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 .
Response to Applicants Arguments/Amendments
The previous examiner has left the office. This application has been transferred to Examiner Van Buren. The former rejection is withdrawn and a new rejection is put forward.
Status of Claims
Claims 50-52,54-68 are pending.
Claims 60, 62 and 63 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species. The election is considered to be an election without traverse in the reply filed on 28 February 2023 to the Restriction/Election Office Action mailed 28 December 2022.
Claims 50-52,54-59, 61 and 64-68 are rejected.
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, or §365(c) is acknowledged. This application discloses and claims only subject matter disclosed in prior application no. 15/762,271, filed 03/22/2018, which is a 371 of PCT/US2016/053438, 09/23/2016, and which claims benefit of 62/233,148, 09/25/2015, and names the inventor or at least one joint inventor named in the prior application. (The specifications filed with applications 17/248,217 and 15/762,271 appear to be the same, i.e., instant application 17/248,217 does not appear to include any subject matter which would constitute new matter (MPEP 201.07).) In addition, the abandonment that issued from parent application 15/762,271 was issued/published either on the same day or after the filing date of the instant application. Accordingly, this application constitutes a continuation. Applicant has claimed the benefit of the filing date of the prior application, and designates the instant application as a "CON" of 15/762,271.
Applicant has complied with all of the conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §120 or §365(c).
Claims 50-52,54-59, 61 and 64-68 have the effective filing date of 25 September 2015.
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.
Enablement Rejection
Claims 50-52,54-59, 61, and 64-68 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The claims recite a method of treating and/or preventing cardiac injury/cardiac fibrosis by administering a therapeutically effective amount of neuregulin peptide or the functional variant or the functional fragment thereof to an individual in need using any method of administration. Claim 55, a dependent claim, states that cells can also be administered with the neuregulin; the method of administration of the cells encompasses all methods of administration. Claim 55 has another enablement issue because the claim recites that embryonal stem cells can be administered with the neuregulin. Embryonal stem cells can cause teratoma development and would therefore not be considered a safe treatment. Claims 56-57 which depend from claim 55 fail to correct the enablement issue of claim 55.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc. 8 USPQD2d 1217 (Fed. Cir. 1988). Whether undue experimentation is required is a conclusion reached by weighing several factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQQ2d 1400 (Fed. Cir. 1988)
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experiment to make and use the invention based on the content of the disclosure is undue.
Nature of the Invention:
The claims recite a method for treating or preventing a cardiac injury in a subject by administering a therapeutically effective amount of neuregulin peptide based on how an isolated population of Sca-1+CD31-ckit-ErbB3+.cardiac progenitor cells from a subject respond to neuregulin peptide. Dependent Claim 55 states that cells including embryonic stem cells can be administered with the neuregulin peptide.
Breadth of the Claims:
The claims recite both methods of treating and preventing cardiac injury/cardiac fibrosis. Prevention means that cardiac injury/cardiac fibrosis can be prevented from ever occurring just by administering the desired neuregulin. The claims are so broad that they encompass any method of administering for the neuregulin and therapeutic cells (claim 55). Dependent claim 55 recites that embryonic stem cells can also be administered as part of the treatment/preventative therapy.
Teachings from the Prior Art
The goal of applicants claimed invention is to improve the ability of cardiac progenitor cells to treat and prevent cardiac conditions through the administration of neuregulin. However, Bryl, “Cardiac progenitor cell therapy: mechanisms of action” Cell Bioscience (2024) 14:30 teaches that using progenitor cells in a clinical setting to treat heart conditions is currently not feasible due to limitations which include: dosage issues, safety, specificity, pharmacokinetics, pharmacodynamics, and methods of proper administration (Abstract of Bryl).
Bryl further teaches “Numerous ongoing preclinical and clinical studies are examining the feasibility of using stem cell therapy for cardiovascular disease. The growing number of patients and heart transplantation, which is often the only possible solution to end stage heart failure, is prompting the development of other treatments. For years, therapies based on regenerative medicine have been creating new possibilities and perspectives. Advanced research and experiments are directed at selecting a population of cells that would be established in the myocardium and differentiate into functioning cardiomyocytes. However, for various reasons, achieving this goal has not been satisfactory to date….(Page 12, left side, 2nd paragraph of Bryl). The priority date of this application dates back to September 25, 2015. The Bryl article is dated 2024 which shows that even after 2015, there is still no effective way to treat and/or prevent cardiac conditions using progenitor cells/stem cells.
