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 .
Status of Claims
Claims 1-14 are pending.
Priority
Claims 1-14 are a 371 of PCT/KR 2023/005222 filed on April 18, 2023, which has priority to KOREA, REPUBLIC OF 10-2022-0049115 filed on April 20, 2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on October 21, 2024, was filed before the mailing of the First Office Action on August 29, 2026. The Non-Patent Literature is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
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.
Claim 14 is 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 claim(s) contains 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 it is most nearly connected, to make and/or use the invention because:
The Nature of the Invention:
The claimed invention is directed to the use of induced neural stem cells derived from fibroblasts as a therapeutic agent for treating brain diseases.
Breadth of the Claims:
Claim 14 broadly encompasses a pharmaceutical composition for treating “a brain disease” where the specification at pg. 16 gives a Markush listing of different diseases with substantially different etiologies and pathophysiologies by administering the claimed therapeutic agent to a subject in need.
Amount of Direction or Guidance Present in the Specification:
Applicant’s specification provides guidance for the generation and preparation of induced neural stem cells from fibroblasts. However, Applicant’s specification provides no guidance demonstrating how the claimed induced neural stem cell composition would provide therapeutic effect for the entire genus “brain diseases” or even the Markush listing of various brain diseases found in Applicant’s specification on pg. 16.
Presence or Absence of Working Examples:
Applicant’s specification provides no working examples demonstrating that administering the claimed therapeutic composition to a subject with a “brain disease”. Applicant has not provided any in vivo animal testing, in vitro disease models, or other experimental data demonstrating therapeutic efficacy of the claimed invention for any of the brain diseases listed in Applicant’s specification. Based on this, it would be difficult for a person of ordinary skill to infer any therapeutic efficacy across the full scope of the claim.
Relative Skill in the Art:
It is argued that the relative skill in the art, is that of a scientist with several years’ experience in the field, but that the Art itself is a recognition of what is understood by the Artisan, and thus, as seen below, does not make the breadth of the claim more predictable.
The Predictability or Lack thereof in the Art:
The predictability of using induced neural stem cells in the art is limited. For example, Andrzejewska et al. teaches that mesenchymal stem cell transplantation has produced beneficial effects in animal models in several neurological diseases that included stroke, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and multiple sclerosis [Table 1, Mesenchymal stem cells for neurological disorders, Adv Sci (Weinh), 2021]. However, Andrzejewska et al. also reports differing therapeutic outcomes among diseases [Table 4]. For example, although symptom alleviation was observed in several neurological disorders, neural stem cell survival and integration with the host had not been observed and that therapeutic effects were often attributed to paracrine activity rather than neuronal replacement [Introduction ¶ 1]. However, Andrzejewska et al. also discloses that many unresolved issues such as delivery, migration, homing, and engraftment, still posed problems [Abstract].
Additionally, the uncertainty is more evident with respect to Creutzfeldt-Jakob disease and other prion diseases. Relano-Giles et al. teaches that prion diseases remain uncurable and that available cell-based treatments only consisted of a few preclinical studies [Abstract, Cell-based therapy against prion diseases, Current Opinion in Pharmacology, 2019]. These studies involved numerous types of cells that included neural stem cells, neuronal precursor cells, mesenchymal stem cels, and microglial cells [Introduction ¶ 1]. Given this, the prior art only demonstrates that stem cell administration may produce therapeutic effects in certain neurological disease models, but it does not establish a predictable therapeutic response from the claimed induced neural stem cells derived from fibroblasts across a broad category of “brain diseases”.
Quantity of Experimentation Needed:
In view of the limited predictability, and the number of different diseases encompassed by the term “brain disease”, substantial experimentation would be required to establish therapeutic efficacy. As stated above, Andrzejewska et al. taught that stem cell delivery to the brain remained an unresolved problem and identified multiple issues related to administration of stem cells for treatment in the brain. Andrzejewska et al. also taught that therapeutic effects varied depending on the neurological disease model. Additionally, Relano-Giles et al. taught the limited availability of clinical studies available regarding therapeutic effects of stem cells in treating prion diseases. Relano-Giles et al. further stated that at the time of publication no treatment existed for prion-based brain diseases. Based on this, a skill artisan would need to undertake disease specific experimentation to determine whether the particular fibroblast-derived induced neural stem cells would be therapeutically effective for whatever specific disease was chosen. This would include determining and developing appropriate disease models, administration routes and parameters, cell survival and engraftment, differentiation or other mechanisms of action, and measurable therapeutic endpoints. Because of this, this would require undue experimentation.
Conclusion:
Based on the above factors, the specification fails to provide sufficient disclosure to allow one of ordinary skill in the art to make and use the claimed invention as it pertains to claim 14 without undue experimentation.
