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 Response to Election/Restriction Filed and Arguments/Remarks, filed 02 April 2026, have been entered. Claims 216-232 are currently pending. Claims 216, 221, and 231 are independent claims. Applicant’s election without traverse of the invention of Group II, drawn to a method of producing a CD163 gene edited porcine embryo, is acknowledged.
Additionally, applicant’s election of the following species:
CD163 protein-encoding gene modifications: a. an 11 bp deletion from nucleotide 3337 to nucleotide 3347 relative to the reference sequence SEQ ID NO: 47.
with traverse is acknowledged.
After further consideration, the species election requirement for CD163 protein-encoding gene modifications has been withdrawn.
Claims 216-220 and 231-232 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 221-230 are currently pending in the application and under examination to which the following grounds of rejection are applicable. An action on the merits follows.
Priority
The present application is a CON of U.S. Application No. 17/036,522, filed 29 September 2020, now U.S. Patent No. 12,219,939, which is a CON of U.S. Application No. 15/750,633, filed 06 February 2018, now U.S. Patent No. 10,827,730, which is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2016/043467, filed 22 July 2016, which claims priority to U.S. Provisional Application No. 62/202,145, filed 06 August 2015.
Thus, the earliest possible priority for the instant application is 06 August 2015.
Information Disclosure Statement
The information disclosure statements filed 30 December 2024 have been considered by the Examiner.
Drawings
The drawings filed 21 March 2025 are objected to because:
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.” In the instant case, the view numbers for the partial views for Figures 13 and 19 that appear on several sheets are followed by "(CONT.)" instead of (for Figure 13) or in addition to (for Figure 19) a capital letter such as FIG. 1A, FIG. 1B, etc.
Additionally, Figure 2 is titled “FIG. 2A-2B” but actually displays FIG. 2A, FIG. 2B, and FIG. 2C.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: the Brief Description of the Drawings does not include a description of each panel. Specifically, the descriptions of Figure 19 does not include individual descriptions of panels A-E. Additionally, the description for Figure 22 recites, “FIG. 22A and 22B” without providing individual description of each panel A and B. Further, Figure 22A does not provide a key nor a description in the brief description to indicate what is being represented by each individual line graph.
See MPEP 608.01(f), which states, “When there are drawings, there shall be a brief description of the several views of the drawings and the detailed description of the invention shall refer to the different views by specifying the numbers of the figures, and to the different parts by use of reference letters or numerals”. Further, MPEP 608.01(f) instructs examiners that “If the drawings show Figures 1A, 1B, and 1C and the brief description of the refers only to Figure 1, the examiner should object to the brief description, and require applicant to provide a brief description of Figures 1A, 1B, and 1C.”
Appropriate correction is required.
The use of the terms “GCG Wisconsin Genetics Software Package” in [0090], “MEGAshortscript” in [0360], “MagMAX-96” in [0382, 0400], “EZ-PRRSV MPX 4.0” in [0382, 0400], “CFX-96 real-time PCR system” in [0382, 0400], “MAGPIX” in [0384, 0401], “Luminex xPONENT 4.2 software” in [0384, 0401], “FUNGIZONE” in [0397, 0398], “ALEXAFLUOR” in [0398], “FCS Express 5 software” in [0399], “BD LSR Fortessa flow cytometer” in [0399], “Tetracore Quantification Standards and Control Sets” in [0400], “GraphPad Prism” in [0400], “Luminex MAGPLEX” in [0401], “Fluostar Omega” in [0402], which are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that the specification has not been inspected sufficiently to identify all instances of trade names and/or marks used in commerce. It is Applicant’s responsibility to ensure complete compliance.
The specification is further objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required:
Claims 225 and 229 each recite a CD163 modification being “an 11 bp deletion from nucleotide 3337 to nucleotide 3347 relative to the reference sequence SEQ ID NO:47” in lines 3-4 of each claim. Figure 16 teaches a CD163 genomic sequence comprising 3000 nucleotides upstream of exon 7 through exon 10, wherein exons 7-10 are indicated by underlining. Therefore, Figure 16 teaches that nucleotides 3337-3347 are comprised within the intron between exons 7 and 8 (i.e., intron 7). As such, the claims recite a CD163 allele having a specific 11 bp deletion corresponding to nucleotides 3337-3347 relative to the sequence of SEQ ID NO: 47 which is a partial deletion of intron 7.
The specification generically teaches deletions within exons 7 and/or exon 8 as well as a variety of specific deletions within the exon7-exon 8 region [0016-0017, 0025, 0109, 0121-0185, 0281-0323, 0329]. The specification specifically teaches an 11 bp deletion corresponding to nucleotides 3137-3147 relative to the sequence of SEQ ID NO: 47 [0017, 0060, 0109, 0126-0127, 0160, 0162, 0164, 0168, 0170, 0286, 0298, 0300, 0302, 0306, 0308, 0394, SEQ ID NO: 102]. Additionally, Figure 17 of the drawings teaches an 11 bp deletion from exon 7 starting at nucleotide 3137 relative to SEQ ID NO: 47. Example 1 teaches the generation of CD163 gene-modified piglets by the instantly claimed method, wherein one piglet (67-1) had a biallelic mutation of CD163 including an 11 bp deletion in exon 7 on one allele, wherein the 11 bp deletion is a deletion from nucleotide 3137 to nucleotide 3147 [Table 10, 0367].
Although the specification teaches deletions which comprise intron 7 [0017], the specification fails to teach any modification falling exclusively within intron 7, nor any data indicating that a modification fully within intron 7 would exhibit reduced cellular uptake of the PRRSV relative to a wild-type porcine animal. Neither the specification nor the drawings provide teachings for a specific 11 bp deletion corresponding to nucleotides 3337-3347 relative to the sequence of SEQ ID NO: 47. As such, the specification fails to provide antecedent basis for an 11 bp deletion corresponding to nucleotides 3337-3347 relative to the sequence of SEQ ID NO: 47.
