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 .
DETAILED ACTION
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-21, drawn to a method of providing lymphocytes while mitigating side effects by administering HPRT deficient lymphocytes, in the reply filed on 03/07/2026 is acknowledged.
Claims 22-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant further elects species of Exon 3 and SEQ ID NO: 41 as the species of guide RNA molecules in claims 5-6, and species of transduction as the species of a delivery method in claims 14-15 in the reply filed on 03/07/2026.
Claims 3-4, 7-8 and 12-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
Claims 1-24 are pending.
Claims 3-4, 7-8, 12-13 and 22-24 are withdrawn.
Claims 1-2, 5-6, 9-11 and 14-21 are considered on the merits.
Priority
This application is a CON of PCT/US21/39022 (filed on 06/25/2021), which claims benefit from provisional application 63/044,697 (filed on 06/26/2020). The priority claim of the instant application has been granted and the earliest benefit date is 06/26/2020 from the application 63/044,697.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/11/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g., page 124). Applicant is required to amend or delete the embedded hyperlink and/or other form of browser-executable code. For example, “http” can be replaced with “hypertext transfer protocol” as the URL code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites the abbreviation “HPRT”. An abbreviation should be preceded in its first occurrence by the specific identity of the entity which said abbreviation is intended to represent. Thereafter, the use of the abbreviation in the claims will be understood.
Appropriate correction is required.
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 10 and 16-17 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.
Claim 10 recites the limitation “the Cas protein” in line 1. There is insufficient antecedent basis for this limitation in the claim because base claim 1 is silent on a Cas protein. It is recommended to change its dependency to claim 9, and is examined as so.
Claims 16 and 17 both recite the term “preferably” or “more preferably”, which renders the claim indefinite because it is a subjective term. A claim that requires the exercise of subjective judgment without restriction may render the claim indefinite. See MPEP § 2173.05(b).
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 1-2, 5-6, 9-11 and 14-21 are rejected under 35 U.S.C. 103 as being unpatentable over Alma et al., (WO 2019/018491A1, published 2019 January 24. Cited in IDS 12/11/2022) in view of Kim et al., (US 2017/0349905 A1).
With respect to claim 1, Alma teaches “a method of providing benefits of a lymphocyte infusion to a patient in need of treatment thereof while mitigating side effects comprising: generating HPRT deficient lymphocytes from a donor sample; positively selecting for the HPRT deficient lymphocytes ex vivo to provide a population of modified lymphocytes; administering an HSC graft to the patient; administering the population of modified lymphocytes to the patient following the administration of the HSC graft; and optionally administering MTX if the side effects arise” (e.g., [0012]). Alma teaches the HPRT deficient lymphocytes are generated through knockout of the HPRT gene (e.g., [0013]) and teaches the lymphocytes are transfected or transduced with (i) endonuclease CRISPR/Cas9 and (ii) a guide RNA (sgRNA) molecule targeting a sequence of the HPRT1 gene (e.g., [0073] and see Example 5, [0155]).
However, Alma is silent on the guide RNA targeting a sequence within Exon 3 of the HPRT1 gene in claim 1 and comprising SEQ ID NO: 41 in claims 5-6.
Kim teaches a method of knocking out a gene (e.g., CCR5, HPRT and DMD genes) using a split Cas9 and sgRNA (single guide RNA) for each of the genes (see e.g., abstract, and Example 2, [0063]-[0069]). Kim teaches the sgRNA targeting HPRT gene comprises the reference SEQ ID NO: 12 (e.g., [0065]) that targets HPRT exon 3 (see p. 15, SEQ ID NO: 12 information: “HPRT exon 3 target sequence”. It is noted that this sequence is mistakenly described as “present in DMD exon 51 was targeted” in [0065]), related to claim 1. The sgRNA sequence of Kim’s SEQ ID NO: 12 has 95.7% sequence identity (22/23) to the instant SEQ ID NO: 41 (see SCORE search 05/08/2026, -41.rni file, result #3), related to claim 5.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of knocking out HPRT gene by Cas9 and a gRNA disclosed by Alma, by choosing the sgRNA sequence targeting Exon 3 of HPRT gene as suggested by Kim with a reasonable expectation of success. Since Kim has reduced to practice a guide RNA sequence targeting HPRT exon 3 with successful knockout efficiency (27% Indel frequency, see Example 3, [0070], and Fig 3), one of ordinary skill in the art would have had a reason to choose the guide RNA sequence of Kim in the method of Alma in order to obtain successful HPRT gene knockout in lymphocytes to provide benefits while mitigating side effects of lymphocyte infusion.
