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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Response to 35 U.S.C 102(a)(1) Arguments
The examiner has reviewed applicant’s remarks and amendments and found them persuasive. The applicant argues that the rejection of claims 1-3,6,8,14-15,19,24,46, and 49 under 35 U.S.C. 102(a)(1) in view of US 11576984 B2 is invalid. The applicant argues the cited prior art does not disclose a fully human FcRn containing part of exon 1, all of exon 2, all of exon 3, all of exon 4, all of exon 5 and a part of exon 6 of the human FcRn nucleotide sequence, wherein the part of exon 1 contains at least 50 bp of nucleotides, and the part of exon 6 contains at least 80 bp of the human FcRn nucleotide sequence. Instead, they argue that the prior art disclosure of an FcRn positioned at the endogenous rodent FcRn locus, comprising a human extracellular domain, a rodent or human transmembrane domain and rodent or human cytoplasmic domain is insufficient to anticipate the claims. They argue that the disclosure lacks the necessary exon-structure information to anticipate the claims (eg: part of exon 1 contains at least 50 bp of nucleotides, and the part of exon 6 contains at least 80 bp). The examiner agrees that claims 1-3,6,8,14-15,19,24,46, and 49 are no longer anticipated by US 11576984 B2.
The rejection of claims 1-3,6,8,14-15,19,24,46, and 49 under 35 U.S.C. 102(a)(1) is hereby withdrawn.
Rejections under 35 U.S.C 103 necessitated by amendment
Claims 1,3,6,10,13-14,19,24,31,46,50,57 are rejected under 35 U.S.C. 103 as being unpatentable over US 11576984 B2.
US 11576984 B2 discloses transgenic animals that have partially and completely humanized FcRns. They also describe animals wherein fully humanized FcRn coding sequence (made from cDNA) is inserted at the endogenous mouse/rat FcRn locus in the chromosomes. They disclose that when the transgene is in the native locus, it can be under control of native and endogenous regulatory elements. Specifically, “…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).
Furthermore, US 11576984 B2 discloses methods to insert human sequences into the mouse FcRn locus. Exemplarily embodiment 3A, “Mouse Comprising Humanized Neonatal Fc Receptor (FcRn) as an In Vivo Model for Studying Human Antibody Recycling” discloses 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). Additionally, they disclose, “In some embodiments the amino acid sequence of the humanized FcRn encoded by the locus is SEQ ID NO: 16.” (paragraph 0182). Importantly, Seq ID: No 16 is 88.5% identical to Seq ID NO: 2 of the instant application.
Additionally, they disclose a method of determining effectiveness of a therapeutic agent targeting FcRn for the treatment of an immune-related disease. Specifically, ““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).
Furthermore, they disclose a method for evaluating pharmacokinetics of an antibody. Specifically, “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 teaches claim 50 as they administer a therapeutic agent comprised of a Fc (aka antibody) and measure pharmacokinetic parameters.
This particular embodiment does not disclose the various exon chimeras detailed in claims 1,10,13-14,24,31.
US 11576984 does disclose alternative embodiments featuring human-to-mouse exon swapping. This generates chimeras identifiable by distinct structural patterns, characterized by a mix of endogenous (mouse) and orthologous (human) exons. Importantly, the modular assembly of the exons directly reflects the domain structure of the FcRn molecule as supported by NCBI ref Seq: NM_004107.4. Specifically, “…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 (see FIG. 4)…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 0182). Furthermore, US 11576984 B2 also teaches truncated exon swapping. Specifically, “In certain embodiments, part of mouse coding exon 1, coding exon 2, coding exon 3, coding exon 4, and coding exon 5 of the mouse FcεRIα are replaced by part of human coding exon 1, coding exon 2, coding exon 3, coding exon 4, and coding exon 5.” (paragraph 0373 and Figure 9). The partial exon exchange is directed by defined genetic sub-regions: the swapped segment dictates the coding sequence, and the un-swapped segment comprises the 5’ UTR.
