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 .
Application Status
This action is written in response to applicant’s correspondence received 03/02/2026. Claims 1-28, 30, and 47-48 are cancelled. Claims 29, 31-46, and 49 are currently pending. Claim 29 has been amended for formalities to remove periods from the claim. No other amendments have been made.
Claim Objections - withdrawn
Objection to claim 29 is withdrawn in view of Applicant’s amendment to remove the additional periods throughout the claim.
Claim Rejections - 35 USC § 103 - maintained
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.
Claims 29 and 31-46 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US20160153005A1; published June 2, 2016, as cited in the IDS filed December 31, 2019, in view of Fierens (US20150018597A1; published 01/15/2015).
Zhang’s disclosure is directed to delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences (see abstract)
Regarding claim 29, Zhang teaches delivery systems and tissues or organs which are targeted as sites for delivery of gene editing reagents to edit or modify a target site in a genomic locus of interest (see abstract). Zhang teaches connecting said organ to a perfusion system (see para 0626 and 1191). Zhang further teaches administering gene editing reagents to ex vivo liver cells (see paras 0009-0011, 0023, 0026-0029, 0047, and 0052, 0627; and claims 8, 28, and 29). Zhang teaches that the perfusion systems with intravenous delivery (see paras 0245-0247, 0314, 0378, 0408, 0459, 0857, and Example 38).
However, Zhang teaches a tube connected to the arterial lumen and a tube connected to the venous lumen of an organ, but does not specifically teach that the same perfusion system includes both a tube connected to an arterial lumen and a tube connected to a venous lumen of said organ.
Fierens’ disclosure is directed to an organ perfusion system and a kit for the delivery a therapeutic agent to an organ blood flow and the removal of excess therapeutic agent from said organ blood flow (see title and abstract).
Regarding claim 29, Fierens teaches perfusion systems for delivering therapeutic agents to organs and further teaches reducing unwanted effects on non-targeted organs in the body (see para 0003). Fierens teaches a kit for the delivery of a therapeutic agent to an organ blood flow and the removal of the excess therapeutic agent from said organ flow, wherein the kit comprises a first catheter connected to an arterial lumen and a second catheter for isolating organ outflow having a distal end and a proximal end comprising a catheter suitable for deploying a self-expanding hollow tubular member (see claim 1, paras 0008-0010 and 0025-0027). Fierens teaches that a preferred embodiment for liver treatment comprises a catheter connected to the hepatic arterial lumen (see paras 0070-0071). Fierens further teaches a separation device comprising at least one filter able to separate the therapeutic agent excess from the organ outflow, having an inlet for the organ outflow having a therapeutic agent excess and an outlet for filtered organ outflow blood, wherein the separation device is located in the second retrievable medical device, wherein said separation device comprises at least one filter which is positioned at the inner proximal end of the tubular member of the second retrievable medical device (see claims 1d, 13-15 and paras 0012, 0025-0027, 0165, and 0188-0189).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute Zhang’s delivery methods with Fierens’ perfusion system that includes a catheter connected to an arterial lumen and a catheter connected to a venous lumen of the organ because it would have amounted to a simple substitution of one known intravenous delivery method with another. As discussed above, Fierens teaches perfusion systems for delivering therapeutic agents to organs and further teaches reducing unwanted effects on non-targeted organs in the body by removing excess therapeutic agents via a second medical device connected to the venous lumen (see paras 0003, 0012, and 0025-0027). One of ordinary skill in the art could have tried of Fierens’ catheter perfusion system and would have had a reasonable expectation of success with predictable results because both Zhang’s and Fierens’ disclosures teach delivering therapeutic agents to organs using perfusion systems. Thus, the claimed invention as a whole is prima facie obvious.
Regarding claim 31, Zhang teaches that the organ is selected from a liver, pancreas, spleen, lungs, prostate, kidney or heart (see paras 0272-0284 and 0472-0473).
Regarding claim 32, Zhang teaches that the organ is selected from a host selected from a human, mouse, rat, dog, pig, sheep, non-human primates (chimpanzee, monkey) or cow (see paras 0352 and 0597; and Figures 72A-E and 75A-B).
Regarding claims 33-35, Zhang teaches that the gene editing reagent is the rare-cutting CRISPR Cas9 nuclease (see paras 0010-0012, 0050 and claim 14).
Regarding claim 36, Zhang teaches that the gene editing reagent is delivered in the form of a protein, nucleic acid or virus particle (see paras 0016-0017, 0019, 0029, 0045 and 0091; and Figures 28A-C).
Regarding claim 37, Zhang teaches that the gene editing reagent is encoded on an AAV vector (see paras 0051, 0091, and 0096-0107).
Regarding claim 38, Zhang teaches that the composition further comprises magnetic nanoparticles or lipid nanoparticles (see paras 0042, 0375, 0670, 0408, 0449, and 0908).
Regarding claim 39, Zhang teaches that the composition comprises the CRISPR nuclease and lipid nanoparticles (see paras 0042, 0375, 0908 and claim 3).
Regarding claim 40, Zhang teaches that the composition comprises the CRISPR nuclease and magnetic nanoparticles (see paras 0670 and 0908).
Regarding claim 41, Zhang teaches that the CRISPR nuclease is encoded as RNA and the composition comprises lipid nanoparticles (see paras 0144, 0375 and 0390; and Figures 28A-C).
Regarding claim 42, Zhang teaches administering an electrical pulse, sound energy or a magnetic field to the organ (see paras 0306, 0468, 0475, 0608, and 0670).
