DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments to the claims and arguments filed on February 17, 2026 have been received and entered. Claims 1, 26, 2934, 36, 37, 42 have been amended, while claims 2, 5-13, 15-25, 35, 38-39 have been canceled.
Claims 1, 3-4, 14, 26-34, 36-37, 40-45 and 46 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-14 (group I) in the reply filed on July 23, 2025 was acknowledged. Applicant’s election of HLA-A2 and HLA-DQ as species for HLA1 polypeptide and HLAII polypeptide respectively is also acknowledged.
Priority
This application is a continuation of PCT/US2020/056771 filed on 10/22/2020, which claims priority from US provisional application no 62/925,859 filed on 10/25/2019 and 62/924,228 filed on 10/22/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/17/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 1, 3-4, 14, 26-34, 36-37, 40-45 and 46 are under consideration.
Maintained-Claim Rejections - 35 USC § 112-scope of enablement
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, 3-4, 14, 26-34, 36-37, 40-45 and 46 remain 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 transgenic swine whose genome comprises (i) a nucleotide sequence encoding HLA-A2 polypeptides inserted down stream of native HLA-A2 promoter at the intron 1/exon 2 junction of the endogenous SLA I locus, and/or (ii) a nucleotide sequence encoding HLA-DQ8a polypeptides inserted down stream of endogenous HLA-DQ8 promoter at the intron 1/exon 2 junction of the endogenous SLA-II locus, wherein said swine thymus expresses HLA-A2 and/or HLA-DQ8a polypeptides, does not reasonably provide enablement for (i) inserting any other HLA-1 and//or HLA-2 at any other site of the native SLA (SLA-1 or SLA-2) locus, a swine without any resulting phenotype or modifying the genome of a swine at endogenous SLA locus with nucleotide sequence encoding HLA-1 and/or HLA-2 without operably linked to endogenous SLA promoter or any other regulatory elements. 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 use the invention commensurate in scope with these claims.
Applicant disagree with the rejection arguing enablement does not require absolute predictability. Rather, enablement requires that a person skilled in the art be able to practice the invention without undue experimentation. In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). As described in the specification, the state of the art provides numerous genetic engineering methods to generate transgenic swine having one or more nucleotide sequences that encode one or more HLA I polypeptides and/or HLA II polypeptides inserted downstream a native SLA promoter at the intron 1/exon 2 junction of the SLA locus (see, e.g., pages 9-22 of the specification as originally filed). Even if a considerable amount of experimentation was required to generate the claimed transgenic swine and perform the method of producing the claimed transgene, there would not be undue experimentation. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, Examiner in part would agree that method of making transgenic swine by itself has become routine, however, resulting phenotype to make use of the transgenic swine continues to be unpredictable.
The breadth of the claimed invention encompasses a transgenic swine, comprising one or more nucleotide sequences encoding one or more HLA I polypeptides and/or any one or more HLA II polypeptides inserted into of native SLA loci of the pig genome. Dependent claims limit the HLA I polypeptides are selected from the group consisting of HLA-A, HLA-A2, HLA-B, HLA-C, HLA-E, HLA-F and HLA-G and/or wherein the HLA II polypeptides are selected from the group consisting of HLA-DP, HLA-DM, HLA-DO, HLA- DQ, and HLA-DR. The specification teaches using fibroblasts from GGTA1 null, SLA haplotype homozygous Sachs Miniature Swine as the starting material for genetic modification. The art summarized by the reference of Fischer (Transgenic Res (2022) 31:391–398) teaches “increased numbers of modifications resulted in complex and very inefficient breeding strategies” (see page 392, col. 2, para. 2) in conjunction with variable expression and segregation of transgene as discussed in previous office action that further complicates the resulting phenotype of the transgenic swine. The guidance provided in the specification is limited to transgenic swine whose genome comprises a nucleotide sequence encoding HLA-A2 polypeptides and/or a transgenic swine whose genome comprises a nucleotide sequence encoding HLA-DQ8a polypeptides at the endogenous SLA1 and/or SLA2 locus expressing HLA-A2 polypeptides and HLA-DQ8a polypeptides in thymus tissue. The specification fails to enable a transgenic swine, comprising one or more nucleotide sequences encoding any other plurality of HLA I polypeptides and/or any other plurality of HLA II polypeptides inserted into one or more of native SLA loci of the pig genome at the endogenous SLA class I and/or II locus as embraced by the breadth of claims. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