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to follow the teachings disclosed in the prior art (aka in US 11576984’s), which has shown the modular architecture of exon and protein structure correlate well, and that it is possible two create mice/rats that are transgenic for the FcRn gene. They teach the use of whole and partial exon swapping to create different FcRn chimeras. Furthermore, the data demonstrate that this exon-swapping strategy is highly effective and operates exactly as intended. When mice are engineered to contain the orthologous human exon 1 while leaving the remainder of the endogenous exon structure intact, they successfully produce a mouse FcRn featuring a human extracellular domain. Importantly, engineering chimeric FcRn in mice and rats by modularly combining protein-coding exons from different species enabling accurate preclinical testing of human-specific monoclonal antibodies, Fc-fusion proteins, and half-life-extended therapeutics. These variants can be used to accurately evaluate pH dependent affinity for human antibodies or used to control expression location and levels. Therefore, the specific exon chimeras detailed in claims 1,10,13-14,24,31 are obvious. Additionally, US 11576984 has also provided a teaching to use Seq ID NO: 16, which is 88.5% identical to Seq ID NO: 2 of the instant application, when creating the transgenic animals. This renders claims 3 and 19 obvious.
Claim 6 (use of mouse/rat model) is also rendered obvious as its limitation is disclosed in the application and the claim from which it depends (claim 1) has been rendered obvious as explained above. The limitation of claim 57 (FcRn sequence is a coding sequence) is disclosed by the art (see above- also see Example 3A, paragraph 1083-1097) and therefore is obvious in light of the claim 14 (from which it depends) being rendered obvious.
Additionally, it would be obvious to a person of ordinary skill in the art, before the effective filings date, to use the method of determining the effectiveness of an agent targeting FcRn disclosed in US 11576984 B2 in the context of the transgenic animals that have partially and/or completely humanized FcRn sequences inserted into the endogenous FcRn locus disclosed by US 11576984 B2, in particular the chimera detailed in claim 1. US 11576984 B2 provides a teaching to use the aforementioned methods in the aforementioned system. Furthermore, when conducting the method, merely swapping out the disclosed FcRn chimeras disclosed with the one detailed in claim 1 is no more than the substitution of one known component for another to achieve predictable results. This renders claim 46 obvious.
Additionally, it would be obvious to a person of ordinary skill in the art, before the effective filings date, to use the method for determining the pharmacokinetic and/or pharmacodynamic properties of an antibody disclosed in US 11576984 B2 in the context of the transgenic animals that have partially and/or completely humanized FcRn sequences inserted into the endogenous FcRn locus disclosed by US 11576984 B2, in particular the chimera detailed in claim 1. US 11576984 B2 provides a teaching to use the aforementioned methods in the aforementioned system. Furthermore, when conducting the method, merely swapping out the disclosed FcRn chimeras disclosed with the one detailed in claim 1 is no more than the substitution of one known component for another to achieve predictable results. This renders claim 50 obvious.
Response to 35 U.S.C 103 Arguments
Claims 9-10, 13, 30-31
The examiner has reviewed applicant’s arguments and amendments and found them to be persuasive. Applicant has amended the independent claims from which claims 9-10,13,30-31 depend. Additionally, applicant argues that the rejection of claims 9-10, 13, 30-31 under 35 U.S.C. 103 in view of US 11576984 B2, Mikulska JE et al 2000, R&D systems product data sheet 2018, and Chaudhury C 2003, is invalid. Applicant argues that 1) there was no motivation to modify the US 11576984 B2 disclosure because it was already working, 2) while Mikulska provides support for modular architecture and domain-coding sequence correspondence, it doesn’t provide motivation to modify the disclosure US 11576984 B2, 3) that outside of the 69% sequence homology in the extracellular domain (provided by R&D data sheet), the transmembrane and intracellular domain only have 57% sequence identity, and 4) that Chaudhury only supports the notion of a functional equivalence between mouse and human FcRn, and provides no motivation to modify the disclosure of US 11576984 B2. However, applicant’s amendment and the of 35 U.S.C 103 rejection necessitated by amendment detailed above render the issue moot.
The rejection of claims 9-10, 13, 30-31 under 35 U.S.C. 103 is hereby withdrawn. However, upon further consideration, a new ground(s) of rejection under 35 U.S.C 103 is made in view of US 11576984 B2. See above for rejection.
Claims 12 and 20
The examiner has reviewed applicant’s arguments and amendments and found them persuasive. The rejection of claims 12,20 under 35 USC 103 are hereby withdrawn. A new ground of rejection has been issued.
Claims 11 and 27
The examiner has reviewed applicant’s arguments and amendments and found them persuasive. The rejection of claims 11,27 under 35 USC 103 are hereby withdrawn. A new ground of rejection has been issued.
New rejections under 35 U.S.C 103
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over US 11576984 B2 as applied to claim 1 above, and further in view of WO 2021195574 A1.
