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 .
Priority
The instant application is a national stage entry of PCT application PCT/US2022/079002, filed 04/29/2024 under 35 USC 371. Acknowledgement is made of the applicant’s claim for benefit to prior-filed U.S. provisional patent application 63/273,854, which was filed 10/29/2021.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See line 6 on page 59. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 6, 8, 13, 22, 27 and 30 are objected to because of the following informalities:
Claim 6 recites “ABC99”, claim 12 recites “7-( 4-Chlorobenzyl)-l,3-dioxohexahydroimidazo[l,5-a]pyrazin-2(3H)-yl 2,3-dihydro-4Hbenzo[b] [1,4 ]oxazine-4-carboxylate”, the two terms refer to the same chemical substance, the claims need to use the same name to enhance the consistency and clarity of the claims.
Claim 8 recites abbreviation “shh”, unlike the abbreviation “Wnt” which is well known in the art, the abbreviation “shh” needs to be spelled out at the first encounter in the claims;
Claim 13 recites “Kruppel-like Factor 2 (Klf3)”, it should be “Kruppel-like Factor 3 (Klf3)”;
Claim 22 does not end with a period. MPEP 608.01(m) requires each claim to start with a capital letter and end with a period;
Claim 22 recites “an glial cell” should be “a glial cell”;
Claim 22 has duplicated phrases “wherein the agent” in lines 2 and 3, one of them needs to be deleted;
Claims 27 and 30 recite “An” after the word “or”, they need to be “an”.
Appropriate correction is required.
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.
Claims 6 and 25 are 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 6 recites “SAG (smoothened agonist)” and “LY411575 (gamma secretase inhibitor/Notch antagonist)”, the use of parentheses renders instant claim indefinite because it is not clear whether the items within the parentheticals are required or optional.
Claim 25 recites the limitation "the nucleic acid molecule" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(a)
Written Description
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 1-16 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.
From M.P.E.P. § 2163, the analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention from the standpoint of one of skill in the art at the time the application was filed. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For claims drawn to a genus, possession may be shown (for example) through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus, and is an inverse function of the skill and knowledge in the art. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
Instant claims are directed to a method of preventing or treating a hypothalamic-regulated behavior in a subject by administering an effective amount of an agent to the subject, wherein the agent decreases the activity or expression of a nuclear factor I (NFI) gene, and the hypothalamic-regulated behavior comprises obesity, type II diabetes, a sleep disorder, hypertension, anorexia nervosa, congenital hypothyroidism, neuropsychiatric disorders linked to dysregulation of cortisol, depression, or post-traumatic stress disorder. Herein the “hypothalamic-regulated” is interpreted under broadest reasonable interpretation (BRI) as the physiological process or the cause of the behaviors are involved by hypothalamus directly or indirectly. Those behaviors or disorders, which can be regulated by i.e., hormones produced by hypothalamus, themselves are result from a combination of biological, genetic, psychological, and environmental factors. These behaviors or disorders are having different symptoms, etiologies, or mechanisms, which require different methods of treatment. The claims also cover a genus of treating (e.g., managing symptoms, controlling the disease, or preventing complications of an exist hypothalamic-regulated behavior or disorder) or preventing (e.g., stop or delay the onset of disease before it occurs) these hypothalamic-regulated behaviors or disorders. Therefore the scope of the claims is very broad. The issue at hand is whether or not Applicant has possession of the full scope of the hypothalamic-regulated behaviors or disorders, as well as the preventing or treating said hypothalamic-regulated behaviors or disorders at the time the application was filed.
In the instant case, Applicant has failed to provide disclosure of species which are representative of the full scope of the claimed hypothalamic-regulated behaviors and the preventing or treating said hypothalamic-regulated behaviors. The specification does not provide any working examples regarding preventing or treating any species of hypothalamic-regulated behavior in a subject by administering the subject an effective amount of an agent which decreases the activity or expression of a nuclear factor I (NFI) gene. Instead, the working examples disclose NFI family of transcription factors Nfia/b/x loss of function induces proliferation and neurogenesis in tanycytes in neonatal mice (Example 1) and older mice (Example 2), identify genes that controlling neurogenesis in tanycytes (Example 3), validate that Shh and Wnt signaling regulate tanycyte proliferation and neurogenic competence (Example 4). The working examples also disclose that Nfia/b/x-deficient tanycytes give rise to a diverse range of hypothalamic neuronal subtypes including glutamatergic and the GABAergic neurons (Example 5), these neurons are integrated into hypothalamic neural circuitry, which are functional neurons showing electrophysiology response such as action potential as well as synaptic activity (Example 6). The specification also discloses working examples 7 and 8, which study the ability of chemicals SAG (activation of SHH signaling), ABC99 (activation of Wnt signaling), and LY411575 (activation of Notch signaling) for stimulating tanycyte-derived neurogenesis. None of the working examples disclose administering a subject an effective amount of an agent which decreases the activity or expression of a NFI gene for the treatment of a hypothalamic-regulated behavior comprises obesity, type II diabetes, a sleep disorder, hypertension, anorexia nervosa, congenital hypothyroidism, neuropsychiatric disorders linked to dysregulation of cortisol, depression, or post-traumatic stress disorder. As such, the instant specification does not provide a sufficient representative sampling of species of the hypothalamic-regulated behaviors and the treating or preventing said hypothalamic-regulated behaviors encompassed in claims.