In regard to the guide RNA comprising SEQ ID NO: 41 in claim 6, it is noted that the corresponding human HPRT exon 3 has a “AGGGG” at the 3’ end (see below) and since a PAM sequence for Cas9 binding is “NGG” (N being any nucleotide) at the 3’ of a guide RNA, one of ordinary skill in the art would have immediately expected that this “AGGGG” sequence contains three PAM sequences (i.e., underlined as AGGGG, AGGGG and AGGGG) allowing strong Cas9 binding. Since Kim has reduced to practice using “AGGGG” as a PAM sequence with successful knockout efficiency (see below and Example 3, [0070], see also Fig 3), one of ordinary skill in the art would have chosen the other options, such as using “AGGGG” as a PAM sequence to design a gRNA to arrive at the instant SEQ ID NO: 41 in claim 6 (see below) with a reasonable expectation of success. Since the corresponding HPRT exon 3 sequence provides a stretch of “AGGGG” that allows strong Cas9 binding because it contains three PAM sequences, and since Kim has reduced to practice using one of the three PAM sequences to design gRNA with success, one of ordinary skill in the art would have immediately envisioned the taught option of using “AGGGG” as a PAM sequence to design a gRNA, among the limited genus of options as taught by Kim. See MPEP 2131.02 (III).
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With respect to claim 2 directed to administering an HSC graft to the patient, as stated supra, Alma teaches the method comprises “administering an HSC graft to the patient” prior to administering the population of modified lymphocytes to the patient (e.g., [0012]).
With respect to claim 9 directed to the endonuclease comprising a Cas protein, and claim 10 directed to the Cas protein comprising a Cas9 protein, as stated supra, Alma teaches the lymphocytes are transfected or transduced with endonuclease CRISPR/Cas9 (e.g., [0073] and see Example 5, [0155]).
With respect to claim 11 directed to the lymphocytes being transduced with a viral delivery vehicle, claim 14 directed to the viral delivery vehicle being an expression vector including a first nucleic acid sequence encoding for the endonuclease and a second nucleic acid encoding for the guide RNA molecule, and claim 15 directed to the expression vector being a lentiviral expression vector, Alma teaches a gene editing approach may be used to knockout HPRT, including CRISPR/Cas9 nuclease mediated methods. Gene editing tools may be delivered via methods including lentiviral vectors (e.g., [0073]), related to claim 11 and claim 15. In regard to claim 14, Alma teaches lentiviral vector is used to transfer genetic material into a cell via transduction (e.g., [0057], [0062], [0064], and Example 1 transducing CAR and shRNA by a lentiviral vector driven by Pol II and Pol III promoters for expression in T cells, e.g., [0146]). Accordingly, one of ordinary skill in the art would have had a reason to choose a lentiviral vector as an expression vector to transduce a nucleic acid sequence encoding for the CRISPR/Cas9 nuclease and a nucleic acid sequence encoding for the guide RNA molecule as suggested by Alma with a reasonable expectation of success. Since Alma suggests the CRISPR/Cas9 nuclease mediated gene editing tools (e.g., including Cas9 endonuclease and guide RNA molecules) may be delivered by lentiviral vectors and reduces to practice a lentiviral expression vector to transduce CAR and shRNA driven by Pol II and Pol III promoters for expression in T cells (e.g., [0146]), one of ordinary skill in the art would have had a reason to choose a lentiviral expression vector to transduce and express endonuclease and guide RNAs in the lymphocytes because Alma teaches lentiviral vectors have emerged as potent and versatile tools as they offer the ability to efficiently infect a wide variety of primary cell types whether dividing or nondividing (e.g., [0071] in page 18).