The art of record further reports limitations and issues concerned with transgenic animal including 1) certain transgenic phenotypes may result in lethality that may compromise animals' health status like impaired reproduction/lactation, immunodeficiency etc., 2) during development there may be physiologic compensation for the loss of a gene product in the knockout animal, thus, complicating the interpretation of the phenotypic changes seen in transgenic animals, 3) one transgenic animal will not be identical to another and strain differences will be a source of variability, and 4) incorporation of new genetic material may alter the control of function of other genes (see Paris et al Indian Journal of Public Health research & Development, 2011 Vol. 2, No. 1, 106-109). In the instant case, example 2 of the specification teaches using fibroblasts from GGTA1 null, SLA haplotype homozygous Sachs Miniature Swine as the starting material for genetic modification. Thus, the resulting phenotype of transgenic swine in part would depend as to how well human immune cells tolerate the resulting xenograft and concurrent gene knockouts (e.g., GGTA1). The specification fails to enable making transgenic swine that has no an enabled use. One of skill in the art would not know how to use such swine in any way that differs from a wild type swine. The claims as written do not limit the phenotype of the swine. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
It is noted that the unpredictability of a particular art area may alone provide reasonable doubt as to the accuracy of the broad statement made in support of enablement of claims. See Ex parte Singh, 17 USPQ2d 1714 (BPAI 1991). It is also well established in case law that the specification must teach those of skill in the art how to make and how to use the invention as broadly claimed. In re Goodman, 29 USPQ2d at 2013 (Fed. Cir. 1994), citing In re Vaeck, 20 USPQ2d at 1445 (Fed. Cir. 1991). Given such differences in the expression of the transgene, particularly when taken with the lack of guidance in the specification for a swine whose genome comprises one or more nucleotide sequences encoding one or more HLA I polypeptides and/or any one or more HLA II polypeptides inserted into one or more of native SLA loci without any specific phenotype, it would have required undue experimentation to establish the levels of the transgene product, the consequences of that product, and therefore, the resulting phenotype. One of ordinary skill in the art would not know how to make use of the transgenic swine with no phenotype particularly in view of unpredictability in the art. 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.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 3 and 36 are 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. Applicant’s amendments to the claims obviate the basis of the rejection.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 1-3, 5, 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tector III (WO2016/210280, dated 12/29/2016, IDS). In view of Applicants’ amendment of base claim 1, introducing the limitation of claim 6, that was not included in the rejection, the previous rejection is rendered moot and hereby withdrawn. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 26-28, and 31 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Macdonald (US20170135329, dated 5/18/2017). In view of Applicants’ amendment of base claim 26, introducing the limitation “ wherein the one or more nucleotide sequences encoding the one or more HLA II polypeptides are inserted downstream a native SLA II promoter at the intron 1/exon 2 junction of a SLA Class II locus.” that is not taught in prior art , the previous rejection is rendered moot and hereby withdrawn. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claims 34-36, 38, 40, 44 and 46 were rejected under 35 U.S.C. 102(a)(2) as being anticipated by Holzer (US Patent 11833270, filed on 10/4/2019). In view of Applicants’ amendment of base claim 26, introducing the limitation “ wherein the one or more nucleotide sequences encoding the one or more HLA I polypeptides are inserted downstream a native SLA I promoter at the intron 1/exon 2 junction of a SLA Class I locus, and the one or more nucleotide sequences encoding the one or more HLA II polypeptides are inserted downstream a native SLA II promoter at the intron 1/exon 2 junction of a SLA Class II locus” that is not taught in prior art , the previous rejection is rendered moot and hereby withdrawn. The claims are however subject to new rejections over the prior art of record, as set forth below.
Maintained- 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 1, 3-4, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Tector III (WO2016/210280, dated 12/29/2016, IDS), Harada (EP3058819, dated 08/24/20216, IDS)/Pascolo (J Exp. Med. 1997, 185, 2043-2051, IDS), Drummond-Samuelson (WO2019067875, dated 04/04/2019, EFD 09/28/2018) and Lunney et al (Developmental and Comparative Immunology 33 (2009) 362–374).