Furthermore, Applicant has failed to provide disclosure of relevant, identifying characteristics, such as the functional characteristics (be able to prevent or treat a hypothalamic-regulated behavior) coupled with known or disclosed structure of NFI gene (decreased activity or expression of a NFI gene). As discussed above, the specification does not provide any disclosure regarding preventing or treating a hypothalamic-regulated behavior in a subject by administering the subject an effective amount of an agent which decreases the activity or expression of a NFI gene, or an increased expression of NFI is causally lead to the recited hypothalamic-regulated behaviors. Therefore Applicant has failed to establish a known structure- function relationship wherein the decreased activity or expression of a NFI gene is capable of preventing or treating a hypothalamic-regulated behavior with any predictability. Thus, one of ordinary skill in the art, in looking to the instant specification, would not be able to determine that Applicant was in possession of the invention, as claimed, at the time the invention was made.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
Claims 1-16 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 enhancing neurogenic competence of tanycytes by decreasing the activity or expression of a NFI gene in hypothalamus, does not reasonably provide enablement for preventing or treating a hypothalamic-regulated behavior in a subject by administering the subject an effective amount of an agent which decreases the activity or expression of a NFI gene. 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.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in Jn re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention and Breadth of the claims:
The disclosure of the instant application is directed to a method of preventing or treating a hypothalamic-regulated behavior in a subject by administering an effective amount of an agent to the subject, wherein the agent decreases the activity or expression of a NFI gene, and the hypothalamic-regulated behavior comprises obesity, type II diabetes, a sleep disorder, hypertension, anorexia nervosa, congenital hypothyroidism, neuropsychiatric disorders linked to dysregulation of cortisol, depression, or post-traumatic stress disorder. The recited behaviors or disorders, which are regulated by hypothalamus (i.e., hypothalamus produced hormone), themselves are result from a combination of biological, genetic, psychological, and environmental factors. These behaviors or disorders are having different symptoms, etiologies, or mechanisms, which require different methods of treatment. The claims also cover a genus of treating (e.g., managing symptoms, controlling the disease, or preventing complications of an exist hypothalamic-regulated behavior or disorder) or preventing (e.g., stop or delay the onset of disease before it occurs) these hypothalamic-regulated behavior or disorder. The breadth of the claims is thus very broad.
Guidance of the Specification and The Existence of Working Examples:
The specification provides working examples to disclose NFI family of transcription factors Nfia/b/x loss of function induces proliferation and neurogenesis of tanycytes in neonatal mice (Example 1) and older mice (Example 2), identify genes that controlling neurogenesis in tanycytes (Example 3), validate that Shh and Wnt signaling regulate tanycyte proliferation and neurogenic competence (Example 4). The working examples also disclose that Nfia/b/x-deficient tanycytes give rise to a diverse range of hypothalamic neuronal subtypes including glutamatergic and the GABAergic neurons (Example 5), these neurons are integrated into hypothalamic neural circuitry, which are functional neurons showing electrophysiology response such as action potential as well as synaptic activity (Example 6). The specification also discloses working examples 7 and 8, which study the ability of chemicals SAG (activation SHH signaling), ABC99 (activation of Wnt signaling), and LY411575 (activation of Notch signaling) for stimulating tanycyte-derived neurogenesis. These examples, while only showing the Nfia/b/x loss of function increase proliferation and neurogenesis in tanycytes, which is able to give rise to a diverse range of hypothalamic neuronal subtypes, does not support these small numbers of new generated hypothalamic neuronal subtypes are capable of preventing or treating a hypothalamic-regulated behavior comprises obesity, type II diabetes, a sleep disorder, hypertension, anorexia nervosa, congenital hypothyroidism, neuropsychiatric disorders linked to dysregulation of cortisol, depression, or post-traumatic stress disorder.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The claimed invention is drawn to preventing or treating a hypothalamic-regulated behavior by decreasing the activity or expression of a NFI gene. The art generally characterizes the function of NFI gene as complex, the effect of decreasing the activity or expression of a NFI gene is unpredictable in nature, particularly with the behaviors or disorders presenting multifactorial etiologies or complex clinical symptoms. Neves et al. (Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11946-51) teach disruption of the Nfia gene causes perinatal lethality, with >95% of homozygous Nfia-/- animals dying within 2 weeks after birth (Abstract). Yoo et al. (Sci Adv. 2021 May 28;7(22):eabg3777) teach NFI loss of function activated both Shh and Wnt signaling in tanycytes and stimulated proliferation and neurogenesis. Zalucki et al. (Cereb Cortex. 