplary nucleotide sequences of FCGRT and amino acid sequences of FcRn can be found, for example, at GenBank Accession No. NM_001136019.3 (SEQ ID NO: 1; reverse complement SEQ ID NO: 2) for Homo sapiens FCGRT variant 1; GenBank Accession No. NM_001357117.1 (SEQ ID NO: 3; reverse complement SEQ ID NO: 4)…” (paragraph 11 in the definitions section). Seq ID 4 is 74% identical to SeqID 7 of the present application. However, the application does not disclose the use of Seq ID: 4 (aka Seq ID 7 of current application) to create a chimeric transgenic animal containing mouse and human FcRn exon segments, or its use to create a fully humanized FcRn mutant animal.
US patent number US7358416B2 discloses the creation of a transgenic mouse that is a homozygous mouse FcRn knockout/heterozygous human FcRn knock-in. Specifically, “To produce mice transgenically expressing a complete human FcRn gene, a 34-kb XhoI fragment was excised from a human-derived bacterial artificial chromosome (Genome Systems) and cloned into a SuperCos vector (Stratagene, La Jolla, CA). This fragment, which encompasses the complete 11-kb FcRn gene plus 10-kb 5 and 3, was microinjected into zygotes from C57BL/6J female mice, and implanted into pseudopregnant female mice. A chimeric, germline transmitting male founder was used to establish the C57BL/6Jhuman FcRn transgenic line 44. Expression of human FcRn was confirmed by RT-PCR (not shown) and by Western blot analysis.” (col. 23).
US patent number US7358416B2 disclosure teaches the use of FcRn-transgenic animals for use in drug discovery/target validation and mechanism of action (MOA) studies. This teaching, supplemented by the discovery and use of the specific FcRn variant seq ID 4 (which is characterized as being 74% homologous to seq ID 7 of the current application) to develop therapeutic compositions as detailed in WO2021195574A1 renders claims 12 and 20 obvious. Together, the two sources emphasize that the claim limitations of claim 12 and 20 amount to no more than the addition of known elements to achieve predictable results.
Claims 11 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over US patent number US6911321B2, published 06/28/2005.
US6911321B2 discloses, “The invention also provides isolated nucleic acid molecules having a polynucleotide sequence encoding a cynomolgus Fc receptor (FcRn) [alpha]-chain.” Furtehrmore, “A nucleic acid encoding a cynomolgus FcRn has about 97% sequence identity when aligned with a human sequence (SEQ ID NO: 28) encoding a human FcRn [alpha]-chain as shown in Table 9 (GenBank Accession No. U12255).” (col. 15-16) Importantly, SeqID 28 is 100% similar to seqID 5 of the current application. The application does not disclose/characterize a transgenic animal with a humanized or transgenic FcRn gene. They also do not disclose a method of creating a transgenic animal with a fully or partially humanized FcRn locus.
However, US6911321B2 does disclose, “The primate FcRns or Fc receptor polypeptides could also be used to screen for variants (e.g. protein-sequence or carbohydrate) of primate or human IgG which exhibit either improved or reduced binding to these receptors or receptor polypeptides; such variants could then be evaluated in vivo in a primate model for altered efficacy of the antibody, e.g. augmentation or abrogation of IgG effector functions.” (Methods of Carrying out the invention, col. 13). Importantly, they also disclose, “Several recombinant methods for the production of the polypeptides of the invention include expression of the polynucleotide molecules in cell free expression systems, in cellular hosts, in tissues, and in animal models, according to known methods.” (Summary of the Invention, col. 4).
Therefore, US6911321B2 contains a suggestion/motivation to create a fully humanized FcRn cynomolgus mutant based on the fact human and cynomolgus FcRn sequences are virtually identical at the primary structure level (97% homology). This fact increases the clinical /translational relevance of efficacy and PK/PD studies in fully humanized FcRn cynomolgus mutants. This renders claim 11 obvious. Additionally, US6911321B2 provides a suggestion/teaching on various methods to create recombinant proteins, including methods that can be used to create humanized FcRn cynomolgus mutants using mutagenesis. This renders claim 27 obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Adam M Smith whose telephone number is (571)272-7517. The examiner can normally be reached Monday- Friday 10:30AM-5PM.
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/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638