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 .
The response filed on 06/24/2026 has been received and entered. Claims 1-3 and 5-20 remain pending and have been examined on the merits.
Priority
Acknowledgement is made that the instant application is a National Stage of International application No. PCT/IB2022/000338 (filed 06/17/2022), which claims the benefits of US Provisional Application No. 63/211,946 (filed 06/17/2021).
However, Applicants have not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of prior-filed applications, Application Nos. PCT/IB2022/000338 and 63/211,946 and previous versions of the instant application fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 1-3 and 5-20 of the instant application lack support in application No. PCT/IB2022/000338 and 63/211,946 for the following reason:
Claim 1 was amended to recite “wherein the cells administered are not subjected to ex vivo culture expansion prior to administration, and wherein the cells are administered without a blood-brain barrier permeabilizer.” There is no support for administering cells that are not subjected to ex vivo culture expansion or administering cells without a blood-brain barrier permeabilizer in application Nos. PCT/IB2022/000338 and 63/211,946. Priority applications and the specification of the instant application do not mention culturing or ex vivo expanding cells nor do they mention a blood-brain barrier permeabilizer either positively or negatively. Any negative limitation or exclusionary provision must have basis in the original disclosure. The mere absence of a positive recitation is not basis for an exclusion (See MPEP 2173.05(i)). Claims 2-3 and 5-20 depend from claim 1 and thus inherit the lack of support. Therefore, the effective filing date for claims 1-3 and 5-20 is 12/15/2023 (i.e. the filing date of the instant application).
Claim Interpretation
Claim 1 recites an “effective amount of mononuclear cells (MNC) or red cell fractions (RCF)…” which is being interpreted as an effective amount of (i) mononuclear cells (MNC) or (ii) red cell fractions (RCF). Additionally, the claim does not require administering isolated MNC or RCF, thus administering an effective amount of MNC or RCF can comprise administering a composition comprising MNC or RCF (e.g. umbilical cord blood).
Furthermore, in claim 1, the limitations “wherein the MNC or RCF are derived from umbilical cord blood” and “wherein the cells administered are not subjected to ex vivo culture expansion prior to administration” are product-by-process limitations. Product-by-process limitations are considered only in so far as the process of production affects the final product. Therefore, if the product as claimed is the same or obvious over a product of the prior art (i.e., is not structurally or chemically distinct), the claim is considered unpatentable over the prior art, even though the prior art product is made by a different process. See MPEP 2113. In the instant case, the process of production of the MNC or RCF of claim 1 involves deriving MNC or RCF from umbilical cord blood and not ex vivo culturing expanding cells.
Regarding deriving MNC or RCF from umbilical cord blood, applicants disclose on pg. 5 of the affidavit filed 06/24/2026 that compared to bone marrow MNCs, UCB MNCs contain a higher proportion of hematopoietic progenitor cells and a unique composition of mesenchymal stem cells, multi-lineage differentiating stress enduring (MUSE) cells, and predominantly naïve T lymphocytes. Thus the MNCs required by the method of claim 1 have a different proportions of hematopoietic progenitor cells, mesenchymal stem cells, MUSE cells, and naïve T lymphocytes compared to MNCs not derived from UBC.
Regarding not ex vivo expanding the cells, applicants disclose on pg. 10 of the affidavit filed (06/24/2026) that culture expansion alters expression level changes of CD34, CD133, growth factor, cytokine release patterns, cell size, viability, biodistribution characteristics, and therapeutic mechanism. Therefore the final product MNCs or RCF cells required by the method of claim 1 are understood to have unaltered cell surface markers, paracrine factor secretion profiles, size, viability and biodistribution characteristics, and therapeutic mechanisms.
Claim 10 has been amended to recite “wherein MNC comprises exosomes, monocytes, progenitor cells, or any combination thereof with cell surface antigens CD45, CD34, CD133, CD14 or any combination thereof…”. The limitations exosomes, monocytes, progenitor cell, or any combinations thereof are listed in the alternative and thus claim 10 only requires MNCs to comprise one of exosomes, monocytes, or progenitor cells. Additionally, “with cell surface antigens CD45, CD34, CD133, CD14 or any combination thereof” is being interpreted as wherein the exosomes, monocytes, progenitor cells, or any combination thereof express cell surface antigens CD45, CD34, CD133, CD14, or any combination thereof”.
Declaration under 37 CFR 1.132
Dr. Hao Lyu, one of the inventors, submitted a declaration under 37 CFR 1.132. The declaration is a full rebuttal to the rejections made in the non-final office action. Each point is addressed below, as it pertains to any remaining rejection.
At pages 14-17 seven NPL documents are cited, and the declarant states they request these references be made of record and considered in examination of the application.
References are only made of record and considered when Applicants provide full copies and make them of record as evidence and/or cite on an IDS.
Statue of Prior Rejections/Response to Arguments
RE: Objection to claim 15
Amendments to the claim overcome the objection. The objection is withdrawn.
RE: Rejection of claim 20 under 35 U.S.C. 112(b)
Amendments to the claim overcome the rejection of record. The rejection is withdrawn.