Claim Objections
Claim 226 is objected to because of the following informalities: claim 22 recites, “animal , wherein” in line 2, which appears to be a typographical error in which an extra space is inserted between “animal” and “,”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 225-230 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Independent claim 221 and dependent claim 226 each recite, “an intron that is contiguous with exon 7 or exon 8 of the gene encoding the CD163 protein” in line 11-12 and 9-10, respectively, which is afforded its broadest reasonable interpretation to encompass the intron prior to exon 7 (i.e., intron 6) or the intron following exon 8 (i.e., intron 8) and to exclude the intron between exon 7 and exon 8 (i.e., intron 7), which is contiguous with both exon 7 and exon 8 and so does not meet the limitation of being contiguous with exon 7 or exon 8.
Claims 225 and 229 each recite “an 11 bp deletion from nucleotide 3337 to nucleotide 3347 relative to the reference sequence SEQ ID NO:47” in lines 3-4 of each claim. The nucleotides corresponding to nucleotides 3337-3347 relative to instant SEQ ID NO: 47 fall within intron 7, which is the intron between exon 7 and exon 8, as depicted in instant Figure 16. Therefore, the limitation of the 11 bp deletion recited in claims 225 and 229 conflict with the limitations recited in claims 221 and 226, upon which 225 and/or 229 depend.
Claims 225 and 229 each recite “the deleted sequence” in lines 8-9. There is insufficient antecedent basis for this limitation in the claims. Claims 225 and 229 each recite deletions in lines 3, 5, and 8. Therefore, it is unclear to which deletion “the deleted sequence” in lines 8-9 is referring within each claim.
As such, the metes and bounds of the claims cannot be determined.
Claim 226 recites the limitation "the modification" in line 6. There is insufficient antecedent basis for this limitation in the claim. Claim 226 is dependent on claim 221. Claim 221 recites “a modification” in lines 7, 9, 10, and 11 and “the modification” in line 8. Claim 226 recites “a modification” in lines 5, 7, 8, and 9. Therefore, both claims 221 and 226 have prior recitations of “a modification” and it is unclear which modification “the modification” of claim 226 line 6 is referring.
Similarly, claims 228, 229, and 230 each recite “the modification” in line 1. Claims 228 and 229 are each dependent on claim 226, which is dependent on claim 221. Accordingly, it is unclear to which modification “the modification” of claims 228, 229, and 230 line 1 are referring.
Claim 226 also recites the limitation "the gene encoding the CD163 protein" in lines 7, 8, and 9-10. There is insufficient antecedent basis for this limitation in the claim. Claim 226 is dependent on claim 221. Claim 221 recites “a gene encoding the CD163 protein” in lines 7-8 and “the gene encoding the CD163 protein” in lines 9, 10, and 11-12. Claim 226 recites “a gene encoding the CD163 protein“ in line 4. Therefore, both claims 221 and 226 have prior recitations of “a gene encoding the CD163 protein” and it is unclear which gene encoding the CD163 protein “the gene encoding the CD163 protein” of claim 226 lines 7, 8, and 9-10 are referring.
As such, the metes and bounds of the claims cannot be determined.
Claim 227 recites the limitation "the porcine animal" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 227 is dependent on claim 226, which is dependent on claim 221. Claim 221 recites, “a wild-type porcine animal” in line 3. Claim 226 recites, “a surrogate porcine animal” in line 2 , “the surrogate porcine animal” in lines 2-3, and “a CD163 gene edited porcine animal” in line 4. Therefore, it is unclear to which porcine animal “the porcine animal” of claim 227 line 1 is referring. As such, the metes and bounds of the claim cannot be determined.
The term “the same allele” in claims 225 and 229 lines 6-7 and 11 both lacks antecedent basis and is a relative term which renders the claim indefinite. The term “the same allele” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim 225 is dependent on claim 221. Claim 229 is dependent on claim 226, which is dependent on claim 221. None of claims 221, 225, 226, nor 229 have any prior recitations of any alleles. To the extent that an allele is inherent to the CD163 gene, it is unclear which allele is “the same allele” as recited in claims 225 and 226 in that “the same” is a relative term and the claim does not specify which allele the allele of lines 6-7 and 11 are the same as. As such, the metes and bounds of the claim cannot be determined.
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.
Claim(s) 221-224, 226-228, and 230 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Prather [US20140096275A1, published 3 April 2014, IDS]; as evidenced by Ritter et al. [1999, Biochem. Biophys. Res. Comm., Vol 260, 466-474, IDS] and Van Gorp et al. [2010, J. Virol., Vol 84(6), 3101-3105, IDS].
Regarding claim 221, Prather discloses a method of producing a CD163 gene edited embryo wherein the CD163 gene edited porcine embryo exhibits reduced cellular uptake of the porcine reproductive and respiratory syndrome virus (PRRSV) relative to a wild-type porcine animal [0014, 0057] comprising:
a) enucleating a porcine oocytes [0014, 0057];
b) fusing the porcine oocyte with a donor porcine somatic cell [0014, 0057], the genome of the porcine somatic cell comprising:
a modification in at least one chromosomal sequence in a gene encoding a CD163 protein [0014], wherein the modification is a modification of the gene encoding the CD163 protein which results in deletion of the SRCR domain 5 [0034, 0045, 0057, 0100],
c) activating the oocyte to produce the CD163 gene edited porcine embryo [0014, 0057].
Prather does not explicitly teach that deletion/ modification of the CD163 SRCR domain 5 corresponds with deletion/ modification of exon 7 in the gene encoding CD163.
However, Ritter et al. teaches that exon 7 encodes, and therefore corresponds to, the SRCR domain 5 of the CD163 protein [Figure 1A].
Regarding claim 222, Prather discloses wherein the donor porcine somatic cell comprises a porcine fibroblast [0014].