US 11576984 B2 discloses transgenic animals that have partially and/or completely humanized FcRn sequences inserted into the endogenous FcRn locus. They disclose multiple FcRn exon structure variants.
US 11576984 B2 does not disclose the use of sequences corresponding to limitations of claim 12.
WO 2021195574 A1 discloses, "Exemplary nucleotide sequences of FCGRT and amino acid sequences of FcRn can be found, for example…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). Importantly, Seq ID 4 is 74% identical to Seq lD 7 of the instant application.
It would be obvious to a person of ordinary skill in the art, before the effective filing date, to use Seq ID: 4 of WO 2021195574 A1 (74% identical to Seq lD 7 of the instant application) to create an animal that is fully humanized for FcRn at the endogenous locus as disclosed in US 11576984 B2. This amounts to no more than a combination of known elements resulting in predictable results. Taking the known sequence WO 2021195574 A1 Seq ID: 4 and putting it into the known transgenic system of US 11576984 B2 would result in a transgenic animal expressing the FcRn variant encoded by WO 2021195574 A1 Seq ID: 4. Therefore, claim 12 is obvious.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over US 11576984 B2 as applied to claim 14 above, and further in view of WO 2021195574 A1.
US 11576984 B2 discloses transgenic animals that have partially and/or completely humanized FcRn sequences inserted into the endogenous FcRn locus. They disclose multiple FcRn exon structure variants.
US 11576984 B2 does not disclose the use of sequences corresponding to limitations of claim 20.
WO 2021195574 A1 discloses, "Exemplary nucleotide sequences of FCGRT and amino acid sequences of FcRn can be found, for example…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). Importantly, Seq ID 4 is 74% identical to Seq lD 7 of the instant application.
It would be obvious to a person of ordinary skill in the art, before the effective filing date, to use Seq ID: 4 of WO 2021195574 A1 (74% identical to Seq lD 7 of the instant application) to create an animal that is fully humanized for FcRn at the endogenous locus as disclosed in US 11576984 B2. This amounts to no more than a combination of known elements resulting in predictable results. Taking the known sequence WO 2021195574 A1 Seq ID: 4 and putting it into the known transgenic system of US 11576984 B2 would result in a transgenic animal expressing the FcRn variant encoded by WO 2021195574 A1 Seq ID: 4. Therefore, claim 20 is obvious.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over US 11576984 B2 as applied to claim 1 above, and further in view of US 6911321 B2.
US 11576984 B2 discloses transgenic animals that have partially and/or completely humanized FcRn sequences inserted into the endogenous FcRn locus. They disclose multiple FcRn exon structure variants.
US 11576984 B2 does not disclose the use of sequences corresponding to limitations of claim 11.
US 6911321 B2 discloses, “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, Seq lD 28 is 100% similar to Seq lD 5 of the current application.
It would be obvious to a person of ordinary skill in the art, before the effective filing date, to use US 6911321 B2’s Seq lD 28 (which is human and is 100% similar to Seq lD 5 of the instant application) to create an animal that is fully humanized for FcRn at the endogenous locus as disclosed in US 11576984 B2. This amounts to no more than a combination of known elements resulting in predictable results. Taking the known sequence of US 6911321 B2 (Seq ID: 28) and putting it into the known transgenic system of US 11576984 B2 would result in a transgenic animal expressing the FcRn variant encoded by US 6911321 B2 Seq ID: 28. Therefore, claim 11 is obvious.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over US 11576984 B2 as applied to claim 24 above, and further in view of US 6911321 B2.
US 11576984 B2 discloses a method of making transgenic animals that have partially and/or completely humanized FcRn sequences inserted into the endogenous FcRn locus. They disclose multiple FcRn exon structure variants.
US 11576984 B2 does not disclose the use of sequences corresponding to limitations of claim 27 in their method.
US 6911321 B2 discloses, “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, Seq lD 28 is 100% similar to Seq lD 5 of the current application.
It would be obvious to a person of ordinary skill in the art, before the effective filing date, to use US 6911321 B2’s Seq lD 28 (which is human and is 100% similar to Seq lD 5 of the instant application) in the method of creating an animal that is fully humanized for FcRn at the endogenous locus as disclosed in US 11576984 B2. This amounts to no more than a combination of known elements resulting in predictable results. Taking the known sequence of US 6911321 B2 (Seq ID: 28) and using the known methods for putting it into the known transgenic system of US 11576984 B2 would result in a transgenic animal expressing the FcRn variant encoded by US 6911321 B2 Seq ID: 28. Therefore, claim 27 is 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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