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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/24/2025 has been entered.
Claims 2-3, 5-6, 12, 16-30, 32-62, 65-66 have been canceled, claim 31 has been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1, 4, 7-11, 13-15, 63-64 and 67-69 have been considered on the merits. All arguments have been considered.
Claim Objections
Claims 10 and 13 are objected to because of the following informalities: the term “(02)” in line 4 of claim 10 and line5 of claim 13 should be “(O2)” instead. Appropriate correction is required.
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.
Claim(s) 1, 4, 7-11, 13, 15 and 63-64 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yivgi-Ohana et al. (US2018/0030413; IDS ref.) as evidenced by Pearson syndrome (2021, NIH-MedicinePlus; of record).
Regarding claim 1, Yivgi-Ohana et al. teach human bone-marrow cells enriched with functional mitochondria, and therapeutic methods utilizing the cells (Abstract). Yivgi-Ohana et al. teach autologous “mitochondrially-enriched” bone-marrow cells of a patient (para. 13), and this would meet the steps (a) and (c) of claim 1.
Regarding the step (a) of claim 1, Yivgi-Ohana et al. teach that the bone marrow cells express the bone-marrow progenitor cell antigen CD34 (para. 22), i.e. CD34+ bone marrow progenitor cells. Yivgi-Ohana et al. also teach the bone-marrow cells are hematopoietic stem cells (para. 21).
Yivgi-Ohana et al. teach that the functional mitochondria are obtained from a human cell or tissue including placenta, placental cells grown in culture or blood cells (para. 136), and isolating functional mitochondria from a blood sample of a healthy donor (para. 177). This teaching meets step (b) of claims 1 and 9.
Regarding step (c) of claim 1, Yivgi-Ohana et al. teach that the CS activity levels in the human CD34+ cells incubated with GFP-labeled mitochondria isolated from human placental cells resulted in 0.003003348 U without centrifugation (Example 9; para. 165; Table 2). This CS activity is converted as 3.0 mU which falls within the claimed range. The 3.0 mU taught by Yivgi-Ohana et al. is considered to meet the limitation of “about 4.4 mU” required in claim 15.
Regarding the step (d) of claim 1, Yivgi-Ohana et al. teach that the mitochondrially-enriched bone marrow cells are administered to the patient for treating a mitochondrial disease (para. 125).
Regarding the intended purpose of increasing levels of leukocyte cells in a subject, while Yivgi-Ohana et al. do not particularly teach the limitation, however, the steps taught by Yivgi-Ohana et al. are identical to the claimed steps, and thus, the results are expected the same.
Regarding the subject having a lymphocyte deficiency-related disease or disorder (claim 1), Yivgi-Ohana et al. teach the patient has a mitochondrial disease including Pearson syndrome (para. 32). It is understood that PS has problems with the development of blood-forming (hematopoietic) cells in the bone marrow, and some of the patients have low numbers of white blood cells (neutropenia). Thus, it is considered that PS is a bone marrow failure disorder (see Pearson syndrome, 2021). As a bone marrow failure disorder, it is expected that the patient having PS would have leukocyte deficiency, i.e. PS is a lymphocyte-deficiency related disease or disorder. Furthermore, the instant specification exemplified a subject having Pearson syndrome (Example 1).
Regarding claim 4, Yivgi-Ohana et al. teach the bone marrow cells and thus, they are obtained from bone marrow (para. 23).
Regarding claim 7, the wherein clause does not provide any active step to be carried out, and it is a product-by-process limitation directed to the exogenous mitochondria. Thus, the limitation does not provide patentable weight in determining patentability of the claimed method. Nevertheless, Yivgi-Ohana et al. teach partially purified functional mitochondria (para. 11) and the mitochondria have undergone a freeze-thaw cycle (paras. 136-140).