Regarding claim 43, Zhang teaches that the organ is a liver and the host is a pig (see paras 0005, 0472-0473, 0496, 0809, and 0352).
Regarding claims 44 and 45, Zhang teaches that the perfusion system include a peristaltic pump (see para 0626).
Regarding claim 46, Zhang teaches that the medical fluid is blood (see paras 0517-0518).
Therefore the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (US20160153005A1; published June 2, 2016, as cited in the IDS filed December 31, 2019, in view of Fierens (US20150018597A1; published 01/15/2015) as applied to claims 29 and 31-46 above, and further in view of Chen et al. (CN109055434A; published December 21, 2018, with priority to July 5, 2018).
The teachings of Zhang and Fierens are applied to claim 49 as they have been applied to claims 29 and 31-46 in the 35 U.S.C. 103 discussion above. Zhang teaches delivery systems and tissues or organs which are targeted as sites for delivery of gene editing reagents to edit or modify a target site in a genomic locus of interest (see abstract). Zhang further teaches targeting the KIT gene to treat diseases and disorders (see Table A; para 0675-0678).
However, Zhang does not teach that the CRISPR nuclease specifically targets SEQ ID NO: 2.
Chen’s disclosure is directed to method of correcting pig KIT gene structural mutation using CRISPR/Cas9 technology (see abstract).
Regarding claim 49, Chen teaches that CRISPR nuclease targets SEQ ID NO: 1 representing an area of the pig KIT gene, comprising 100% sequence identity to the sequence set for in Applicant’s SEQ ID NO: 2. (See alignment below. Qy is SEQ ID NO: 2 and DB is SEQ ID NO: 1.)
(Applicant SEQ ID NO: 2)
Qy 1 AGTGGAGGTGATTCTCATGG 20
||||||||||||||||||||
Db 1 AGTGGAGGTGATTCTCATGG 20
(Chen et al. SEQ ID NO: 1)
It further would have been obvious to a person of ordinary skill in the art before the effective filing date of the instant application to arrive at the instant invention by further modifying the combined perfusion techniques of Zhang and Fierens to specifically target the genomic site having the sequence of SEQ ID NO: 2 because Zhang teaches targeting the KIT gene using CRISPR-Cas systems (see Table A; paras 0675-0678) and Chen provides a specific target within the KIT gene and demonstrates editing the site using CRISPR-Cas systems. The ordinary artisan would have had a reasonable expectation of success because both Zhang and Chen teach methods of delivering CRISPR/Cas9 to cells in organs of pigs for gene editing and all three prior art references teach delivering therapeutic agents to organs. Thus, the claimed invention as a whole is prima facie obvious.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive. Applicant argues the Office has failed to establish a prima facie case of obviousness for claim 29, the sole independent claim, for at least the reasons that (i) the Office's reliance on the "simple substitution" rationale is not applicable in this case and (ii) the Office has not presented a valid reason or motivation to combine the cited art to arrive at the method of claim 29. Applicant further argues that the Office is treating the Fierens apparatus as a "simple substitution" of a "similar element" to Zhang's apparatus but has not made (and cannot make) the required findings because (i) the two delivery apparatus do not serve the same function(s) (or not the same function in the relevant way), (ii) the substitution would not yield predictable results in the claimed context, and/or (iii) implementing Fierens apparatus into the Zhang's method is not a "substitution" at all; it requires reconstruction/redesign. Applicant argues that the Office has not identified any teaching, problem to be solved, design incentive, known disadvantage, or market/clinical driver that would have lead one of ordinary skill in the art to replace the delivery apparatus of Zhang with the structurally/operationally different apparatus of Fierens because the two apparatus do not work the same way, replacing Zhang's apparatus with Fieren's to reach the claimed method is not a "simple substitution" but a complete redesign, one which involves a change in the principle of operation of Zhang's method. Applicant argues that Chen does not remedy the deficiencies of Zhang or Fierens, as Chen does not describe a dual catheter-based system for delivery and removal of gene editing agents.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Zhang teaches delivery, engineering, and optimization of systems, methods, and compositions for gene editing through delivery systems for tissues and organs (abstract). Accordingly, modifying the perfusion system of Zhang with that of Fierens would have been a simple substitution of known elements of perfusion systems because one of ordinary skill in the art would have recognized it as such.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). One of ordinary skill would have recognized the benefits of improved perfusion delivery systems to deliver therapeutics agents to organs and to further optimize the systems as described in the 103 rejection above.
Allowable Subject Matter
SEQ ID NO: 1 in claim 49 is a 20 bp region of the pig KIT gene. The closest prior Bancel et al. (US20140010861A1; published January 9, 2014), directed to modified polynucleotides for the production of proteins associated with human disease teaches SEQ ID NO: 238252 (with a length of 852 nucleotides; see OA Appendix for sequence alignment) with 87% sequence identity to the sequence of Applicant’s SEQ ID NO: 1. (See alignment below. Qy is SEQ ID NO: 1 and DB is SEQ ID NO: 238252.)
(Applicant SEQ ID NO: 1)
Qy 2 CCCTGAGGAGGTAGTTCAA 20
||||||||| |||||||||
Db 195 CCCTGAGGACGTAGTTCAA 213
(Bancel et al. SEQ ID NO: 1)
SEQ ID NO: 1 is free of the prior art in the context of CRISPR/Cas9 targeting SEQ ID NO: 1.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KHALEDA B HASAN/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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