RE: Rejection of claims 1-3, 10, 11, and 18 under 35 U.S.C. 102 over Laskowitz et al as evidenced by Merriam Webster Dictionary (definition for intravascular) and Hu et al
Applicants amended claim 1 to require administering MNCs or RCF. The umbilical cord blood (UCB) of the method of Laskowitz et al comprises MNCs thus, Laskowitz et al teach administering MNCs.
Regarding claim 1: Applicants point to differences between the UCB of Laskowitz et al and RCF in (a-b) (See pg. 6 remarks). Applicants further argue Laskowitz does not teach isolated MNC or RCF as separate purified therapeutics.
In response, the argument has been fully considered but is not found convincing. The claims do not require MNC or RCF to be isolated or administered as separate purified therapies. UCB comprises MNCs and thus reads on the claimed method (See claim interpretation above).
Regarding claim 10: applicants argue Laskowitz et al does not disclose exosomes as components of the administered cells nor the full combination of cell surface antigens CD45, CD34, CD133, and CD14 on enriched lymphocytes, monocytes, and progenitor cell populations. Furthermore, Hu does not provide data or evidence that exosomes in MNC or RCF preparations contain meaningful therapeutic levels.
In response, the argument has been fully considered but is not found convincing. Claim 10 has been amended to recite exosomes, monocytes, progenitor cells, or any combination thereof in the alternative thus, the UCB of Laskowitz et al is only required to comprise one of exosomes, monocytes, or progenitor cells. Additionally, the cell surface antigens CD45, CD34, CD133, CD14, or any combination thereof are also listed in the alternative. The UCB of Laskowitz et al, comprises CD34+ cell which reads on progenitor cells. Furthermore, the argument regarding exosomes not being present at meaningful therapeutic levels is drawn to limitations not in the claims, specifically, the claims do not place any limit on the amount of exosomes.
Regarding claim 18: Applicants amended claim 18 to require administering 1x107 to 1x108 cells. The method of Laskowitz et al comprises administering 0.84-2.92 × 108 cells. Amendments to claim 18 thus overcome the rejection of record.
The rejection over claims 1-3, 10, and 11 is maintained.
The rejection over claim 18 is withdrawn.
RE: Rejection of claims 1-3, 5, 6, 11, 12, 18, and 20 under 35 U.S.C. 102 over Wang.
Applicants amended claim 1 to require administering MNCs or RCF. In (a) applicants state Wang discloses PD-UCB which retains all cells including RBCs and MNCs… but does not teach administering MNC or RCF (See pg. 8 of Remarks). In response, the argument has been fully considered but is not found convincing. As stated by applicants, the PD-UCB of Wang et al includes MNCs. Thus, Wang discloses administering MNCs. It is emphasized the claims do not require administration of isolated MNC fraction.
Applicants further amended claim 1 to exclude administering cells with a blood brain barrier (BBB) permeabilizer. The method of Wang can optionally comprise a BBB permeabilizer (See pg. 11 lines 9-11 and pg. 2, lns 23-25). Thus, in some embodiments, the method of Wang does not comprise a BBB permeabilizer.
Additionally, applicants argue the claimed invention is distinct from Wang because in the method of the instant invention, the administered cells remain substantially in the vasculature and the mechanism is paracrine. However, this argument is not found persuasive because this argument is drawn to limitations not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding claim 6: In (b) applicants argue that Wang teaches administering a BBB permeabilizer is required for the synaptogenesis, proliferation of immature neurons, and migration of neuronal cells in their method. Wang does not disclose these specific effects in the absence of a BBB permeabilizer thus the argument is found convincing regarding claim 6.
Regarding claim 18: Applicants amended claim 18 to require administering 1x107 to 1x108 cells. The cited passage recites administering 2-5 x 108 monocytes. The amendment therefore overcomes the rejection of record. However, Wang further discloses alternate embodiments in which 1x107 or 1x108 mononucleated cells are administered (See pg. 11, lns 16-22). The rejection is thus modified in response to claim amendments.
Regarding claim 20: Applicants amended the claim to require less than about 50 cells per 25 mg of brain tissue of the administered cells cross a BBB of the subject. Wang does not disclose how many cells cross a BBB in embodiments where no BBB permeabilizer is administered. Amendments to the claims thus overcome the rejection of record.
The rejections over claims 1-3, 5, 11, 12, and 18, are maintained and modified in response to claim amendments.
The rejection over claim 6 and 20 is withdrawn.
RE: Rejection of claims 1-3, 6, 8, 9, 11, and 12-18 under 35 U.S.C. 102 over Nakano-Doi et al as evidenced by Proteintech and Merriam Webster Dictionary (definition for intravascular).
The references cited in the arguments and inventor disclosure have not been considered as they are not included in an IDS and copies of the references have not been provided.
Applicants amended claim 1 to require MNCs derived from UCB. MNCs derived from UCB have a different proportions of cells compared to MNCs derived from other sources (See claim interpretation above). Given that Nakano-Doi et al uses MNCs derived from bone marrow, Nakano-Doi et al does not anticipate claim 1. Thus, amendments to the claim overcome the rejection of record.
The rejection of claims 1-3, 6, 8, 9, and 11-18 is withdrawn in response to the claim amendments.
Applicants arguments are addressed below for completion.
Regarding claims 8-9: Applicants argue Nakano-Doi teaches angiogenesis rather than vasculogenesis. Applicants argue vasculogenesis is a distinct process of de novo blood vessel formation from endothelial progenitor cells that occurs during embryonic development or in response to injury. However, claims 8-9 are drawn to results produced by the method of claim 1. Thus, any reference which anticipates or renders obvious the method of claim 1 can also anticipate or render obvious claims 8-9 as no special active steps are specified in claims 8-9 which are required to achieve to claimed results. Vasculogenesis is therefore considered an inherent result of the treatment method recited in claim 1.
Regarding claims 12-13: Applicants argue Nakano-Doi measures locomotion during a light phase as an indicator of cortical function and not sensory perception. Applicants state sensory perception refers to the ability to detect, process and respond to sensory stimuli. In response, the argument is not found convincing. The broadest reasonable interpretation of sensory perception includes responding to stimuli which includes light.
Applicants further argue that while Nakano-Doi teaches increased neuronal numbers in the cortex, they do not demonstrate that new neurons replace lost neurons or that function in the cortex is restored.
In response, it is not clear how producing new neurons is not considered replacing neurons. Furthermore, claims 12-13 are drawn to results produced by the method of claim 1. Thus, any reference which anticipates or renders obvious the method of claim 1 can also anticipate or render obvious claims 12-13 as no special active steps are specified in claims 12-13 which are required to achieve to claimed results.
Regarding claims 14-17: Applicants argue BrdU+ and Ki67+ cells are overlapping but distinct populations of cells with Ki67 labeling approximately 50% more cells than BrdU. Specifically, BrdU incorporates into cells undergoing DNA synthesis (i.e. S phase) and persists indefinitely regardless of whether the cells continue to dive, exit the cell cycle, differentiate, or undergo apoptosis whereas Ki67 is only expressed during active phases of the cell cycle (i.e. G1, S, G2, and M). Additionally, applicants argue the Proteintech product page cited in the non-final rejection of 03/24/2026 is not a peer-reviewed scientific publication and thus cannot be used to establish inherency.
In response, the argument has been considered but is not found convincing. The MPEP does not require a reference used for inherency to be a peer-reviewed scientific publication. The examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teaching of the applied prior art (See MPEP2112(IV)). Thus, as applicants pointed out on pg. 12 of the remarks filed 06/24/2026 BrdU+ cells and Ki67+ cells represent overlapping populations because Ki67 marks cells throughout the cell cycle (i.e. G1, S, G2, and M phases) whereas BrdU only incorporates during S phase. Thus there is a technical reasoning to reasonably support the presence of Ki67+/BrdU+ cells.
Additionally, claims 14-17 are drawn to results produced by the method of claim 1. Thus, any reference which anticipates or renders obvious the method of claim 1 can also anticipate or render obvious claims 14-17 as no special active steps are specified in claims 14-17 which are required to achieve to claimed results.
RE: Rejection of claims 1, 2, 10-12, 18, 20, and 21 under 35 U.S.C. 102 over Nakanishi et al as evidenced by Sahoo
Applicants amended claim 1 to require cells which have not been ex vivo culture expanded. The cells used in the method of Nakanishi et al have been expanded in an ex vivo culture. Thus amendments to the claims overcome the rejection of record.
The rejection over claims 1, 2, 10-12, and 20 is withdrawn.
Claim 21 has been cancelled rendering its rejection moot.
Applicants arguments are addressed below for completion.
Applicants argue Nakanishi teaches IP injection as the route of administration which would result in fundamentally different biodistribution and pharmacokinetics compared to the intravascular routes recited in the claimed invention.
In response, the argument has been considered but is not relevant to the instant rejection. Route of administration is only limited in claims 3 and 5 which are not included in the rejection over Nakanishi et al.
Applicants further argue the RCF of the claimed invention is distinct from the stem cell enriched UCBCs of Nakanishi.
In response, MNC and RCF are presented as alternatives in the claims and thus a composition is not required to comprise both MNC and RCF.
Regarding claim 10: Applicants further argue Sahoo teaches CD34+ cells release exosome but it does not teach all CD34+ cell preparations contain exosomes as a compositional element.
In response, applicants amended claim 10 to recite exosomes, monocytes, progenitor cells, or any combination thereof. CD34+ cells in the composition of Nakanishi are progenitor cells and thus meet the limitations of the claim as amended.
Regarding claim 20: Applicants argue the weight of a whole brain is approximately 500-600 mg and thus the density of transplanted cells which crossed the blood brain barrier in the method of Nakanishi is 1.8-2.2 cells/25 mg which is not 50 cells/25 mg. In response, claim 20 recites less than 50 cells/25 mg of brain tissue and 1.8-2-2 is less than 50.
RE: Rejection of claims 1-3, 11, 12, 18, and 19 under 35 U.S.C. 102 over Borlongan et al as evidenced by Merriam Webster Dictionary (definition for intravascular).
Applicants amended claim 1 to state the cells are administered without a BBB permeabilizer. The cells of Borlongan et al are administered with a BBB permeabilizer. Thus, amendments to the claims overcome the rejection of record.
The rejection over claims 1-3, 11, 12, 18, and 19 is withdrawn.
RE: Rejection of claims 1-3, 7, 11, 12, and 18 under 35 U.S.C. 102 over Nan et al as evidenced by Merriam Webster Dictionary (definition for intravascular).
Regarding claim 1: Applicants amended claim 1 to require administering MNCs or RCF. The umbilical cord blood (UCB) of the method of Nan et al comprises MNCs thus, Nan et al teach administering MNCs. Applicants argue in (b) that Nan does not use isolated MNC or RCF (See pg. 20 of remarks). However, the claims do not require MNC or RCF to be isolated from UCB.
Additionally, applicants argue Nan does not teach non-cultured cells or BBB non-crossing in (c) (See pg. 20 of remarks). In response, the argument is not found convincing. The method of Nan comprises rinsing, centrifuging, and resuspending mononucleated cells from human UCB then injecting rats intravenously with UCB suspension (See Sec. Preparation of Human Umbilical Cord Blood Cells and Administration of Umbilical Cord Blood Cells). Nan does not disclose culturing the cells. Furthermore, not crossing the BBB is only a limitation of claim 19 which is not included in the instant rejection.
Regarding claim 7: Applicants amended claim 7 to require endogenous gliogenesis. Nan et al teaches HUCB cells are able to differentiate into astrocytes. Thus, Nan et al does not teach endogenous gliogenesis. However, claim 7 is drawn to results produced by the method of claim 1. Thus, any reference which anticipates or renders obvious the method of claim 1 can also anticipate or render obvious claim 7 as no special active steps are specified in claim 7 which are required to achieve to claimed results. Endogenous gliogenesis is therefore considered an inherent result of the treatment method recited in claim 1. Nan anticipates claim 1. Additionally, while Nan teaches the presence of MAB 1281/GFAP double positive cells, not all GFAP positive cells are MAB 1281. Therefore, although Nan does not quantify new GFAP cells that are not MAB 1281 positive this does not indicate endogenous gliogenesis is not occurring.
Additionally applicants that while repair of BBB is a biological function of astrocytes, Nan does not measure BBB repair and thus does not anticipate the limitation. In response, the argument has been fully considered but is not found convincing. Astrocytes inherently repair the BBB. Not quantifying the amount of repair does not affect the inherent process.
Regarding claim 18: Applicants amended claim 18 to require administering 1x107 to 1x108 cells. The method of Nan et al comprises administering 2.4 × 106 to 3.2 to 106 cells. Amendments to claim 18 thus overcome the rejection of record.
The rejection over claims 1-3, 7, 11, and 12 is maintained.
The rejection over claims 18 is withdrawn.
New/Maintained Rejections
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 and 5-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 was amended to recite, inter alia, “wherein the cells administered are not subjected to ex vivo culture expansion prior to administration, and wherein the cells are administered without a blood-brain barrier permeabilizer.” There is no support for administering cells that are not subjected to ex vivo culture expansion or administering cells without a blood-brain barrier permeabilizer in the specification or in priority applications. The specification of the instant application does not mention culturing or ex vivo expanding cells nor do they mention a blood-brain barrier permeabilizer either positively or negatively. Any negative limitation or exclusionary provision must have basis in the original disclosure. The mere absence of a positive recitation is not basis for an exclusion (See MPEP 2173.05(i)). Thus these limitations are considered new matter. The introduction of new matter necessitated withdrawal of some prior art rejections, removal of the new matter may result in reinstatement of the prior art rejections. Claims 2-3 and 5-20 depend from claim 1 and thus inherit the lack of support.
Claim Rejections - 35 USC § 112(b)
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.
Claim 15 is 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 15 recites the limitation "administration of UCB" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 10, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Laskowitz et al (Stem Cells Translational Medicine, 2018) as evidenced by Merriam Webster Dictionary (definition for intravascular) and Hu et al (Theranostics, 2018).
Laskowitz discloses a method of treating ischemic stroke comprising intravenous infusion of allogeneic umbilical cord blood (UCB) to patients with ischemic stroke (See abstract and study design and overview). The patients were infused with 0.84 -2.92 x 109 total nucleated cells (See Table 1). Laskowitz further teaches the UCB units were tested for viable CD34+ cells. The treatment resulted in improvement of at least one grade in the mRS scale and at least 4 points in NIHSS scale (See abstract). Improvements in mRS, NIHSS, and BI scales were quantified at 3 months post infusion (See Table 2).
Regarding claims 1-2: Laskowitz discloses a method of treating ischemic stroke (reads on a neurological dysfunction) comprising administering UCB to the patients. UCB contains MNCs, thus Laskowitz discloses a method comprising administering MNCs. The method of Laskowitz does not comprise culture expanding UCB cells or administering a BBB permeabilizer. The treatment method resulted in improvement of at least one grade in the mRS scale and at least 4 points in the NIHSS scale which reads on whereby treatment of a neurological dysfunction results.
Regarding claim 3: Following the discussion of claim 1 above, Laskowitz discloses administering the UBC intravenously. Given that veins are blood vessels and intravascular is defined as administered into a blood vessel (See Merriam Webster Dictionary), the intravenous administration of Laskowitz reads on intravascular.
Regarding claim 10: Following the discussion of claim 1 above, Laskowitz discloses treating ischemic stroke with human UCB which comprises viable CD34+ cells (reads on progenitor cells expressing cell surface antigen CD34) and thus anticipates claim 10 as amended.