With respect to claim 1-3 and 5, Tector teaches a transgenic pig whose genome comprises replacement of endogenous SLA 1 with insertion of HLA-A2 at the endogenous SLA 1 locus, wherein said HLA-A2 is under the control of the endogenous SLA class I promoter (para. 35, claims 28-30, fig. 13 and 14), and wherein said swine expresses HLA-A2 (para. 40, 57).
Regarding claim 14, Tector teaches that the HLA nucleotide sequence encodes a class I HLA polypeptide selected from the group comprising HLA-A, HLA-B, HLA-C, HLA-C and HLA-A2 (see claim 30 of 280).
The transgenic pig disclosed in Tector has same genotype and phenotype as claimed. However, Tector differs from claimed invention by not disclosing (i) HLA1 polypeptide is fused to human beta 2-microglobulin and (ii) HLA-1 nucleotide sequences are inserted at the intron 1/exon 2 junction of the SLA I locus.
Harada cure the deficiency by disclosing a transgenic nonhuman animal whose genome comprises chimeric protein comprising a fusion of b2 microglobulin and HLA class I under the control of a promoter (claims 1-14 of ‘819 and para. 47) 14), and wherein said nonhuman animal is pig (see para. 47). Pascolo teaches HLA-A2.1 monochains that is engineered, as illustrated in Fig. 1, by introducing between the first and second exon of the genomic HLA-A2.1 gene a B2m cDNA resulting in a chimeric exon 1 that codes for the leader sequence of HLA-A2.1, the B2m domain. However, combination of reference differs from claimed invention by not disclosing HLA-1 nucleotide sequences are inserted at the intron 1/exon 2 junction of the SLA I locus.
Before the effective filing date of instant application, it was generally known in prior art to retain endogenous promoter and signal sequence while humanizing a gene. For instance, Drummond-Samuelson teaches a non-human animal comprising in its genome a genetically modified endogenous gene (Ttr locus) comprising a human gene (TTR) sequence comprising both TTR coding sequence and non-coding sequence, wherein a region of the endogenous Ttr locus comprising both Ttr coding sequence and non-coding sequence has been deleted and replaced with a corresponding human TTR sequence comprising both TTR coding sequence and non-coding sequence, wherein the genetically modified endogenous Ttr locus comprises the endogenous Ttr promoter, wherein the human TTR sequence is operably linked to the endogenous Ttr promoter and wherein the genetically modified endogenous Ttr locus encodes a transthyretin precursor protein comprising a signal peptide, and the region of the endogenous Ttr locus encoding the signal peptide encoded by first exon and first intron has not been deleted and replaced with the corresponding human TTR sequence. Thus, Drummond-Samuelson teaches the concept of retaining endogenous promoter and endogenous leader sequence (first exon and first intron) upstream of human coding sequence that replaces the corresponding nonhuman coding sequence at an endogenous gene locus of the nonhuman animal. The combination of references fails to disclose endogenous genomic exon/intron structure of SLA-1 gene l.
