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 .
Election/Restrictions
Applicant’s election of Group 1 (1-7 and 18) in the reply filed on 10/30/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 8-17 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions. Claims 1-7 and 18 are under examination herein.
Priority
The instant claims herein are examined utilizing the accepted effective filing date of 12/15/2016 for the basis of any prior art rejections.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
Independent claim 1 is broadly drawn to “a mammalian synthetic chromosome comprising at least one stably-integrated expression cassette expressing at least two genes selected from the group consisting of: a) a gene that controls telomere length; b) a gene involved in an anti-oxidant response pathway; and c) a gene involved in an anti-inflammatory response.” This is extremely problematic because the specification fails to support possession of all mammalian synthetic chromosomes having these broadly claimed components.
In support of the claimed genera, the specification discloses a single species of retrofitted BACs containing hTERT, SIRT1, and NFE2l2 loaded into hSynC platform chromosome, as well as transfection validation (working examples 1-11). The data generated for the human synthetic chromosome of the instant specification cannot be reasonably extrapolated to and applied to support possession of the entire claimed genus of mammalian synthetic chromosomes because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a rewards for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1996).
The specification, then, is considered devoid of sufficiently detailed, relevant, identifying characteristics demonstrating that Applicant was in possession of the claimed genus of mammalian synthetic chromosomes, variants, or fragments, i.e., additional complete or partial structures, other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure, or some combination thereof demonstrating possession of the claimed genus. Therefore, claims 1-2 are rejected under 35 U.S.C. 112(a) for lack of written description.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 3 and 7 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Oshimura et al (JP5175814B2, 8/10/2009, published 4/3/2013).
Oshimura teaches human artificial chromosome vector (“HAC”, title). The reference teaches con struction of hTERT gene insertion vector into human chromosome 21-derived HAC vector (Example 15 of Oshimura) (“mammalian synthetic chromosome comprising at least one of a stably-integrated expression cassette expressing TERT” as in instant claim 3; “The mammalian synthetic chromosome of claim 3, wherein the mammalian synthetic chromosome is a human synthetic chromosome” as in instant claim 7).
Accordingly, Oshimura anticipates the instant invention of claims 3 and 7.
Claim Rejections - 35 USC § 103
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 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.
Claim(s) 1-2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshimura et al (JP5175814B2, 8/10/2009, published 4/3/2013) in view of Palacios et al (J Cell Biol. 2010 Dec 27; 191(7):1299-313).
Oshimura teaches human artificial chromosome vector (“HAC”, title). The reference teaches con struction of hTERT gene insertion vector into human chromosome 21-derived HAC vector (Example 15 of Oshimura) (“mammalian synthetic chromosome comprising at least one stably-integrated expression cassette expressing at least two genes selected from the group consisting of: a) a gene that controls telomere length” as in instant claim 1 in-part; “The mammalian synthetic chromosome of claim 1, wherein the mammalian synthetic chromosome is a human synthetic chromosome” as in instant claim 2).
Oshimura differs from the instant invention in that it does not teach that the synthetic chromosome also contains either a gene involved in an anti-oxidant response pathway or a gene involved in an anti-inflammatory response.
Palacios teaches SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity (abstract; “a gene involved in an anti-oxidant response pathway” as in instant claim 1 in-part). SIRT1super MEFs showed a modest but significant increase in mean telomere length compared with wild-type MEFs both by TRF and Q-FISH analyses (Fig. 1 A; and Fig. S1, A and B; Results para 1). Q-FISH analysis further indicated that increased telomere length in SIRT1super MEFs is accompanied by a significant decrease of signal-free ends (SFEs) or chromosome ends with undetectable telomere signals and by a decrease in the proportion of short telomeres (<30 kb) and an increase in the proportion of long telomeres (>80 kb; Fig. 1 B; same para). These results indicate that elevated SIRT1 expression leads to improved telomere length maintenance in cultured primary MEFs (same para). SIRT1 also improved telomere length maintenance (“Increased SIRT1 expression attenuates telomere erosion with age in adult tissues” para 1).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a human synthetic chromosome containing hTERT as taught by Oshimura, where the chromosome also includes SIRT1 as taught by Palacios, to arrive at the instantly claimed invention. As Palacios shows SIRT1 is a positive regulator of telomere length, one of ordinary skill would have been motivated to modify the artificial chromosome containing TERT of Oshimura to include SIRT1 with a reasonable expectation of advantageously attenuating telomere shortening in a telomerase activity-dependent manner as taught by the prior art.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshimura et al (JP5175814B2, 8/10/2009, published 4/3/2013) as applied to claims 3 and 7 above, and further in view of Palacios et al (J Cell Biol. 2010 Dec 27; 191(7):1299-313).
