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 .
Applicant’s amendment and response filed on 7/28/2025 has been received and entered into the case.
Claims 2 and 18 have been canceled, claim 25 is newly added, and claims 1, 3-17 and 19-25 have been considered on the merits. All arguments have been considered.
Terminal Disclaimer
The terminal disclaimers filed on 7/28/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US PAT. 10,426,798 and 11,213,548 have been reviewed and is accepted. The terminal disclaimers have been recorded.
The corresponding double patenting rejection have been withdrawn.
Claim Rejections - 35 USC § 112 (New Rejection)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 12 and 14 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 12 discloses that the knockout of the HPRT gene comprises contacting lymphocytes with an HPRT-targeted CRISPR/Cas9 RNP. As claim 1, upon the instant amendment, discloses CRISPR/Cas9 and an anti-HPRT sgRNA, which would be identical to CRIPSR/Cas9 RNP, claim 12 does not further limit the subject matter of claim 1. Similarly, claim 14 discloses that the knockout of the HPRT gene comprises contacting lymphocytes with CRISPR/Cas9 and an anti-HPRT sgRNA. However, claim 1 discloses the identical limitation already in step (a) and thus, claim 14 does not further limit the subject matter of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 3-7, 9-12 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Valton et al. (of record) in view of Liao et al. (of record) and Ortinski et al. (of record) in further view of Ruiz-Argüelles et al. (of record).
Valton et al. teach at paragraphs (0125-0130):
1) A method of engineering allogeneic and drug resistant T-cells for immunotherapy comprising:
(a) Providing a T-cell;
(b) Selecting at least one chemotherapy drug, said T-cell is sensitive to:
(c) Modifying said T-cell by inactivating at least one gene encoding a T-cell receptor (TCR) component;
(d) Modifying said T-cell to confer drug resistance to said chemotherapy drug;
(e) Expanding said engineered T-cell, optionally in the presence of said drug.
Valton et al. teach at paragraphs (0132):
3) The method of claim 1 or 2 wherein said drug resistance is conferred to the T-cell by inactivating at least one drug sensitizing gene.
Valton et al. teach at paragraphs (0138):
9) The method of claim 3 or 5 wherein said drug resistance gene is HPRT.
Valton et al. teach at paragraphs (0159):
30) The method according to any one of claims 1 to 28, wherein said engineered T-cells are expanded in-vitro.
Thus, Valton et al. teach the step (a) and (b) of claim 1.
Regarding the HPRT deficient lymphocytes being generated through knockout of the HPRT gene by using CRIPSR/Cas9 and anti-HPRT sgRNA in step (a) of claim 1, Valton et al. teach that the drug sensitizing genes can be inactivated by using a rare-cutting endonuclease including CRISPR/Cas9 nuclease (para. 61). However, Valton et al. do not particularly teach the CRISPR/Cas9 and anti-HPRT sgRNA (claim 1 and 14) or HPRT-CRISPR/Cas9 RNP (claim 12).
Liao et al. teach the method of editing HPRT gene using CRISPR/Cas9 system, and they utilize gRNA targeting HPRT gene (Abstract).
Ortinski et al. teach knockout of gene using CRISPR/Cas9 gene editing system comprising sgRNA and Cas9 protein (i.e. Cas9-sgRNA RNP) (Abstract).
It would have been obvious to a person skilled in the art to use CRIPSR/Cas9 gene editing system including the HPRT-CRISPR/Cas9 RNP, which comprises sgRNA targeting HPRT and Cas9 protein, for editing HPRT in the method of Valton et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because it is extremely well known in the art that CRISPR/Cas9 is a suitable alternative to TALE-nuclease (TALEN) according to Valton et al. (para. 61) and Liao et al. disclose that HPRT gene editing using a CRISPR/Cas9 nuclease as discussed above.
Regarding step (c) of claim 1, Valton et al. teach that the T cells according to their invention can be used for treating cancer, infections or auto-immune disease in a patient in need thereof (para. 101-103). Valton et al. teach that the cell compositions of their invention are administered to a patient in conjunction with (e.g. before, simultaneously or following) bone marrow transplantation (para. 112). Valton et al. also teach, “in one embodiment, subjects may undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation. In certain embodiments, following the transplant, Subjects receive an infusion of the expanded immune cells of the present invention” (bridging col. 1-2 of para. 0112). The bone marrow transplantation and the peripheral blood stem cell transplantation taught by Valton et al. are considered the same as an HSC graft to the patient in the step (c) of claim 1, particularly based on the definition given in the instant specification (para. 52).
Regarding the limitation of step (d) directed to the administration of (certain doses of) methotrexate (MTX) to the patient (claim 1); the amount of methotrexate (claim 3) or the methotrexate being administered in titrated doses (claim 4), Valton et al. do not teach using methotrexate if side effects arise from the administration of the modified lymphocytes.
Ruiz-Argüelles et al. teach that method of titrating doses of conditioning drugs was developed to diminish the toxic effects of these drugs during HSC allografts that experience GVHD (Introduction section, page 146, col.1, parag.1). Furthermore, Ruiz-Argüelles teach that 5mg/m2 of methotrexate was administered by intravenous infusion as part of a low intensity conditioning regimen (bridging pages 146-147). Accordingly, Valton et al. in view of Ruiz-Argüelles teach the limitations of instant claims 3-4.
Claims 5-7 disclose that the positive selection for the HPRT deficient lymphocytes is performed using 6TG (6-thioguanine). Valton et al. teach that the engineered T-cells of their invention are selected by use of 6TG for 6TG resistant T cell (para. 256 and 260). It is noted that “positive selection comprises contacting the generated HPRT deficient lymphocytes with a purine analog” as claimed is understood that the selected cells are resistant to the purine analog. Thus, Valton et al. teach the limitation of claims 5-7.
Valton et al. teach using single dose, multiple dose, and 105 to 106 cells/kg body weight at paragraph [0110], thereby meet the limitations of claims 9-11.
Regarding the non-integrating lentiviral vector (claims 15-16), Ortinski et al. teach integrase-deficient lentiviral vector for delivery of CRISPR/Cas9 gene editing system comprising sgRNA and Cas9 protein (i.e. Cas9-sgRNA RNP) (Abstract). The integrase-deficient lentiviral vector of Ortinski et al. is understood as non-integrating lentiviral vector (see p.154, 2nd col., 1st full para.).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Valton et al. in view of Liao et al., Ortinski et al. and Ruiz-Argüelles et al. as applied to claims 1, 3-7, 9-12 and 14 above and further in view of Pizzorno et al. (2003; of record) and Brackett et al. (2014, Pediatr. Blood Cancer; of record)
Claim 8 is directed to the positive selection by contacting the modified lymphocytes with both a purine analog and allopurinol. While Valton et al. in view of Liao et al., Ortinski et al. and Ruiz-Argüelles et al. teach a purine analog, 6TG, however, they do not teach allopurinol.
However, it is well known in the art that allopurinol is another purine analog according to Pizzorno et al. (p.3, 4th full para.).
It would have been obvious to a person skilled in the art to use allopurinol along with 6TG for the positive selection step in the method of Valton et al. in view of Liao et al., Ortinski et al. and Ruiz-Argüelles et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because Valton et al. teach the engineered immune cells (i.e. modified lymphocyte) are resistant to purine nucleotide analogs (PNA) chemotherapy drugs, so they can be used in cancer immunotherapy treatment in patients pre-treated with conventional chemotherapies. As Pizzorno et al. teach that allopurinol is important adjuvant to antineoplastic therapy (p.3, 4th full para.) and it is known that allopurinol can be used along with thiopurine drugs (e.g. 6-MP or 6-TGN) (see Brackett et al.; Abstract), one skilled in the art would select modified lymphocytes that are resistant both 6-TGN and allopurinol for the patients treated with these two combination of drugs.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 13 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Valton et al. in view of Liao et al., Ortinski et al. and Ruiz-Argüelles et al. as applied to claims 1, 3-7, 9-12 and 14-16 above and further in view of Zazulia et al. (of record) and Mout et al. (of record)
Regarding claim 13 directed to the HPRT-targeted CRISPR/Cas9 RNP formulated within a nanocapsule, Valton et al. in view of Liao et al., Ortinski et al. and Ruiz-Argüelles et al. do not teach the limitation.
