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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/1/2026 has been entered. Claim(s) 31,47,49-50,52-53 and 55-58 are under examination in this Office action and claims 1-30, 32-46, 48, 51, 54 were cancelled. Any rejection or objection not reiterated herein has been overcome by amendment. Applicant's amendments and arguments have been thoroughly reviewed but are not persuasive to place the claims in condition for allowance for reasons that follow.
Claim Rejections - 35 USC § 112
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.
Claim(s) 31, 47, 49, 50,52,53, and 55, 56-58 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 31 is indefinite in the recitation of “wherein the expression of VDR is increased relative to expression of VDR in a reference human subject that does not have cancer.” Does it mean the human subject with the cancer has increased expression of VDR relative to a reference human, or that the cancer cells have increased expression relative to any type of cell or tissue in the reference human, or a particular tissue type, or something different. Claims 56-58 depend directly or indirectly from claim 31, do not remedy the deficiency, and therefore are indefinite for the same reason.
Claim 47 is indefinite in the recitation “wherein:(i) if VDR expression level is increased in the sample from the human subject relative to the healthy reference then administering vitamin D having a nucleobase sequence that hybridizes to a segment of VDR nucleic acid to the human subject. Vitamin D is a compound and it is not comprised of nucleotides so it does not have a nucleobase sequence. Thus, it is not clear what the actual intent of the amendment to “Viamin D having a nucleobase sequence…” means, since this is not articulated in the specification or known in the art as written, since vitamin D sequence was not submitted. The claim was amended to delete reference to the RNA interference agent or antisense oligonucleotide, but the reference to the nucleobase sequence was not deleted at that time Claim(s) 49,50,52,53, and 55 depend directly or indirectly from claim 49, do not remedy the deficiency, and therefore are indefinite for the same reason.
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 31, 47, 49,52, 53, 55, 56, 57, 58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for treating glioma or AML cancer when increased VDR expression is identified, in a human being, by administering Vitamin D, or for adding an HDAC7 inhibitor to this treatment without other data, or for measuring HDAC7 and inhibiting HDAC7 after considering expression, or for measuring other genes.
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.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosure in the specification alone or in combination with information known in the art, without undue experimentation (see MPEP 2164.01(a)), (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in: In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). The most relevant factors are addressed below:
Nature of the Invention: The claims are directed to a method of human cancer treatment by administration of Vitamin D to a human, when the cancer has increased VDR expression. Additional claims do (and do not) measure additional genes (HDAC7) and administer (HDAC7) inhibitors, to a human. Additional gene expression measures (for 1 or more of SOX2, SNAI2, BHLEHE40, ZFP1) are compared to expression to healthy individuals, though no further treatment is claimed. Accordingly, enablement of the claims would require one of ordinary skill in the art to be able to treat a human with glioma or acute myeloid leukemia by administering Vitamin D at a minimum. This may be supplemented with HDAC7 inhibitor when HDAC7 expression is increased.
Breadth of the Claims: The claims broadly recite treatment of two different types of cancer: glioma, a brain and spinal cord cancer of glial cells, and acute myeloid leukemia: a blood and bone marrow cancer, by administration of Vitamin D, when VDR is relatively highly expressed in a human subject (claims 31, 47).
Additional measurement of HDAC7 that depicts relatively high expression additionally requires administering an HDAC7 inhibitor (claim 49). The glioma and drugs are further described (claims 50, 55, (56, 57), 58). Additional genes are further recited for expression measurement, though no action is taken regarding the treatment, but only comparison is made to healthy subjects of the additional gene expression (claim 52, 53).
There are no details recited regarding any standards, particulars of treatment such as dosages or even dose-ranges, frequency of treatment, duration of treatment, method or route of administration, form of Vitamin D, when to start treatment, or similar features of treatment.
Teachings in the Specification (Direction Provided and Existence of Working Examples):
The Specification does not provide working examples of any treatment, nor any particular detail regarding treatment, dosages, form of administration, duration or frequency of treatment, who may need to avoid treatment, whether factors such as age, sex, or race impact treatment, or other relevant, necessary factual information that would allow a patient to be effectively or safely treated. Laboratory animal studies on treatment are not disclosed either.
