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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/18/2025 has been entered.
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 11/18/2025 is acknowledged. Claims 77-79,81,83,84 and 8-90 were cancelled. Claims 71,75 and 80 were amended. Claims 71-76,80,82 and 85-87 are pending and under examination.
Priority
This application is a 371 of PCT/US2020/028826, filed 04/17/2020 which claims benefit of 62/839,475, filed 04/26/2019 and claims benefit of 62/836,544, filed 04/19/2019 as reflected by the most recent filing receipt.
Response to Arguments
Applicant’s arguments and amendments, see pages 4-5, filed 11/18/2025, with respect to the 35 U.S.C. 102(a)(1) rejection of claims 71,72,85-90 as anticipated by Mennerick et al. as evidenced by WO 2005063275; the 102(a)(1) rejection of claims 71-76,78,80,84-90 as anticipated by Duke; the 102(a)(1) rejection of claims 71-73,75-77,85-90 as anticipated by Parhami et al.; the 102(a)(1) rejection of claims 71,72,74-76,81,83,86,88-90 as anticipated by WO 20106001870; the 103 rejection of claim 79 as obvious over Parhami et al. and further in view of Johnson et al.; and the 103 rejection of claims 71,75,76,82,85-88 and 90 as obvious over Ausptiz et al. in view of ‘870 have been fully considered and are persuasive due to the amendments to the claims and therefore the cited art does not apply to the claims as amended. Therefore, the above rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendments to claims 71,75 and 80 regarding art, and, a new ground of rejection based on 35 U.S.C. 112(a) Scope of Enablement. See the new rejections below.
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 Rejections-Scope of Enablement
Claims 71-76,80,82 and 85-87 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 a method of treating eczema in a subject comprising administering to the subject an effective amount of 25-hydroxycholesterol or 24(S)-hydroxycholesterol by way of the prior art, and while being enabling for an in vitro method of killing senescent fibro adiopogenic progenitor cells (FAPs) and senescent dermal fibroblasts (DFs) by administering 25HC, and killing senescent IMR-90 cells by administering 24(S)HC or 27HC, does not reasonably provide enablement for a method of treating oral mucositis, eczema, idiopathic pulmonary fibrosis or kyphosis by administering to the subject an effective amount of the recited agents. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
The Breadth of the Claims and The Nature of the Invention
Claims 71 and 85-87 encompass treating oral mucositis, eczema, idiopathic pulmonary fibrosis or kyphosis by administering to the subject in need thereof an effective amount of 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 27-hydroxycholesterol, 22(R)-hydroxycholesterol, 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, 7a,25-dihydroxycholesterol, (3S,10R,13R)-17-(5-(dimethylamino)pentan-2-yl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol, rel-(3R,l0S,13S)-17-[(2S)-6-hydroxy-6-phenylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13, 14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol, 27-nor-25-ketocholesterol, (3 alpha, 9xi, 14xi)-3-hydroxychol-5-en-24-oic acid, or a salt of any one of the foregoing.
Claims 72-74 still encompass treating any of the 4 recited diseases with one specific agent, 25-hydroxycholesterol in claim 72, 24(S)-hydroxycholesterol in claim 73, and 27-hydroxycholesterol in claim 74.
Claim 75 recites treating any of the 4 recited diseases with 22(R)-hydroxycholesterol, 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol or 7a,25-dihydroxycholesterol.
Claim 76 encompasses treating just oral mucositis but with any of the recited agents of claim 71, claim 80 recites treating eczema with any of the recited agents of claim 71, and claim 82 recites treating idiopathic pulmonary fibrosis with any of the recited agents of claim 71.
The State of the Prior Art
Regarding the state of the art of treating oral mucositis, eczema, idiopathic pulmonary fibrosis, or kyphosis with the recited agents, the state of the art is limited. The English translation of Takahashi (WO 2017209270, Published 2017-12-07), teaches administering 25-hydroxycholesterol to a patient in need thereof (page 3, paragraph 18), using 25-hydroxycholesterol (25 OHC) in a cell death inducing method or cell death promoting method selective for activated cells among T cells and/or B cells, and for use in a method of treating a disease exhibiting enhanced or abnormality of immune function by activated T cells (paragraph 57, page 5). Takahashi teaches the 25 OHC cell death inducer or cell death promoter treats a disease exhibiting enhanced or abnormal immune function by activated B cells, including eczema (page 5, bottom paragraph; page 10). Takahashi teaches an analogue cholesterol of 25 OHC may be used instead or together with 25 OHC, and preferred analogues include 24(R/S) (page 2, Technical field), and teaches administering an analog cholesterol of 25 OHC which is 24 (R/S) OHC (page 3 bottom paragraph, page 5). Takahashi teaches systemic administration of 25 OHC by oral or parenteral route (page 11, top paragraph), topically administering 25 OHC to the skin, as well as transdermal administration (page 11, top paragraph).