Claim 14 is 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 14 also uses the generic phrase “a method for treating brain disease” as it also relates to administering autologous neural stem cells derived from fibroblasts.
The specification provides antecedent basis for the use of direct differentiation of fibroblasts into neurons for the treatment of intractable brain diseases [Pg. 2 ¶ 1].
Applicant’s specification states “…direct differentiation of fibroblasts into neurons using fibroblasts for the treatment of intractable brain diseases has been actively studied” [Pg. 2 ¶ 1]. The specification further states that the claimed invention is directed to providing a cell therapeutic agent for treating a brain disease [pg. 3 ¶ 4]. The specification, in paragraph 4 of page 16, lists numerous brain diseases that encompass a broad and heterogenous group of disorders having substantially different etiologies and pathophysiological mechanisms that include neurodegenerative, vascular, autoimmune/inflammatory, prion-associated, and neuronal excitability disorders. In Example 6, Applicant’s specification describes a method of inducing neural stem cells using fibroblasts of patients who suffer from Huntington’s disease [Example 6 pg. 21]. Applicant provides numerous examples that are related to induction of cross-differentiation, comparison of direct cross-differentiation, confirmation of expression markers related to differentiated neural stem cells, chromosomal stability, inducing neural stem cells from adult fibroblasts, inducing neural stem cells using fibroblasts from patients diagnosed with Huntington’s disease, confirming differentiation ability, gene introduction using mRNA for inducing neural stem cells, and lastly, induction of neural stem cells using miRNA. However, the specification provides no working examples demonstrating the claimed therapeutic use of induced neural stem cells for treating brain diseases, especially across such a diverse range of brain disease etiologies and pathophysiology’s. Citing MPEP § 2163(I) “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.” Here, there is no experimental data demonstrating that the induced neural stem cells are effective for treating any of the brain diseases recited in the specification. Furthermore, the specification provides no therapeutic efficacy data, disease-model data, or other experimental evidence establishing Applicant was in possession of the claimed method for treating “brain diseases”. Additionally, the term “brain disease” encompasses substantially different brain disorders with diverse etiologies and pathophysiological mechanisms. For example, Alzheimer’s disease is a neurodegenerative disorder characterized by neuronal loss and amyloid-β and tau pathology [Chu-Min Ou et al., Stem cell therapy in Alzheimer’s disease: current status and perspectives, Front Neurosci., 2024, Abstract]. On the other hand, Creutzfeldt-Jakob disease is a rapidly progressive degenerative brain disorder caused by prions [ClevelandClinic.org “Creutzfeldt-Jakob Disease (CJD)”, 2025]. The phrase “brain disease” also includes diseases such as Kuru, although similar to Creutzfeldt-Jakob disease, is a distinct prion-associated neurodegenerative disease associated with cannibalism [Liberski et al., Kuru: genes, cannibals and neuropathology, Journal of Neuropathology & Experimental Neurology, 2012]. Given the current state of the art, the claimed genus for “brain disease” and the vast number of diseases that are encompassed that include vastly different pathological mechanisms, the specification’s lack of disclosure or providing any data showing actual treatment whether in vitro or in vivo of any of the listed diseases would not inform a person of ordinary skill that Applicant was in possession of the claimed invention.
Given the generic scope of “brain disease” as it relates to administering/treating a subject in need and the absence of any teachings describing how the neural stem cells are used to treat a range of diseases with a wide variety of pathological mechanisms, the Artisan would not understand Applicant to be in possession of the generic scope of a method of treating a “brain disease” using the claimed induced neural stem cell therapy.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 4 fails to further limit claim 1 because human-derived fibroblasts are encompassed by the fibroblasts already recited in claim 1 where the added limitation is merely identifying a source without substantively limiting the claimed composition. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 5 fails to further limit claim 1 given the recited differentiation of the neural stem cells into the listed cell types does not impart a further structural or functional limitation on the composition of claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1-14 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Meyer et al. [Derivation of adult human fibroblasts and their direct conversion into expandable neural progenitor cells, J Vis Exp., 2015], as evidenced by Terry et al. [Experimental Autoimmune Encephalomyelitis in Mice, Multiple Sclerosis Methods and Protocols, 2014], where Terry et al. is being cited to provide an explanation of a term used in the primary reference, Meyer et al. under MPEP § 2131.01. MPEP § 2131.01 states “only one reference should be used in making a rejection under 35 U.S.C. §102. However, a 35 U.S.C. §102 rejection over multiple references has been held to be proper when the extra references are cited to:
(A) Prove the primary reference contains an "enabled disclosure;"
(B) Explain the meaning of a term used in the primary reference; or
(C) Show that a characteristic not disclosed in the reference is inherent.