With respect to claim 16 directed to the level of HPRT1 gene expression being reduced, Alma teaches a 6-TG selection for HPRT knockout population of lymphocytes (e.g., [0155]) and at day 15 of selection, almost 100% of cells have InDel knockout (see e.g. Fig 9B, selection with 600nM and 900nM 6TG), indicating the HPRT knockout lymphocytes have no functional expression of HPRT1 gene, thus the level of HPRT1 gene expression would likely be reduced by at least about 70%.
With respect to claim 17 directed to the positive selection comprising contacting the cells with a purine analog such as 6-TG, as stated supra, Alma teaches a 6-TG positive selection for HPRT knockout population of lymphocytes (e.g., [0155]) and at day 15 of selection, almost 100% of cells have InDel knockout (see e.g. Fig 9B).
With respect to claim 18 directed to the positive selection comprising contacting the cells with both a purine analog and allopurinol, Alma teaches the generated HPRT-deficient cells are contacted with both a purine analog and with allopurinol, which is an inhibitor ofxanthine oxidase (e.g., [0081] and reference claim 7).
With respect to claims 19-21 directed to administering a dihydrofolate reductase inhibitor, such as MTX, if the side effects, such as GvHD, arise, it is noted that these limitations are directed to a contingent limitation based on the limitation that the side effects arise. MPEP 2111.04 (II) states “[T]he broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. Thus, the limitations in claims 19-21 do not provide any patentable weight in determining patentability of the claimed method, and thus claims 19-21 are rejected in the same way as claim 1 as discussed above.
Nevertheless, Alma teaches administering MTX to the patient if the side effects arise (e.g., [0012] and Fig 3) and the side effects include GVHD (e.g., [0093] and Fig 3), thus teaches claims 19-21.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Double Patenting Rejections
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 1-2, 5-6, 9-11 and 14-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of US Patent Nos: 10,426,798 (‘798) and 11,213,548 (‘548) in view of Alma et al., (WO 2019/018491A1, published 2019 January 24. Cited in IDS 12/11/2022) and Kim et al., (US 2017/0349905 A1). Although the claims at issue are not identical, they are not patentably distinct from each other.
Patented claims recite a method of providing benefits of a lymphocyte infusion to a patient in need of treatment thereof comprising: (a) generating HPRT deficient lymphocytes from a donor sample, (b) positively selecting for the HPRT deficient lymphocytes ex vivo to provide a population of modified lymphocytes; (c) administering at least a portion of the population of modified lymphocytes to the patient following an administration of an HSC graft to the patient; and (d) administering one or more doses of methotrexate or mycophenolic acid if side effects from the administration of the modified lymphocytes, such as graft versus host disease, arise (related to instant claims 1-2 and 19-21). The positive selection comprises contacting the generated HPRT deficient lymphocytes with a purine analog 6-TG and an inhibitor of xanthine oxidase (related to instant claims 17 and 18).
However, the reference patents recite the HPRT deficient lymphocytes are generated through knockdown of the HPRT gene by shRNA, but are silent on generating HPRT knockout cells by an endonuclease Cas9 and guide RNAs delivered by a lentiviral expression vector in claims 1, 5-6, 9-11, 14-16.