Lunney teaches that comparative genomic organization of the human and swine major histocompatibility complex (MHC) class I region (see fig. 1). It is disclosed that classical SLA class I genes consist of eight exons: exon 1 encodes the leader sequence; exon 2–4 encode corresponding extracellular a1, a2 and a3 domains; exon 5 the transmembrane domain; and exon 6–8 the cytoplasmic domain (see fig. 3).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art seeking to overexpress human HLA-A2.1 in a swine to provide a source of an organ to be transplanted would insert human leukocyte antigen as disclosed in Tector using method of making humanized nonhuman animal as disclosed in Drummond-Samuelson by using a large targeting vector containing a homology arm of endogenous swine sla-1 upstream and downstream homology arms flanking a human genomic fragment comprising hla-1 such that the hla-1 gene is operably linked to endogenous regulatory elements as disclosed in Drummond-Samuelson, with a reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be further motivated to modify the HLA-A2 molecule as disclosed in Tctore by fusing HLA-A2 to beta-2 microglobulin in order to ensure the functional expression of the human HLA class I molecule on the cell surface as suggested in Harada. Additionally, Tector et al provided explicit motivation for targeted knock-in at the endogenous loci by its human counterpart. Other limitation of nucleotide sequences of hla-1 are inserted at the intron 1/exon 2 junction of the SLA I locus would be obvious modification of known method based on the teachings of Samuelson in view of Lunney who reported genomic organization of human and swine leukocyte antigen genes. One of ordinary skill in the art to retain the endogenous swine promoter and leader sequence coding exon 1 and use targeting construct to successfully insert HLA-2 prior to endogenous exon 2 to produce a human leukocyte antigen-1 knock-in swine with a reasonable expectation of success as prior art successfully teaches humanization of gene of interest as evident from the teaching of Samuelson. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 26-33 are rejected under 35 U.S.C. 103 as being unpatentable over Macdonald (US20170135329, dated 5/18/2017), Drummond-Samuelson (WO2019067875, dated 04/04/2019, EFD 09/28/2018) and Lunney et al (Developmental and Comparative Immunology 33 (2009) 362–374) as evidenced by Ge (Experimental Evidence for the Peptide Competition Between Type 1 Diabetes Associated HLA-DQ8 and DR4 Molecules. Doctoral Dissertation, University of Pittsburgh, 2006)).
With respect to claim 26-27, Macdonald teaches a non-human animal comprising at an endogenous MHC II α gene [SCL-1 loci in pig)] locus a nucleotide sequence encoding a chimeric human/non-human MHC II α polypeptide., wherein human portion of the chimeric polypeptide is derived from a human HLA class II protein selected from the group consisting of HLA-DR, HLA-DQ, and HLA-DP or HLA-DR4 protein (see para. 10) and wherein nonhuman animal is a pig (see para. 60).
Regarding claims 27-28 and 30, Macdonald teaches that the nonhuman animal genome comprises the nucleotide sequence encodes a chimeric HLA-DQ8/H-2A protein (see para. 89). It is further disclosed that the nucleotide sequence is expressed under regulatory control of endogenous non-human MHC II promoter and regulatory elements. (in pig it is SLA-II promoter) (see para. 89). Macdonald differs from claimed invention by not disclosing HLA-1I polypeptide is behind the native promoter and nucleotide sequences are inserted at the intron 1/exon 2 junction of the SLA DQa locus.
Before the effective filing date of instant application, it was generally known in prior art to retain endogenous promoter and signal sequence while humanizing a gene. For instance, Drummond-Samuelson teaches a non-human animal comprising in its genome a genetically modified endogenous Ttr locus comprising a human TTR sequence comprising both TTR coding sequence and non-coding sequence, wherein a region of the endogenous Ttr locus comprising both Ttr coding sequence and non-coding sequence has been deleted and replaced with a corresponding human TTR sequence comprising both TTR coding sequence and non-coding sequence, wherein the genetically modified endogenous Ttr locus comprises the endogenous Ttr promoter, wherein the human TTR sequence is operably linked to the endogenous Ttr promoter and wherein the genetically modified endogenous Ttr locus encodes a transthyretin precursor protein comprising a signal peptide, and the region of the endogenous Ttr locus encoding the signal peptide encoded by first exon and first intron has not been deleted and replaced with the corresponding human TTR sequence. Thus, Drummond-Samuelson teaches the concept of retaining endogenous promoter and endogenous leader sequence (first exon and first intron) upstream of human coding sequence that replaces the corresponding nonhuman coding sequence at an endogenous gene locus of the nonhuman animal. The combination of references fails to disclose endogenous genomic structure of SLA-1I gene locus.