Regarding claims 223 and 227, Prather disclose wherein the CD163 gene edited porcine embryo comprises a mutation that alters the activity of CD163 such that it cannot bind and/or uncoat a porcine reproductive and respiratory syndrome virus (PRRSV) [0014, 0057].
Regarding claims 224 and 228, Prather disclose wherein the modification in at least one chromosomal sequence in a gene encoding a CD163 protein comprises an insertion and/or a deletion [0034, 0038, 0045, 0100].
Regarding claim 226, Prather disclose wherein the method further comprises transferring the CD163 gene edited porcine embryo into a reproductive tract of a surrogate porcine animal, wherein the surrogate porcine animal has initiated estrus but has not yet completed ovulation [0057]; and wherein gestation and term delivery produces a CD163 gene edited porcine animal whose genome comprises a modification in at least one chromosomal sequence in a gene encoding a CD163 protein, wherein the modification is a modification in exon 7 of the gen encoding the CD163 protein [0057].
Regarding claim 230, Prather does not explicitly teach wherein the replacement of CD163 SRCR domain 5 with the CD163L SRCR domain 8 constitutes an in-frame deletion within exon 7 of the gene encoding CD163.
However, as referenced by Prather, Van Gorp teaches the same hybrid construct and further recites the amino acid sequence of the CD163 domain 5, the amino acid sequence of the CD163L domain 8, and the primer sequences used to make the hybrid constructs (Supplemental Figure S1 and Supplemental Table S2). Comparing the sequence overlap used to fuse fragments 1 and 2 of the hybrid construct of Van Gorp with the sequence disclosed by the present application as the sequence of exon 7 (starting with nucleotide 3001 of SEQ ID NO: 47), one can see that the hybrid CD163 sequence retains the first 27 nucleotides of exon 7 corresponding to nucleotides 3001 to 3027 of SEQ ID NO: 47. Therefore, the hybrid construct as recited by Van Gorp et al. is in fact an in-frame deletion within exon 7 in which an additional insertion is included. The porcine animal comprising an in-frame deletion within CD163 exon 7 does not exclude the possibility of an accompanying insertion. Therefore, the hybrid CD163 of Prather and Van Gorp discloses a modification in exon 7 of the gene encoding the CD163 protein, wherein the modification comprises an in-frame deletion in exon 7.
Accordingly, by teaching all of the limitations of claims 221-224, 226-228, and 230, Prather anticipates the instant invention as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 221-224, 226-228, and 230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 9,820,475, hereafter referred to as the ‘475 patent, in view of Van Gorp et al. [2010, J. Virol., Vol 84(6), 3101-3105, IDS].
The ‘475 patent claims recite a method for producing a genetically modified swine comprising inactivating mutations in both alleles of the CD163 gene, comprising enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
The ‘475 patent claims further recite that at least one allele has been inactivated by partial or complete deletion; wherein the CD163 allele has been inactivated by replacing exon 7 with SRCR domain 8 of CD163L; wherein the inactivating mutation in at least one of or both of the CD163 alleles results in a CD163 protein which cannot bind and/or uncoat a PRRSV; wherein the mutations alter the expression or activity of CD163; wherein the somatic cell is a fibroblast; and wherein the mutations comprise insertions, partial deletions, complete deletions, frame shift mutations, nonsense mutations, missense mutations, point mutations, or a combination thereof.
By reciting a modification in which the CD163 exon 7 has been replaced with the SRCR domain 8 of CD163L, the ‘475 patent claims recite a deletion of exon 7. As referenced by ‘475 patent, Van Gorp teaches the same hybrid construct and further recites the amino acid sequence of the CD163 domain 5, the amino acid sequence of the CD163L domain 8, and the primer sequences used to make the hybrid constructs (Supplemental Figure S1 and Supplemental Table S2). Comparing the sequence overlap used to fuse fragments 1 and 2 of the hybrid construct of Van Gorp with the sequence disclosed by the present application as the sequence of exon 7 (starting with nucleotide 3001 of SEQ ID NO: 47), one can see that the hybrid CD163 sequence retains the first 27 nucleotides of exon 7 corresponding to nucleotides 3001 to 3027 of SEQ ID NO: 47. Therefore, the hybrid construct as recited by Van Gorp and the ‘475 patent claims is in fact an in-frame deletion within exon 7 in which an additional insertion is included.
Note that MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for ODP rejections. In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. The court in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
The porcine animal comprising an in-frame deletion within CD163 exon 7 does not exclude the possibility of an accompanying insertion. Therefore, the hybrid CD163 of the ‘475 patent claims is a modification in exon 7 of the gene encoding the CD163 protein, wherein the modification comprises an in-frame deletion in exon 7. Therefore, the modification is a species of the modifications claimed in claims 221 and 226 of the present application. Additionally, the broader modifications claimed by the ‘475 patent, including insertions, partial deletions, complete deletions, frame shift mutations, nonsense mutations, missense mutations, point mutations, or a combination thereof, encompass the modifications claimed in claims 221 and 226 of the instant application. As such, the ‘475 patent claims anticipate, encompass, and render obvious claims 221-224, 226-228, and 230 of the present application.
Claims 221-224, 226-228, and 230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10,080,353, hereafter referred to as the ‘353 patent, in view of Ritter et al. [1999, Biochem. Biophys. Res. Comm., Vol 260, 466-474, IDS]; Van Gorp et al. [2010, J. Virol., Vol 84(6), 3101-3105, IDS]; and Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘353 patent claims recite a method for producing a genetically modified swine comprising inactivating mutations in both alleles of the CD163 gene, the method comprising editing the genetic content of a porcine cell to create a modification which alters the expression or activity of CD163 and generating an animal from the cell, wherein the editing comprises the use of ZFN or TALEN nucleases and results in partial or complete deletion of a CD163 allele and an animal that produces CD163 protein which cannot bind and/or uncoat a PRRSV. The ‘353 patent claims further recite wherein the CD163 mutation comprises an insertion, a deletion, a frame shift mutation, a nonsense mutation, a missense mutation, or a point mutation.