State of the Art regarding embryonic stem cells:
Lee et al. (PNAS 110(35):E3281-E3290, 2013) states, “The unique properties of human pluripotent stem cells (hPSCs) such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSC) [i.e., indefinite self-renewal in vitro while maintaining their ability to differentiate into all cell types of the body upon exposure to relevant differentiation signals (1–3)] make them the best potential cell source for cell-based regenerative therapy and/or personalized medicine (4). Thus, enormous efforts have been undertaken to establish hESC- and hiPSC-based therapies for a variety of degenerative diseases (4–7). However, there are major technical and scientific obstacles remaining to be overcome before hPSC-based cell therapy becomes a realistic therapeutic modality. Most of all, it is of utmost importance to avoid possible teratoma/ tumor formation that can arise from any remaining undifferentiated pluripotent stem cells present in the differentiated cell mixture (8). Indeed, a systematic transplantation study demonstrated that the teratoma-forming propensity of various mouse iPSC-derived neurospheres correlated with the persistence of residual undifferentiated cells (9). Because hESCs and hiPSCs also exhibit marked variations in differentiation efficiencies (and remaining undifferentiated cells) (10–13), it is critical to remove all residual hiPSCs with teratoma potential before their clinical application. Despite numerous attempts at blocking teratoma formation, including introduction of suicide genes (14) or selecting the desired cell type (15), immunodepletion (16), or introducing cytotoxic antibody (17), a clinically viable strategy to eliminate teratoma formation remains to be developed (8,18)”. See p. E3281, paragraph bridging col 1 and 2.
Lee teaches that differentiated cells derived from pluripotent cells, such as the cell differentiated from the stem cells of the stem cells bank of the instant invention, and totipotent cells or pluripotent stem cells, failed to be used for any type of cell therapy to treat a disorder in a patient because a means of predictably providing a homogenous differentiated cell population that predictably eliminates undifferentiated cells in the population had not been achieved. Lee further highlights the absolute need for a homogenous population the differentiated cell type. A problem that can arise from having a heterologous population of ESC-derived somatic cells and undifferentiated cells is tumor formation from the undifferentiated cell, thus causing a non-therapeutic effect, but further, a mixed population causes unpredictability in determining a therapeutic dose of cells because of the variability in an unknown number and non-known character of the undifferentiated cell population.
Sylvester teaches that pluripotent stem cells have demonstrated dysregulated cell growth with transplantation into an immunocompromised host, results in teratoma formation (Sylvester et al. Arch Surg 139:93-99, 2004. See page 95, col 1, first full paragraph). Similarly, Moon (Moon et al. International Journal of Stem Cells 4(1):24-34, 2011) teaches that a major problem involving the use of hESC is the possibility of cell misbehavior following transplantation. This potentially serious complication can occur if any transplanted undifferentiated hESC form teratomas. Careful and previse protocols for collecting only differentiated cells are necessary to circumvent this problem. As of 2011 researchers still needed to develop way to screen pluripotent cell derivatives for contamination with undifferentiated cells and derivative cells that have optimized chromosomally stable induction systems in vivo (p.30, col 1, past full paragraph starting with, “Another major risk…”; paragraph bridging col 1 and 2 of pp. 31). Moon further teaches that during prolonged maintenance of undifferentiated pluripotent cell in vitro, chromosomal instability gives rise to numerous changes in ploidy, especially chromosomes 13 and 17. Moon states, “Chromosomal instability seriously affects cell function and is well known to be a hallmark of many tumors. In addition, the generation of chromosomal instability by the presence of extra centrosomes can give rise to multiple aneuploidy daughter cells with proliferative advantages, chemoresistance, or metastatic potential (66, 67). Their potential for tumor progression is a significant challenge facing the safe therapeutic application of hESC, Recently, Moon et al. demonstrated aberrant cell division in karyotypically abnormal hESC during in vitro culture. These authors subsequently show a post-transplant tumor-like growth arising from the hESC transplant derivative (68). These results emphasize that sustaining normal human chromosome number during in vitro culture and differentiation is indispensable for safe transplantation of hESC derivatives. For therapeutic use”.
Regarding chromosomal instability, Lee teaches accumulation of mutations in early embryonic cells and ESC would result in enormous harmful effects to all subsequent derived somatic cells arising at later developmental stages and/or those of further generations. Thus, it is critical that these cells maintained their genomic integrity by establishing unique mechanisms, such as significantly lower mutations rates and lower frequencies of mitotic mutations than their differentiated counterparts (E3288, col 1, paragraph 1 under ‘Discussion’ section.)
Thus Moon and Lee both highlight the obstacle of chromosomal instability in pluripotent stem cells and somatic cell differentiated from them. Both describe not only how enormously harmful these chromosomally instable cells can be to the safety of someone receiving these cells, but the grave degree of cellular dysfunction and change of cellular function that occurs in these cell derivatives. Thus, not only are they describing a hindrance to safe therapeutic use of differentiated cell derived from pluripotent cell, they are describing a lack of predictable function (i.e. function as the intended differentiated cell type) because the genomic instability leads to cellular dysfunction.
