DETAILED ACTION
Claims 144-163 are pending and under examination in this application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 5/5/25, 1/30/26, 3/2/26, 5/4/26, and 9/11/26 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner, and initialed and signed copies of the 1449s are attached to this action.
Claim Rejections - 35 USC § 112
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 144-153 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.
Claims 144 recites a method for expressing Factor IX in a liver cell or population of liver cells comprising administering three components (i)-(iii). However, while the preamble states that the method is for expressing Factor IX in liver cells and the claim ends by reciting, “thereby expressing Factor IX in the liver cell or population of liver cells”, the single method of “administering” does actually indicate where or to what the three components are to be administered. As such, it is unclear, for example, whether the components are administered directly or indirectly to cells in vitro, or directly or indirectly to cells in vivo. Thus, the metes and bounds of the claim cannot be determined. Claims 145-153 depend on claim 144 and thus are included in this rejection.
Claim Rejections - 35 USC § 103
Claims 144-163 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent 11,091,756 (August 17, 2021), hereafter referred to as Baltes, with an effective filing date of 10/16/18, in view of U.S. Patent Application Publication 2015/0056705 (2015), hereafter referred to as Conway et al., US Patent Application Publication 2019/0382798 (December 19, 2019), hereafter referred to as Cowan et al., with an effective filing date of 11/6/15, and Schneller et al. (2017) BMC Medicine, Vol. 14:43; doi 10.1186/s12916-017-0798-4, page 1-12.
Baltes teaches a bidirectional promoterless transgene comprising a first and second coding sequences in forward and reverse directions (tail to tail orientation), flanked by first and second splice acceptors for integration into an endogenous gene such that the integration of the transgene in either direction results in transcription and translation of the coding sequence by the endogenous gene’s promoter (Baltes, columns 2, 6, 11, and 16, Figure 1, and claims 1-10). Baltes teaches that the coding sequence encodes a polypeptide associated with a genetic disease such as hemophilia, and in particular Factor IX (Baltes, column 19). Baltes also teaches that the transgene can be harbored on a vector, particularly a viral vector such as an adeno-associated viral vector (Baltes, column 17). Baltes further teaches that the transgene is integrated into an endogenous gene locus in a mammalian cell using a CRISPR system comprising a Cas nuclease, such as Cas9, and a gRNA, where the Cas nuclease can be provided as protein or a nucleic acid, DNA or RNA, encoding the nuclease (Baltes, columns 18 and 23, and claims 1-10).
Baltes et al. differs from the instant invention by not teaching that the endogenous gene locus is a “safe harbor” locus such as the albumin locus, and further does not teach to target integration of the transgene into intron 1 of the albumin locus gene. Schneller et al. supplements Baltes et al. by teaching to correct hemophilia B by targeting a transgene encoding human Factor IX to the first intron of the albumin gene (Schneller et al., page 4). Schneller et al. teaches directing the therapeutic transgene into the albumin locus, an ideal safe-harbor locus due to its high transcriptional activity, and corresponding increased efficiency of integration, by homologous recombination, where when a promoterless transgene encoding human Factor IX (hFIX) is inserted into this locus it is expressed from the endogenous and liver-specific Alb promoter (Schneller et al., page 4). Schneller et al. teaches that ZFN mediated homologous recombination of promoterless hFIX coding sequence into intron 1 in mice resulted in high circulating hFIX levels (Schneller et al., page 4). Conway et al. further supplements Baltes and Schneller et al. by teaching the integration of transgenes such as Factor IX into an endogenous “safe harbor” locus, such as the albumin gene locus, using CRISPR/Cas system where a single guide RNA (gRNA) comprises sequence to target the albumin gene is used for targeted integration of the transgene such that the coding sequence of the transgene is expressed using albumin expressional control elements (Conway et al., paragraphs 7, 56, 60, and 62-63). Conway et al., like Baltes, teaches that that the Cas nuclease can be provided to cells as a nucleic acid, and further teaches that the Cas nuclease can be delivered to the cells as an mRNA (Conway et al., paragraph 28). Conway et al., like Schneller et al. teaches that in addition to providing a “safe harbor”, i.e. a targeted insertion site in a gene positioned for minimal risk of gene silencing or activation of nearby oncogenes, insertion of a transgene into the albumin gene locus results in high levels of expression of the protein encoded by the transgene into the bloodstream (Conway et al., paragraph 60). Conway et al. teaches that delivery of a transgene coding for Factor IX to a safe harbor locus and expression of Factor IX can be used for restoring clotting activity in patients with Hemophilia B (Conway et al., paragraphs 62-63).
Therefore, in view of the motivation provided by Schneller et al. to insert a promoterless hFIX coding sequence into intron 1 of the “safe harbor” albumin gene in order to generate high liver specific expression levels of hFIX in the blood, and the further motivation provided by Conway that the albumin locus is a perfect “safe harbor” locus for targeted insertion site in a gene positioned for minimal risk of gene silencing or activation of nearby oncogenes, that insertion of a transgene into the albumin gene locus using Cripsr results in high levels of expression of the protein encoded by the transgene into the bloodstream, and that such expression of FIX in the bloodstream can be used to treat Hemophilia B, it would have been prima facie obvious to the skilled artisan at the time of filing to integrate coding sequence encoding FIX or hFIX into intron 1 of the albumin gene using the bidirectional promoterless transgene construct comprising a first and second FIX coding sequences in forward and reverse directions (tail to tail orientation), flanked by first and second splice acceptors for integration into an endogenous gene such that the integration of the transgene in either direction using Cas9 and a gRNA results in transcription and translation of the coding sequence by the endogenous gene’s promoter in order to express high levels of FIX in liver cells in the liver and achieve high levels of FIX in the bloodstream for the treatment of hemophilia with a reasonable expectation of success.