Lunney teaches that comparative genomic organization of the human and swine major histocompatibility complex (MHC) class II region (see fig. 1). It is disclosed that the class II DQA genes consist of four exons, with exon 1 encoding the leader sequence, exon 2 and 3 encoding the corresponding extracellular a1 and a2 domains, and exon 4 bicistronic vector encoding both transmembrane and cytoplasmic domains (Fig. 3). Further, the use of bicistronic vector encoding HLA-DQ8 (HLA- DQA1:03:01:01 and HLA-DQB1:03:02:01) comprising IRES was known in prior art as evidenced by Ge (see fig. 13, page 59).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art seeking to overexpress human HLA-DQ8 in a swine to provide a source of an organ to be transplanted would insert human leukocyte antigen as disclosed in Macdonald using method of making humanized nonhuman animal as disclosed in Drummond-Samuelson by using a large targeting vector containing a homology arm of endogenous swine HLA-DQ8 upstream and downstream homology arms flanking a human genomic fragment comprising HLA-DQ8 such that it is operably linked to endogenous regulatory elements, with a reasonable expectation of success, before the effective filing date of instant application.. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because Macdonald et al provided explicit motivation for targeted knock-in at the endogenous loci by its human counterpart. Other limitation of nucleotide sequences of HLA-DQ8 is inserted at the intron 1/exon 2 junction of the HLA-DQ8 locus would be obvious modification of known method based on the teachings of Drummond-Samuelson in view of Lunney who reported genomic organization of human and swine HLA-DQ8 genes. One of ordinary skill in the art to retain the endogenous swine promoter and leader sequence coding exon 1 and use targeting construct to successfully insert HLA-DQ8 prior to endogenous exon 2 to produce a human leukocyte antigen-II knock-in swine with a reasonable expectation of success as prior art successfully teaches humanization of gene of interest as evident from the teaching of Drummond-Samuelson. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82
USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 34, 36-37, 40-45 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Holzer (US Patent 11833270, EFD 10/4/2019) Tector III (WO2016/210280, dated 12/29/2016, IDS), Macdonald (US20170135329, dated 5/18/2017), Harada (EP3058819, dated 08/24/20216, IDS)/ Pascolo (J Exp. Med. 1997, 185, 2043-2051, IDS), Drummond-Samuelson (WO2019067875, dated 04/04/2019, EFD 09/28/2018), Lunney et al (Developmental and Comparative Immunology 33 (2009) 362–374), Ge (Experimental Evidence for the Peptide Competition Between Type 1 Diabetes Associated HLA-DQ8 and DR4 Molecules. Doctoral Dissertation, University of Pittsburgh, 2006and).
The teaching of Tector III, Macdonald, and Harada/ Pascolo, Drummond, Lunney and Ge have been described above and relied in same manner. However, combination of references differs from claimed invention by not disclosing swine, comprising one or more nucleotide sequences encoding one or more HLA I polypeptides and one or more HLA II polypeptides inserted into one or more native SLA loci of the pig genome.
However, before the effective filing date of instant application, Holzer cures the deficiency by teaching a genetically engineered swine whose genome comprises scarless exchange of one or more endogenous swine leukocyte antigen alleles with one or more human leukocyte antigen alleles, wherein corresponding human leukocyte antigen nucleotide region is DQ, in combination with HLA-E, HLA-G, or both HLA-E and HLA-G (see claims 9-11 of ‘270). Given that Holzer contemplates knock-out of endogenous SLA-11; SLA-6,7,8; SLA-MIC2; and SLA-DQA; SLA-DQB1; SLA-DQB2, and to knock-in HLA-C; HLA-E; HLA-G; and HLA-DQ. (see example 7), therefore insertion (knock in) must necessarily be inherently downstream of the endogenous regulatory sequence (limitation of claim 38 40, 44).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art seeking to overexpress HLA I and HLA2 polypeptide in a swine to provide a source of an organ to be transplanted would insert human leukocyte antigen-1 and human leukocyte antigen-2 as disclosed in Holzer by breeding transgenic swine as disclosed in Tector with one disclosed in Macdonald, with a reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because Holze provided explicit motivation for targeted knock-in of HLA I and HLA2 at the endogenous SLA-1 and/or/II loci. One of ordinary skill would have reasonable expectation of success in producing a transgenic swine whose genome comprises HLA I and HLA2 at the endogenous locus because prior art successfully reported producing genetically engineered swine whose genome comprises scarless exchange of one or more endogenous swine leukocyte antigen alleles with one or more human leukocyte antigen alleles, wherein corresponding human leukocyte antigen nucleotide region is DQ, in combination with HLA-E, HLA-G, or both HLA-E and HLA-G (see claims 9-11 of ‘270).. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Response to arguments