Ritter et al. teaches that exon 7 encodes, and therefore corresponds to, the SRCR domain 5 of the CD163 protein (Figure 1A). Ritter also teaches that exon 8 encodes, and therefore corresponds to, the SRCR domain 6 of the CD163 protein (Figure 1A).
Van Gorp further teaches that a deletion mutation of CD163 comprising deletion of the SRCR domains 4, 5, and 6 confers resistance to infection with PRRSV [column 2 ¶ 1, and Figure 1b], that the SRCR domain 5 is essential for PRRSV infection [column 2 ¶ 1, column 5 ¶ 1, column 7 ¶ 2, Abstract, Figure 2, and Conclusion] and that removal of SRCR domain 5 (and replacement with CD163L domain 8) reduces the protein levels in the cell [Figure 2]. Van Gorp additionally teaches that replacing CD163 SRCR domain 6 (which Ritter teaches is encoded by exon 8) with CD163L domain 9 results in reduced PRRSV infection efficiency [column 4 ¶ 1, Figure 2]. Van Gorp further teaches that CD163 is involved in hemoglobin internalization via SRCR domain 3 and that SRCR domain 2 is involved in erythroblast binding [Column 6 ¶ 2]. Therefore, a skilled artisan at the time of filing would have been motivated to disrupt the CD163 SRCR domains 5 and/or 6, corresponding to exons 7 and 8, via a mutation within exon 7 and/or exon 8 of the CD163 gene to reduce PRRSV susceptibility, without deleting other regions of the protein, such as SRCR domains 2 and 3.
Additionally, the broad modifications claimed by the ‘353 patent, including insertions, partial deletions, complete deletions, frame shift mutations, nonsense mutations, missense mutations, point mutations, or a combination thereof, encompass the modifications claimed in claims 221 and 226 of the instant application.
The ‘353 patent claims do not recite that the method for generating an animal from the modified cell comprises enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
However, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs from somatic cells comprising altered genomes, and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer to generate an animal from a genetically modified swine cell.
Therefore, the ‘353 patent claims recite a genetically modified swine made by the instant method as well as methods of making the genetically modified swine which encompass the instantly claimed method. As such, the ‘353 patent claims encompass and render obvious claims 221-224, 226-228, and 230 of the instant application.
Claims 221-224, 226-228, and 230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,405,526, hereafter referred to as the ‘526 patent, in view of Ritter et al. [1999, Biochem. Biophys. Res. Comm., Vol 260, 466-474, IDS]; Van Gorp et al. [2010, J. Virol., Vol 84(6), 3101-3105, IDS]; and Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘526 patent claims recite a genetically modified swine comprising an alteration in a CD163 gene sequence, wherein the alteration reduces the expression of CD163, wherein the alteration is in a non-coding sequence of the CD163 gene, wherein the swine exhibits increased resistance to PRRSV, wherein the non-coding sequence comprises an intron, a promoter, a 5’ UTR, or a 3’ UTR, and wherein the alteration comprises an insertion, deletion, frameshift mutation, a nonsense mutation, a missense mutation, and/or a point mutation.
The ‘526 patent claims additionally recite a genetically modified swine comprising an alteration in a CD163 gene sequence wherein the swine exhibits increased resistance to PRRSV, wherein the alteration reduces the expression of CD163, wherein the alteration in the CD163 gene sequence comprises an alteration in a coding region or a non-coding region of the CD163 gene sequence, including an insertion, deletion, frameshift mutation, a nonsense mutation, a missense mutation, and/or a point mutation.
Ritter et al. teaches that exon 7 encodes, and therefore corresponds to, the SRCR domain 5 of the CD163 protein (Figure 1A). Ritter also teaches that exon 8 encodes, and therefore corresponds to, the SRCR domain 6 of the CD163 protein (Figure 1A).
Van Gorp further teaches that a deletion mutation of CD163 comprising deletion of the SRCR domains 4, 5, and 6 confers resistance to infection with PRRSV [column 2 ¶ 1, and Figure 1b], that the SRCR domain 5 is essential for PRRSV infection [column 2 ¶ 1, column 5 ¶ 1, column 7 ¶ 2, Abstract, Figure 2, and Conclusion] and that removal of SRCR domain 5 (and replacement with CD163L domain 8) reduces the protein levels in the cell [Figure 2]. Van Gorp additionally teaches that replacing CD163 SRCR domain 6 (which Ritter teaches is encoded by exon 8) with CD163L domain 9 results in reduced PRRSV infection efficiency [column 4 ¶ 1, Figure 2]. Van Gorp further teaches that CD163 is involved in hemoglobin internalization via SRCR domain 3 and that SRCR domain 2 is involved in erythroblast binding [Column 6 ¶ 2]. Therefore, a skilled artisan at the time of filing would have been motivated to disrupt the CD163 SRCR domains 5 and/or 6, corresponding to exons 7 and 8, via a mutation within exon 7 and/or exon 8 of the CD163 gene to reduce PRRSV susceptibility, without deleting other regions of the protein, such as SRCR domains 2 and 3.
Additionally, the broad modifications claimed by the ‘526 patent claims, including insertions, partial deletions, complete deletions, frame shift mutations, nonsense mutations, missense mutations, point mutations, or a combination thereof, within the non-coding region of the gene or the coding of the gene encompass the modifications claimed in claims 221 and 226 of the instant application, including wherein the modifications are within intronic sequences contiguous with exon 7 or exon 8.
The ‘526 patent claims do not recite that the method for generating an animal from the modified cell comprises enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
However, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs from somatic cells comprising altered genomes, and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer to generate an animal from a genetically modified swine cell.
Accordingly, the ‘526 patent claims recite a genetically modified swine made by the instant method. As such, the ‘526 patent claims encompass and render obvious claims 221-224, 226-228, and 230 of the instant application.
Claims 221-224, 226-228, and 230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,019,809, hereafter referred to as the ‘809 patent, in view of Van Gorp et al. [2010, J. Virol., Vol 84(6), 3101-3105, IDS]; and Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘809 patent claims recite a method for producing a genetically modified swine comprising editing the genetic content of a porcine cell to create a modification which alters the expression or activity of CD163 and generating an animal from the cell, wherein the editing comprises the use of ZFN or TALEN nucleases and results in a deletion of a CD163 gene sequence encoding the SRCR domain 5 with or without replacement of the SRCR domain 5 with a sequence which encodes the SRCR domain 8 of CD163L, and then generating an animal from the cell that produces CD163 protein which cannot bind and/or uncoat a PRRSV.
The ‘809 patent claims further recite mating a female genetically modified swine produced by the method above with a male genetically modified swine produced by the method above to produce F1 progeny and screening the F1 progeny to identify genetically modified swine wherein both alleles of the CD163 gene have been inactivated. The ‘809 patent claims further recites that at least one allele has been inactivated by deletion of the SRCR domain 5 with or without replacement by SRCR domain 8 of CD163L; wherein the inactivating mutation in at least one of or both of the CD163 alleles results in a CD163 protein which cannot bind and/or uncoat a PRRSV; and wherein the mutations comprise insertions, partial deletions, complete deletions, frame shift mutations, nonsense mutations, missense mutations, point mutations, or a combination thereof.
By reciting a modification in which the CD163 exon 7 has been replaced with the SRCR domain 8 of CD163L, the ‘809 patent claims recite a deletion of exon 7. As referenced by ‘475 patent, Van Gorp teaches the same hybrid construct and further recites the amino acid sequence of the CD163 domain 5, the amino acid sequence of the CD163L domain 8, and the primer sequences used to make the hybrid constructs (Supplemental Figure S1 and Supplemental Table S2). Comparing the sequence overlap used to fuse fragments 1 and 2 of the hybrid construct of Van Gorp with the sequence disclosed by the present application as the sequence of exon 7 (starting with nucleotide 3001 of SEQ ID NO: 47), one can see that the hybrid CD163 sequence retains the first 27 nucleotides of exon 7 corresponding to nucleotides 3001 to 3027 of SEQ ID NO: 47. Therefore, the hybrid construct as recited by Van Gorp and the ‘809 patent claims is in fact an in-frame deletion within exon 7 in which an additional insertion is included.
Note that MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for ODP rejections. In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. The court in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
The porcine animal comprising an in-frame deletion within CD163 exon 7 does not exclude the possibility of an accompanying insertion. Therefore, the hybrid CD163 of the ‘809 patent claims is a modification in exon 7 of the gene encoding the CD163 protein, wherein the modification comprises an in-frame deletion in exon 7. Therefore, the modification is a species of the modifications claims in claims 221 and 226 of the present application. Additionally, the broader modifications claimed by the ‘809 patent, including comprise insertions, partial deletions, complete deletions, frame shift mutations, nonsense mutations, missense mutations, point mutations, or a combination thereof, encompass the modifications claimed in claims 221 and 226 of the instant application.
The ‘809 patent claims do not recite that the method for generating an animal from the modified cell comprises enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
However, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs from somatic cells comprising altered genomes, and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer to generate an animal from a genetically modified swine cell.
Therefore, the ‘809 patent claims recite a genetically modified swine made by the instant method as well as methods of making the genetically modified swine which encompass the instantly claimed method. As such, the ‘809 patent claims encompass and render obvious claims 221-224, 226-228, and 230 of the instant application.
Claims 221-224, 226-228, and 230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,527,305, hereafter referred to as the ‘305 patent, in view of Ritter et al. [1999, Biochem. Biophys. Res. Comm., Vol 260, 466-474, IDS]; Van Gorp et al. [2010, J. Virol., Vol 84(6), 3101-3105, IDS]; and Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘305 patent claims recite a method for producing a genetically modified swine wherein the swine comprises an alteration in a CD163 gene sequence and wherein the swine exhibits increased resistance to PRRSV, comprising enucleating a porcine oocyte; fusing the porcine oocyte with the donor porcine somatic cells, the genome of the donor porcine somatic cell comprising the alteration in a CD163 gene sequences; and activating the porcine oocyte fused with the donor porcine cell to produce a genetically altered porcine embryo; generating a genetically altered porcine animal from the genetically altered porcine embryo by implanting the genetically altered porcine embryo in a surrogate female porcine animal and allowing gestation to generate a genetically altered porcine animal (claim 1). The ‘305 patent claims additionally recite that the alteration comprises a deletion of a portion of the CD163 gene sequence that encodes the SRCR domain 5 (claim 1).
The ‘305 patent claims do not recite that the deletion of a portion of the CD163 gene sequence that encodes the SRCR domain 5 is an in-frame deletion nor wherein the surrogate swine has initiated estrus but has not yet complete ovulation.
Ritter et al. teaches that exon 7 encodes, and therefore corresponds to, the SRCR domain 5 of the CD163 protein (Figure 1A). Ritter also teaches that exon 8 encodes, and therefore corresponds to, the SRCR domain 6 of the CD163 protein (Figure 1A).
