DETAILED ACTION
Applicant's amendment and response received on 11/10/25 has been entered. Claims 1-12 remain pending and under examination in the instant application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/10/25 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner, and an initialed and signed copy of the 1449 is attached to this action.
Claim Rejections - 35 USC § 103
The rejection of claims 1-12 under 35 U.S.C. 103 as being obvious over U.S. Patent Application Publication 2017/0306352 (May 23, 2017), hereafter referred to as Wabl et al., with an effective filing date of 5/23/16, OR U.S. Patent 10,662,256 (May 26, 2020), with an effective filing date of 5/23/16, in view of U.S. Patent Application Publication 2013/0167256 (June 27, 2013), hereafter referred to as Green et al., CanFam3.1- Canis lupus familiaris genome assembly (2011) https://www.ncbi.nlm.nih.gov/datasets/genome/GCF_000002285.3/, Webster et al. (2014) AJVR, Vol. 75(6), 532-535, and Gearing et al. (2013) BMC Vet. Res., Vol. 9:226: www.biomedcentral.com/1746-6148/9/226, pages 1-11, is maintained. Applicant’s amendments to the claims, arguments, and supporting evidence have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that there were other dog breed whose genomes has been sequenced prior to the effective filing date, citing a number of references and sources, and that the rejection of record does not articulate or provide a reason why one of skill in the art would have, rather than simply could have, used boxer dog DNA in the instant invention over other dog breeds. Specifically, the applicant states that the NCBI website shows that the genomes of breeds such as poodle, beagle, and Yorkshire terrier had been published before the effective priority date. Applicant’s response provides 3 separate GenBank entries for a poodle, beagle, and Yorkshire terrier published between 2009-2017. The applicant also references Decker et al., a publication from 2015, and Kim, a publication from 2012, and Wang et al. a publication from 2013, as showing that specific dog genomes other than boxer dog were available in the prior art. According to applicant, none of the cited references provide any motivation to select boxer dog as the genome source for the canine V, D, and J gene segments to be inserted into the mouse genome.
In regards to the alleged lack of motivation as to the selection of boxer dog genomic sequence for the V, (D), and J gene sequences, it is not agreed that the rejection failed to provide motivation to utilize genomic DNA of the boxer dog as the source of the canine heavy and light chain V region, D region, and J region genes for insertion into the mouse genome. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). 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). As set forth in the rejection of record, Wabl et al. teaches a rodent cell and a transgenic rodent whose genome comprises a partly canine Ig locus with canine VL and JL gene segments and endogenous non-canine regulatory and scaffold sequences inserted into an endogenous light chain locus, preferably replacing the endogenous VL-JL gene sequences (Wabl et al., paragraphs 15, 17, and 21). Wabl et al. teaches that the rodent is a mouse or rat (Wabl et al., paragraphs 16, and 32). In addition, Wabl et al. teaches a rodent cell or transgenic rodent whose genome further comprises a partly canine Ig locus comprising canine VH, DH, and JH gene segments, endogenous mouse/rat non-coding regulatory and scaffold sequence, and an ADAM6 gene sequence inserted into endogenous heavy chain locus and preferably replacing endogenous VH-DH-JH (Wabl et al., paragraphs 19 and 23). Wabl et al. teaches that the endogenous regulatory sequences include promoters, splice sites, RSS, and enhancers, such as an intronic enhancer (Wabl et al., paragraphs 24, 53, and 69). Wabl et al. also teaches that the transgenic rodents express chimeric antibodies consisting of fully canine heavy and/or light chain variable domains in conjunction with endogenous/native constant regions (Wabl et al., paragraph 33). Wabl et al. further teaches method of making the transgenic rodents using genetically modified ES cells where a combination of homologous recombination and site-specific recombination is used to introduce (Wabl et al., paragraphs 27, 74-76, and 90). Wabl et al. also teaches B cells derived from the transgenic rodents, immortalized B cells, and hybridomas made using B cells from the transgenic rodents (Wabl et al., paragraphs 34 and 36). In addition, Wabl et al. teaches sequences encoding canine immunoglobulin variable regions cloned from B cells from the transgenic rodents (Wabl et al., paragraph 53). Wabl et al. also teaches partly canine antibodies specific for a particular antigen and the use of the antibodies comprising the canine variable regions for preventative and therapeutic use (Wabl et al., paragraphs 34-35). Wabl et al. further teaches to generate fully canine antibodies where the cloned canine immunoglobulin H and L chain variable domains are each joined to canine constant region to produce a fully canine antibody that is not immunogenic when injected into dogs (Wabl et al., paragraphs 37-38).