Additionally, Takahashi teaches the lack of predictability regarding the physiological function of 25HC and other cholesterol species with regard to treatment of diseases whose pathology is attenuation or enhancement of immune reaction, autoimmune reaction, or allergic reaction problems. Takahashi teaches, “It is also reported that oxycholesterol is involved in signal transduction system relating to inflammation control, and is also involved in pathogenesis of chronic diseases such as Alzheimer's disease and arteriosclerosis. However, in vivo, the presence of various molecular species such as 26-hydroxycholesterol (synonymous with 27-hydroxycholesterol), 24-hydroxycholesterol, 7α-hydroxycholesterol, 25 OHC, 7β- although it has been identified, the function sharing of each molecular species has not been sufficiently elucidated (Non-Patent Document 1). For example, there is a report that 25 OHC is involved in feedback control of cholesterol biosynthesis, but the contribution of the molecular species to cholesterol synthesis is not clear since mice that are mostly deficient in 25 OHC show normal cholesterol metabolism and homeostasis (Non-Patent Document 2). There is also a report that 25 OHC is involved in innate immune function and works to improve resistance to viral infection (Patent Document 1), but there is also a report reporting that virus infectivity is raised diametrically opposite (Non Patent Literature 3). Therefore, it is not clear how to work on immune function. In addition to this, suggestions on the physiological function of 25 OHC were obtained from various experiments, but in the experiments, the majority were administered 25 OHC at a concentration on the order of μM, such as 10 μM, which is a physiological concentration, so it was not enough to unravel the original physiological function of 25 OHC. For example, according to Table 1 on page 403 of the non-patent document 1, which is a review article, it is reported that the concentration of 25 OHC in human plasma (or serum) is 0.002 to 0.026 μM. Therefore, what kind of function of 25 OHC plays a role in the immune reaction and allergic reaction of the living body, and whether it is effective for prevention or treatment of diseases whose pathology is attenuation or enhancement of immune reaction, autoimmune reaction, or allergic reaction problems were left as unresolved. Likewise, for various cholesterol molecular species other than 25 OHC, its function and therapeutic utility were not sufficiently elucidated (pages 1-2).
Regarding extrapolating in vitro results to in vivo use, Jansson-Lofmark et al. (Clinical Pharmacology and Therapeutics, Vol. 108, No. 2, August 2020) taught a study was undertaken to address the relationship between clinical unbound concentrations and in vitro potency, and how can drug discovery and development benefit from a better understanding of this linkage. A survey of 164 drugs was done to identify important points to consider when assessing new molecular entities. The compilation includes pharmacokinetic properties (clearance, bioavailability, plasma protein binding, volume of distribution, half-life, and active metabolites), clinically unbound concentrations, intracellular or extracellular target localization, in vitro binding affinities, type of in vitro property parameter (target binding, function; dissociation constant (Kd), inhibitory constant (Ki), concentration of drug producing 50% inhibition of maximal inhibition (IC50), concentration of drug producing 50% of its maximum effect (EC50)), mechanism of action, target type, and therapeutic area (page 299, left column). Jansson-Lofmark et al. taught the results of their study underscore that predictions of in vivo efficacious concentration based on generic in vivo–to–in-vitro Ratios may be highly variable, and may even lack biological significance. To advance compound selection during drug discovery, we would like to stress the need to further develop more in vivo–like in vitro systems and setups, such as sophisticated cell/organ arrangements, microphysiological systems, and as well the usage of mechanistic-based pharmacokinetic–pharmacodynamic modeling. The current analysis also strongly supports further in vivo pharmacological evaluation of test compounds, even if they display a low Ratio. Our data suggest that in vitro potency assay conditions, in vivo potency estimations from pivotal disease models, defining the required level of receptor occupancy, and probing in vivo target turnover properties are key components to the understanding of the links between clinical drug exposure and in vitro binding affinity (page 304, Conclusion).
Therefore, there is a lack of teaching in the state of the art regarding treating oral mucositis, idiopathic pulmonary fibrosis or kyphosis by administering any of the recited agents, as well as a lack of teaching in the art for treating eczema by administering the recited agents, other than 25-hydroxycholesterol and 24(R/S)-hydroxycholesterol, and the state of the art teaches the unpredictability of extrapolating in vitro results to in vivo or clinical efficacy.
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable due to the claims encompassing treating oral mucositis, eczema, idiopathic pulmonary fibrosis or kyphosis which affect different organs and tissues, by administering the recited agents. As discussed above, Takahashi teaches the unpredictability regarding the in vivo function of molecular species such as 26-hydroxycholesterol (synonymous with 27-hydroxycholesterol), 24-hydroxycholesterol, 7α-hydroxycholesterol, 25 OHC, 7β, and what kind of function of 25 OHC plays a role in the immune reaction and allergic reaction of the living body, and whether it is effective for prevention or treatment of diseases whose pathology is attenuation or enhancement of immune reaction, autoimmune reaction, or allergic reaction problems were left as unresolved. Likewise, for various cholesterol molecular species other than 25 OHC, its function and therapeutic utility were not sufficiently elucidated.