Regarding claim 8 directed to the exogenous mitochondria constituting at least 1% of the total mitochondria content in the mitochondrially-enriched target cells, Yivgi-Ohana et al. do not particularly teach the limitation. However, it would have been obvious to a person skilled in the art that the mitochondrially enriched bone marrow of Yivgi-Ohana et al. would have at least 1% of exogenous mitochondria in the total mitochondria content because Yivgi-Ohana et al. teach that human bone-marrow cells are more receptive to be enriched with mitochondria reaching over 8 fold of their natural mitochondrial content (para. 54), and the mitochondrial content of the human bone-marrow cells in the fourth composition (bone marrow cells of the first composition contacted with functional mitochondria) is at least 50% higher than the mitochondrial content of the human bone-marrow cells in the first composition (see para.19). As the bone marrow cells of the fourth composition (i.e. mitochondrially-enriched target cells) has at least 50% higher than the bone marrow cells prior to the mitochondrial enrichment, this result would inherently meet the at least 1% of total mitochondria being exogenous as claimed.
Regarding claim 10, the wherein clause discloses a method step to determine the mitochondrial content and this step is not disclosed as an active step, and thus, it is considered as an optional step. Nevertheless, Yivgi-Ohana et al. teach measurement of citrate synthase (CS) activity assay or O2 consumption (para. 59).
Regarding claim 11, Yivgi-Ohana et al. teach the administration route being intravenous, intraarterial or intramuscular (para. 135).
Regarding claim 13 directed to the characteristics of the mitochondrially-enriched target cells, Yivgi-Ohana et al. teach that ATP levels in cells incubated with mitochondria (i.e. mitochondrially-enriched target cells) were increased by about 5.3 compared to control (para. 163).
Regarding claims 63-64 directed to the leukocyte being lymphocyte including T cells and B cells, the limitation directed to the leukocyte is a part of intended purpose or outcome of the claimed method, and this does not require any active step to be carried out. Rather the use of target cells enriched with exogenous mitochondria in the method would necessarily produce the intended results. As Yivgi-Ohana et al. teach the use of bone marrow cells which comprise hematopoietic progenitor cells and hematopoietic stem cells capable of differentiating into lymphocytes, it is expected that the mitochondrially-enriched bone marrow cells of Yivgi-Ohana et al. would inherently produce lymphocytes including T cells and B cells upon the administration in a patient having PS.
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.
Claim(s) 1, 4, 7-11, 13-15 and 63-64 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yivgi-Ohana et al. (US2018/0030413; IDS ref.) as evidenced by Pearson syndrome (2021, NIH-MedicinePlus; of record)
Regarding claim 1, Yivgi-Ohana et al. teach human bone-marrow cells enriched with functional mitochondria, and therapeutic methods utilizing the cells (Abstract). Yivgi-Ohana et al. teach autologous “mitochondrially-enriched” bone-marrow cells of a patient (para. 13), and this would meet the steps (a) and (c) of claim 1.
Regarding the step (a) of claim 1, Yivgi-Ohana et al. teach that the bone marrow cells express the bone-marrow progenitor cell antigen CD34 (para. 22), i.e. CD34+ bone marrow progenitor cells. Yivgi-Ohana et al. also teach the bone-marrow cells are hematopoietic stem cells (para. 21).
Yivgi-Ohana et al. teach that the functional mitochondria are obtained from a human cell or tissue including placenta, placental cells grown in culture or blood cells (para. 136), and isolating functional mitochondria from a blood sample of a healthy donor (para. 177). This teaching meets step (b) of claims 1 and 9.
Regarding step (c) of claim 1, Yivgi-Ohana et al. teach that the CS activity levels in the human CD34+ cells incubated with GFP-labeled mitochondria isolated from human placental cells resulted in 0.003003348 U without centrifugation (Example 9; para. 165; Table 2). This CS activity is converted as 3.0 mU which falls within the claimed range. The 3.0 mU taught by Yivgi-Ohana et al. is considered to meet the limitation of “about 4.4 mU” required in claim 15. Even if assuming arguendo the CS activity of 3.0 mU taught by Yivgi-Ohana et al. does not meet the claimed “about 4.4 mU”, however, Yivgi-Ohana et al. teach the range from 3.0 mU up to 11 mU according to Table 2. Thus, one skilled in the art would recognize that CS activity can be achieved between 3.0 mU up to 11 mU by using centrifugation in CD34+ cells by incubating with exogenous mitochondria.
Regarding the step (d) of claim 1, Yivgi-Ohana et al. teach that the mitochondrially-enriched bone marrow cells are administered to the patient for treating a mitochondrial disease (para. 125).