Further, in specific embodiments, Wabl et al. teaches that the genome of the transgenic rodents can comprises partly canine VH, Vlambda, or V kappa loci, or combinations thereof (Wabl et al., paragraph 68), and in example 2 teaches to replace the endogenous mouse heavy chain V, D, and J gene segments with a partly canine heavy chain locus comprising 80 canine VH gene segments, 6 canine DH gene segments, and 3 canine JH gene segments embedded in mouse non-coding and regulatory sequence such that the partly canine locus is integrated upstream of the endogenous mouse constant region genes (Wabl et al., paragraphs 73, 100, and 103). Example 4 and Figure 9 of Wabl et al. teaches to replace the mouse Vk-Jk genomic sequence at the endogenous mouse kappa locus with a partly canine Vk-Jk locus (K-K) or a partly canine Vlambda-Jlambda locus (L-K) (Wabl et al., paragraphs 133, 135, and 138). Wabl teaches that the partly canine Vk-Jk locus comprises 19 canine Vk gene segments and 5 canine Jk gene segments embedded in mouse noncoding and regulatory sequence (Wabl et al., paragraphs 133-134). Wabl et al. also teaches that the partly canine Vlambda-Jlambda locus comprises 7 canine V lambda gene segments and 5 canine J lambda gene segments embedded in mouse noncoding and regulatory sequence (Wabl et al., paragraph 135). Wabl et al. teaches that the endogenous kappa locus can be homozygous for K-K or that one allele of endogenous kappa locus is K-K and the other is L-K (Wabl et al., paragraphs 138-139). Wabl et al. teaches that these mice are bred to the partly canine heavy chain mice (Wabl et al., paragraph 139). Wabl et al. also provides an example 5 which teaches to replace the mouse endogenous J-C units of lambda locus with canine Vlambda gene segments and an array of canine/mouse lambda- J-C units where each unit comprises a canine Jlambda gene segment and mouse Clambda constant gene embedded within noncoding sequence from the mouse lambda locus, and where the mouse Clambda constant gene segments are C1 and/or C2 and/or C3 (Wabl et al., paragraph 148 and 152). Wabl et al. further teaches in the examples to breed the various mouse strains to create mice that carry a homozygous partly canine heavy chain locus, a homozygous partly canine K-K kappa locus, and a homozygous partly canine (L-L) lambda locus, OR mice carrying a homozygous partly canine heavy chain locus, a heterozygous partly canine K-K kappa locus on one allele and a heterozygous partly canine L-K kappa locus on the other allele, and a homozygous partly canine (L-L) lambda locus (Wabl et al., paragraph 153). In the latter example, lambda variable domains are derived from both the L-K locus and the L-L locus (Wabl et al., paragraph 153).
Green et al. supplements the teachings of Wabl in two aspects. In the first aspect, Green was cited for teaching, similar to Wabl et al., chimeric antibody producing mammals whose genome comprises a replacement of the endogenous V, (D), and J genes by non-endogenous V, (D), and J genes (Green et al., paragraphs 98 and 99). Green et al. teaches introducing the replacement non-endogenous locus into the genome of a mouse or rat ES cell and using the genetically modified ES cell to produce a transgenic animal heterozygous or homozygous for a modified IgH and/or IgL loci, either Igkappa or Ig lambda or both (Green et al., paragraph 117). Green et al. teaches that the non-endogenous Ig gene segments can be inserted into a region from the mouse Ig locus present in a BAC using homologous recombination (Green et al., paragraph 65). Green et al. teaches a transgene comprising an IgH sequence which comprises mouse DNA except for sequences encoding VH, DH, and JH, which are from a species relevant to animal healthcare, and specifically lists canine as the relevant animal species, where the canine VH, DH, and JH replace their mouse orthologues, and a transgene comprising an IgL sequence which comprises mouse DNA except for sequences encoding VL, JL, and optionally CL from a species relevant to animal healthcare, again specifically reciting canine, where the canine VL, and JL replace their mouse orthologues (Green et al., paragraph 147). In addition, Green et al. teaches methods of producing antibodies in the transgenic mice by immunizing the mice with an antigen, and obtaining antibodies by selecting B cells expressing the antibodies or by using hybridoma technology (Green et al., paragraph 150-151). Green et al. teaches that genes encoding the non-endogenous VH and VL domains of the antibodies can be obtained and appended to DNA encoding a non-endogenous constant region to produce a fully non-endogenous mAb (Green et al., paragraph 152). Green et al. further teaches that purified antibodies derived from the transgenic animals can be administered to humans and non-human animals for the treatment or prevention of diseases such as cancer or pathogenic infections (Green et al., paragraphs 153 and 155-156).