Very brief, very general comments on treatment occur in “Examples” (that are prophetic) and in vague, insufficient statements such as: “As an example, subjects having increased expression of VDR or VDR-related genes may be given Vitamin D” [0041].
The specification does recite broad generalizations: “in some embodiments we describe methods of treating cancer comprising using or administering a combination of one or more master regulator antagonists or inhibitors” [0064].
The most information is provided in Table A, which is insufficient for cancer treatment. Table A lists “master regulators” (genes), with cancers in parentheses next to them, and inhibitors, drugs or hormones that can block or mitigate abnormal signals emanating from these master regulators. The two relevant examples: for VDR (GBM, AML) it is recited “Vitamin D: In gbm cells with high VDR expression, which has abnormal signaling leading to higher sox2 expression and driving cancer stem cell growth. Treating cells with Vitamin D reduces this abnormal signal from VDR, leading to lower Sox2, while VDR expression is relatively unaffected. In the second relevant example is “HDAC7(with several different cancers recited), and “HDAC inhibitors, e.g. vorinostat, romidepsin, belinostat, Panobinostat, entinostat, valproic acid”.
[0063] indicates methods are described for treating cancer using one or more antisense oligonucleotides or RNAi agents, but subsequent is only a general descriptor that an antisense oligo is a single stranded oligo that permits hybridization to a corresponding region of a target [0063]. Similar disclosure appears in prophetic example 8 (below) which does not provide detail for treatment.
The specification does point out that glioblastoma and AML are very different cancers (Pg 28 end to Pg 29, top).
The specification is focused on genes as regulators and associated prognosis, and this information does not provide sufficient detail for treatment:
“Example 1: Identifying Masters Regulators of Poor Prognosis using GeneRep algorithm” is the only working example. Cancers in a table were analyzed by GWAS profiles to identify regulators of particular cancer, and regulator genes are presented for different cancers.
“Example 2: Cancer diagnosis” indicates master regulator analysis can be used in cancer diagnosis and expression of genes can be compared to predict risks associated with cancer. Suites of genes are recited that should they have increased expression, indicate possible presence of a particular cancer, or risk of developing or poor prognosis if that cancer is present.
“Example 3: Predicting patient survival” addresses calculating risk scores related to increased expression of “master regulator genes”. Here is it disclosed in a general statement that prognosis/prediction of patient survival can be analyzed across cancer types by analyzing expression of “master regulators” in various pathways.
There is no Example 4.
“Example 5” indicates VDR is “ranked first in glioblastoma multiforme and 2nd in AML”, and both cancers share three masters of death genes: VDR, HDAC7 and NFKB/RELB. It is disclosed that a role for VDR in regulating cancer stem cell factors (SOX2, BHLHE40, SNAI2) was not previously recognized. It is disclosed that it is possible that regulation of immune activation could be the mechanism of how VDR regulates poor prognosis and survival by regulating cancer stem cells [00101]. Gene networks and VDR connectedness to other genes is discussed.
“Example 6” will ask questions about the role of VDR and SOX2 in glioblastoma prognosis. This prophetic discourse asks questions about what happens when VDR is knocked down, and whether Vitamin D will affect VDR or it’s removal may be related to harmful pro-tumor signal.
“Example 7” recites genes that are not addressed in the claims (MYBL2, FOXMI and PTTG1) but that are correlated with poor survival for cancers.
“Example 8” states that the cancers listed in Tables 2 and 3 can be treated by administering immunotherapy compositions, small molecules, RNAi agents, antisense oligonucleotides, or combinations thereof that target master regulators associated with cancer. [00115]. There is no detail or RNAi agent/ antisense functionality presented.
State of the Prior Art:
The state of the art does not suggest that one of ordinary skill would be sufficiently informed on how to treat glioma or AML with Vitamin D and whether and for which patients it would be valuable. The art renders several factors unpredictable in understanding the relationship between Vitamin D and these illnesses.