Additionally, Jansson-Lofmark et al. (See above in the State of the Art Section) taught a multitude of factors involved in assessing clinical efficacy from in vitro potency and the lack of predictability regarding generic predictions of in vivo efficacious concentration based on in vitro potency may be highly variable and may lack biological significance.
Therefore, given the lack of predictability regarding the in vivo function that the recited compounds have with regards to treating the recited diseases, the instant invention remains highly unpredictable.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
Regarding claims 71-76,80,82 and 85-87, the specification does not enable any person skilled in the art to which it pertains to make and/or use the invention commensurate in scope with the claims. The instant specification contains only one example on page 120-121, and which is an in vitro example to identify genes uniquely associated with senescence in skeletal muscle, specific cell populations purified from skeletal muscle, satellite cells, and fibro adiopogenic progenitors (FAPs), and CRYAB was identified as a potential target gene and senescent mDFs and FAPs upregulated CRYAB (paragraphs 0400-0401). The description of Figures 11-13 in paragraphs 0410-0412 disclose in Figure 10, that 25HC treatment specifically kills senescent FAPs at early-timepoints after senescence induction; Figure 11 that 25HC treatment specifically kills senescent mDFs at early-timepoint after senescence induction, and in Figure 12 that 25 HC treatment kills senescent mDFs at late-timepoint after senescence induction, and Figure 13 that treatment of 24(S)HC and 27HC kills senescent IMR-90 cells at early-timepoint after senescence induction.
There are no working examples, showing administration of any of the recited agents to any subject in need thereof in an effective amount that results in treating the recited diseases of oral mucositis, eczema, idiopathic pulmonary fibrosis or kyphosis. Given the lack of any working examples or data showing that the recited method is carried out in vivo, and the lack of guidance in the state of the art, the instant invention remains unpredictable.
The Quantity of Experimentation Necessary
Regarding claims 71-76,80,82 and 85-87, in light of the unpredictability surrounding the breadth of the claimed method, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Further experimentation would need to be done in appropriate animal disease models showing the in vivo effect and function of the recited agents as being capable of treating oral mucositis, eczema, idiopathic pulmonary fibrosis or kyphosis. Therefore, given the lack of guidance present in the specification for the recited method and lack of guidance in the state of the art, further experimentation would be required and would be considered undue.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 71-76,80,82 and 85-87, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above. Therefore, claims 71-76,80,82 and 85-87 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to use the invention commensurate in scope with these claims.
Claim Interpretation
The instant specification discloses an effective amount to be from about 0.1 mg/kg to about 500 mg/kg (paragraph 0362). Therefore, art that teaches a method of administering the same effective amount of any of the recited agents to a subject in need thereof, anticipates the instant claims.
Claim Rejections - 35 USC § 102
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 71-73,80,85 and 86 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the English translation of Takahashi (WO 2017209270, Published 2017-12-07).
Regarding claims 71,72 and 80, Takahashi teaches administering 25-hydroxycholesterol to a patient in need thereof (page 3, paragraph 18), using 25-hydroxycholesterol (25 OHC) in a cell death inducing method or cell death promoting method selective for activated cells among T cells and/or B cells, and for use in a method of treating a disease exhibiting enhanced or abnormality of immune function by activated T cells (paragraph 57, page 5). Takahashi teaches the 25 OHC cell death inducer or cell death promoter treats a disease exhibiting enhanced or abnormal immune function by activated B cells, including eczema (page 5, bottom paragraph; page 10). Takahashi teaches the effective dose of 25-hydroxycholesterol (25 OHC) for one day when administered systemically by oral or parenteral route is a dose of 1-10000 mg, or a dose of 10-100 mg (page 11).
Regarding claim 73, Takahashi teaches in the inventions, an analogue cholesterol of 25 OHC may be used instead or together with 25 OHC, and preferred analogues include 20 alpha-hydroxycholesterol, and 24(R/S), and 25 epoxy cholesterol (page 2, Technical field), and teaches administering an analog cholesterol of 25 OHC which is 24 (R/S) OHC (page 3 bottom paragraph, page 5).
Regarding claim 85, Takahashi teaches systemic administration of 25 OHC by oral or parenteral route (page 11, top paragraph).
Regarding claim 86, Takahashi teaches topically administering 25 OHC to the skin, as well as transdermal administration (page 11, top paragraph).
Conclusion
Claims 71-76,80,82 and 85-87 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636