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 .
Claims 1-20 are pending and examined below on their merits.
Priority
The application is a CON of US App. No. 17/252,674, which was a 35 U.S.C. 371 national stage filing of the International Application No. PCT/IL2019/050828, filed July 22, 2019. Applicant’s claim for the benefit of a prior-filed parent provisional application 62/701,674 filed on July 22, 2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is July 22, 2018.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 24, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the submitted drawings have cross-out correction to labels in Figs. 5 and 6. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
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 1-20 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.
Independent claim 1 recites “…at least about 105 to 109 human stem cells per kilogram…” This phrase is indefinite because it recites both a range (105 to 109) and “at least”. It is, therefore, unclear if the top end of the that range (109) constitutes a limit (e.g. more than about 109) is not being claimed or if only at least the lowest concentration recited (105) is required and any concentration over this (even above about 109) is encompassed by the claim.
Claim 2 narrows the recited range (at least 5x105 to 2x107), but does not resolve the ambiguity of whether the limitation is intended to be a range or intended only to recite a minimal amount that is required.
Claims 3-20 depend from claim 1 and do not rectify the indefiniteness; they are rejected on the same basis as claim 1.
For the purpose of examination, the claims are interpreted as reciting a range that is limiting – (e.g. “comprising about 105 to 109 human stem cells per kilogram”).
Claim 12 is further rejected, as it recites the limitation "the healthy functional mitochondria". Claim 12 depends from claim 1. There is insufficient antecedent basis for this limitation in the claim, as only “functional exogenous mitochondria” is recited in claim 1.
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 (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.
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) 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Vignais et al. (WO 2016/008937) in view of Golpanian et al. (J Gerontology,: Series A, 2017).
The claims recite methods for treating or diminishing aging, age-related disease(s) or a sequalae of anti-cancer treatments through administration of a pharmaceutical composition of about 105 to 109 human stem cells per kilogram where the stem cells are enriched with functional exogenous mitochondria.
With respect to independent claim 1, Vignais et al. teach treating a disorder associated with nonfunctional or dysfunctional mitochondria by administering to a subject, a pharmaceutical composition including an effective amount of human stem cells that have been enriched with human exogenous mitochondria, thereby using the stem cells as delivery system for the functional mitochondria to tissues and cells (Abs.; p. 2, line 29 - p. 3, line 19; p. 4, line 13-33; p. 9, line 9- 17; p. 11, line 25-26; claims 1, 11, 12, 24, 26). Vignais et al. teach that the transfer of exogenous mitochondria to target cells as a therapeutic remedy to restore mitochondrial function in cells that have poorly functioning/non-functioning mitochondria as a result of inherited defect, progression of disease process or aging. (p. 9, line 9- 17, p. 9, l. 32 – p. 10, l. 18). Vignais et al. teach a pharmaceutical composition including an effective amount of human stem cells that have been enriched with human exogenous mitochondria (Abs.; p. 2, line 29 - p. 3, line 19; p. 4, line 13-33; p. 9, line 9- 17; p. 11, line 25-26; claims 1, 11, 12, 24, 26).
Vignais et al. does not teach the claimed concentration of 105 to 109 human stem cells per kilogram for therapeutic administration.
Golpanian et al. teach administration of mesenchymal stem cells to treat aging frailty that includes administration of 2x 107 to 108 cells. (Abstract, entire doc). Assuming an average human weight of 60 kg, Golpanian teaches administration of 3.33 105 to 106 cells, within the claimed range.
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the preparation and method of administering stem cells by Vignais et al. to incorporate dosing within the claimed range (as taught by Golpanian et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating this modification would have led to predictable results with a reasonable expectation of success because both Vignais et al. and Golpanian et al. are concerned with treating age-related issues with human stem cells. If aging related frailty can be safely treated with a range of 2x 107 to 108 cells per patient (as taught by Golpanian), this would then be a reasonable place to start when considering dosing with a “therapeutically effective amount” of the human stem cells enriched with exogenous functional mitochondria taught by Vignais et al.
With respect to claim 2, the range taught by Golpanian et al. overlaps with the claimed 5x 105 to 2x107 cells, rendering the limitation obvious. (abstract)
With respect to claims 3 and 18, Vignais et al. teach that mitochondrial detection and quantification in the cells can be determined using a citrate synthase assay. (pg. 8, l. 22 – pg. 9, l. 5). As Vignais et al. teach that the citrate synthase assay demonstrates how effectively the cells have taken up the exogenous mitochondria and further teach administration of a therapeutically effective amount of stem cells to treat the desired condition, it would have been prima facie obvious to have optimized this result-effective variable. See MPEP 2144 IIB.
With respect to claims 4-7, Vignais et al. teach that the human stem cells that have been enriched in mitochondria can be mesenchymal stem cells (claim 5), pluripotent or induced pluripotent stem cells (claims 4), that the cells may come from any organ, including blood (claim 6) and from “any organ”. (p. 3, ll. 16-27). As bone marrow is a common source for mesenchymal stem cells and Vignais et al. teach mesenchymal stem cell and that cells can be from any organ, bone marrow mesenchymal stem cells (claim 7) are rendered obvious.
With respect to claim 8, Vignais et al. teach that that the cells may be progenitor cells, from the blood or lymph system (p. 3, ll. 16-27), rendering obvious common myeloid progenitor cells or common lymphoid progenitor cells.
With respect to claim 9, Vignais et al. teach that the recipient cells (the cells which are exogenously enriched with mitochondria) can be immune cells, specifically B-cells and lymphocytes, or cancer cells. (p. 3, l. 16 – p. 5, l. 2; p. 12, ll. 2- 9). As these cells are CD34+, it would have been prima facie obvious to select these cells as recipient cells in the claimed method.
With respect to claims 10 and 11, Vignais et al. teach that the stem cells are isolated (“at least partially purified”) and suspended in a pharmaceutically acceptable liquid medium capable of supporting the viability of the cells. (pg. 36, “Day 2: Mitochondria Isolation and MitoCeption”).
With respect to claim 12, Vignais et al. teach mitochondria are isolated from human MSC isolated from bone marrow of healthy donors. (pg. 27-28, Example 2).
With respect to claims 13-15, Vignais et al. teach the claimed routes of administration. (p. 11, 23-31)
With respect to claim 16, Vignais et al. teach the functional mitochondria can be from a source that is autologous, allogeneic and xenogeneic. (pg. 10, ll. 20-33).
With respect to claim 17, Vignais et al. teach administration of cells from an allogeneic donor (p. 10, ll. 20-32); as such, administering an agent that can prevent, delay, minimize or abolish an adverse immunogeneic reaction between the subject and the stem cells of the allogeneic donor in conjunction with the stem cells would have been an obvious modification.
Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over Vignais et al. (WO 2016/008937) and Golpanian et al. (J Gerontology,: Series A, 2017 as applied to claims 1-18 above, and further in view of Yamaguchi et al. (Cell Death and Differentiation, 2007)
Vignais et al. teach use of healthy exogenous mitochondria, as the mitochondria are isolated from human MSC isolated from bone marrow of healthy donors. (pg. 27-28, Example 2).
Vignais et al., as modified by Golpanian et al. does not teach that the exogenous mitochondria are frozen-thawed.
Yamaguchi et al. teach that mitochondria can be frozen with trehalose and retain much of the functionality of fresh mitochondria, including preserved ultrastructure and ATP synthesis.
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the preparation and method of administering stem cells by Vignais et al. to incorporate using mitochondria that have been freeze-thawed (as taught by Yamaguchi et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating this modification would have led to predictable results with a reasonable expectation of success because Yamaguchi et al. teach that doing so allows mitochondria to retain much of their biological function, including structure and APT synthesis and doing so would enable the exogeneously-enriched stem cells taught by Vignais to include mitochondria from sources that are either temporally or physically not in sync with the stem cells being enriched.
Claim(s) 20 is rejected under 35 U.S.C. 103 as being unpatentable over Vignais et al. (WO 2016/008937) and Golpanian et al. (J Gerontology,: Series A, 2017 as applied to claims 1-18 above, and further in view of Gorini et al. (Oxidative Med Cell Longevity, 2018).
Vignais et al., as modified by Golpanian et al. does not teach mitochondrial enriched stem cells are administered to treat or diminish a sequalae of anti-cancer treatment.
Gorini et al. teach that mitochondrial dysfunction is likely a main mechanism that mediates the cytotoxicity of many anti-cancer drugs, including doxorubicin, trastuzumab and sunitinib. (entire doc).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the preparation and method of administering stem cells by Vignais et al. to incorporate using the treatment as a means to mitigate a sequalae of anti-cancer treatment, such as administration of doxorubicin, trastuzumab or sunitinib, (as taught by Gorini et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating this modification would have led to predictable results with a reasonable expectation of success because Vignais et al. explicitly teach administration of exogenously enriched mitochondrial stem cells to treat cells that have poorly functioning/non-functioning mitochondria and Gorini et al. teach that at least the specific chemotherapeutic drugs doxorubicin, trastuzumab or sunitinib cause mitochondria to poorly function or cease functioning; as such it would have been obvious to extend the therapeutic teachings of Vignais et al. to the context of treating a sequalae of anti-cancer treatment.
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 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,951,135 (the ‘135 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims teach treating a muscle disease or disorder through administration of about 104 to 108 human stem cells enriched with exogenous mitochondria. Furthermore, the ‘135 patent defines a “muscle disease or muscle disorder” as refering to damage to, or disease of, a muscle, e.g. the heart.” The specification of the claims at issue define age-related disease” as including cardiovascular disease (a disease of the heart).
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,239,672 (the ‘672 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims teach treating an ocular disease or disorder through administration of about 104 to 108 human stem cells enriched with exogenous mitochondria. Furthermore, the ‘672 patent defines an “ocular disese” as one that includes cataracts. The specification of the claims at issue defines “age-related disease” as including cataracts.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,440,515 (the ‘515 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims teach treating a brain disease or disorder through administration of about 5 x 104 to 108 human stem cells enriched with exogenous mitochondria. Furthermore, the ‘515 patent indicates that brain disease include Alzheimer’s disease, a disease which the specification of the claims at issue define as an “age-related disease” (p. 27).
Conclusion
No claims are allowed.
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/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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