Baltes, Schneller et al., and Conway et al. differ from the instant invention by not teaching to introduce Cas9 or an mRNA coding for Cas9, and/or the gRNA using lipid nanoparticles, or where the Cas9 mRNA and gRNA are present in the same lipid nanoparticle, or where the nucleic acid construct comprising the FIX coding sequence is delivered using a viral vector such as an AAV vector. Cowan et al. supplements Baltes, Schneller and Conway by also teaching methods of insert the coding sequence of a gene into an endogenous albumin gene using a CRISPR/Cas system, and further teaches particular methods for delivery of the transgene, Cas9, and the gRNA for targeting the Albumin locus. In particular, Cowan et al. teaches that Cas9 can be delivered as either a protein or an mRNA in a lipid nanoparticle, either separately or together with the gRNA (Cowan et al., paragraph 52). Cowan et al. teaches other methods such as delivery of Cas9 mRNA by lipid nanoparticle, delivery of the gRNA by lipid nanoparticle and delivery of the transgene in a viral vector such as AAV (Cowan et al., paragraph 52-55).
Thus, in view of the teachings and motivation provided by Cowan et al. that Cas9 mRNA and gRNA can be administered separately or together using a lipid nanoparticle, and wherein a nucleic acid construct encoding a transgene for integration into the albumin locus can be delivered using an AAV, it would have been prima facie obvious to the skilled artisan at the time of filing to practice the methods of using Crispr comprising Cas9 and gRNA to insert a FIX coding sequence into intron 1 of the albumin gene in order to express FIX in liver cells and treat hemophilia according to Baltes in view of Schneller et al. and Conway et al. where Cas9 mRNA and the gRNA can be administered separately or together using a lipid nanoparticle, and wherein a nucleic acid construct encoding a transgene for integration into the albumin locus can be delivered using an AAV with a reasonable expectation of success.
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 144-163 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of U.S. Patent No. 12,214,023, hereafter referred to as the ‘023 patent, in view of Schneller et al. (2017) BMC Medicine, Vol. 14:43; doi 10.1186/s12916-017-0798-4, page 1-12, and US Patent Application Publication 2019/0382798 (December 19, 2019), hereafter referred to as Cowan et al., with an effective filing date of 11/6/15.
Independent claims 1 and 10 of the ‘023 patent recite methods which are similar to those recited in instant independent claims 144 and 154 with the exception that the ’023 patent claims limit the target sequence for the gRNA to SEQ ID NO:8, and do not limit the target cells to liver cells. Note that SEQ ID NO:8 is present in intron 1 of the albumin gene. Thus, the ’023 patent claims are both broader and narrower than the instant claims. However, while the ‘023 patent claims do not recite that FIX is expressed in liver cells, it was well known at the time of filing that albumin is a liver specific protein such that integration of a transgene into the albumin gene in operable linkage to the endogenous albumin promoter results in liver specific expression. See for example Schneller et al. who teaches directing therapeutic transgene into the albumin locus, an ideal safe-harbor locus due to its high transcriptional activity, and corresponding increased efficiency of integration, by homologous recombination, where when a promoterless transgene encoding human Factor IX (hFIX) is inserted into this locus it is expressed from the endogenous and liver-specific Alb promoter (Schneller et al., page 4). Thus, based on the evidence of Schneller et al., the skilled artisan at the time of filing would have expected expression of FIX in liver cells using the ‘023 patent method.
In regards to the elements of the Crispr system, the structure of the transgene construct, and the means for delivery of Cas9, the gRNA, and the transgene construct, such as recited in instant claims 143-153 and 155-163, it is noted that claims 2 and 3 of the ’023 patent recite that the RNA -guided DNA binding agent is Cas9 or an mRNA encoding Cas9, and claims 4-5 recite that the nucleic acid construct is administered in a viral vector or an AAV vector respectively. Cowan et al. further supplements the ‘023 patent claims by teaching methods of insert the coding sequence of a gene into an endogenous albumin gene using a CRISPR/Cas system, and further teaches particular methods for delivery of the transgene, Cas9, and the gRNA for targeting the Albumin locus. In particular, Cowan et al. teaches that Cas9 can be delivered as either a protein or an mRNA in a lipid nanoparticle, either separately or together with the gRNA (Cowan et al., paragraph 52). Cowan et al. teaches other methods such as delivery of Cas9 mRNA by lipid nanoparticle, delivery of the gRNA by lipid nanoparticle and delivery of the transgene in a viral vector such as AAV (Cowan et al., paragraph 52-55).
Thus, in view of the teachings and motivation provided by Cowan et al. that Cas9 mRNA and gRNA can be administered separately or together using a lipid nanoparticle, and wherein a nucleic acid construct encoding a transgene for integration into the albumin locus can be delivered using an AAV, it would have been prima facie obvious to the skilled artisan at the time of filing to practice the methods of the ‘023 patent claims where Cas9 mRNA and the gRNA can be administered separately or together using a lipid nanoparticle, and wherein a nucleic acid construct encoding a transgene for integration into the albumin locus can be delivered using an AAV with a reasonable expectation of success.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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