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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Acknowledgment is made of applicants' claim for foreign priority to Japanese application JP 2021-110601 filed on 07/02/2021. Certified copies of the foreign priority document(s) are present in the application file.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/02/2025 and 12/28/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of claims
Claim 1-17 are pending and under examination.
Claim Rejections - 35 USC § 112
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, 1-17 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.
Regarding claim 1: The claim encompasses irradiation of any cell including a population of hematopoietic cells for treatment of any ischemic disease. It is submitted that as currently worded the claim encompasses mixed heterogenous population of cells, mesenchymal cells, endothelial cells among many others. However, the specification provides experimental support for umbilical cord derived mononuclear cells or umbilical cord derived CD34+ cells. There are no examples for using any other heterogenous mixtures of cells. It is submitted that written description requires the specification to demonstrate possession of a claimed genus by disclosure of representative species across the entire genus or identification of structural or functional features common to the claimed genus such that a skilled artisan can recognize that the inventor possessed the full scope.
Further, the claims encompass treatment for any and all ischemic diseases, including angina pectoris, cardiac failure, myocardial infraction, arterial dissection, among other ischemic diseases. However, the specification provides data only for brain infraction. There are no working examples for any other diseases or disease models. It is submitted that disclosure of a single species is insufficient for demonstrating possession of entire claimed genus.
It is submitted that the specification failed to reasonably convey the full breadth of “a population of cells including hematopoietic cells” or methods of treating all ischemic diseases.
It is additionally pointed out that the claims as drafted encompass any number of cells including extremely low number of cells. The specification however only demonstrates therapeutic efficacy in examples using cell population for e.g.:
1
×
10
5
cells. There are no examples, data or discussion in the specification to support therapeutic efficacy of significantly lower umber of cells, nor is there any teaching to determine the effective minimal dosage. Therefor the specification fails to convey to a person of ordinary skill in the art that the inventor possessed the full scope of the claimed invention, namely all populations of cells including hematopoietic stem cells, including extremely small populations.
As such claims 1-17 lack adequate written description.
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.
Claims 1-7, 9-13 and 15-17 are is/are rejected under 35 U.S.C. 103 as being unpatentable over Perotti et al (Stem Cells Dev. 2013 Oct 15; hereinafter "Perotti;" See IDS filed on 12/28/2023), in view of Wei et al (Oncol Lett. 2017 Jun; hereinafter "Wei;" See PTO-892) as evidenced by Rallapalli et al (Cell Tissue Res. 2019 Feb; hereinafter "Rallapalli;" See PTO-892).
Regarding claims 1, 3-7, and 10-13: Perotti taught that injection of lethally γ-irradiated non-human leukocyte antigen (HLA)-matched cord blood (CB)-derived mononuclear cells in a no-option critical limb ischemia (CLI) patient (As required by claim 7, 11), to induce therapeutic neo-angiogenesis, with evidence of successful outcome supported by clinical findings (ulcer healing and pain relief ), instrumental assessment (transcutaneous O2 pressure, ankle/brachial index, and contrast-enhanced ultrasonography), and histological demonstration of muscular tissue repair and capillary network expansion. Perotti indicated that while a “number of studies employed bone marrow- or peripheral blood-derived stem cells, contained in the mononuclear cell (MNC) fraction [including endothelial progenitor cells (EPCs)] (as required by claim 3, 13) to induce tNA in ischemic diseases like PAD,” “[t]he use of autologous stem and progenitor cells in cell therapy is limited by their rarity in adult peripheral blood.” Perotti taught that “cord blood (CB) contains a higher number of progenitor cells, more functional and efficient than those in peripheral blood, able to induce the formation of stable vascular structures inside the ischemic tissues. Thus, CB-derived progenitor cells represent an interesting and easy available option.” However, “[t]o avoid transfusion graft versus host disease (tGvHD), we used lethally γ-irradiated, not HLA-matched, CB-derived MNCs (g-MNCs) to treat a patient with CLI.” (as required by claims 1, 5) (See Perotti, p. 2806, col 2). As such Perotti explicitly taught that cord-blood-derived mononuclear cells, containing stem and progenitor cells are effective for treating ischemic diseases such as critical limb ischemia, but notes the risk of developing GVHD using such allogenic cells. Perotti lethally γ-irradiated the cells to avoid tGVHD to address the unwanted side effects of cord-blood-derived mononuclear cell transfusion.
Wei explored the effect of different X‑ray doses on the proliferation and cytotoxic activity of peripheral blood mononuclear cells (PBMCs), particularly lymphocytes, in order to assess whether this reduces the incidence of graft vs. host disease (GVHD) while preserving the graft vs. tumor (GVT) effect in patients with hematological malignancies following hematopoietic stem cell transplantation (HSCT). Wei found that the activity of PBMC was preserved with 7.5Gy of X-ray doses while suppressing GVHD in patients with hematological malignancies. (as required by claim 6, 10) (See Wei Abstract). As such Wei taught that irradiation of peripheral blood mononuclear cells inactivates T cells to reduce GVHD while preserving other cellular functions.
As such it would have been obvious for a person of ordinary skill in the art to apply Wei’s irradiation technique to Perotti’s CD-MNCs to reduce GVHD risk in ischemic patients. A skilled artisan would reasonably predict that low dose irradiation inactivates T-cells without eliminating HSC or the pro-angiogenic functions of progenitor cells. Therefore, the artisan would expect that the irradiated CB-MNC would retain therapeutic efficacy for ischemia while reducing immune complications. It is noted that as evidenced by Rallapalli, “UCB MNCs expressed high levels of CD45+ (~ 92%), which is usually expressed on almost all hematopoietic cells except for mature erythrocytes and low levels of hematopoietic progenitor marker CD34+ (~ 3.5%)” (as required by claim 4, 12) (See Rallapalli p. 441, col. 2 last para). It is submitted that the combination of the cited prior art provides application of known techniques to known cell populations (CB-MNC) to solve a recognized problem yielding predictable results.
Regarding claim 2: Wei taught optimization of radiation doses from 0-50 Gy to obtain cells with preserved viability (measured using LDH cytotoxicity assays). Wei tested the inhibition rates of PBMCs irradiated with varying doses of X-rays and found an optimal radiation dose for inhibition of proliferation of cancer. As such one of ordinary skill would easily to able to apply the teachings of Wei in an ischemic disease. It is submitted that determination of viability following radiation, in a desirable time widow is within the purview of one of ordinary skill in the art.
Regarding claim 9: The teachings of Perotti in view of Wei further as evidenced by Rallapalli are set forth above. It is noted that Wei taught “PBMCs were isolated using Ficoll-Hypaque density gradient centrifugation of blood samples from three healthy donors at the Peking University First Hospital (Beijing, China) between January 2015 and March 2015, and separation of the samples using a continuous automated flow cell separator.” “PBMCs were irradiated with 0, 2.5, 5, 7.5, 10, 15, 25, or 50 Gy using an X-ray source” (See Perotti p. 4102, col. 1, para 1). As such Wei reads on method (b) of the claim.
Regarding claims 15-16: Wei taught infusion of PBMC irradiated with 7.5Gy of X-ray. (See Wei, p. 4102, col. 2, para 1). It is noted that infusions are generally carried out through arteries or veins. Additionally, the choice of the artery or vein (such as carotid artery) is well within the purview of a person of ordinary skill in the art with a knowledge of systemic administration routes.
Regarding claim 17: Wei taught that “irradiation of peripheral blood mono-nuclear cells (PBMCs) with at ≥25 Gy prior to infusion decreases the probability of GVHD” (See Wei p. 4101, col. 2, 2nd para).
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Perotti et al (Stem Cells Dev. 2013 Oct 15; hereinafter "Perotti;" See IDS filed on 12/28/2023), in view of Wei et al (Oncol Lett. 2017 Jun; hereinafter "Wei;" See PTO-892) as evidenced by Rallapalli et al (Cell Tissue Res. 2019 Feb; hereinafter "Rallapalli;" See PTO-892) and further over Huang et al (Stem Cell Res Ther. 2017 Mar 22; hereinafter “Huang;” See PTO-892).
Regarding claim 8: As indicated above, Perotti taught treatment of ischemic disease using administration of cord-blood derived mononuclear cells to promote therapeutic neoangiogenesis in ischemic tissues. Further, Wei taught a method to adjust the dosage and that X-ray radiation at 7.5 Gy preserved the activity of PBMC while suppressing GVHD in patients with hematological malignancies. It is noted that Brain infraction is an ischemic condition, but was not explicitly taught by the cited prior art. Huang taught that “CBF to the stroke-affected region at 28 days was improved (normalized CBF value: 1.41 ± 0.30 versus 0.49 ± 0.07) by intraarterial transplantation of hUCB MNCs in the hyperacute stroke phase, compared to vehicle control.” (See Huang Abstract). Huang also reported that intraarterial transplantation of huCB-MNC significantly improved cerebral blood flow in stroke-affected regions and increased vascular density, indicating enhanced angiogenesis and vascular remodeling following treatment. As such Huang taught that UCB-derived mononuclear cells are effective for treatment for brain infarction.
It would have been obvious for a person of ordinary skill in the art to apply the UCB-derived mononuclear cell-therapy for ischemic diseases taught by Perotti to the specific ischemic condition of brain infraction as taught by Huang, because Huang demonstrates that the same class of cells promoted vascular regeneration and improves vascular regeneration and improved perfusion in stroke models. As such the claim represents predictable use of prior art elements according to their established functions with a reasonable expectation of success.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Perotti et al (Stem Cells Dev. 2013 Oct 15; hereinafter "Perotti;" See IDS filed on 12/28/2023) in view of Wei et al (Oncol Lett. 2017 Jun; hereinafter "Wei;" See PTO-892) and Meyer et al (Cytotherapy. 2006; hereinafter "Meyer;" See PTO-892) as evidenced by Rallapalli et al (Cell Tissue Res. 2019 Feb; hereinafter "Rallapalli;" See PTO-892).
Regarding claim 14: The teachings of Perotti in view of Wei further as evidenced by Rallapalli are set forth above. None of the cited prior art taught addition of a cryoprotectant. However, preserving cells using cryoprotectants for transport is well known for a person with ordinary skill in the art. For example, Meyer taught cryopreservation of umbilical cord derived cells is critical for UCB banking and transplantation as well as for research applications by providing readily available specimens. “The optimal conditions for cryopreservation of CD34+ HPC in MNC preparations were 10% DMSO and 2% human albumin at high cell concentrations (5 x 10(7) MNC/mL) with fast addition and removal of DMSO. After cryopreservation using a computer-controlled freezer, high viabilities (89%) and recoveries for CD34+ cells (89%) as well as for CFU (88%) were observed. Microbial contamination of the collected UCB samples was reduced to a rate of 6.4%.” (Se Meyer Abstract).
One of ordinary skill in the art would have been motivated to add a cryoprotectant to preserve the irradiated cells and arrive at the claimed pharmaceutical composition for banking or transportation purposes.
Conclusion
No claim is free of art.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633