Applicants disagree with the rejection arguing none of the prior art teach or suggest teach that one or more nucleotide sequences encoding the one or more HLA I polypeptides are inserted downstream a native SLA I promoter at the intron 1/exon 2 junction of the SLA Class I locus. Applicants’ arguments have been fully considered, but are not found persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicants have further engaged in selective reading of the teachings of Tector III to formulate the grounds for not teaching the invention. It should be noted that the ultimate goal is to produce a transgenic swine comprising a nucleotide sequence encoding HLA I polypeptides and/or HLA II polypeptides inserted into native SLA loci of the swine genome intended to use using swine thymus tissue for xenotransplantation to humans. As previously indicated, Tector III teaches the insertion of the human class I HLA-A2 in place of the swine SLA-1 and the expression of HLA-A2 from the SLA promoter at the SLA locus (see paragraphs 32-35, legend of figures 11-14). It is further evident from figure 14 that shows no promoter is inserted in the construct upstream of the HLA-A2 coding site Therefore, the homology arms in figure 14 place the HLA-A2 under the control of the SLA I promoter. Additionally, it was generally known in prior art to retain endogenous promoter and signal sequence while humanizing a gene as evident from the teaching of Drummond-Samuelson. The art teaches the concept of retaining endogenous promoter and endogenous leader sequence upstream of human coding sequence that replaces the corresponding nonhuman coding sequence at an endogenous gene locus of the nonhuman animal (Drummond-Samuelson), while Lunney reported genomic organization of the human and swine major histocompatibility complex (MHC) class I region (see fig. 1) showing exon 1 encodes the leader sequence. It would have been obvious for one of ordinary skill in the art seeking to humanizing HLA1 in swine would be motivated to retain endogenous promoter and endogenous leader sequence (first exon and first intron) upstream of human coding sequence (human HLA-A2), with reasonable expectation of success. To the extent that prior art describes retaining endogenous promoter and endogenous leader sequence (first exon and first intron) upstream of human coding sequence that replaces the corresponding nonhuman coding sequence at an endogenous gene locus, the rejection is applicable to the instant case. Applicants' selective reading of Tector III/Macdonald ignores the teachings of the Drummond-Samuelson. There is no requirement for Tector III/Macdonald to teach that which is clearly suggested by Drummond-Samuelson. Absent any requirement of any specific phenotype, a person of skill in the art would be motivated to use a large targeting vector containing a homology arm of endogenous swine sla-1 upstream and downstream homology arms flanking a human genomic fragment comprising hla-1 such that the hla-1 gene is operably linked to endogenous regulatory elements as suggested in Drummond-Samuelson, with a reasonable expectation of success.
Applicant disagree with the rejection arguing none of Macdonald, Drummond-Samuelson, Lunney, and Ge teach or suggest one or more nucleotide sequences encoding the one or more HLA II polypeptides are inserted downstream a native SLA II promoter at the intron 1/exon 2 junction of the SLA Class II locus. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that Macdonald teaches expression of chimeric human MHC class II under the control of the endogenous regulatory element. As stated in previous office action, Macdonald teaches a non-human animal comprising at an endogenous MHC II α gene [SCL-1 loci in pig)] locus a nucleotide sequence encoding a chimeric human/non-human MHC II α polypeptide., wherein human portion of the chimeric polypeptide is derived from a human HLA class II protein selected from the group consisting of HLA-DR, HLA-DQ, and HLA-DP or HLA-DR4 protein (see para. 10) and wherein nonhuman animal is a pig (see para. 60). It is further disclosed that the nucleotide sequence is expressed under regulatory control of endogenous non-human MHC II promoter and regulatory elements. (in pig it is SLA-II promoter) (see para. 89). In the instant case, Macdonald produces animal to study human immune system suggesting said animal requires HLA molecule to correctly express to study regulators of the human immune system. Before the effective filing of instant application, it was known in the art that regulatory elements includer UTR and promoter element. As stated above, prior art recognized retaining endogenous promoter and signal sequence while humanizing a gene as evident from the teaching of Drummond-Samuelson. The prior art of record teaches the concept of retaining endogenous promoter and endogenous leader sequence upstream of human coding sequence that replaces the corresponding nonhuman coding sequence at an endogenous gene locus of the nonhuman animal (Drummond-Samuelson), while Lunney reported genomic organization of the human and swine major histocompatibility complex (MHC) class II region (see fig. 1) showing exon 1 encodes the leader sequence. It would have been obvious for one of ordinary skill in the art seeking to humanizing HLAII in swine would be motivated to retain endogenous promoter and endogenous leader sequence (first exon and first intron) upstream of human coding sequence (human HLA-DQ), with reasonable expectation of success. To the extent that prior art describes retaining endogenous promoter and endogenous leader sequence (first exon and first intron) upstream of human coding sequence that replaces the corresponding nonhuman coding sequence at an endogenous gene locus, the rejection is applicable to the instant case. Absent any requirement of any specific phenotype in the claimed transgenic swine, a person of skill in the art would be motivated to use a large targeting vector containing a homology arm of endogenous swine sla-II upstream and downstream homology arms flanking a human genomic fragment comprising hla-II (HLA-DQ8) such that the hla-1I gene is operably linked to endogenous regulatory elements as suggested in Drummond-Samuelson, with a reasonable expectation of success.