Regarding the intended purpose of increasing levels of leukocyte cells in a subject, while Yivgi-Ohana et al. do not particularly teach the limitation, however, the steps taught by Yivgi-Ohana et al. are identical to the claimed steps, and thus, the results are expected the same.
Regarding the subject having a lymphocyte deficiency-related disease or disorder (claim 1), Yivgi-Ohana et al. teach the patient has a mitochondrial disease including Pearson syndrome (para. 32). It is understood that PS has problems with the development of blood-forming (hematopoietic) cells in the bone marrow, and some of the patients have low numbers of white blood cells (neutropenia). Thus, it is considered that PS is a bone marrow failure disorder (see Pearson syndrome, 2021). As a bone marrow failure disorder, it is expected that the patient having PS would have leukocyte deficiency, i.e. PS is a lymphocyte-deficiency related disease or disorder. Furthermore, the instant specification exemplified a subject having Pearson syndrome (Example 1).
Regarding claim 4, Yivgi-Ohana et al. teach the bone marrow cells and thus, they are obtained from bone marrow (para. 23).
Regarding claim 7, the wherein clause does not provide any active step to be carried out, and it is a product-by-process limitation directed to the exogenous mitochondria. Thus, the limitation does not provide patentable weight in determining patentability of the claimed method. Nevertheless, Yivgi-Ohana et al. teach partially purified functional mitochondria (para. 11) and the mitochondria have undergone a freeze-thaw cycle (paras. 136-140).
Regarding claim 8 directed to the exogenous mitochondria constituting at least 1% of the total mitochondria content in the mitochondrially-enriched target cells, Yivgi-Ohana et al. do not particularly teach the limitation. However, it would have been obvious to a person skilled in the art that the mitochondrially enriched bone marrow of Yivgi-Ohana et al. would have at least 1% of exogenous mitochondria in the total mitochondria content because Yivgi-Ohana et al. teach that human bone-marrow cells are more receptive to be enriched with mitochondria reaching over 8 fold of their natural mitochondrial content (para. 54), and the mitochondrial content of the human bone-marrow cells in the fourth composition (bone marrow cells of the first composition contacted with functional mitochondria) is at least 50% higher than the mitochondrial content of the human bone-marrow cells in the first composition (see para.19). As the bone marrow cells of the fourth composition (i.e. mitochondrially-enriched target cells) has at least 50% higher than the bone marrow cells prior to the mitochondrial enrichment, this result would inherently meet the at least 1% of total mitochondria being exogenous as claimed.
Regarding claim 10, the wherein clause discloses a method step to determine the mitochondrial content and this step is not disclosed as an active step, and thus, it is considered as an optional step. Nevertheless, Yivgi-Ohana et al. teach measurement of citrate synthase (CS) activity assay or O2 consumption (para. 59).
Regarding claim 11, Yivgi-Ohana et al. teach the administration route being intravenous, intraarterial or intramuscular (para. 135).
Regarding claim 13 directed to the characteristics of the mitochondrially-enriched target cells, Yivgi-Ohana et al. teach that ATP levels in cells incubated with mitochondria (i.e. mitochondrially-enriched target cells) were increased by about 5.3 compared to control (para. 163).
Regarding claim 14 directed to the step of adding a pharmaceutically acceptable carrier to the mitochondrially-enriched target cells prior to the administration, Yivgi-Ohana et al. do not particularly teach the limitation.
However, it would have been obvious to a person skilled in the art to use a pharmaceutically acceptable carrier for the composition comprising human bone marrow cells enriched with exogenous mitochondria taught by Yivgi-Ohana et al. with a reasonable expectation of success.
Yivgi-Ohana et al. teach a pharmaceutical composition comprising the mitochondrially enriched bone marrow cells (para. 36), and the pharmaceutical composition is administered locally to a tissue or an organ (para. 135). Yivgi-Ohana et al. also teach that PBS was used for washing the mitochondrially-enriched cells prior to the injection (para. 161).
As it is extremely well known in the art that a pharmaceutical composition comprising cells would require a liquid carrier for delivery to the body, and the teaching of PBS for washing prior to the injection as taught by Yivgi-Ohana et al., one skilled in the art would use a suitable liquid carrier known in the art such as PBS for the delivery of the pharmaceutical composition of Yivgi-Ohana et al. to a desired tissue or organ with a reasonable expectation of success.