Van Gorp teaches that a deletion mutation of CD163 comprising deletion of the SRCR domains 4, 5, and 6 confers resistance to infection with PRRSV [column 2 ¶ 1, and Figure 1b], that the SRCR domain 5 is essential for PRRSV infection [column 2 ¶ 1, column 5 ¶ 1, column 7 ¶ 2, Abstract, Figure 2, and Conclusion] and that removal of SRCR domain 5 (and replacement with CD163L domain 8) reduces the protein levels in the cell [Figure 2]. Van Gorp additionally teaches that replacing CD163 SRCR domain 6 (which Ritter teaches is encoded by exon 8) with CD163L domain 9 results in reduced PRRSV infection efficiency [column 4 ¶ 1, Figure 2]. Van Gorp further teaches that CD163 is involved in hemoglobin internalization via SRCR domain 3 and that SRCR domain 2 is involved in erythroblast binding [Column 6 ¶ 2]. Therefore, a skilled artisan at the time of filing would have been motivated to disrupt the CD163 SRCR domains 5 via a mutation within exon 7 of the CD163 gene to reduce PRRSV susceptibility without disruption the other regions of the protein, such as by introducing an in-frame mutation in exon 7 which would allow expression of the remaining regions of the protein, including SRCR domains 2 and 3.
Further, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer followed by transferring the genetically altered porcine embryo into a reproductive tract of a surrogate porcine animal, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, to generate an animal from a genetically modified swine cell.
By reciting a method for producing a genetically modified swine with increased PRRSV resistance by deleting a portion of the CD163 gene sequence encoding the SRCR domain 5 in at least one allele using a TALEN or ZFN nuclease in a porcine cell, using that cell to generate a porcine animal by steps of enucleating a porcine oocyte, fusing the enucleated oocyte with a genetically modified donor porcine somatic cell comprising a modification in the gene encoding CD163, activating the fused cell to produce a genetically altered porcine embryo, and generating a genetically altered porcine animal by implanting the embryo into a surrogate pig and allowing gestation, the ‘305 patent claims encompass and render obvious claims 221-224, 226-228, and 230 of the present application.
Claims 221-230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 10,091,975, hereafter referred to as the ‘975 patent, in view of Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘975 patent claims recite a porcine animal or offspring thereof or a porcine cell comprising a modified chromosomal sequence in at least one allele of a gene encoding a CD163 protein, wherein the modified chromosomal sequence in the at least one allele comprises a deletion comprising an 11 base pair deletion from nucleotide 3,137 to nucleotide 3,147 as compared to reference sequence SEQ ID NO: 47 (which is identical to SEQ ID NO: 47 of the instant application). The ‘975 patent claims further recite that the animal, offspring, or cell is heterozygous or homozygous for the deletion (claims 26-28), that the deletion is produced by the action of a CRISPR, TALEN, or ZFN nuclease (claims 7-9), that the second allele comprises a 1467 bp deletion from nucleotide 2431 to 3897 (claim 34) or a 377 bp deletion from nucleotides 2573-2949 accompanied by a 2 bp insertion between nucleotides 3149 and 3150 (claim 35), and that the modification(s) reduces the susceptibility/ increases resistance of the animal, offspring, or cell to a PRRSV (Type 1, Type 2, both Type 1 and Type 2, and/or specific isolates, claims 2-5, 10), and that the cell is a fibroblast (claims 19-20).
The ‘975 patent claims do not recite that the method for generating an animal from the modified cell comprises enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
However, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs from somatic cells comprising altered genomes, and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer to generate an animal from a genetically modified swine cell.
By reciting a porcine animal, offspring thereof, or cell whose genome comprises a specific deletions as recited in claims 226 and 229 of the instant application, having increased PRRSV resistance (decreased susceptibility), the ‘975 patent claims recite an animal produced by the instant method. Additionally, by reciting that the claimed porcine animal is produced by a method comprising modifying at least one chromosomal sequence in a gene encoding a CD163 protein in the porcine animal, offspring, or cell using a ZFN, TALEN, or CRISPR/Cas9 nuclease, the ‘975 patent claims recite wherein the animal is produced by a method which encompasses the instantly claimed method. Accordingly, the ‘975 patent claims anticipate and/or encompass and render obvious claims 221-230 of the instant application.
Claims 221-230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10,827,730, hereafter referred to as the ‘730 patent, in view of Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘730 patent claims recite a porcine animal or offspring thereof whose genome comprises a deletion selected from the groups consisting of a 1467 bp deletion from nucleotide 2,431 to nucleotide 3,897 relative to the reference sequence SEQ ID NO:47 and a 1280 bp deletion from nucleotide 2818 to nucleotide 4097 relative to the reference sequence SEQ ID NO:47, wherein the deletion results in lack of detectable surface expression of CD163 protein on alveolar macrophages, a wherein when the deletion reduces the susceptibility of the animal or offspring to a Type 1 and/or Type 2 PRRSV relative to a wild-type animal. The ‘730 patent claims further recite that the genetically modified porcine animal has been genetically edited using a homing endonuclease, such as a CRISPR/Cas9, TALEN, or ZFN nuclease, and that the CD163 production or activity is reduced as a consequence of the deletion.
The ‘730 patent claims do not recite that the method for generating an animal from the modified cell comprises enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
However, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer to generate an animal from a genetically modified swine cell.
Accordingly, by reciting a porcine animal or offspring thereof whose genome comprises a specific deletion selected from the group recited in claims 225 and 229 of the instant application, having increased PRRSV resistance, produced by a method comprising modifying at least one chromosomal sequence in a gene encoding a CD163 protein in the porcine animal, offspring, or cell using a ZFN, TALEN, or CRISPR/Cas9 nuclease, the ‘730 patent claims recite an animal produced by a method which encompasses the instantly claimed method, wherein the animal recited in the ‘730 patent claims is an animal produced by the instantly claimed method. As such, the ‘730 patent claims anticipate and/or encompass and render obvious claims 221-230 of the instant application.
Claims 221-224, 226-228, and 230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,219,939, hereafter referred to as the ‘939 patent, in view of Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘939 patent claims recite a porcine animal or offspring thereof comprising an in-frame deletion in exon 7 of the gene encoding the CD163 protein, wherein the in-frame deletion comprises a 123 bp deletion from nucleotides 3024-3146 as compared to SEQ ID NO: 47. This is a species of the in-frame deletion in exon 7 recited in claims 221 and 226 of the instant application. The ‘939 patent claims further recite that the deletion reduced susceptibility of the animal or offspring to infection by PRRSV, that the animal has been genetically edited using a homing nuclease, such as a CRISPR/Cas, TALEN, or ZFN nuclease to produce the deletion, and that the CD163 production or activity is reduced as a consequence of the deletion.