The teachings of Oshimura was recited in the above 35 U.S.C. 102 rejection as applied to claim 3 of which claim 4 depends. The teachings will not be repeated here.
The difference between Oshimura and the invention as instantly claimed is that it does not teach that the synthetic chromosome also contains either a gene involved in an anti-oxidant response pathway or a gene involved in an anti-inflammatory response.
Palacios teaches SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity (abstract; “a stably-integrated expression cassette expressing SIRT1” as in instant claim 4). SIRT1super MEFs showed a modest but significant increase in mean telomere length compared with wild-type MEFs both by TRF and Q-FISH analyses (Fig. 1 A; and Fig. S1, A and B; Results para 1). Q-FISH analysis further indicated that increased telomere length in SIRT1super MEFs is accompanied by a significant decrease of signal-free ends (SFEs) or chromosome ends with undetectable telomere signals and by a decrease in the proportion of short telomeres (<30 kb) and an increase in the proportion of long telomeres (>80 kb; Fig. 1 B; same para). These results indicate that elevated SIRT1 expression leads to improved telomere length maintenance in cultured primary MEFs (same para). SIRT1 also improved telomere length maintenance (“Increased SIRT1 expression attenuates telomere erosion with age in adult tissues” para 1).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a human synthetic chromosome containing hTERT as taught by Oshimura, where the chromosome also includes SIRT1 as taught by Palacios, to arrive at the instantly claimed invention. As Palacios shows SIRT1 is a positive regulator of telomere length, one of ordinary skill would have been motivated to modify the artificial chromosome containing TERT of Oshimura to include SIRT1 with a reasonable expectation of advantageously attenuating telomere shortening in a telomerase activity-dependent manner as taught by the prior art.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshimura in view of Palacios as applied to claim 4 above, and further in view of Ahmad et al (Cell Death Dis. 2016 May 5; 7(5):e2213).
The teachings of Oshimura and Palacios in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 4 of which claim 5 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach a stably-integrated expression cassette expressing NFE2L2 (NRF2).
Ahmad teaches NRF2-driven TERT expression (title). The reference teaches TERT knock-down abrogated Nrf2 levels, overexpression of Nrf2 increased TERT expression (abstract). A decrease in Nrf2 levels was observed in Costunolide-treated cells in an ROS-dependent manner (“Existence of Nrf2-TERT loop” para 1; Figure 2A). However, no change in Nrf2 levels was observed in p53 mutant cell line T98G (Supplementary Figure 2A). A similar decrease in Nrf2 was observed in cells transfected with dominant-negative hTERT (Figure 2b) or hTERT siRNA (Figure 2c). This decrease in Nrf2 is crucial in regulation of hTERT, as overexpression of Nrf2 increased hTERT levels (Figure 2d). In addition, Nrf2 overexpression increased telomerase activity (Figure 2e) and decreased Costunolide-induced increase in ROS generation (Figure 2f).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a human synthetic chromosome containing hTERT and SIRT1 as taught by Oshimura and Palacios in combination, where the chromosome also includes NRF2 as taught by Ahmad, to arrive at the instantly claimed invention. As Ahmad shows NRF2 drives TERT expression, one of ordinary skill would have been motivated to modify the artificial chromosome of Oshimura and Palacios in combination to include NRF2 with a reasonable expectation of advantageously regulating and increasing TERT activity and decrease ROS generation as taught by the prior art.