Regarding claims 63-64 directed to the leukocyte being lymphocyte including T cells and B cells, the limitation directed to the leukocyte is a part of intended purpose or outcome of the claimed method, and this does not require any active step to be carried out. Rather the use of target cells enriched with exogenous mitochondria in the method would necessarily produce the intended results. As Yivgi-Ohana et al. teach the use of bone marrow cells which comprise hematopoietic progenitor cells and hematopoietic stem cells capable of differentiating into lymphocytes, it is expected that the mitochondrially-enriched bone marrow cells of Yivgi-Ohana et al. would inherently produce lymphocytes including T cells and B cells upon the administration in a patient having PS.
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(s) 67-69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yivgi-Ohana et al. (supra) as applied to claim 1 above, and further in view of Castagnoli et al. (2019, Frontiers in Pediatrics; of record), Takihara et al. (2019, Blood Adv.; of record) and Booth et al. (2016, Trends in Molecular Medicine; of record)
Regarding the limitation directed to the gene therapy (claim 67), subject having a primary immune deficiency disorder (claim 68) or the species of PID (claim 69), Yivgi-Ohana et al. do not teach the limitation.
However, it is extremely well known in the art that HSC transplantation is a life-saving and curative treatment for primary immunodeficiencies (PID) according to Castagnoli et al. (see p.2, Overview). Castagnoli et al. teach that the first successful HSCT in PID includes SCID and Wiskott-Aldrich Syndrome (p.2, 1st col.).
Booth et al. teach a method of treating immunodeficiency by using HSC gene therapy (see entire document). Booth et al. teach that by using retroviral vector to express functional gene defective in the patients with immune deficiencies using CD34+ cells from bone marrow, i.e. HSCs. (Fig.1). Booth et al. teach that gene therapy has been most extensively investigated for the primary immune deficiencies (PID) include X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase-deficient SCID (ADA-SCID), WAS (Wiskott-Aldrich Syndrome) and chronic granulomatous disease (CGD). Booth et al. teach that somatic gene therapy can be considered as a frontline approach to treat inherited immunodeficiency in addition to more conventional allogeneic procedures (p.325).
It would have been obvious to a person skilled in the art to modify mitochondrially augment the CD34+ HSCs taught by Yivgi-Ohana et al. to express a gene that corrects the genetic deficiency causing PID for the method of treating a subject having PID based on the teachings of Yivgi-Ohana et al., Castagnoli et al. and Booth et al.
A person of ordinary skilled in the art would have been motivated to do so because one skilled in the art would recognize that autologous HSCT gene therapy is readily known in the art according to Booth et al. and the autologous HSCs can be mitochondrially augmented as taught by Yivgi-Ohana et al. because Takihara et al. teach that high mitochondrial mass is associated with reconstitution capacity of HSCs (entire document). Thus, one skilled in the art would expect that the mitochondrially HSCs for HSCT gene therapy treating PID would have greater reconstitution capacity.
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 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 1, 4, 7-11, 13-15, 63-64 and 67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,329,781 in view of Yivgi-Ohana et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘781 patent disclose a method of treating a renal disease or disorder comprising administering a pharmaceutical composition comprising at least about 5x105 to 5x109 human stem cells enriched with human exogenous mitochondria. While the claims of the ‘781 patent do not particularly disclose the intended purpose or outcome of the claims of the instant application, however, as the method steps of the ‘781 patent are identical to the instant claims, and thus, the results are expected the same. The claims of the ‘781 patent disclose that the human stem cells are CD34+ cells, hematopoietic stem cells, and derived from bone marrow, and the human exogenous mitochondria are isolated from placenta, placental cells grown in culture or blood cells. The renal disease or disorder is disclosed in claim 6. The claims of the ‘781 patent also disclose the amount of mitochondrially-enriched cells for the administration, a route of administration (systemic, thus, encompasses intravenous, etc.) and the amount of exogenous mitochondria in total mitochondria in the mitochondrially enriched cells.
Regarding the limitation directed to lymphocyte deficiency related disease or disorder, the claims of the ‘781 patent do not teach the limitation. Yivgi-Ohana et al. teach Pearson syndrome (PS) which is considered as renal disease, and yet it is considered as a lymphocyte-deficiency related disease as discussed above. Thus, it would have been obvious to a person skilled in the art that the method of the ‘781 patent can be used for PS with a reasonable expectation of success.
Regarding the ratio of exogenous mitochondria being 0.88-4.4 mU CS CS activity per 106 CD34+ cells, Yivgi-Ohana et al. teach that the CS activity levels measured in human CD34+ cells incubated with mitochondria is about 3.0 mU to 11 mU (Table 2). The 3.0 mU taught by Yivgi-Ohana et al. is considered to meet the limitation of “about 4.4 mU” required in claim 15. Even if assuming arguendo the CS activity of 3.0 mU taught by Yivgi-Ohana et al. does not meet the claimed “about 4.4 mU”, however, Yivgi-Ohana et al. teach the range from 3.0 mU up to 11 mU according to Table 2. Thus, one skilled in the art would recognize that CS activity can be achieved between 3.0 mU up to 11 mU by using centrifugation in CD34+ cells by incubating with exogenous mitochondria.
Regarding claim 8, the claims 9-10 of the ‘781 patent teach at least 1-30% of the total mitochondria being exogenous.
Regarding the deficiency including frozen-thawed human mitochondria (claim 7); assay (claim 10); route of administration (claim 11); characteristics of mitochondrially enriched cells (claim 13); a pharmaceutically acceptable carrier (claim 14), Yivgi-Ohana et al. teach the limitation. Regarding claim 7, Yivgi-Ohana et al. teach partially purified functional mitochondria (para. 11) and the mitochondria have undergone a freeze-thaw cycle (paras. 136-140). Regarding claim 10, claim 5 of the ‘781 patent disclose the characteristics of mitochondrially-enriched human stem cells. While the claims of the ‘781 patent do not disclose the assay, however, it would have been obvious to a person skilled in the art to carry out assays to determine the characteristics. Furthermore, Yivgi-Ohana et al. teach measurement of citrate synthase (CS) activity assay or O2 consumption (para. 59).
Regarding claim 11, Yivgi-Ohana et al. teach the administration route being intravenous, intraarterial or intramuscular (para. 135).
Regarding claim 13 directed to the characteristics of the mitochondrially-enriched target cells, Yivgi-Ohana et al. teach that ATP levels in cells incubated with mitochondria (i.e. mitochondrially-enriched target cells) were increased by about 5.3 compared to control (para. 163).
Regarding claim 14 directed to the step of adding a pharmaceutically acceptable carrier to the mitochondrially-enriched target cells prior to the administration, the claims of the ‘781 patent in view of Yivgi-Ohana et al. do not particularly teach the limitation.
However, it would have been obvious to a person skilled in the art to use a pharmaceutically acceptable carrier for the composition comprising human bone marrow cells enriched with exogenous mitochondria with a reasonable expectation of success.
Regarding claims 63-64 directed to the leukocyte being lymphocyte including T cells and B cells, the limitation directed to the leukocyte is a part of intended purpose or outcome of the claimed method, and this does not require any active step to be carried out. Rather the use of target cells enriched with exogenous mitochondria in the method would necessarily produce the intended results. As Yivgi-Ohana et al. teach the use of bone marrow cells which comprise hematopoietic progenitor cells and hematopoietic stem cells capable of differentiating into lymphocytes, it is expected that the mitochondrially-enriched bone marrow cells of Yivgi-Ohana et al. would inherently produce lymphocytes including T cells and B cells upon the administration in a patient having PS.
Thus, the claims of the ‘781 patent in view of Yivgi-Ohana et al. render the claims of the instant application obvious.
Claims 1, 4, 7-11, 13-15, 63-64 and 67-69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 30-32, 36-37 of copending Application No. 18/714,544 in view of Yivgi-Ohana et al.(supra) and Booth et al. (supra). The claims of the ‘544 application disclose the method of restoring hematopoietic lineage function or cell count in a subject by administering stem cells or progenitor cells enriched with exogenous mitochondria, and the method improved cell differentiation of hematopoietic lineage, which encompasses increase level of leukocytes including lymphocytes. While the claims of the ‘544 application do not teach many of limitations required by the claims of the instant application, however, the deficiency is overcome by combining the teachings of Yivgi-Ohana et al.
Yivgi-Ohana et al. teach the deficiency including frozen-thawed human mitochondria (claim 7); assay (claim 10); route of administration (claim 11); characteristics of mitochondrially enriched cells (claim 13); a pharmaceutically acceptable carrier (claim 14).