MPEP § 2131 states “A claim is anticipated only if each and every element as set forth in the claim is found, either expressly or inherently described, in a single prior art reference." Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987). "When a claim covers several structures or compositions, either generically or as alternatives, the claim is deemed anticipated if any of the structures or compositions within the scope of the claim is known in the prior art." Brown v. 3M, 265 F.3d 1349, 1351, 60 USPQ2d 1375, 1376 (Fed. Cir. 2001)”.
Regarding claim 1, Meyer et al. teaches a direct cross-differentiation-inducing composition for inducing direct conversion into neural stem cells from fibroblasts [Abstract], comprising: one or more small molecule compounds selected from the group consisting of thiazovivin, valproic acid, purmorphamine, A8301, SB43154, CHIR99021, 5-aza-2’-deoxycytidine, and DZNep, and Sendai virus [2. Infection of human fibroblasts with Sendai virus and transdifferentiation].
Regarding claim 2, Meyer et al. teaches the composition of claim 1, further comprising: a medium for cell culture [Introduction ¶ 3].
Regarding claim 3, Meyer et al. teaches the composition of claim 1, wherein the Sendai virus includes a Yamanaka factor [Introduction ¶ 3].
Regarding claim 4, Meyer et al. teaches the composition of claim 1, wherein the fibroblasts are derived from a human [Abstract].
Regarding claim 5, Meyer et al. teaches the composition of claim 1, wherein the neural stem cells differentiated into one or more selected from the group consisting of an astrocyte, an oligodendrocyte, a neuron, a dopamine neuron, a GABA neuron, a motor neuron, and choline neuron [Introduction ¶ 3].
Regarding claim 6, Meyer et al. teaches a method of preparing neural stem cells, comprising: culturing human fibroblasts in a medium including one or more small molecule compounds [Abstract] selected from the group consisting of thiazovivin, valproic acid, purmorphamine, A8301, SB43154, CHIR99021, 5-aza-2’-deoxycytidine, and DZNep, and Sendai virus [2. Infection of human fibroblasts with Sendai virus and transdifferentiation].
Regarding claim 7, Meyer et al. teaches the method of claim 6, wherein the Sendai virus includes a Yamanaka factor [Introduction ¶ 3].
Regarding claim 8, Meyer et al. teaches the method of claim 6, wherein the medium is DMEM/F12 including N2, B27, bFGF, and EGF [2. Infection of human fibroblasts with Sendai virus and trans differentiation, 4. Analysis of NPCs after directed differentiation into neural glial lineages].
Regarding claim 9, Meyer et al. teaches the method of claim 6, wherein the culturing is performed for 10 to 20 days [2. Infection of human fibroblasts with Sendai virus and transdifferentiation Part 8].
Regarding claim 10, Meyer et al. teaches the method of claim 6, wherein the neural stem cells differentiate into one or more selected from the group consisting of an astrocyte, an oligodendrocyte, a neuron, a dopamine neuron, a GABA neuron, a motor neuron, and a choline neuron [Introduction ¶ 3].
Regarding claim 11, Meyer et al. teaches a cell therapeutic agent, comprising: the composition of claim 1; or neural stem cells prepared by a method of culturing human fibroblasts in a medium including the one or more small molecule compounds [Abstract] selected from the group consisting of thiazovivin, valproic acid, purmorphamine, A8301, SB43154, CHIR99021, 5-aza-2’-deoxycytidine, and DZNep, and Sendai virus [2. Infection of human fibroblasts with Sendai virus and transdifferentiation].
Regarding claim 12, Meyer et al. teaches a pharmaceutical composition for treating a brain disease comprising the cell therapeutic agent of claim 11 [Introduction ¶ 4].
Regarding claim 13, Meyer et al. teaches the pharmaceutical composition of claim 12, wherein the brain disease is selected from the group consisting of stroke, apoplexy, cerebral hemorrhage, cerebral infarction, Alzheimer’s disease, dementia, Huntington’s disease, Parkinson’s disease, multiple sclerosis, multiple neurotrophy, epilepsy, Pick’s disease, and Creutzfeldt-Jakob’s disease [Introduction ¶ 4, as evidenced by Terry et al. where Terry et al. is being cited to establish the recognized meaning of “experimental autoimmune encephalomyelitis” as an animal model of multiple sclerosis stated in Terry et al. Abstract].
Regarding claim 14, Meyer et al. teaches a method for treating a brain disease, comprising administering to a subject in need thereof the cell therapeutic agent of claim 11 [Introduction ¶ 5]
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5.
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 on 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.
/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights