DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/02/2023 has been considered.
Status of Application/Claims
Claims 1-20, filed 10/06/2023, are pending. Claims 1-20 are the subject of the present Official action.
Claim Objections
Claims 4, 8, 14, and 17 objected to because of the following informalities: The phrase “an PSEN1 protein” should read “a PSEN1 protein”. Appropriate correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 4-6, 8-9, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jakobsen et al. (Journal of Alzheimer’s Disease, 2016; hereinafter Jakobsen). Jakobsen teaches genetically modified swine with Alzheimer’s disease-associated mutations APP695sw and PSEN1M146I resulting in PSEN1 and APP protein that does not function.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Jakobsen in further view of Cohen et al. (The Journal of Neuroscience, 2013; hereinafter Cohen), Chen Shi et al. (CN106282118A; hereinafter Chen Shi), Fuqiang Chen et al. (US20140273233A1; hereinafter Fuqiang Chen), and Whitworth et al. (Biology of Reproduction, 2014; hereinafter Whitworth).
With regard to Claims 1, 4-6, 8-9, and 11, Jakobsen teaches genetically modified swine with Alzheimer’s disease-associated mutations APP695sw and PSEN1M146I resulting in PSEN1 and APP protein that does not function, for use as a more representative model for Alzheimer’s disease due to the higher anatomical, physiological, and genetic similarities of porcine models to humans compared to rodent models.
With regard to Claims 2 and 3, Jakobsen does not teach genetically modified swine with deletion of exon 9 of PSEN1 and a deletion in exon 1 of APP.
Cohen teaches a genetically modified rat with the APPsw mutation and deletion of exon 9 of PSEN1 resulting in a PSEN1 protein that does not function, which Cohen teaches are both independent causes of Alzheimer’s disease.
Madsen teaches a high degree of conservation of the porcine PSEN1 primary sequence and expression patterns during embryonic brain development compared to those observed in humans and rodents. There was 92% sequence identity between the porcine and human PSEN1 primary sequence, and 11 of the 34 amino acid changes were conservative substitutions. There was 89% sequence identity between porcine and mouse PSEN1 primary sequence, and 16 of the 50 amino acid changes were conservative. None of the amino acid changes between pig and human were located in positions known to cause Alzheimer’s disease. Madsen teaches that the porcine model shows promise for studying the biological functions of PSEN proteins due to the higher physiological and anatomic similarities between pigs and humans.
It would have been prima facie obvious to one of ordinary skill in the art to combine the deletion of exon 9 of PSEN1 of Cohen and the porcine model of Jakobsen additionally supported by the sequence alignment of Madsen to develop a porcine model of Alzheimer’s disease with deletion of exon 9 of PSEN1. One of ordinary skill in the art would have been motivated to make such a combination because Cohen teaches that deletion of exon 9 of PSEN1 is known in the art as a cause of Alzheimer’s disease and Cohen introduces the deletion to develop a rat model of Alzheimer’s disease. One of ordinary skill in the art would understand that deletion of exon 9 of PSEN1 in a porcine model would provide for more representative modeling of how Alzheimer’s disease manifests in humans due to the higher anatomical, physiological, and genetic similarities to humans compared to rodent models. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because of the sequence alignment provided by Madsen and the methodologies detailed in Jakobsen and Cohen.
Chen Shi teaches the use of CRISPR to knock out APP expression in a mammalian cell strain for the purpose of modeling Alzheimer’s disease.
Fuqiang Chen teaches CRISPR-based methods for modifying chromosomal sequences near desired locations such as disease SNPs, small exons, start codons, stop codons, and other locations using RNA-guided endonucleases. See paragraph 0010 of Fuqiang Chen.
