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 .
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 32, 34-44, 47-56, as amend, previously presented, originally presented, or newly added, are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the following:
A method of providing mature neurons in the brain of a subject comprising administering a subject neural precursor cells (NPCs) into the brain of a subject, wherein the NPCs comprise expression vectors encoding a Ki67 promoter operably linked to a suicide gene, wherein the suicide gene is a CMV UL97 gene or a mutant HSV-TK gene, and administering to the subject an amount of a prodrug that is activated by the suicide gene, wherein the prodrug eliminates cycling NPCs comprising the expression vectors, wherein the NPCs differentiated into mature neurons.
However, the specification does not reasonably provide enablement for the following:
- a replacement cell therapy…wherein the cell replacement therapy replaces non-dividing cell of any type
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention: A cell replacement therapy that provides a precursor cell that eliminates cycling precursor cells and replaces cells that are known to be non-dividing cells in said patient.
Breadth of the Claims: The claims are broadly written to encompass replacing any non-dividing cells anywhere in any subject. The breadth of “cell replacement therapy” that “replaces non-dividing cells” encompasses the administered precursor cells provide non-diving cells that partially or completely replace non-dividing cell structure and function that is lost or is in needed of being substituted.
Specification Guidance: The specification contemplates the generic term “cell replacement therapy” but does not provide any specific definition for the term. Narrowing embodiments generically describe the use of dopaminergic NPCs administered to a subject with Parkinson. The specification generically describes administering endothelial cell precursor cells for vascular/tumor angiogenesis disease, cardiomyocyte precursor cells for heart diseases, and pancreatic precursor cells for pancratia diseases, and other known precursor cell species can be generically used in the invention. See [0023], [0167]; [0192]-[0193].
Working Examples: The working examples described the following:
[0218] Transplantation of TK-NPCs produced mature neurons which were not sensitive to ganciclovir treatment: The in vivo results, shown so far, were obtained with transplantation of undifferentiated pluripotent stem cells. However, the final goal of neuronal cell therapy is the transplantation of neural precursor cells, which should differentiate into mature neurons and be resistant to ganciclovir treatment. Therefore, 2-3 weeks-NPC containing neurospheres were transplanted (FIGS. 3C, 8). Under these conditions, no tumor formation was observed, even in the absence of ganciclovir treatment (FIG. 8A). In line with these observations, the transplanted cells (assessed by immunofluorescence 7 weeks after transplantation) were abundantly positive for beta 3 tubulin (FIG. 8B, upper panel), while a smaller fraction of cells was TH-positive (FIG. 8B, lower panel). Occasionally nestin-positive cells were observed. None of these markers were affected by ganciclovir treatment.
[0221] Thus, the present methods provide a novel tool that allows in vivo removal of proliferating, potentially tumorigenic cells from neural transplants. The system is based on the expression of HSV-TK under the control of the cell cycle-dependent Ki67 promoter. It will be particularly useful for the transplantation of pluripotent stem cell-derived neurons. Indeed, HSV-TK expressing cells can be eliminated by treatment of patients with the clinically used, CNS-permeant drug ganciclovir. As the Ki67 promoter will be inactive in mature neurons, treatment with ganciclovir will only eliminate proliferating precursors, but preserve the integrity of differentiated post-mitotic neurons.
Thus the specification does not provide adequate specific guidance to replacement of any non-dividing cell in the subject that results in replacing the non-dividing cell structures and functions partially and function as the breath of the cell replacement therapy embraces. Rather the working example more narrowly provide guidance to introducing new mature neurons into a subject by administering one specific cell species, NPCs comprising one species cell cycle dependent promoter (Ki67 promoter) operably linked to one specific suicide gene, the HSV-TK gene. Thus the specifications fail to enable the breadth of the claimed cell replacement therapy using any precursor cell comprising any cell cycle dependent promoter operably linked to any suicide gene to eliminate any cycling precursor cells and replacing any non-dividing cells.
State of the Art: At the file of effective filing, Lane et al. (Expert Rev Neurother. 2017 17(5):433-440, doi:10.1080/14737175.2017.1270206. pp 1-15 of Author Manuscript) reports, “NPCs provide a source of new cells to substitute for cells lost or damaged post-SCI (including neurons, oligodendrocytes and astrocytes). Complete cell ‘replacement,’ however, remains a very difficult challenge as it requires specific differentiation, and precise anatomical and functional integration that replicates the uninjured spinal cord. Instead, the goal of NPC transplants is typically to provide the cellular and molecular components capable of promoting repair and enhancing functional improvement.” Page 2, last paragraph.