Zazulia et al. teach the use of a gelatin nanocapsule comprising Cas9 protein and sgRNAs (p.5, Example 1, A. Production of gelatin nanocapsules).
It would have been obvious to a person skilled in the art to use the gelatin nanocapsule taught by Zazulia et al. for the HPRT-targeted CRIPSR/Cas9 RNP taught by Liao et al. and Ortinski et al. for the method of Valton et al. with a reasonable expectation of success.
Furthermore, Mout et al. teach the delivery of CRISPR/Cas9 RNP for gene editing using nanoparticles forming nanoassemblies (i.e. nanocapsule) (see Abstract).
Regarding claim 25, the limitations of the claim have been addressed by the combined teachings of Valton et al. in view of Liao et al., Ortinski et al., Ruiz-Argüelles et al., Zazulia et al. and Mout et al. as discussed above.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 17 and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Valton et al. (supra) in view of Guitart et al. (Arch Dermatol. 2002; 138: 1359-1365; of record) and Ruiz-Argüelles et al. (supra).
Valton et al. teach at paragraphs (0125-0130):
1) A method of engineering allogeneic and drug resistant T-cells for immunotherapy comprising:
(a) Providing a T-cell;
(b) Selecting at least one chemotherapy drug, said T-cell is sensitive to:
(c) Modifying said T-cell by inactivating at least one gene encoding a T-cell receptor (TCR) component;
(d) Modifying said T-cell to confer drug resistance to said chemotherapy drug;
(e) Expanding said engineered T-cell, optionally in the presence of said drug.
Valton et al. teach at paragraphs (0132):
3) The method of claim 1 or 2 wherein said drug resistance is conferred to the T-cell by inactivating at least one drug sensitizing gene.
Valton et al. teach at paragraphs (0138):
9) The method of claim 3 or 5 wherein said drug resistance gene is HPRT.
Valton et al. teach at paragraphs (0159):
30) The method according to any one of claims 1 to 28, wherein said engineered T-cells are expanded in-vitro.
Thus, Valton et al. teach the step (a) and (b) of claim 17.
Regarding step (c) of claim 17, Valton et al. do not particularly teach the step of inducing at least a partial graft versus malignancy effect by administering an HSC grafts to the patient. However, Valton et al. teach that the cell compositions of their invention are administered to a patient in conjunction with (e.g. before, simultaneously or following) bone marrow transplantation (para. 112), and this step would inherently induce the graft versus malignancy as Valton et al. teach the bone marrow transplantation.
Regarding the HPRT deficient lymphocytes being generated through knockout of the HPRT gene, Valton et al. teach HPRT KO T cells and the HPRT gene was inactivated using TALE-nuclease (para. 256-257).
Regarding the step (d) of claim 17 directed to the step of administering the population of modified lymphocytes to the patient following the detection of residual disease or disease recurrence, Valton et al. do not teach the limitation.
However, Guitart et al. teach allogeneic hematopoietic stem cells transplantation and administration of donor lymphocytes. Furthermore, Guitart et al. teach, “administering the population of modified lymphocytes to the patient following the detection of residual disease or disease recurrence” (page 1363, col.2, 1st para.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to practice a method of hematopoietic stem cell transplantation wherein following HSC transplantation, a population of engineered T-cells is administered following detection of residual disease or disease recurrence, wherein the engineered T-cells had a knockout/knockdown of HPRT and was expanded using 6-thioguanine.
Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Each of the elements (HPRT-knockout/knockdown engineered T-cells expanded by 6TG; methods of HSC transplantation followed by administration of engineered T-cells; use of MTX to treat HVGD during HVL treatments; administering donor lymphocytes following detection of residual disease or disease recurrence) are taught by Valton or Guitart and further they are taught in various combinations and are shown to be used as methods of treating blood cancers using HSCT. It would be therefore predictably obvious to use a combination of these elements in a method of HSC transplantation that further comprises administration of HPRT-knockout/knockdown engineered T cells.
The skilled artisan would have had a reasonable expectation of success in combining the various teachings of Valton et al. and Guitart because medical professionals were experienced in administering donor lymphocytes to HSC allograft patients prior to the instant invention.
Regarding the step of administering methotrexate, Valton and Guitart do not teach the step (e) of claims 17, the amount of methotrexate (claim 19) or the methotrexate being administered in titrated doses (claim 20).
Ruiz-Argüelles et al. teach that method of titrating doses of conditioning drugs was developed to diminish the toxic effects of these drugs during HSC allografts that experience GVHD (Introduction section, page 146, col.1, parag.1). Furthermore, Ruiz-Argüelles et al. teach that 5 mg/m2 of methotrexate was administered by intravenous infusion as part of a low intensity conditioning regimen (bridging pages 146-147). Accordingly, Ruiz-Argüelles suggest the limitations of instant claims which are deficient in Valton et al. in view of Guitart et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to practice a method of hematopoietic stem cell transplantation wherein following HSC transplantation, a population of engineered T-cells is administered following detection of residual disease or disease recurrence, wherein the engineered T-cells had a knockout/knockdown of HPRT and was expanded using 6-thioguanine and further practice a method of a low intensity conditioning regimen comprising methotrexate.
Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
The skilled artisan would have had a reasonable expectation of success in combining the various teachings of Valton et al., Guitart et al. and Ruiz-Argüelles et al. because medical professionals were experienced in administering MTX to HSC allograft patients prior to the instant invention.
Claim 21 discloses that the positive selection for the HPRT deficient lymphocytes is performed using 6TG (6-thioguanine). Valton et al. teach that the engineered T-cells of their invention are selected by use of 6TG for 6TG resistant T cell (para. 256 and 260). It is noted that “positive selection comprises contacting the generated HPRT deficient lymphocytes with a purine analog” as claimed is understood that the selected cells are resistant to the purine analog. Thus, Valton et al. teach the limitation of claim 21.
Valton et al. teach using single dose, multiple dose, and 105 to 106 cells/kg body weight at paragraph [0110], thereby meet the limitations of claims 22-23.
Therefore the method as taught by Valton et al. in view of Guitart et al. and Ruiz-Argüelles et al. would have been prima facie obvious over the method of the instant application.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Valton et al. in view of Guitart et al. and Ruiz-Argüelles et al. as applied to claims 17 and 19-23, and further in view of Liao et al. (supra) and Ortinski et al. (supra)
Valton et al. in view of Guitart et al. and Ruiz-Argüelles et al. teach the subject matter of claims 17 and 19-23 as discussed above.
Regarding claim 24, while Valton et al. teach that the inactivation of drug sensitizing genes can be carried out using CRIPSR/Cas9 nuclease (para. 61), however, Valton et al. in view of Guitart et al. do not particularly teach the HPRT-CRISPR/Cas9 RNP and anti-HPRT sgRNA. However, these are well known components used in the gene editing technique based on CRISPR/Cas9.
Liao et al. teach the method of editing HPRT gene using CRISPR/Cas9 system, and they utilize gRNA targeting HPRT gene (Abstract).
Ortinski et al. teach knockout of gene using CRISPR/Cas9 gene editing system comprising sgRNA and Cas9 protein (i.e. Cas9-sgRNA RNP) (Abstract).
It would have been obvious to a person skilled in the art to use the known technologies for CRIPSR/Cas9 gene editing system for editing HPRT including the HPRT-CRISPR/Cas9 RNP and anti-HPRT sgRNA taught by Liao et al. and Ortinski et al. for the method of Valton et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so, not only Valton et al. disclose CRISPR/Cas9 system for an alternative tool for producing HPRT KO cells, Liao et al. teach the HPRT gene editing using CRISPR/Cas9 system.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 3-17 and 19-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 18/078,977 in view of Ruiz-Argüelles et al. (supra), Valton et al. (supra), Ortinski et al. (supra), Guitart et al.(supra). The claims of the ‘977 application disclose a method of providing benefits of a lymphocyte infusion to a patient by (a) generating HPRT deficient lymphocytes based on CRISPR/Cas system (utilizing Cas9, guide RNA), (b) selecting the HPRT deficient lymphocyte resistant to a purine analog including 6-TG and allopurinol, and administering the modified lymphocyte to the patient; the method further comprises administering MTX or MPA upon the side effects of GVHD. Claims of the ‘977 application disclose the use of viral delivery vehicle such as a nanocapsule or a lentiviral vector.