Regarding the ratio of exogenous mitochondria being 0.88-4.4 mU CS CS activity per 106 CD34+ cells, Yivgi-Ohana et al. teach that the CS activity levels measured in human CD34+ cells incubated with mitochondria is about 3.0 mU to 11 mU (Table 2). The 3.0 mU taught by Yivgi-Ohana et al. is considered to meet the limitation of “about 4.4 mU” required in claim 15. Even if assuming arguendo the CS activity of 3.0 mU taught by Yivgi-Ohana et al. does not meet the claimed “about 4.4 mU”, however, Yivgi-Ohana et al. teach the range from 3.0 mU up to 11 mU according to Table 2. Thus, one skilled in the art would recognize that CS activity can be achieved between 3.0 mU up to 11 mU by using centrifugation in CD34+ cells by incubating with exogenous mitochondria.
Regarding claims 63-64, the limitation directed to the leukocyte is a part of intended purpose or outcome of the claimed method, and this does not require any active step to be carried out. Rather the use of target cells enriched with exogenous mitochondria in the method would necessarily produce the intended results.
Regarding the subject having a primary immune deficiency disorder, claim 30 of the ‘544 application discloses a subject in need of restoring hematopoietic lineage function or cell count, and one skilled in the art would recognize that the scope of the subject would include those with PID because it is known in the art that the patients having a PID such as SCID would lack T, B and NK lymphocytes (see Booth et al. p.318, Treating SCIDs). Thus, it would have been obvious to a person skilled in the art that the method disclosed in the ‘544 application would be used for treating a PID.
Thus, the claims of the ‘544 application in view of Yivgi-Ohana et al. and Booth et al. render the claims of the instant application obvious.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
The 1.132 declaration
The declaration under 37 CFR 1.132 filed 11/24/2025 is insufficient to overcome the rejection under 35 U.S.C. 103 as set forth in the last Office action because: the declaration showed the data supporting that the higher the dose of citrate synthase activity per million cells the higher the augmentation rate, and this is up to 4.4 mU per million cells as there was no increase in augmentation when the dose if higher than 4.4 mU (i.e. 8.8 or 17.6 mU). While there is no additional augmentation when the CS activity is above 4.4 mU according to the data of the declaration, however, this does not teach away or render the teaching of Yivgi-Ohana et al. cited in the claim rejection to use the CS activity higher than the claimed range. Furthermore, as newly discussed in the claim rejection above, Yivgi-Ohana et al. in fact teach the CS activity of 3.0 mU, and this CS activity falls within the claimed range. Thus, it is the Examiner’s position that the teaching of Yivgi-Ohana et al. in view of secondary references cited in the claim rejection render the claimed invention obvious.
Remarks
Applicant’s arguments have been fully considered and are persuasive in view of the instant amendment. The claim rejections under 35 U.S.C. 112 have been withdrawn.
Regarding the 103 rejection, it is noted that the contents of the 103 rejection based on Yivgi-Ohana et al. have been modified and indicated in bold as seen the rejection above. Applicant’s amendment to narrow the range of CS activity per a million target cells to 0.88-4.4 mU is acknowledged. As discussed above, the 103 rejection now discloses the teaching of Yivgi-Ohana et al. showing the CS activity at 3.0 mU, referring to Example 9. The CS activity taught by Yivgi-Ohana et al. would meet the range as amended.
Regarding the 103 rejection to claims 67-69, for the same reason above, it is the Examiner’s position that the combined teachings of Yivgi-Ohana et al. and the secondary references would render the claims obvious.
Regarding the double patenting rejections, it is noted that the rejections have been modified in order to address the instant amendment. As pointed out by applicant, the double patenting rejections based on ‘135 and ‘672 patents have been withdrawn as they are not directed to the lymphocyte deficiency-related disease or disorder. It is noted that the double patent rejection based on the ‘781 patent in the previous OA did not include claim 5 inadvertently while the limitation was addressed therein. Thus, the rejection based on the ‘781 patent is maintained.
Applicant stated that applicant wishes to defer response to the rejection until after allowable claims have been identified. Thus, the rejections are maintained.
Conclusion
No claims are allowed.
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
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