The ‘939 patent claims do not recite that the method for generating an animal from the modified cell comprises enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
However, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer to generate an animal from a genetically modified swine cell.
Accordingly, by reciting a porcine animal or offspring thereof whose genome comprises a species of the deletions recited in claims 221 and 226 of the instant application, having increased PRRSV resistance, produced by a method comprising modifying at least one chromosomal sequence in a gene encoding a CD163 protein in the porcine animal, offspring, or cell using a ZFN, TALEN, or CRISPR/Cas9 nuclease, the ‘939 patent claims recite an animal produced by a method which encompasses the instantly claimed method, wherein the animal recited in the ‘939 patent claims is an animal produced by the instantly claimed method. As such, the ‘939 patent claims anticipate and/or encompass and render obvious claims 221-224, 226-228, and 230 of the instant application.
Claims 221-230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,225,889, hereafter referred to as the ‘889 patent.
The ‘889 patent claims recite a method of producing a porcine animal with increased PRRS resistance relative to a wild-type porcine animal comprising:
a) enucleating an oocyte;
b) fusing the oocyte with a donor somatic cell, the genome of the donor somatic cell comprising: a modification in at least one chromosomal sequence in a gene encoding a CD163 protein, wherein the modification is selected from the group consisting of:
i) a modification in exon 7 of the gene encoding the CD163 protein,
ii) a modification in exon 8 of the gene encoding the CD163 protein,
iii) a modification in an intron that is contiguous with exon 7 or exon 8 of the gene encoding the CD163 protein, and
iv) a combination thereof,
wherein the modification is selected from the group consisting of:
1) an 11 bp deletion from nucleotide 3137 to nucleotide 3147 relative to the reference sequence SEQ ID NO:47,
2) a 377 bp deletion from nucleotide 2573 to nucleotide 2949, with a 2 bp addition between nucleotides 3149 to nucleotide 3150 relative to the reference sequence SEQ ID NO:47 on the same allele,
3) a 1930 base pair deletion from nucleotide 488 to nucleotide 2,417, wherein the deleted sequence is replaced with a 12 base pair insertion beginning at nucleotide 488, with a 129 base pair deletion from nucleotide 3044 to nucleotide 3172 relative to the reference sequence SEQ ID NO: 47 on the same allele,
4) a 1467 bp deletion from nucleotide 2,431 to nucleotide 3,897 relative to the reference sequence SEQ ID NO:47,
5) a 1280 bp deletion from nucleotide 2818 to nucleotide 4097 relative to the reference sequence SEQ ID NO:47, and
6) combinations thereof;
c) activating the oocyte to produce an embryo; and transferring the embryo into a reproductive tract of a surrogate porcine animal,
wherein the surrogate porcine animal has initiated estrus but has not yet completed ovulation; and wherein gestation and term delivery produces a porcine animal with increased porcine reproductive and respiratory (PRRS) resistance relative to a wild-type porcine animal (claim 8).
The ‘889 patent claims further recite wherein the somatic cell is a fibroblast (claim 11).
Accordingly, the ‘889 patent claims anticipate and/or encompass and render obvious claims 221-230 of the instant application.
Claims 221-230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,160,260, hereafter referred to as the ‘260 patent; in view of Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘260 patent claims recite a method for protecting a porcine fetus from infection with PRRSV in utero, comprising breeding a female porcine animal with a male porcine animal, wherein the female porcine animal comprises modified/ genetically edited chromosomal sequences in both alleles of its CD163 gene, wherein the modified chromosomal sequences reduce the susceptibility of the female porcine animal to infection by PRRSV compared to a wild-type porcine animal, and wherein the male porcine animal comprises two wild-type CD163 alleles. The ‘260 patent claims further recite that the genetic editing was done using a homing nuclease, including a CRISPR/Cas, TALEN, or ZFN nuclease, and that the two alleles of the female animal’s CD163 gene can comprise different modifications (and therefore be heterozygous). The ‘260 patent claims also recite that the modification is a deletion, wherein the modification is selected from a group of modifications which include an in-frame deletion in exon 7 (a 123 bp deletion from 3024 to 3146 as compared to SEQ ID NO: 47), which is a species of the deletions recited in claims 221 and 226 of the instant application, along with the specific 1930 bp, 1467 bp, and 1280 bp deletions as recited in claims 225 and 229 of the instant application (which are also species of the modifications recited in claims 221 and 226 of the instant application). The ‘260 patent claims further recite that the modification causes CD163 protein production or activity to be reduced, and that the breeding produces one or more fetuses which comprise a modified chromosomal sequence in a single allele of the CD163 gene, wherein the fetuses have reduced susceptibility to infection by PRRSV, and wherein the breeding comprises mating of the male and female porcine animals.
The ‘260 patent claims do not recite that the method for generating an animal from the modified cell comprises enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
However, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer to generate an animal from a genetically modified swine cell.
Accordingly, by reciting a porcine animal or offspring thereof whose genome comprises a species of the deletions recited in claims 221 and 226 of the instant application, including specific deletions recited in claim 225 and 229 of the instant application, having increased PRRSV resistance (decreased susceptibility), produced by a method comprising modifying at least one chromosomal sequence in a gene encoding a CD163 protein in the porcine animal, offspring, or cell using a ZFN, TALEN, or CRISPR/Cas9 nuclease, the ‘260 patent claims recite an porcine animal produced by the instantly claimed method. As such, the ‘260 patent claims encompass and render obvious claims 221-230 of the instant application.