Takahashi et al (Sc Rep 2018 8:2339) evaluated the relationship between Vitamin D and glioma risk and articulate no association was found between circulating Vitamin D levels and gliomas in general but an inverse relationship was found for glioblastoma (GBM) and Vitamin D levels. The authors consider that a possible protective role for Vitamin D may exist for glioblastoma but not for all gliomas (Discussion) They do not address VDR expression in their work. However age also factored into whether higher levels of Vitamin D appeared protective against high grade glioma (Discussion). Caveats are addressed in the work as a caution where findings may compliment future studies which test more robustly for Vitamin D and glioma and subtypes. There is no Vitamin D treatment recommended in this work.
Cleveland Clinic (my.cleveland.clinic.org/health/diseases/21969-glioma), as of 9/3/2025, recited glioma treatment options as: surgery is often the first treatment (e.g. laser ablation), radiation and chemotherapy after surgery. Vitamin Di is not mentioned.
Regarding acute myeloid leukemia, variability of results and potential treatment with Vitamin D, Mouchel et al (Blood Adv 2023 7:6886-6897) disclosed that for patients undergoing intensive chemotherapy, supplementation with Vitamin D and C was associated with lower rate of bacterial/fungal infection, but no difference in response rate, relapse incidence or overall survival occurred (Abstract). This was true, except for survival of the NPM1 mutant patients, which was higher (Abstract). VDR pathway gene expression is increased in another mutation (IDH1 mutated) AML compared to wild-type (IDH), where (IDH) mutations activate a VDR pathway, priming mutant AML cells to differentiation (Pg. 6887, left col, para 3). Lower vitamin D levels are associated with poorer overall survival in AML in general (Pg 6887 left col, final para). However, there is unpredictability in therapeutic intervention results with Vitamin D analogs, which result in inconclusive data because of adverse effects (Pg 6887, left col, final para), clearly indicating that understanding a treatment option, if one existed, with Vitamin D would require dosing data.
In 2014, Lee et al (Cancer, 2014 120:521-529) found a relationship between low vitamin D3 and AML, where microRNA and SNPs in vitamin D3 pathway genes were evaluated and correlated with vitamin D3 level and treatment outcome (Abstract). Low vitamin D3 was associated with worse relapse-free survival (Fig 1). MicroRNAs and SNPs were found associated with vitamin D3 levels, but none were significant with respect to AML. Lee et al., concluded, it remains to be determined what role microRNA and SNP profiles play in contributing to low vitamin D3 level and whether supplementation will improve outcomes for patients with AML (Abstract). Thus, treatment was not disclosed, however Lee discussed Vitamin D as a potential treatment adjunct in AML for AML with partial loss of 7q (Pg. 6, penultimate para) as well as the fact that if a SNP signature is inherent in AML, supplementing these patients may not affect their outcome (Pg. 6 final para). Therefore factors would need to be considered that may vary, before even adjunct Vitamin D treatment could be considered in Lee’s view.
Even as of 2024, it is disclosed that HDAC7 could potentially function as a predictor for tumor prognosis and for mitigating drug resistance in tumors (Liu, C., et al., Front in Oncol, 2024, 14:1327933). However, unpredictability exists in use for cancer depending on multiple factors (Pg 7, all), which requires a more precise understanding for different types of cancer and the molecular mechanisms that operate in them (Pg 7 lef col final para). Also, in balancing the role of HDAC7 in tumors with it’s normal physiological role must be understood (Pg 7 right col, penult para). As well methods that modulate expression require more work since for example, comprehensive knockdown of HDAC7 during embryonic development can result in lethality (Pg 7 right col, first full para). HDAC7 was found aberrantly expressed in various tumors, with high expression in some tumors, low in others, and Table 1 indicates HDAC7 promotes proliferation of glioma when expression is high. However, HDAC7 inhibitors also display inhibitory impacts on additional class IIa and I HDACS (Pg 7, left col, para 1), so use may not be straightforward. Additional research is required to investigate the pharmacological approaches employed by CHDI, who identified HDAC4 brain penetrating inhibitors for Huntington’s disease, at least two of which demonstrated HDAC7 inhibition as well, which would require additional research for cancer treatment (Pg 7 left col, para 1).