Alma teaches a method of providing benefits of a lymphocyte infusion to a patient in need of treatment thereof while mitigating side effects comprising: generating HPRT deficient lymphocytes; positively selecting for the HPRT deficient lymphocytes; administering an HSC graft to the patient; and then administering the population of modified lymphocytes to the patient; and administering MTX if the side effects arise (e.g., [0012]), related the same method in the cited patents. Alma teaches the HPRT deficient lymphocytes are generated through knockout of the HPRT gene (e.g., [0013]) and teaches the lymphocytes are transfected or transduced with (i) endonuclease CRISPR/Cas9 and (ii) a guide RNA (sgRNA) molecule targeting a sequence of the HPRT1 gene (e.g., [0073] and see Example 5, [0155]), related to instant claims 1 and 9-10. Alma teaches gene editing tools may be delivered via methods including lentiviral vectors (e.g., [0073]), related to instant claim 11 and claim 15. Alma teaches lentiviral vector is used to transfer genetic material into a cell via transduction (e.g., [0057], [0062], [0064], and Example 1 transducing CAR and shRNA by a lentiviral vector driven by Pol II and Pol III promoters for expression in T cells, e.g., [0146]), related to instant claim 14. Alma teaches a 6-TG selection for HPRT knockout population of lymphocytes (e.g., [0155]) and at day 15 of selection, almost 100% of cells have InDel knockout (see e.g. Fig 9B, selection with 600nM and 900nM 6TG), indicating the HPRT knockout lymphocytes have no functional expression of HPRT1 gene, thus the level of HPRT1 gene expression would likely be reduced by at least about 70%, related to instant claim 16.
Kim teaches a method of knocking out a gene (e.g., CCR5, HPRT and DMD genes) using a split Cas9 and sgRNA (single guide RNA) for each of the genes (see e.g., abstract, and Example 2, [0063]-[0069]). Kim teaches the sgRNA targeting HPRT gene comprises the reference SEQ ID NO: 12 (e.g., [0065]) that targets HPRT exon 3 (see p. 15, SEQ ID NO: 12 information: “HPRT exon 3 target sequence”), related to instant claim 1. The sgRNA sequence of Kim’s SEQ ID NO: 12 has 95.7% sequence identity (22/23) to the instant SEQ ID NO: 41 (see SCORE search 05/08/2026, -41.rni file, result #3), related to instant claim 5. It is noted that the corresponding human HPRT exon 3 has a “AGGGG” at the 3’ end, one of ordinary skill in the art would have immediately expected that this “AGGGG” sequence contains three PAM sequences (i.e., underlined as AGGGG, AGGGG and AGGGG) allowing strong Cas9 binding. Since Kim has reduced to practice using “AGGGG” as a PAM sequence with successful knockout efficiency (see Example 3, [0070], see also Fig 3), one of ordinary skill in the art would have chosen the other options, such as using “AGGGG” as a PAM sequence to design a gRNA to arrive at the instant SEQ ID NO: 41 in instant claim 6 with a reasonable expectation of success. One of ordinary skill in the art would have immediately envisioned the taught option of using “AGGGG” as a PAM sequence to design a gRNA, among the limited genus of options as taught by Kim. See MPEP 2131.02 (III).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the claimed method of generating HPRT deficient lymphocytes recited in the cited patents, by choosing or substituting with knocking out HPRT by transducing Cas9 and guide RNA in a lentiviral expression vector so as to obtain the level of HPRT1 gene expression reduced by at least about 70% as suggested by Alma and further choosing the guide RNA sequence suggested by Kim with a reasonable expectation of success. Since Alma teaches the 6-TG selection process occurs much faster on HPRT knockout cells as compared with the HPRT knockdown cells because there is some level of residual HPRT by the RNAi knockdown approach as compared with the full elimination of HPRT by the knockout approach. Therefore, HPRT-knockout cells were believed to have a much higher tolerance against 6TG and are believed to grow much faster at higher dosages of 6TG (900nM) compared with HPRT-knockdown cells (e.g., [0155]), and since Kim has reduced to practice a guide RNA sequence targeting HPRT exon 3 with successful knockout efficiency (27% Indel frequency, see Example 3, [0070], and Fig 3), one of ordinary skill in the art would have had a reason to choose or substitute with HPRT knockout as suggested by Alma and choose the gRNA sequence as suggested by Kim in order to obtain efficient full elimination of HPRT to take advantage of their much higher tolerance against 6TG and growing much faster at higher dosages of 6TG compared with HPRT-knockdown cells.
Since the instant application claims are obvious over cited patent claims, in view of Alma and Kim, said claims are not patentably distinct.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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