In regards to the use of canine versus mouse regulatory sequence, it is noted that while specific embodiments taught by Wabl et al. and Green regarding the insertion of canine VH, DH, and JH, and/or VL and JL into the mouse heavy or light chain loci respectively indicate that non-coding regulatory sequences of the modified loci are endogenous mouse non-coding regulatory sequence, Green et al. does teach alternative embodiments where the heterologous VH, DH, and JH gene sequences, and/or the VL and JL gene sequences comprise heterologous non-coding regulatory sequences naturally associated with the V, (D), or J genes. In one specific example, Green et al. teaches the insertion of human VH, DH, and JH gene sequences, and/or human VL and JL gene sequences into the mouse heavy or light loci respectively where each of the human heavy chain V, D, and J genes or human light chain V and J genes comprises human regulatory sequences (Green et al., paragraphs 53, 85, 94, and 97). In further embodiments, Green et al. teaches that the VH, (DH), and JH sequences are from a xenogeneic species other than a human (Green et al., paragraph 89). Therefore, based on the teachings of Green et al. that xenogeneic regulatory sequences associated with the xenogeneic heavy or light chain V, (D), and J gene sequences can be introduced in mouse heavy or light chain loci respectively, it would have been prima facie obvious to the skilled artisan that the canine V, (D), and J coding sequences can be inserted into the mouse heavy or light chain loci as set forth in both Wabl et al. and Green et al. in conjunction with their respective canine non-coding regulatory sequences with a reasonable expectation of success in generating and expressing canine antibody chains in the mouse. Furthermore, based on the teachings of Wabl et al. for injecting canine antibodies comprising canine variable regions derived from transgenic mice as therapeutics in dogs, and the teachings of Green et al. for administering antibodies comprising xenogeneic variable regions, such as canine variable regions, obtained from transgenic mice to humans and non-human animals for the treatment or prevention of diseases such as cancer or pathogenic infections, it would have been prima facie obvious to the skilled artisan at the time of filing to administer canine antibodies obtained or obtainable from the transgenic mice taught by Wabl et al. in view of Green et al. to dogs for the treatment of disease with a reasonable expectation of success.