Regarding claims 3-4 and 19-20 directed to the dosage of MTX, as discussed above in the 103 rejection, Ruiz-Argüelles et al. teach the limitation as discussed in the 103 rejection above.
Regarding claims 9-11 and 23, as discussed above in the 102 rejection, Valton et al. teach the limitations with regard to the dosages as claimed as discussed in the 103 rejection above.
Regarding claim 16 directed to non-integrating lentiviral vector, Ortinski et al. teach the limitation as discussed in the 103 rejection above.
Regarding claim 17, step (d) of administering the modified lymphocytes to the patient following the detection of residual disease or recurrence, Guitart et al. teach the limitation as discussed in the 103 rejection above.
It would have been obvious to a person skilled in the art to modify the subject matter of the claims of ‘977 application based on the teachings of the above cited references as discussed in the 103 rejections above with a reasonable expectation of success.
Therefore, the claims of the ‘977 application in view of the cited references render the claims of the instant application obvious.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 7/28/2025 have been fully considered but they are not persuasive. It is noted that the previous claim rejection under 102 has been withdrawn due to the instant amendment. Further, the 103 rejections have been modified in order to address the newly added limitation and claim. It is also noted that the claim rejection has been separated to clarify how the references are applied to the claimed subject matter.
In the remarks, applicant argued that Valton does not provide any guidance to the skilled artisan for using any rare-cutting endonuclease other than a TALE-nuclease for the modification of any gene, and the Office do not supply the motivation to modify Valton to use the CRISPR/Cas9 taught by Liao. The Examiner respectfully disagrees with this allegation. First, Valton clearly discloses CRISPR/Cas9 nuclease as an alternative to the TALEN-nuclease (see para. 61). Furthermore, it is extremely well known in the art that these are nucleases utilized for gene editing. This is supported by Liao et al. who utilizes CRISPR/Cas9 to edit HPRT genes. While applicant argues the efficiency of gene editing based on the effectiveness of gRNA, and Valton does not particularly teach the use of sgRNA, however, this does not teach away of using CRISPR/Cas9 to knockout HPRT genes. Furthermore, one skilled in the art would select the best gRNA targeting HPRT gene for the successful outcome of editing the desired gene. In addition, the “co-targeting” either teaches away of using CRISPR/Cas9 for the purpose. It is submitted that the combined teachings of the claim rejection do not require “co-targeting” of Liao et al. The combined teaching is to use CRIPSR/Cas9 system in place of TALEN system in the method of Valton. As Valton teaches CRISPR/Cas9 an alternative to TALEN, Liao et al. teach CRISPR/Cas9 being used in HPRT editing taught by, and Ortinski et al. teach the use of sgRNA along with CRISPR/Cas9, the combined teachings of these references would render the claimed subject matter for the step (a) of claim 1 and claim 25. Applicant’s argument with regard to the other references, i.e. Ortinski, Zazulia or Mout, is not persuasive as these references teach that CRISPR/Cas9 system being encapsulated or in the form of vector system such as lentiviral vector. There are extremely well known in the art that CRISPR/Cas9 system is expressed via a vector system as taught by Ortinski. Upon the use of CRISPR/Cas9 replacing TALEN system in Valton, one skilled in the art would have reasonable expectation of success in delivering the CRISPR/Cas9 in a nanoparticle. It is the examiner’s position that the claim rejections provide sufficient rationale to combine the teachings of the cited references and the motivation for replacing TALEN with CRISPR is provided by Valton as they teach CRISPR is an alternative to TALEN.
Applicant’s argument directed to claim 17 and its dependent claims is mainly the same as above, and the claim rejection has addressed all the limitation and the combined teachings of the cited references would render the subject matter obvious.
Regarding the double patenting rejections, the terminal disclaimers filed were accepted and thus, the rejections based on US PAT. 10,426,798 and 11,213,548 have been withdrawn. However, the rejection based on 18/078,977 is maintained based on the 103 rejections.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631