Additionally, Hu teaches exosomes are present in human UCB and can be isolated by centrifugation (See Sec. isolation from human UCB plasma). Given that Laskowitz does not disclose removing exosomes from UCB, the UCB of Laskowitz inherently comprises exosomes.
Regarding claim 11: Following the discussion of claim 1 above, Laskowitz discloses measuring improvements in mRS, NIHSS, and BI scales at three months post UCB infusion which reads on neurological dysfunction is treated within about 10 minutes to about 1 year after administration of UCB.
Claims 1-3, 5, 10-12, and 18, are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wang (WO2021034996A2).
Wang discloses a method of treating or ameliorating a cardiovascular disease or brain injury comprising administering an effective amount of umbilical cord blood (See claim 1). In exemplary embodiments, the UCB of Wang is plasma-depleted UCB (PD-UCB) (See pg. 29 Example 1). Wang further teaches the UCB comprises CD34+ cells (See pg. 20, lns 1-2).The disease can comprise an ischemic stroke (See pg. 3, lns 31-33). The treatment method comprises injecting UCB containing 2-5 x 108 monocytes intravenously (See pg. 36, step 5). Wang further discloses alternate embodiments in which 1x107 or 1x108 mononucleated cells are administered (See pg. 11, lns 16-22). Alternatively, the UCB cells can be grafted into a patient’s brain or spinal cord or administered intraarterially (See pg. 12, lns 31-33). Patients showed improved motor function 7-14 days after UCB infusion (See pg. 39, lns 24-30). Additionally, the treatment method results in improvement, lessening of the severity of, or slowing of the progression of altered smell, taste, hearing, or vision loss (See pg. 13, ln 33 – pg. 14, ln 16). The method of Wang can optionally comprise a BBB permeabilizer, allowing the UCBs to cross the blood-brain-barrier resulting in synaptogenesis, proliferation of immature neurons, and migration of neuronal cells (See pg. 2, lns 23-25, pg. 11 lines 9-11 and pg. 40, lns 15-18).
Regarding claims 1 and 2: Wang discloses a method of treating a neurological disease such as an ischemic stroke by administering UCBs to a patient. The UCB of Wang comprises MNCs thus the method of Wang reads on a method of treating a neurological dysfunction in a subject comprising administering an effective amount of MNC whereby treatment of a neurological dysfunction results. The method of Wang can optionally comprise administering a BBB permeabilizer. Thus in some embodiments, the method does not comprise administering a BBB permeabilizer. Additionally, Wang does not disclose culture expanding the UCB.
Regarding claims 3 and 5: Following the discussion of claim 1 above, Wang discloses the UCB can be administered intravenously (reads on intravascular), intra-arterially, or grafted into a patient’s brain or spinal cord (reads on intracerebral and intraspinal and the MNC are administered in brain tissue).
Regarding claim 10: Following the discussion of claim 1 above, the UCB of Wang comprises CD34+ cells which reads on comprising progenitor cells with cell surface antigen CD34.
Regarding claim 11: Following the discussion of claim 1 above, Wang discloses the treatment results in improvement 7-14 days after UCB administration which reads on the neurological dysfunction is treated within about 10 minutes to about 1 year after administration of UCB.
Regarding claim 12: Following the discussion of claim 1 above, Wang discloses the treatment method results in improvement, lessening of the severity of, or slowing of the progression of altered smell, taste, hearing, or vision loss which reads on enhances visual and auditory function, and smell and taste function.
Regarding claim 18: Following the discussion of claim 1 above, Wang discloses an exemplary embodiment wherein the treatment method comprises injecting UCB containing 1x107 or 1x108 monocytes intravenously which reads on 1 x103 to about 1 x 109 cells.
Claims 1-3, 7, 11, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nan et al (Ann. N.Y. Acad. Sci, 2005) as evidenced by Merriam Webster Dictionary (definition for intravascular).
Nan teaches a method of treating intracerebral hemorrhage (ICH) in rats by administering human umbilical cord blood (HUCB) intravenously (See abstract). Twenty four hours after the induction of ICH rats received intravenous infusions of 2.4 × 106 to 3.2 to 106 cells (See abstract). Rats receiving HUCB had improvements in step tests by the seventh day after ICH and body-swing tests by 14 days after ICH (See Figs. 1 and 2). Limb placement tests which measure combined sensorimotor deficits also showed improvement at days 7 and 16 in mice treated with HUCB (See Fig. 3). HUCB cells were stained with human nuclei marker MAB1281. Cells were further stained for astrocyte marker GFAP and MAB1281 GFAP double positive cells were found in the wall of cavity formed by hemorrhage (See Fig. 4).
Regarding claims 1 and 2: Nan teaches a treatment method for rats with intracerebral hemorrhage (reads on neurological dysfunction and stroke). The treatment method comprises administering HUCB. HUCB comprises MNCs, thus Nan teaches administering an effective amount of MNCs whereby treatment of neurological dysfunction results.
Regarding claim 3: Following the discussion of claim 1 above, Nan discloses administering the HUCBs intravenously. Given that veins are blood vessels and intravascular is defined as administered into a blood vessel (See Merriam Webster Dictionary), the intravenous administration of Nan reads on intravascular.
Regarding claim 7: Following the discussion of claim 1 above, claim 7 is drawn to results produced by the method of claim 1 without further defining any special steps required to achieve the claimed results. Thus given a reasonable basis that the method of claim 1 inherently results in the claimed results, claim 7 will stand or fall with the rejection of claim 1.
Nan discloses the presence of human nuclei marker MAB1281 and astrocyte marker GFAP double positive cell in the wall of cavity formed by hemorrhage. However, not all GFAP expressing cells express MAB 1281. Nan does not quantify the percentages of GFAP positive cells that do not express MAB 1281. Given that Nan discloses the method of claim 1, the presence of GFAP positive cells which do not arise from HUCB populations, there is a reasonable expectation that the method of Nan inherently results in endogenous gliogenesis and incorporation of new astrocytes. “[T]o repair a blood brain barrier” is an inherent function performed by astrocytes thus the GFAP positive cells repair the blood brain barrier in the ICH rats of Nan.
Regarding claim 11: Following the discussion of claim 1 above, Nan discloses improvement in sensorimotor deficit 7 days after ICH (i.e. 6 days after HUCB administration) which reads on within 10 minutes to about 1 year after administration of UCB.
Regarding claim 12: Following the discussion of claim 1 above, Nan discloses improvement in sensorimotor deficit tests, step tests, and body-swing tests which reads on enhances locomotor function and motor coordination.
Claims 1-3, 11, 12, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lyu et al (Frontiers in Cellular Neuroscience, March 2022) as evidenced by Merriam Webster Dictionary (definition for intravascular).
Lyu et al discloses treating rats with hypoxic ischemic encephalopathy (HIE) by intravenously injected the HIE rat pups with UCB, MNC, or RCF (See abstract). MNCs and RCF were prepared from human UCB by density gradient centrifugation (See pgs. 2-3, Sec Human Umbilical Cord Blood, Mononuclear Cell, and Red Cell Fraction Preparation). Rat pups were intravenously injected with 1 x 107 of cells of UCB, MNC, or RCF (See pg. 3, Sec. Experimental Grouping and Cell Transplantation). Lyu et al discloses treating 12 rat pups per group (See pg. 4 Sec. Animal Sex, Number, Mortality and Grouping). Quantification of UCB-derived MNCs in the brain was performed and less than 50 cells were detected in the brains of 3 pups (See Sec. Expression of Human Alu Yb8 and Fig. 1B.) In negative geotaxis tests, performed on day 7, MNC-transplanted pups showed a better performance compared to HIE-only pups (See Sec. Negative Geotaxis and Fig. 2). In motor behavior tests performed at 1 and 3 months after cell transplantation, UCB, MNC, and RCF treated rats all showed better motor balance and coordination than HIE-only rats after 1 month and MNC treated rats showed better motor performance than HIE only rats at 3 months as well (See Sec. Motor Behaviour Test and Fig. 3). Spatial learning and memory function tests were performed at 1 and 3 months. At 1 month HUCB and MNC treated groups performed better than HIE only rats at 1 month (See Sec. Morris Water Maze). One day 7, MNC treated groups had greater number of NeuN positive cells compared to other HIE groups; at 1 month, UCB, MNC, and RCF treated all showed higher numbers of neurons compared to saline treated HIE groups (See Sec. Immunohistochemical Analysis of NeuN-Positive Cells). HUCB and MNC treated groups had more neurons in the motor-sensory cortex at 1 and 3 months (See Sec. Immunohistochemical Analysis of NeuN-Positive Cells). The quantitative analysis of NeuN demonstrated the average number of cortical neurons increased at 1 and 3 months after cell transplantation compared to day 7 suggesting neurogenesis (See Sec. Neurogenesis).
Regarding claims 1 and 2: Lyu et al disclose a method of treating HIE in rats comprising administering UCB, MNC, or RCF. The treatment method results in better performance in negative geotaxis test, spatial learning and memory function tests and motor behavior tests which reads on wherein treatment of a neurological dysfunction results. The MNC and RCF of Lyu et al are isolated from UCB by gradient centrifugation which reads on the MNC or RCF are derived from umbilical cord blood. The method of Lyu et al does not include a step of ex vivo culture expansion. Additionally, the method of Lyu et al does not include administering a BBB permeabilizer.
Regarding claim 3: Following the discussion of claim 1 above, the method of Lyu et al comprises injecting UCB, MNC, or RCF intravenously. Given that veins are blood vessels and intravascular is defined as administered into a blood vessel (See Merriam Webster Dictionary), the intravenous administration of Lyu et al reads on intravascular.
Regarding claim 11: Following the discussion of claim 1 above, Lyu et al quantifies improvements at 7 days, 1 month, and 3 months post UCB, MNC, or RCF administration which reads on within about 10 minutes to 1 year.
Regarding claim 12: Following the discussion of claim 1 above, the treatment method of Lyu et al results in improvement in spatial learning and memory function tests and motor behavior tests.
Regarding claim 18: Following the discussion of claim 1 above, the method of Lyu et al comprises administering 1 x 107 cell of UCB, MNC, or RCF.
Regarding claim 20: Following the discussion of claim 1 above, Lyu et al discloses detecting fewer than 50 MNCs in the brains of treated rats. While Lyu et al does not disclose the weight of the brains, given that fewer than 50 MNCs were detected in the whole brain there would inherently be fewer than 50 MNCs per 25 mg of brain tissue.
Claims 1-3, 5, 12, and 19-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Willing et al (Journal of Neuroscience Research 2003) as evidenced by Merriam Webster Dictionary (definition for intravascular).
Willing et al discloses a method of treating a rodent model of stroke by administering human umbilical cord blood (hUCB) either intravenously or intrastriatally (See abstract). Behavioral recovery was observed in both transplant models while step test improvements were only found after femoral vein delivery (See abstract). Elevated body swing tests showed improvements with both transplant methods at 1 month (See Fig. 4). Step tests demonstrated improved motor symmetry in rodents receiving intravenous hUCB (See Fig. 5). Willing et al further discloses there were no cellular infiltrates detected in animals receiving hUCB via femoral vein (See Sec. Histology/Immunohistochemistry and Fig. 7).
Regarding claims 1 and 2: Willing et al disclose a method of treating stroke (reads on a neurological dysfunction), in a rodent model, by administering umbilical cord blood. Umbilical cord blood comprises mononuclear cells. Thus, the method of Willing et al comprises administering mononuclear cells. The treatment method resulted in behavioral recovery which reads on treatment of the neurological dysfunction results. Willing et al does not disclose steps of ex vivo culture expansion or administering a blood-brain barrier permeabilizer.
Regarding claims 3 and 5: Following the discussion of claim 1 above, the method of Willing et al comprises administering hUCB either intravenously or intrastriatally. Given that veins are blood vessels and intravascular is defined as administered into a blood vessel (See Merriam Webster Dictionary), the intravenous administration of Willing et al reads on intravascular. Additionally transplantation into the striatum reads on intracerebral and administering in brain tissue.
Regarding claim 12: Following the discussion of claim 1 above, Willing et al discloses improvements in step tests and elevated swing tests (reads on motor coordination).
Regarding claims 19 and 20: Following the discussion above, Willing et al discloses there was no cellular infiltrate in the brain of animals receiving intravenous hUCB which reads on no crossing a blood-brain barrier of the subject and less than about 50 cells per 25 mg of brain tissues cross the blood-brain barrier.
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.
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 1-3, 6, 8, 9, and 11-17 are rejected under 35 U.S.C. 103 as being unpatentable over Nakano-Doi et al (Stem Cells, 2010) as evidenced by Proteintech (Proliferating cells: BrdU and Ki-67 cellular markers, 2026) and Merriam Webster Dictionary (definition for intravascular) and in view of Umeda et al (US20140072954A1).
Nakano-Doi discloses using bone marrow mononuclear cells (BMMCs) to treat ischemic stroke in mice (See abstract). Focal cerebral ischemia was produced in mice by ligation and disconnection of the distal portion of the left middle cerebral artery (See Sec. Induction of Focal Cerebral Ischemia). On post stroke day 2, 1 x 106 BMMCs were injected intravenously via the tail vein (See Sec. BMMCs Transplantation in Poststroke Mice). Seven days after stroke induction BMMC treated mice had significantly increased CD31/BrdU double positive endothelial cells in ischemic core and peri-stroke regions compared to controls indicating endothelial cell proliferation in the cortex (See Sec. BMMCs Increase ECs in and Around the Poststroke Cortex and Fig. 4). Seven days after stroke induction BMMC treated mice further had an increase in Nestin/BrdU double positive cells in the ischemic core and Nestin/Ki67 double positive cells were also found in the ischemic core indicating endogenous proliferation (See Sec. BMMCs Promotes the Proliferation of Ischemia-Induced NSPs and Accelerates Neurogenesis with Functional Recovery, ECs Induce the Proliferation of Endogenous Ischemia-Induced NSPCs, and Fig. 2). On post-stroke day 30, BMMC treated mice had a larger number of NeuN/BrdU double positive cells compared to controls (See Sec. BMMCs Promotes the Proliferation of Ischemia-Induced NSPs and Accelerates Neurogenesis with Functional Recovery). Functional recovery of mice subjected to stroke and then treated with BMMCs was investigated by behavioral testing measuring locomotion during a light phase 30 days post stroke. Mice treated with BMMCs had significantly improved cortical function (i.e. reduction of locomotion) during the light phase (See Sec. BMMCs Promotes the Proliferation of Ischemia-Induced NSPs and Accelerates Neurogenesis with Functional Recovery, last paragraph).
Regarding claims 1 and 2: Nakano-Doi discloses using bone marrow mononuclear cells to treat ischemic stroke in mice which reads on a method of treating a neurological dysfunction in a subject comprising administering an effective amount of mononuclear cells to a subject, whereby treatment of neurological dysfunction results. The method of Nakao-Doi does not include steps of culture expanding the BMMCs or administering a BBB permeabilizer.
Nakano-Doi does not disclose using MNCs derived from umbilical cord blood.
Umeda discloses mononuclear cell preparations for the treatment of ischemic diseases (See ¶0001-0001 and 0032). Umeda further discloses mononuclear cell fractions of bone marrow, umbilical cord blood, and peripheral blood have been used to treat ischemic disease (See ¶0002-0003).