Turning to the breed of canine VH, DH, and JH gene segments, and VL and JL gene segments, the rejection of record acknowledged that while both Wabl et al. and Green et al. broadly teach canine light chain V and J genes, and heavy chain V, D, and J genes for insertion into the mouse genome as discussed in detail above, neither Wabl et al. nor Green et al. teach a specific breed of canine genomic sequences such as canine genomic sequences derived from a boxer dog. However, at the time of filing, the full genome of the boxer dog had been sequenced and was publicly available- see CanFam3.1- Canis lupus familiaris genome assembly (2011) https://www.ncbi.nlm.nih.gov /datasets/genome/GCF_000002285.3/, pages 1-6. The applicant argues that the genome of other breeds of dog had been sequenced prior to 4/10/17, the effective filing date for this application, citing Wang et al., Decker et al., and Kim et al., provided in the IDS filed on 11/10/25, and several GenBank submissions related to the Poodle, Beagle, and Terrier genomes, and that none of the cited references provides the requisite motivation to select the boxer dog genome over other dog genomes known in the prior art. In response, it is first noted that the GenBank submission for Terrier genome sequence only provides for a partial genome sequence from the Y chromosome of this dog breed. It is also noted that while Wang et al. discusses using whole genome sequencing and SNP analysis for a number of canid species including wolves, and domesticated dogs, the Wang publication does not indicate that whole genome sequence obtained from any of the dog breeds was published or made available of the public. Decker et al. also teaches genome sequencing of various canids including domesticated dog breeds useful for SNP analysis. While Decker et al. indicates that sequence for canid genomes was submitted to the NCBI Sequence Read Archive, and provides several accession numbers for this database, the data indexed under each accession number does not identify the canid breed from which the sequences were obtained. Kim et al. does provide an accession number for what is characterized as a whole genome for the Korean Jindo dog. The GenBank entry for the Poodle genome sequence, however, refers to a genome size of 1.4 Gb, which appears to therefore be partial sequence as the genome of dogs was understood at the time of filing to be similar to the reference genome of the Boxer dog, which is approximately 2.4 Gb. The GenBank entry for the Beagle genome sequence does appear to contain sequence for the whole genome. Thus, the submitted references and GenBank entries appear to provide evidence that at the time of filing complete whole genome sequences had been obtained and were publicly available for only two dog breeds, the Beagle and the Korean Jindo, in addition to the Boxer dog genome sequence provided by CanFam3.1. Despite the availability of genomic sequence from the Beagle and Korean Jindo at the time of filing, it is maintained that it would have obvious to the skilled artisan at the time of filing to utilize the Boxer dog genome sequence of CanFam3.1 as the a source of canine immunoglobulin heavy and light chain V,(D), and J gene segment sequence to be inserted into the mouse heavy and/or light chain loci as set forth in both Wabl et al. and Green et al. in conjunction with their respective canine boxer dog non-coding regulatory sequences for the following reasons. First, the Boxer dog genome sequence was considered the standard whole genome reference sequence for the domestic dog as evidenced by statements made in several of the evidentiary references submitted by applicant. Wang refers to the Boxer genome downloaded from the NCBI as a “reference genome”, and used the “reference Boxer genome” to identify SNPs in their genome sequence obtained from other breeds (Wang et al., page 3). Decker et al. likewise utilized the CanFam3 Boxer dog sequence as a “reference genome” for analyzing their genomic sequence obtained from other dog breeds (Decker et al., page 1652). Kim et al. also identifies the CanFam boxer genome as a reference genome (Kim et al., page 276). Thus, it is clear that at the time of filing, the Boxer genome, and particularly the CanFam genome sequence cited in the instant rejection, was commonly considered to be a “reference” genome sequence for the domesticated dog, predating later genome sequencing efforts in other dog breeds. Therefore, based on the well-known characterization of the Boxer genome, particularly the CanFam genome sequence, as a “reference” sequence for the domestic dog, the skilled artisan at the time of filing would have been well motivated to selected the CanFam Boxer genome sequence as the canine genome sequence source for canine immunoglobulin heavy and light chain V, D, and J genomic gene segment sequence. Thus, in view of the motivation for using the CanFam Boxer genome sequence as canine genomic sequence based on its art recognized status as a reference genomic sequence for the domesticated dog, it is maintained that based on the teachings of both Wabl et al. and Green et al to generate transgenic mice whose heavy and light chain loci comprise a replacement of endogenous light chain and heavy chain variable region gene segments with canine light chain and heavy chain gene segments, the teachings of Green et al. that xenogeneic regulatory sequences associated with the xenogeneic heavy or light chain V, (D), and J gene sequences can be introduced in mouse heavy or light chain loci respectively, and the teachings of CanFam3.1 for the complete genomic sequence of the boxer dog including at least 80 IgH V genes and at least 160 IgL V genes, it would have been prima facie obvious to the skilled artisan at the time of filing to insert canine boxer dog V, (D), and J coding sequences into the mouse heavy and/or light chain loci as set forth in both Wabl et al. and Green et al. in conjunction with their respective canine boxer dog non-coding regulatory sequences and to further obtain boxer dog variable region antibodies from said transgenic mice and administer said boxer dog variable region antibodies in dogs for treatment of disease with a reasonable expectation of success.
Alternatively, based the evidence of record, it is clear that very few complete genome sequences for the domesticated dog were publicly available at the time of filing. Aside from the Boxer dog genome sequence CanFam3, the evidence of record only supports publicly available complete genome sequence for the Beagle and the Korean Jindo. As such, based on the teachings of both Wabl et al. and Green et al to generate transgenic mice whose heavy and light chain loci comprise a replacement of endogenous light chain and heavy chain variable region gene segments with canine light chain and heavy chain gene segments, the teachings of Green et al. that xenogeneic regulatory sequences associated with the xenogeneic heavy or light chain V, (D), and J gene sequences can be introduced in mouse heavy or light chain loci respectively, and the teachings of CanFam3.1 for the complete genomic sequence of the boxer dog including at least 80 IgH V genes and at least 160 IgL V genes, it would have been prima facie obvious to the skilled artisan at the time of filing to insert canine boxer dog V, (D), and J coding sequences into the mouse heavy and/or light chain loci as set forth in both Wabl et al. and Green et al. in conjunction with their respective canine boxer dog non-coding regulatory sequences and to further obtain boxer dog variable region antibodies from said transgenic mice and administer said boxer dog variable region antibodies in dogs for treatment of disease with a reasonable expectation of success because the choice to insert Boxer dog heavy and light chain heavy and light chain V, (D), and J gene sequences into the mouse genome over the insertion of heavy and light chain V, (D), and J gene sequences from another dog breed represents nothing more than the choosing of one dog breed genome sequence from a finite number of three identified, publicly available, and predictable dog breed complete genome sequences with a reasonable expectation of success.
Finally, in regards to the breed of dog to be treated by the boxer breed canine variable region antibodies, it is noted that the rejection of record sets forth that while Wabl et al. teaches that canine antibodies obtained from transgenic mice can be used as therapeutics in dogs, and Green et al. teaches to administer antibodies, including canine antibodies, obtained from transgenic mice for therapy, neither references specifically teaches to administer a antibody whose variable region comprises boxer dog variable gene segment sequence to dog breeds other than boxer dogs. However, it is noted that at the time of filing, the prior art teaches antibody therapy of various dog breeds where the antibody is not tailored to the dog breed. For example, Webster et al. teaches monoclonal antibody therapy of dog with osteoarthritis with a caninized monoclonal antibody against NGF (anti-NGF mAb), where the antibody was successfully administered to a number of different dog breeds including Golden Retrievers, Rottweilers, Cavalier King Charles Spaniels, Australian Cattle Dogs, Border Collies, Greyhounds and crossbreed dogs (Webster et al., pages 533-534). Thus, Webster et al. shows that antibodies, even antibodies which are not fully canine, can be successfully used to treat disease in dogs, and further that it is not required that canine sequences present in the antibody must be derived from the same dog breed to be treated. Webster indicates that the caninized anti-NGF mAb is further described by Gearing et al. (Webster et al., pages 533 and 535, and citation 12). Gearing et al. teaches that a rat anti-NGF antibody was caninized to reduced immunogenicity in dogs by modifying framework sequences of the antibody to sequences more abundant in canine IgG cDNA sequences as determined by sequence alignment (Gearing et al., pages 2-3). Gearing et al. teaches a lack of fully canine antibodies for therapy, and teaches that fully caninized mAb are required in order to avoid an immune responses in dogs (Gearing et al., pages 1-2). Gearing does not teach that the caninization must be breed specific, and Webster demonstrated that caninized antibody, with rat CDRs and more dog like framework sequences was effective across numerous dog breeds.
Therefore, in view of the teachings of Gearing to use fully caninized antibodies for treating osteoarthritis in dogs to decrease immunogenicity, the teachings of Webster demonstrating successful treatment of various dog breeds using a caninized anti-NGF antibody not specific for any particular dog breed, and the teachings of Wabl et al. that fully canine antibodies, where the cloned canine immunoglobulin H and L chain variable domains are derived from a transgenic mouse with canine light chain and heavy chain variable gene segments as discussed above, are not immunogenic when injected into dogs and can be used as therapeutics, it would have been prima facie obvious to the skilled artisan at the time of filing to administer fully canine antibodies comprising boxer gene variable region sequences obtained from transgenic mice as taught by Wabl et al. in view Green et al., and CanFam 3.1 to a variety of dogs breeds with a reasonable expectation of treating diseases.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634