It would have been prima facie obvious to one of ordinary skill in the art to combine the use of CRISPR to knock out APP of Chen Shi, the desired target locations of Fuqiang Chen, and the porcine model of Jakobsen to develop a porcine model of Alzheimer’s disease with loss of function of APP through a deletion in exon 1 of APP. Based on the teachings of Jakobsen and the secondary references, one of ordinary skill in the art would have been motivated to develop a porcine model of Alzheimer’s disease with loss of function of APP. It would have been obvious to one of ordinary skill in the art to target exon 1 of APP to achieve knock-out of APP expression given that there are a finite number of exons of APP to select from that contain desired target locations. One of ordinary skill in the art would understand that a deletion in exon 1 of APP leading to loss of function of APP in a porcine model would provide for more representative modeling of how Alzheimer’s disease manifests in humans due to the higher anatomical, physiological, and genetic similarities to humans compared to rodent models. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because the methodologies were detailed in Jakobsen and the secondary references.
Additionally, MPEP 2144.06 states, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Therefore, it would have been obvious for one of ordinary skill in the art to have developed a porcine model with both a deletion of exon 9 of PSEN1 and a deletion in exon 1 of APP for the purpose of more representative modeling of Alzheimer’s disease.
With regard to Claim 7, Jakobsen does not teach genetically modified swine with deletion of exon 9 of PSEN1.
As stated above, Cohen teaches a genetically modified rat with the APPsw mutation and deletion of exon 9 of PSEN1 resulting in a PSEN1 protein that does not function, which Cohen teaches are both independent causes of Alzheimer’s disease.
Madsen teaches a high degree of conservation of the porcine PSEN1 primary sequence and expression patterns during embryonic brain development compared to those observed in humans and rodents. There was 92% sequence identity between the porcine and human PSEN1 primary sequence, and 11 of the 34 amino acid changes were conservative substitutions. There was 89% sequence identity between porcine and mouse PSEN1 primary sequence, and 16 of the 50 amino acid changes were conservative. None of the amino acid changes between pig and human were located in positions known to cause Alzheimer’s disease. Madsen teaches that the porcine model shows promise for studying the biological functions of PSEN proteins due to the higher physiological and anatomic similarities between pigs and humans.
It would have been prima facie obvious to one of ordinary skill in the art to combine the deletion of exon 9 of PSEN1 of Cohen and the porcine model of Jakobsen additionally supported by the sequence alignment of Madsen to develop a porcine model of Alzheimer’s disease with deletion of exon 9 of PSEN1. One of ordinary skill in the art would have been motivated to make such a combination because Cohen teaches that deletion of exon 9 of PSEN1 is known in the art as a cause of Alzheimer’s disease and Cohen introduces the deletion to develop a rat model of Alzheimer’s disease. One of ordinary skill in the art would understand that deletion of exon 9 of PSEN1 in a porcine model would provide for more representative modeling of how Alzheimer’s disease manifests in humans due to the higher anatomical, physiological, and genetic similarities to humans compared to rodent models. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because of the sequence alignment provided by Madsen and the methodologies detailed in Jakobsen and Cohen.
With regard to Claim 10, Jakobsen does not teach genetically modified swine with a deletion in exon 1 of APP.
Chen Shi teaches the use of CRISPR to knock out APP expression in a mammalian cell strain for the purpose of modeling Alzheimer’s disease.
Fuqiang Chen teaches CRISPR-based methods for modifying chromosomal sequences near desired locations such as disease SNPs, small exons, start codons, stop codons, and other locations using RNA-guided endonucleases. See paragraph 0010 of Fuqiang Chen.
It would have been prima facie obvious to one of ordinary skill in the art to combine the use of CRISPR to knock out APP of Chen Shi, the desired target locations of Fuqiang Chen, and the porcine model of Jakobsen to develop a porcine model of Alzheimer’s disease with loss of function of APP through a deletion in exon 1 of APP. Based on the teachings of Jakobsen and the secondary references, one of ordinary skill in the art would have been motivated to develop a porcine model of Alzheimer’s disease with loss of function of APP. It would have been obvious to one of ordinary skill in the art to target exon 1 of APP to achieve knock-out of APP expression given that there are a finite number of exons of APP to select from that contain desired target locations. One of ordinary skill in the art would understand that a deletion in exon 1 of APP leading to loss of function of APP in a porcine model would provide for more representative modeling of how Alzheimer’s disease manifests in humans due to the higher anatomical, physiological, and genetic similarities to humans compared to rodent models. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because the methodologies were detailed in Jakobsen and the secondary references.
With regard to Claims 12-14, Jakobsen does not teach introducing a guide RNA targeting the PSEN1 gene or the APP gene to a zygote to result in a deletion in the PSEN1 and APP genes.
Whitworth teaches a method of generating genetically modified swine comprising introducing a guide RNA targeting a gene into a zygote to introduce double-strand breaks to result in deletion of the gene. Whitworth also teaches culturing the zygote and transferring the cultured zygote to a recipient female and allowing the zygote to develop in the recipient female to produce the genetically modified swine.
As stated above, Cohen teaches a genetically modified rat with the APPsw mutation and deletion of exon 9 of PSEN1 resulting in a PSEN1 protein that does not function, which Cohen teaches are both independent causes of Alzheimer’s disease.
Madsen teaches a high degree of conservation of the porcine PSEN1 primary sequence and expression patterns during embryonic brain development compared to those observed in humans and rodents. There was 92% sequence identity between the porcine and human PSEN1 primary sequence, and 11 of the 34 amino acid changes were conservative substitutions. There was 89% sequence identity between porcine and mouse PSEN1 primary sequence, and 16 of the 50 amino acid changes were conservative. None of the amino acid changes between pig and human were located in positions known to cause Alzheimer’s disease. Madsen teaches that the porcine model shows promise for studying the biological functions of PSEN proteins due to the higher physiological and anatomic similarities between pigs and humans.
One of ordinary skill in the art would have been motivated to combine the teachings of Jakobsen and the secondary references Cohen, Whitworth, and Madsen to develop a porcine model of Alzheimer’s disease with deletion of exon 9 of PSEN1 in the method of Whitworth. One of ordinary skill in the art would have been motivated to make such a combination because Cohen teaches that deletion of exon 9 of PSEN1 is known in the art as a cause of Alzheimer’s disease and Cohen introduces the deletion to develop a rat model of Alzheimer’s disease. One of ordinary skill in the art would understand that deletion of exon 9 of PSEN1 in a porcine model would provide for more representative modeling of how Alzheimer’s disease manifests in humans due to the higher anatomical, physiological, and genetic similarities to humans compared to rodent models. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because the methodology is detailed in the secondary reference Whitworth.
Chen Shi teaches the use of CRISPR to knock out APP expression in a mammalian cell strain for the purpose of modeling Alzheimer’s disease.
Fuqiang Chen teaches CRISPR-based methods for modifying chromosomal sequences near desired locations such as disease SNPs, small exons, start codons, stop codons, and other locations using RNA-guided endonucleases. See paragraph 0010 of Fuqiang Chen.
Based on the teachings of Jakobsen and the secondary references Cohen, Chen Shi, Fuqiang Chen, and Cohen, one of ordinary skill in the art would have been motivated to develop a porcine model of Alzheimer’s disease with loss of function of APP in the method of Whitworth. It would have been obvious to one of ordinary skill in the art to target exon 1 of APP to achieve knock-out of APP expression given that there are a finite number of exons of APP to select from that contain desired target locations such as a start codon. One of ordinary skill in the art would understand that a deletion in exon 1 of APP leading to loss of function of APP in a porcine model would provide for more representative modeling of how Alzheimer’s disease manifests in humans due to the higher anatomical, physiological, and genetic similarities to humans compared to rodent models. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because the methodology is detailed in the secondary reference Whitworth.
Additionally, MPEP 2144.06 states, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Therefore, it would have been obvious for one of ordinary skill in the art to have developed a porcine model with both a deletion of exon 9 of PSEN1 and a deletion in exon 1 of APP for the purpose of more representative modeling of Alzheimer’s disease.
With regard to Claims 15-17, Jakobsen does not teach introducing a guide RNA targeting the PSEN1 gene to a zygote to result in a deletion in the PSEN1 gene.
Whitworth teaches a method of generating genetically modified swine comprising introducing a guide RNA targeting a gene into a zygote to introduce double-strand breaks to result in deletion of the gene. Whitworth also teaches culturing the zygote and transferring the cultured zygote to a recipient female and allowing the zygote to develop in the recipient female to produce the genetically modified swine.
As stated above, Cohen teaches a genetically modified rat with the APPsw mutation and deletion of exon 9 of PSEN1 resulting in a PSEN1 protein that does not function, which Cohen teaches are both independent causes of Alzheimer’s disease.
Madsen teaches a high degree of conservation of the porcine PSEN1 primary sequence and expression patterns during embryonic brain development compared to those observed in humans and rodents. There was 92% sequence identity between the porcine and human PSEN1 primary sequence, and 11 of the 34 amino acid changes were conservative substitutions. There was 89% sequence identity between porcine and mouse PSEN1 primary sequence, and 16 of the 50 amino acid changes were conservative. None of the amino acid changes between pig and human were located in positions known to cause Alzheimer’s disease. Madsen teaches that the porcine model shows promise for studying the biological functions of PSEN proteins due to the higher physiological and anatomic similarities between pigs and humans.
One of ordinary skill in the art would have been motivated to combine the teachings of Jakobsen and the secondary references Cohen, Whitworth, and Madsen to develop a porcine model of Alzheimer’s disease with deletion of exon 9 of PSEN1 in the method of Whitworth. One of ordinary skill in the art would have been motivated to make such a combination because Cohen teaches that deletion of exon 9 of PSEN1 is known in the art as a cause of Alzheimer’s disease and Cohen introduces the deletion to develop a rat model of Alzheimer’s disease. One of ordinary skill in the art would understand that deletion of exon 9 of PSEN1 in a porcine model would provide for more representative modeling of how Alzheimer’s disease manifests in humans due to the higher anatomical, physiological, and genetic similarities to humans compared to rodent models. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because the methodology is detailed in the secondary reference Whitworth.
With regard to Claims 18-20, Jakobsen does not teach introducing a guide RNA targeting the PSEN1 gene or the APP gene to a zygote to result in a deletion in the PSEN1 and APP genes.
Whitworth teaches a method of generating genetically modified swine comprising introducing a guide RNA targeting a gene into a zygote to introduce double-strand breaks to result in deletion of the gene. Whitworth also teaches culturing the zygote and transferring the cultured zygote to a recipient female and allowing the zygote to develop in the recipient female to produce the genetically modified swine. Whitworth does not teach introducing a guide RNA targeting exon 9 of the PSEN1 gene or targeting the APP gene.
As stated above, Chen Shi teaches the use of CRISPR to knock out APP expression in a mammalian cell strain for the purpose of modeling Alzheimer’s disease.
Fuqiang Chen teaches CRISPR-based methods for modifying chromosomal sequences near desired locations such as disease SNPs, small exons, start codons, stop codons, and other locations using RNA-guided endonucleases. See paragraph 0010 of Fuqiang Chen.
Based on the teachings of Jakobsen and the secondary references Cohen, Chen Shi, Fuqiang Chen, and Cohen, one of ordinary skill in the art would have been motivated to develop a porcine model of Alzheimer’s disease with loss of function of APP in the method of Whitworth. It would have been obvious to one of ordinary skill in the art to target exon 1 of APP to achieve knock-out of APP expression given that there are a finite number of exons of APP to select from that contain desired target locations such as a start codon. One of ordinary skill in the art would understand that a deletion in exon 1 of APP leading to loss of function of APP in a porcine model would provide for more representative modeling of how Alzheimer’s disease manifests in humans due to the higher anatomical, physiological, and genetic similarities to humans compared to rodent models. One of ordinary skill in the art would have considered there to be a reasonable expectation of success because the methodology is detailed in the secondary reference Whitworth.
Conclusion
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/H.P./Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631