2019 Jul 22;29(8):3590-3604) teach conditional ablation of Nfix from the adult mouse brain and demonstrated that the removal of this gene from either neural stem and progenitor cells, or neuroblasts, within the V-SVZ culminated in neuroblast migration defects. Chen et al. (Cancer Lett. 2017 Dec 1;410:124-138) review the nuclear factor I transcription factors in development and cancer. NFI transcription factors regulate cell proliferation and differentiation during the development of multiple organ systems, including the central nervous system (CNS), mammary gland, and lungs (p124, right column). NFI deregulation can lead to uncontrolled cell proliferation or a failure to differentiate, and could therefore potentially contribute to tumour growth (p126, left column). Regarding a hypothalamic-regulated behavior as recited in instant invention, Holsboer et al. (US 2012/0039812 A1) teach method of identifying a predisposition for developing posttraumatic stress disorder (PTSD) in a subject comprising assessing in a sample obtained from said subject the expression level of one or more genes selected from the FK506 binding protein 5 (FKBP5) gene, the signal transducer and activator of transcription (STAT5B) gene and the nuclear factor I/A (NFIA) gene, wherein a decrease in the expression level of said one or more genes as compared to the expression level of the corresponding gene(s) of a control is indicative of a predisposition for developing PTSD. These teachings recognize the function of NFI gene as a transcription factor and play critical role during development and in stem cells, however, it’s function in physiological or pathological conditions (i.e., cancer or hypothalamic-regulated behaviors) is not clearly studied, the effect of decreasing the activity or expression of NFI is unpredictable. There was no evidence at the time the invention was made that decreases the activity or expression of a NFI gene is capable of preventing or treating a hypothalamic-regulated behavior. There was no known link between the decreased activity or expression of a NFI gene and the therapeutic effect of a hypothalamic-regulated behavior. Furthermore, even though the specification and Yoo et al. teach the neurogenesis of tanycytes following the loss of the NFI gene is able to give rise to a diverse range of hypothalamic neuronal subtypes, there is a huge gap between the a slightly increased number of hypothalamus neurons and the therapeutic effect of treating hypothalamic-regulated behaviors by these newly generated hypothalamus neurons.
In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled commensurate with full scope. An artisan of skill would have required undue experimentation to practice the invention with a reasonable expectation of success.
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.
Claim 22 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yoo et al. (Sci Adv. 2021 May 28;7(22):eabg3777, cited in IDS).
Yoo et al. teach tanycyte-specific disruption of the nuclear factor I (NFI) family of transcription factors (Nfia/b/x) robustly stimulates tanycyte proliferation and tanycyte-derived neurogenesis (Abstract).
Regarding claim 22, Yoo et al. teach induction of proliferative and neurogenic competence by selective loss of function of Nfia/b/x leads to the robust generation of hypothalamic neuronal precursors that undergo outward radial migration, mature, fire action potentials, and receive synaptic inputs (p10, right column). To disrupt the expression of NFI, Yoo et al. generated Rax-CreER; Nfialox/lox; Nfiblox/lox; Nfixlox/lox; CAG-lsl-Sun1-GFP mice, which allow inducible, tanycyte-specific disruption of Nfia/b/x function (p2, left column), intraperitoneal injections of 4-hydroxytamoxifen (4-OHT) between postnatal days 3 and 5 (P3 and P5) to induce cre activity (p2, left column) which decrease/eliminate the Nfia/b/x gene. Herein The 4-OHT is considered as an agent decrease the activity or expression of NFI gene, administrating of 4-OHT can decrease /eliminate the activity or expression of NFI. Therefore the teaching of Yoo et al. anticipates instant claim.
Claims 27 and 30 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Khoshakhlagh et al. (US 2021/0171902 A1, published 6/10/2021).
Khoshakhlagh et al. teach pluripotent stem cells comprising particular combinations of transcription factor for the production of oligodendrocyte progenitor cells (OPCs) (Abstract).
Regarding claims 27 and 30, Khoshakhlagh et al. teach a nucleic acid encoding SOX9 is at least 80% (e.g., at least 85%, 90%, 95%, 98% or 100%) identical to SEQ ID NO: 2 (parag 0052). Herein the SEQ ID NO: 2 is 92.9% identical to SEQ ID NO:5 in instant claims (sequence alignment is provided below). Khoshakhlagh et al. teach nucleic acids encoding the transcription factors may be introduced into a pluripotent stem cell using any known methods, including but not limited to chemical transfection, viral transduction (e.g. using lentiviral vectors, adenovirus vectors, sendaivirus, and adeno associated viral vectors) and electroporation (parag 0070). This teaching reads on an adeno-associated virus (AAV) comprising a nucleic acid molecule having a sequence identity of at least 75% to SEQ ID NO:5 as recited in instant claim 27, and the pluripotent stem cells transfected by the AAVs encoding SOX9 having the nucleic acid sequence of SEQ ID NO:2 reads on an isolated cell comprising an adeno-associated virus (AAV) comprising a nucleic acid molecule having a sequence identity of at least 75% to SEQ ID NO:5 as recited in instant claim 30.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QINHUA GU whose telephone number is (703)756-1176. The examiner can normally be reached M-F: 9:00 - 5:00.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
Sequence Alignment
SEQ ID NO:5 v.s. SEQ ID NO:2 of US 2021/0171902 A1 (US 16/768,384)
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220
902
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672
756
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672
752
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301
771
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Prosecution Insights