Claims 221-230 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,433,263, hereafter referred to as the ‘263 patent, in view of Lai & Prather [2003, Cloning and Stem Cells, Vol. 5(4), 233-241, IDS].
The ‘263 patent claims recite a method for protecting a porcine fetus from infection with a porcine reproductive and respiratory syndrome virus (PRRSV) in utero, the method comprising breeding a female porcine animal with a male porcine animal, wherein the female porcine animal comprises modified chromosomal sequences in both alleles of its CD163 gene, wherein the modified chromosomal sequences reduce production or activity of the CD163 protein as compared to a female porcine animal which lacks the modified CD163 sequence (claim 1). The ‘263 patent claims further recite wherein each allele of the CD163 gene of the female porcine animal comprises an insertion, deletion, or a combination thereof (claim 6); and wherein each allele of the CD163 gene of the female porcine animal comprises a modification in exon 7, a modification in exon 8, a modification in an intron that is contiguous with exon 7 or exon 8, or a combination of any thereof (claim 7).
The ’263 patent claims additionally recite specific CD163 modifications which include: an 11 base pair deletion from nucleotide 3,137 to nucleotide 3,147 as compared to reference sequence SEQ ID NO: 47; a 2 base pair insertion between nucleotides 3,149 and 3,150 as compared to reference sequence SEQ ID NO: 47, with a 377 base pair deletion from nucleotide 2,573 to nucleotide 2,949 as compared to reference sequence SEQ ID NO: 47 on the same allele; a 1280 base pair deletion from nucleotide 2,818 to nucleotide 4,097 as compared to reference sequence SEQ ID NO: 47; a 1467 base pair deletion from nucleotide 2,431 to nucleotide 3,897 as compared to reference sequence SEQ ID NO: 47; a 1930 base pair deletion from nucleotide 488 to nucleotide 2,417 as compared to reference sequence SEQ ID NO: 47, wherein the deleted sequence is replaced with a 12 base pair insertion beginning at nucleotide 488, and wherein there is a further 129 base pair deletion in exon 7 from nucleotide 3,044 to nucleotide 3,172 as compared to reference sequence SEQ ID NO: 47; and combinations of any thereof (claim 8).
The ‘263 patent claims do not recite that the method for generating an animal from the modified cell comprises enucleating a swine oocyte, fusing the oocyte with a donor swine somatic cell, the genome of the somatic cell comprising at least one inactivated CD163 allele, activating the oocyte to produce an embryo, and transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet complete ovulation, and wherein gestation and term delivery produces a genetically modified swine whose genome comprises at least one inactivated CD163 allele.
However, Lai & Prather teaches somatic cell nuclear transfer for the production of transgenic pigs and that somatic cell nuclear transfer involves enucleation of an oocyte, insertion of donor nuclei from a somatic cell (e.g., fibroblast) into enucleated oocytes by fusing the oocyte with the donor cell, artificial activation of reconstructed oocytes to produce an embryo, and embryo transfer into a surrogate 5-36 hours following the onset of estrus, followed by gestation and term delivery [column 1 ¶ 1, column 2 ¶ 2, column 10 ¶ 1-3, column 12 ¶ 1, column 14 ¶ 2-4]. Lai & Prather additionally teach that nuclear transfer allows the production of animals with specific genetic modifications and the use of genetic modification procedures to produce tissues and organs from cloned pigs with reduced immunogenicity for use in xenotransplantation [column 1 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated and able to use somatic cell nuclear transfer to generate an animal from a genetically modified swine cell.
Accordingly, by reciting a porcine animal whose genome comprises a species of the deletions recited in claims 221 and 226 of the instant application, including specific deletions recited in claim 225 and 229 of the instant application, having increased PRRSV resistance (decreased susceptibility), the ‘260 patent claims recite a porcine animal produced by the instantly claimed method. As such, the ‘260 patent claims encompass and render obvious claims 221-230 of the instant application.
Claims 221-224, 226-228, and 230 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 70, 74, 77-78, 82, and 85-92 of copending Application No. 18/640,282, hereafter referred to as the ‘282 application.
The ‘282 application claims recite a modified swine produced by a method comprising: enucleating a swine oocyte; fusing the oocyte with a donor swine cell, the genome of the donor swine cell comprising a deletion, an insertion, and combinations thereof in at least one allele of the CD163 gene, wherein the modified CD163 gene results in an alteration of at least one extracellular domain of a CD163 protein; and activating the oocyte to produce an embryo (claim 77). The ‘282 application claims further recite wherein the modified swine comprises at least one allele of a CD163 gene modified with an alteration of at least one extracellular domain of a CD163 protein, wherein the altered extracellular domain comprises SRCR5 domains, and wherein the altered extracellular domain results in reduced or eliminated uptake of a PRRSV by loss of interaction of the altered extracellular domain of the CD163 protein to PRRSV (claim 77). The ’282 application claims also recite wherein the at least one modified CD163 allele is exon 7 (claim 82).
The ’282 application claims additionally recite wherein the method further comprises transferring the embryo into a reproductive tract of a surrogate swine, wherein the surrogate swine has initiated estrus but has not yet completed ovulation; and wherein gestation and term delivery produces a swine whose genome comprises at least one inactivated CD163 allele (claim 78).
Accordingly, by reciting a porcine animal or offspring thereof whose genome comprises a species of the deletions recited in claims 221 and 226 of the instant application (i.e., a modification of exon 7 of a CD163 gene), having increased PRRSV resistance (decreased susceptibility), produced by a method comprising enucleating a porcine oocyte, fusing the enucleated oocyte with a genetically modified donor porcine somatic cell comprising a modification in the gene encoding CD163, activating the fused cell to produce a genetically altered porcine embryo, and transferring the embryo into a surrogate swine to produce a swine whose genome comprises at least one modified CD163 allele, the ‘282 application claims anticipate and/or encompass and render obvious claims 221-224, 226-228, and 230 of the present application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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