C Applicant disagree with the rejection arguing Holzer does not teach or suggest a transgenic swine comprising one or more nucleotide sequences that encode the one or more HLA I polypeptides inserted downstream a native SLA I promoter at the intron 1/exon 2 junction of the SLA class I locus; and one or more nucleotide sequences that encode the one or more HLA II polypeptides inserted downstream a native SLA II promoter at the intron 1/exon 2 junction of the SLA class II locus. Holzer discusses genetically reprograming a swine where the swine MHC gene is replaced with human MHC gene (see, paragraph bridging Cols. 8-9 of Holzer). However, nowhere does Holzer specify an SLA intron 1/exon 2 junction for HLA I or HLA II. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two product each of which is taught by the prior art to be useful for the same purpose in order to produce a third product that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. In the instant case, Tector III and Macdonald each individually teach a transgenic swine comprising one or more nucleotide sequences that encode the one or more HLA I polypeptides inserted downstream a native SLA I promoter of the SLA class I locus; and one or more nucleotide sequences that encode the one or more HLA II polypeptides inserted downstream a native SLA II promoter at the SLA class II locus respectively. Holzer contemplate a genetically engineered swine whose genome comprises scarless exchange of one or more endogenous swine leukocyte antigen alleles with one or more human leukocyte antigen alleles, wherein corresponding human leukocyte antigen nucleotide region is DQ, in combination with HLA-E, HLA-G, or both HLA-E and HLA-G (see claims 9-11 of ‘270). As stated in preceding section, the prior art of record teaches the concept of retaining endogenous promoter and endogenous leader sequence upstream of human coding sequence that replaces the corresponding nonhuman coding sequence at an endogenous gene locus of the nonhuman animal (Drummond-Samuelson), while Lunney reported genomic organization of the human and swine major histocompatibility complex (MHC) class I and II region (see fig. 1) showing exon 1 encodes the leader sequence. It would have been obvious for one of ordinary skill in the art seeking to humanizing HLAI and II in swine would be motivated to retain endogenous promoter and endogenous leader sequence (first exon and first intron) upstream of human coding sequence (human HLA-A2 and HLA-DQ), with reasonable expectation of success. In the instant case the idea of combining Tector III and Macdonald them flows logically from their having been taught in the prior art. Absent evidence of any phenotype required by the transgenic swine, it would have been prima facie obvious for a person of ordinary skill in the art seeking to overexpress HLA I and HLA2 polypeptide in a swine to provide a source of an organ to be transplanted would insert human leukocyte antigen-1 and human leukocyte antigen-2 as disclosed in Holzer by breeding transgenic swine as disclosed in Tector with one disclosed in Macdonald, with a reasonable expectation of success, before the effective filing date of instant application.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Tu (US 6639122) teaches transgenic swine, whose genome includes an HLA-DQ transgene, wherein said HLA-DQ transgene comprises a combination of human HLA-DQA1 and HLA-DQB1 transgene operably linked to a constitutive promoter (claim1).
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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