Given that Nakano-Doi teaches a method of treating ischemic stroke comprising administering mononuclear cells derived from bone marrow and Umeda teaches mononuclear cells derived from bone marrow and umbilical cord blood are recognized alternatives in the art for the treatment of ischemic disease, it would have been prima facie obvious to substitute the mononuclear cells of Nakano-Doi with mononuclear cells derived from umbilical cord blood, in the method of Nakano-Doi. One would have expected mononuclear cells derived from umbilical cord blood to work equivocally with BMMCs in the method of Nakano-Doi because Umeda teaches mononuclear cells used for treating ischemic disease can be derived from bone marrow, umbilical cord blood, and peripheral blood and thus the cells are recognized alternatives in the art. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Regarding claim 3: Following the discussion of claim 1 above, Nakano-Doi discloses administering the BMMCs intravenously. Given that veins are blood vessels and intravascular is defined as administered into a blood vessel (See Merriam Webster Dictionary), the intravenous administration of Nakano-Doi reads on intravascular.
Regarding claim 6: Following the discussion of claim 1 above, claim 6 is drawn to results produced by the method of claim 1 without further defining any special steps required to achieve the claimed results. Thus given a reasonable basis that the method of claim 1 inherently results in the claimed results.
Nakano-Doi teaches administration of BMMCs to ischemic mice results in endogenous proliferation of neurons in in the ischemic core which reads on administration of MNC stimulates neurogenesis and incorporation of new neurons into neuronal circuitry of brain.
Regarding claims 8 and 9: Following the discussion of claim 1 above, claims 8 and 9 are drawn to results produced by the method of claim 1 without further defining any special steps required to achieve the claimed results. Thus given a reasonable basis that the method of claim 1 inherently results in the claimed results.
Nakano-Doi teaches administration of BMMC to ischemic mice results in proliferation of endothelial cells in the ischemic core and peri-stroke regions. While Nakano-Doi does not perform experiments to quantify vasculogenesis, Nakano-Doi teaches a method of treating ischemic stroke which obviates the method of claim 1 and further teaches the method results in proliferation of endothelial cells in the ischemic core. Therefore, there is a reasonable basis that the method of Nakano-Doi inherently stimulates vasculogenesis and incorporation of new vascular cells to repair vascular damage to at least one organ or tissue wherein the organ or tissue is brain.
Regarding claim 11: Following the discussion of claim 1 above, claim 11 is drawn to results produced by the method of claim 1 without further defining any special steps required to achieve the claimed results. Thus given a reasonable basis that the method of claim 1 inherently results in the claimed results.
Nakano-Doi performs measurements at 7 and 30 days post stroke induction and finds increased proliferation of endothelial cells and neurons and improved cortical function which reads on the neurological dysfunction is treated within about 10 minutes to about 1 year after administration of MNCs.
Regarding claim 12: Following the discussion of claim 1 above, claim 12 is drawn to results produced by the method of claim 1 without further defining any special steps required to achieve the claimed results. Thus given a reasonable basis that the method of claim 1 inherently results in the claimed results.
Nakano-Doi teaches BMMC treated mice showed improved cortical function during exposure to light phase. The broadest reasonable interpretation of sensory perception includes response to changes in light. Thus the method of Nakano-Doi teaches administration of MNCs enhances sensory perception.
Regarding claim 13: Following the discussion of claim 1 above, claim 13 is drawn to results produced by the method of claim 1 without further defining any special steps required to achieve the claimed results. Thus given a reasonable basis that the method of claim 1 inherently results in the claimed results.
Nakano-Doi teaches BMMC treatments in mice results in proliferation of neurons in the cortex. Nakano-Doi further teaches BMMC treated mice demonstrated improved cortical function in sensory response tests. Thus, Nakano-Doi teaches administration of UCB replaces neurons and restores function in the sensory cortex.
Regarding claims 14 and 15: Following the discussion of claims 1 and 6 above, claims 14-15 are drawn to results produced by the method of claim 1 without further defining any special steps required to achieve the claimed results. Thus given a reasonable basis that the method of claim 1 inherently results in the claimed results.
Nakano-Doi teaches treating mice with BMMCs 2 days post stroke then measuring an increase in Nestin/BrdU double positive neurons and the presence of Nestin/Ki67 double positive cells 7 days post stroke (reads on 5 days after administration of BMMCs which reads on less than 1 week).
Regarding claims 16 and 17: Following the discussion of claims 1 and 6 above, claims 16-17 are drawn to results produced by the method of claim 1 without further defining any special steps required to achieve the claimed results. Thus given a reasonable basis that the method of claim 1 inherently results in the claimed results.
Nakano-Doi teaches treating mice with BMMCs 2 days post stroke then measuring an increase in NeuN/BrdU double positive neurons 30 days post stroke (reads on about 1 month).
Nakano-Doi does not specifically state the NeuN/BrdU double positive neurons express Ki67.
Proteintech teaches BrdU labels cells during the S phase of cell proliferation while Ki67 labels cells in the G1, S, G2, and M phases (Proteintech, See BrdU & Ki67 FAQs).
Given that BrdU and Ki67 both label cells in the S phase of cell proliferation, there is a reasonable basis to conclude the NeuN/BrdU double positive cells of Nakano-Doi inherently express Ki67.
Conclusion
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.
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/MARISOL ANN O'NEILL/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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