Quantity of experimentation necessary to make and use the invention based upon the disclosure:
Given the very high level of unpredictability found the art on the potential use of Vitamin D in these two diseases in general (not even just as a sole treatment), the possible interactions, and as well unpredictability in HDAC7 inhibitor use, combined with the lack of guidance or teachings in the specification, which does not provide particular guidelines or details for treatment by disease, the quantity of experimentation necessary to make and use the invention, particularly since no art was found saying treat these disorders with Vitamin D when VDR demonstrates relative elevated expression, would be very high.
In conclusion, taking into consideration the factors addressed above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, including working examples or absence thereof, an undue amount of experimentation would be required to make and use the invention as claimed.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 31, 47, 49, 50, 52, 53, 55-58 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The instant claims recite a law of nature, that is a natural correlation between having cancer (glioma or AML) and increased expression of VDR relative to a reference human subject that does not have cancer.
Regarding laws of nature, their unpatentability was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012). “Laws of nature, natural phenomena, and abstract ideas” are not patentable. Diamond v. Diehr, 450 U.S. 175, 185 (1981); see also Bilski v. Kappos, 561 U.S. 593, 604, 95 USPQ2d 1001, 1007 (2010).
Regarding 101 Analysis and step 1: Yes, the claims are directed to a method, a valid statutory category.
Re: step 2A, prong 1: Yes, the claims recite a judicial exception (law of nature, natural phenomena, natural products, or an abstract idea); a natural correlation between cancer (glioma or AML) and increased expression of VDR relative to a reference human subject that does not have cancer. Additional judicial exception in claims 31 and 47, include an abstract idea or basic mathematical calculation, that is the comparison made to identify increased expression relative to a reference. The same correlation issue holds for claim 49 which also recites the same type of gene expression-based comparison, and for claim 52.
Re: step 2A, prong 2: No, claims 31, 47, 49, and 52, 53, 55, 56 including any additional elements, do not integrate the judicial exception into a practical application, since they do not apply or use the judicial exception in a manner that imposes a meaningful limit on the exception, such that the judicial exception is not monopolized (see MPEP 2106.04(d)).
While the method of claim 31 includes treating cancer by administering Vitamin D to a human if the cancer “has increased expression of Vitamin D receptor”, this is not sufficiently particular’. Per MPEP 2106.04(d)(2)a) particular means “specifically identified so that it does not encompass all applications of the judicial exception(s)”, and the claim 31 recitation encompasses all applications of the exception of increased VDR expression associated with glioma or AML. Notably however, not all subjects are treated, only those with high VDR expression; others remain untreated and where no treatment is not required, nothing further occurs, which contributes to monopolizing the judicial exception. Claim 56 merely repeats administration of Vitamin D.
For contrast, when the “Federal Circuit” held claims at issue in Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018), were eligible under 35 U.S.C. § 101, the eligible method recited a particular method of treating a patient with schizophrenia with a specific drug, iloperidone, in a designated manner. Specifically, a determination of whether the patient was a CYP2D6 poor metabolizer occurred, by using a genotyping assay, followed by administering iloperidone in an effective amount, based on determination that: in one dosage range if the CYP2D6 poor metabolizer genotype was present, and in a second dosage range (a larger amount of drug) if the patient did not have the poor metabolizer genotype, such that all patients were treated, but in a differential and particular manner, dependent upon genotype. Thus, the claims were directed to a method of using an effective amount of iloperidone to treat the schizophrenia patients, in a manner that was more than simply “apply it” and as such, this integrated the judicial exception.