“NPC transplantation is also associated with unique challenges that must be addressed to both maximize its effectiveness and assure safety. Some of these include: (i) choice of appropriate population(s) of NPCs with respect to lineage potential and source of tissue (e.g. spinal cord vs. brain, embryonic vs. adult, allogeneic vs. isogeneic); (ii) expansion and storage of sufficient numbers of cells in a uniform manner and without compromising their beneficial properties; (iii) achieving long-term integration, defined differentiation and functional maturation without the generation of unwanted lineages, persistent proliferation or ectopic localization; (iv) need for noninvasive monitoring of transplanted cells; (v) optimization of the timing and method of delivery; (vi) potential need for long-term immunosuppression in allogeneic transplantation; (vii) invasive nature of transplantation (particularly with direct intraparenchymal injection); and (viii) ethical considerations associated with the source material used for obtaining NPCs (e.g. fetal tissue).” Page 3, last paragraph of section 2.
Thus the art at the time of the invention teaches cell replacement therapy wherein the cell completely or partially “replace” non-diving cells lost by various pathologies remains highly unpredictable and unattainable. As such, the goal of particularly NPC therapy is to provide the cellular and molecular components capable of promoting repair and enhancing functional improvement instead of replacement. Further the art at the time of the invention teaches multiple hurdles that stand in the way of NPC used of replacement therapy.
Sharma et al. (Cells 2021 10, 2538 pages 1-35) report, “Several cell types have been investigated for their regenerative ability, each with its own set of benefits and side effects…; among these are mesenchymal stem cells, bone marrow cells, and cardiac progenitor cells. These have been shown to improve heart function in preclinical studies and are currently being studied in clinical trials…. Cell therapy using mesenchymal stem cells and bone marrow cells has been effective to some extent, but these cells are unable to differentiate into cardiomyocytes due to their restricted differentiation potential.” Page 4 end of paragraph. Cardiomyocytes, smooth muscle cells, and endothelial cells can all be differentiated from cardiovascular lineage-specific progenitor cells which reside in the heart. Injection after MI demonstrated in vivo regenerative capacity, but progenitor cells were rejected by the host. Cell viability preservation and survival in the hostile environment of the infarcted heart, and further effective coupling to the existing myocardium, remain significant challenges.” Page 5, paragraph 1.
As such, at the time of the invention and continuing well beyond, cardiomyocyte precursor use for cell replacement therapy was unattainable and thus was unpredictable. Like reported for NPC therapies, cardiomyocyte precursor cells could only be used as a means to enhance repair and improve function in the heart.
Regarding pancreatic precursor cell replacement therapy, Abdalla (World J Gastroenterol 30(40):4339-4353, 2024) reports, “stem cell therapy for beta-cell regeneration holds substantial promise but also faces numerous challenges”. MSC cell are able to differentiate into beta cells and secrete factors that support beta-cell survival and function, thus able to improve function and potential to support repair. Pancreatic progenitor cell transplantation showed improvement of glucose regulation and reduced need for exogenous insulin administration. However, challenges remain with longer survival, functionality of resultant beta cells and also from incomplete differentiation (p. 4434, Stem cell therapy section). Thus the art teaches like other progenitor cell therapies, precursor cells, while having therapeutic promise, fall short of cell replacement therapy.
Amount of Experimentation: The combined descriptions of the instant application and the art before, at, and after effective filing teach that precursor cell therapy is highly unpredictable and requires significant discovery experimentation to arrive at the claimed Cell replacement therapy. The specification teaches a means of provide new neurons to the brain of a subject from NPC precursor cell able to solely provide non-dividing differentiated neurons. The art also teaches that ability of precursor cell therapy to support improved function and facilitated repair. However, like the guidance provide by the specification, the state of the art falls short of cell replacement therapy. As such, the level of experimentation would be undue.
In conclusion, the breadth of the claims to a cell replacement therapy as claimed lack enablement because the specification solely provides specific guidance to NPC cell comprising the claimed suicide expression vector that is able to introduce neuron into the brain of the subject and fails to provide any type of cell replacement therapy. The description provided by the instant application is consistent with the state of the art that teaches cell replacement therapy wherein non-dividing cells are replaced is highly unpredictable and unattainable. Further discovery research would be required to obtain a precursor cell and a method of using it that is capable of replacement therapy. This level of experimentation would be considered undue.
Response to Arguments
Applicant's arguments filed 2/6/ have been fully considered but they are not persuasive.
Applicant submits that claim 32 has been amend to administration of neural precursor cells, which differentiated into mature neurons. Applicant requests reconsideration and withdrawal of the rejection.
In response, the amendments to the claims while addressing some of the issues of enablement but additional issues are still outstanding. More specifically, “cell replacement therapy” and replacing neuronal cells as the claims recite and embrace. The enablement concerns regarding cell replacement therapy discussed in the rejection have not been address by the amendments or remarks that demonstrate enablement. As such, the preponderance of the evidence from the specification and the art suggests the claims still lack enablement as written.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632