Claim(s) 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshimura as applied to claim 3 and 7 above, and further in view of Zhao et al (Genes Chromosomes Cancer. 2009 Nov; 48(11):963-74).
The teachings of Oshimura was recited in the above 35 U.S.C. 102 rejection as applied to claim 3 of which claim 4 depends. The teachings will not be repeated here.
The difference between Oshimura and the invention as instantly claimed is that it does not teach that the TERT expression cassette comprises TERT clone RP11-117B23.
Zhao teaches an hTERT BAC reporter was constructed from a BAC clone RP11CI-117B23, which contained 160 kb human genomic DNA encompassing the CRR9, hTERT, and Xtrp2 (also called SLC6A18) loci (“hTERT Promoter Activity From Chromosomally Integrated BAC Reporters” para 1; Fig. 2A). This shows that RP11-117B23 clone can be used in an artificial chromosome construct.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create an artificial chromosome containing hTERT as taught by Oshimura, where the TERT is BAC clone RP11-117B23 as taught by Zhao, to arrive at the instantly claimed invention. It would have been a matter of routine optimization to select this particular clone to make an artificial chromosome for one of ordinary skill in the art. One of ordinary skill in the art would have been motivated to simply substitute the hTERT of Oshimura for the clone hTERT of Zhao with a reasonable expectation of advantageously having a functional artificial chromosome construct as taught by the prior art.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Oshimura in view of Palacios and Ahmad as applied to claim 5 above, and further in view of Perez-Luz et al (J Biomed Biotechnol. 2010;2010:642804; Epub 2010 Aug 24).
The teachings of Oshimura, Palacios, and Ahmad in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 5 of which claim 18 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the expression cassette comprises an endogenous TERT promoter driving expression of TERT, an endogenous SIRT1 promoter driving expression of SIRT1, and an endogenous NFE2L2 promoter driving expression of NFE2L2.
Perez-Luz teaches the prospects for the use of artificial chromosomes and mini chromosome-like episomes in gene therapy (title). The reference teaches artificial chromosomes and mini chromosome-like episomes are large DNA molecules capable of containing whole genomic loci, and be maintained as nonintegrating, replicating molecules in proliferating human somatic cells (abstract). Most constructs used for gene therapy are “minigenes”, consisting of cDNA sequences (instead of entire genes) under the control of heterologous promoters (usually small compacted promoter sequences of viral origin) (“Rationale behind the Use of Large DNA Molecules in Gene Therapy”, para 6). These “minigene constructs” often exhibit variable expression or lack tissue specificity, and they may not be properly regulated in somatic cells, being completely “silenced” in many cases, which obviously restricts their usefulness in gene therapy (same para). The reference further teaches that studies performed in transgenic mice have highlighted the advantages of using large fragments of genomic DNA that permit the delivery of intact mammalian genes with all their introns, promoters, enhancers, and long-range controlling elements (para 7). By using gene's normal promoter and controlling elements, the level and control of expression is comparable to the endogenous expression of the gene (same para). The experience gained from using yeast artificial chromosomes (YACs) and bacterial artificial chromosomes (BACs) has shown that large genomic fragments drive tissue-specific expression at endogenous levels (same para). While this reference does not explicitly teach the use of TERT, NRF2, and SIRT1 specific promoters, it does show the advantages of using of endogenous promoters instead of heterologous promoters.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create an artificial chromosome as taught by Oshimura, Palacios, and Ahmad in combination, where endogenous promoters are used in the chromosome as taught by Perez-Luz, to arrive at the instantly claimed invention. Perez-Luz shows that endogenous promoters can be successfully used in artificial chromosomes. One of ordinary skill would have been motivated to include endogenous promoters in the chromosome constructs of Oshimura, Palacios, and Ahmad in combination with a reasonable expectation of advantageously having construct expression comparable to endogenous gene expression as taught by the prior art. One of ordinary skill in the art would recognize that the improvements caused by the addition of endogenous promoter sequences would improve similar artificial chromosome constructs in the same way.
Conclusion
No claim is allowed.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632