Claims 47, 49, 52, 53, 55, 57, 58 also do not integrate the judicial exception into a practical application, since they do not apply or use it in a manner that imposes a meaningful limit on the exception, such that the exception is not monopolized (see MPEP 2106.04(d)). Re: claim 49, 52, measuring increased expression of a gene encompasses all practical applications of this law of nature. Here again, a fraction of subjects are administered an inhibitor, while others receive nothing. Claim 52 only incorporates measuring and comparing gene expression and claim 53 has no additional elements.
Claims 55 and 58 are Markush claims that broadly encompasses “the inhibitor of HDAC7”, where alternative options recited are Pan-HDAC non-selective inhibitors, as well as any and all hybridizing RNAi agent/antisense oligonucleotides, which is not considered particularly limiting. Claim 57 similarly recites administering an inhibitor of HDAC7, not a particular treatment/administration.
Yoon (Yoon, S. et al., 2016 Chonnam Med J) disclosed principal HDAC inhibitors approved by FDA as including: Vorinostat, Romidepsin, Panobinostat and Belinostat, for cancer (Abstract) and there appear to be no FDA-approved drugs that specifically target HDAC7, therefore, the claim is not considered to be particularly limiting since the Markush claim protects broadly against infringement of use of any and all of the recited inhibitors, not a particular inhibitor.
Re: step 2B: Additional elements do not amount to significantly more than the judicial exception, and here, these do constitute insignificant extra-solution activity since the claims employ well-understood, routine and conventional activity.
For claims 1, 47, administration of Vitamin D to a human is routine as disclosed by deSevaux et al (2008, J Am Soc Nephol 13:1608-1614), who discussed treatment with Vitamin D for loss of bone mineral density in renal transplant recipients (Abstract, left col). Similarly, measuring VDR expression relative to a reference has been known for at least nearly two decades (Menezes et al, 2008, Cancer Epidemiol Biomarkers Prev 17:1104-1110). Menezes et al. compared VDR expression in healthy and tumorous lung tissue (Pg 1104, Abstract left col). Re: claim 47, To perform their work, Menezes et al. obtained sample from human subject (Pg. 1105, left col para 2) and then measured and compared VDR expression (above), which suffices for claim 49 as well. Nevertheless, it is also true that HDAC7 expression has been previously measured when Yu compared HDAC7 expression between cancerous and noncancerous samples (Yu, Y et al., 2017, Clin. Transl. Oncol., 19 (8: 1045-1054), though to be entirely clear, when addressing additional elements, it is not required that particular genes are encompassed by the art, since the insignificant extra solution activity does not relate to any particular gene, merely the measurement of gene expression, which means the measuring expression and comparing expression of claims 52 and 53 is also met by prior art.
Further re: claim 49, administration of an HDAC7 inhibitor to a human has been performed. Cook et al (Cook, A CNS Drugs 2016 30:71-77) reviewed records of patients receiving infusion of valproic acid, an HDAC7 inhibitor (Abstract), as discussed in the instant specification.
The comparing the expression of a gene in a sample with that of a reference sample found in claims 31, 47, 49, 52, to identify higher expression is considered a mental process that amounts to an abstract idea since the calculation relies upon the application of a mathematical formula and can be “performed within the mind.” MPEP 2106.04(a)(2)(III). Notably, the courts do not distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer MPEP 2106.04(a)III., Mental Processes.
The additional claim, claim 50, is considered a field of use limitation, here that narrows the law of nature to consider a particular cancer but that does not further characterize the exception of claim 47 in a manner so as to integrate the claim or concept into a practical application (see MPEP 2106.04(d)(2)).
Thus, claims 31, 47, 49, 50, 52, 53, 55-58 constitute judicial exceptions that are not integrated into a practical application, and are considered judicial exception without significantly more (see MPEP 2106.04(d)(2)) and therefore are patent ineligible under 35 § U.S.C. 101.
Response to Remarks:
Applicant’s comments address amended claims and support, 112(b), and the Claim 31 rejection under 35 U.S.C. § 103, and amendments in view thereof, none of which requires a response.
Conclusion
All claims rejected.
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/LISA HORTH/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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