Thus, the art teaches that at the time the claimed invention was made and after, the use of cell differentiated from pluripotent stem cells for regenerative therapy had not been established due to complications of the presence of undifferentiated cells and cells with genomic instability. The art teaches not only a hindrance to the safe use of these cells for therapeutic purposes but also concern and obstacle to correct, predictable function of the pluripotent cell derived somatic cells. Thus the art teaches that the use of totipotent cells, pluripotent cells, and cells differentiated from totipotent and pluripotent cells in a regenerative therapy method as claimed is unpredictable.
In conclusion, the instant claim lack enablement because while the specification provide general guidance to a method that transplants stem cells into a person, it fails to provide specific guidance to such a method that will predictably treat said person. Further, the art teaches that at the time of the invention and continuing post filing therapeutic methods that administered stem cells to a person would not predictably treat a person because of an inability to direct differentiation of those cells to a specific and homogenous cell type and that differentiation to produce tissues for transplantation also had not been developed.
Volarevic et al. “Ethical and Safety Issues of Stem Cell-Based Therapy” which was published in 2018 after applicants priority date states that as of 2018, the use of embryonal stem cells/pluripotent/iPSC stem cells was still not safe and not proven as an effective therapy. Volarevic states, “As for hESCs the main safety issue regarding the use of such cells is the risk of teratoma formation which can happen if the patient receives iPSC/embryonal/pluripotent derived cells that contain undifferentiated iPSC/embryonal/pluripotent cells….thus development of more effective methods for generation of purified populations of autologous iPSCs/embryonal/pluripotent differentiated cells remains a challenge for personalized and regenerative medicine (Page 40, 1st paragraph).
Applicants Specification:
According to the specification, the purpose of the neuregulin is to stimulate the cardiac progenitor cells to preferentially differentiate into cardiac myocytes where such cells have reduced differentiation into fibroblasts or myofibroblasts upon exposure to NRG. Applicants specification as evidenced in the drawings and brief drawing description cultures cells under in-vitro conditions. Figure 1 shows that Sca-1+CD31- cells express ErbB2 and ErbB3 receptors. Figure 3 shows that NRG-1 can prevent transition of murine cardiac progenitor cells into myofibroblasts, thus allowing them to differentiate into cardiac cells. The results of Figure 3 are in-vitro cell culture. There is no actual mouse model or human clinical data that shows that cardiac progenitor cells treat or prevent cardiac injury after administering neuregulin (NRG) peptide. The specification does not present actual evidence that shows that administration of neuregulin actually impacts cardiac progenitor cells in-vivo and actually results in a positive effect or treatment that ameliorates the effect of cardiac injury. Furthermore, the specification fails to show that administration of neuregulin always prevents cardiac injury from occurring.
Paragraph 17 of the specification states that the NRG peptide/variant/fragment is administered intravenously or subcutaneously. In the Compositions, Administrations, and Dosage section (Paragraph 94 of the Specification), the specification states that the NRG peptide can be administered to subjects in a pharmaceutically acceptable diluent or carrier and be administered orally, intranasally, or by aerosols. There was no evidence presented by applicant that these forms of administration actually reached the target cardiac progenitor cells. Paragraph 59 of the specification states that the therapeutic cells can be administered directly to the heart, however, there is no supporting evidence that this method of administration actually works. The specification does not support all methods of administration including adding the NRG peptide and/or therapeutic cells to a topical lotion or cream and subsequently putting the lotion or cream on the subject in need of treatment.
Conclusion:
As of 2024, cardiac progenitor cells are still not known to be a satisfactory treatment or prophylactic for cardiac injury. There is no agent that has been identified as making cardiac progenitor cells effective at treating cardiac injury in individuals in-vivo. Therefore, anything that would impact cardiac progenitor cells such as neuregulin/NRG administration is not recognized as an effective treatment/preventative. Therefore, the claimed method is not a valid treatment method or a method of prevention of cardiac injury. There is no evidence presented that the methods of administration disclosed in the specification for the NRG peptide and/or therapeutic cells (claim 55) even allow the NRG peptide to successfully reach the cardiac progenitor cells and promote effective treatment. Furthermore, claim 55 states that embryonal stem cells can be used as an effective therapy cell. This is inaccurate since using cells derived from embryonal stem cells can result in teratoma formation. Therefore, the claimed methods are not enabled.
Conclusion
All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN K VAN BUREN whose telephone number is (571)270-1025. The examiner can normally be reached M-F:9:30am-5:40pm; 9:00-10:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights