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 .
Claim Status
Claims 191-203 and 208-225 are withdrawn from consideration.
Claims 204-207 are examined on the merits.
Election/Restrictions
Claims 191-203 and 208-225 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/25/2025.
Applicant’s election without traverse of Group II corresponding to claims 204-207, in the reply filed on 08/25/2025 is acknowledged.
Priority
This application is a national stage application, of International Patent Application No. PCT/US2021/041934, filed 07/16/2021, which claims priority from U.S. Provisional Application 63054531, filed 07/21/2020 is acknowledged.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show color as described in the drawings.
Fig. 8D, indicates “Green”: upstream plus gRNA binding site and “Red”: downstream of gRNA binding site, but there is no color, the drawings are indicated in black and white .
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency #1– Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. For example see Figures: 4A, 4C, 8B, 8C, 8D.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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 204-206 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.
The phrase “treating a medical condition” is recited in the claim at the level of breadth that is not adequately supported in the specification. The disclosure does not describe which medical conditions are intended to be treated, nor does it provide sufficient experimental data, examples or rationale, to demonstrate that administration of polynucleotide SEQ ID NO 1 or administering RUNX1 protein conjugated to polynucleotide SEQ ID NO 1 would be effective across the full scope of all possible “medical conditions”. Absent of description of disorders or diseases and without supporting evidence of therapeutic utility in any defined context, the specification fails to reasonably convey to one of ordinary skill in the art that the inventors were in possession of a method of “treating a medical condition” as broadly claims.
Claims 204-206 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 administration of LncRNA LOUP, does not reasonably provide enablement for treating a medical condition or cancer. 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 the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404: Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The instant claim 204 is drawn to a method of treating a medical condition in a subject, wherein the method comprises:(a) administering the polynucleotide of claim 191 to the subject; or (b) administering a construct comprising a RUNX1 protein, or fragment thereof, conjugated to the polynucleotide of claim 191 to the subject. The claim 205 The method of claim 204, wherein the medical condition is a cancer. The nature of the claim is complicated, because the claim requires the outcome of “treating a medical condition in a subject”, yet the claim is drawn to administering a polynucleotide SEQ ID NO 1 alone, or conjugated with RUNX1 protein as the only step.
Breadth of the claim: The claims encompass the use of polynucleotide alone or conjugated to RUNX1 to treat a medical condition in a subject. The breadth of the claim far exceeds the limited disclosure in the specification. The phrase “treating a medical condition” is unclear and encompasses an indeterminate range of diseases or disorders, leaving one of ordinary skill uncertain as to the boundaries of the claim. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification and existence of working examples: The specification envisions a method of treating a medical condition in a subject in need thereof by administering polynucleotide, construct, vector, and/or cell of any one of the above embodiments. In some embodiments, the medical condition is a cancer (e.g., a blood cancer (e.g., acute myeloid leukemia (AML) or myeloma), or a liver cancer (e.g., metastatic hepatocellular carcinoma (HCC))). (e.g., paragraphs 6-7th, page 5). The specification envisions a “therapeutically effective amount" refers to an amount, e.g., a pharmaceutical dose of a composition described herein (e.g., a composition containing featured polynucleotides (e.g., polynucleotides including a nucleic acid sequence with at least 20 nucleotides of SEQ ID NO: 1, and variants thereof with at least 85% sequence identity thereto), constructs including the lncRNA (e.g., constructs including a protein linked to a LOUP polynucleotide (e.g., paragraph 4th, page 16). The specification envisions the terms "treatment" and "treating" refer to reducing or ameliorating a medical condition (e.g., a disease or disorder associated with PU.1 expression (e.g., a cancer (e.g., acute myeloid leukemia, liver cancer, or myeloma)), Alzheimer's disease, or asthma) and/or symptoms associated therewith (e.g., paragraph 2nd, page 17). The specification envisions that LOUP cooperates with RUNX1 to facilitate URE-PrPr interaction (e.g., paragraph 2nd, page 21; Figs. 10A-G).
The specification discloses the discovered that an uncharacterized myeloid-specific lncRNA, termed "bong noncoding RNA Originating from the URE of PU.1 or LOUP, induces gene-specific long-range transcription by modulating enhancer docking to a specific proximal promoter. LOUP is a product of unidirectional transcription, and undergoes splicing and polyadenylation, thereby exhibiting all the features of a 1 de RNA. At single-cell resolution, LOUP and PU. 1 expression is stringently associated with myeloid lineage identity. Both gain- and loss-of-function experiments demonstrated a LOUP-dependent expression of PU.1. We further discovered that LOUP associates with chromatin and induces interaction between the URE and the PrPr, resulting in the formation of an active chromatin loop at the PU. 1 locus. Finally, we showed that LOUP recruits RUNX1 to its DNA-binding motifs at both the URE and the PrPr via a region
embedded with transposable element (TE) variants (e.g., paragraph 3rd, page 22). The specification envisions methods of treatment: a subject in need of treatment for a disease or disorder associated with reduced expression of the transcription factor PU. 1 (e.g., a cancer, such as AML, liver cancer, or myeloma) can be administered a composition described herein that increases expression of PU.1 (e.g., paragraph 5th, page 39).
The specification does not teach working examples indicating treating a medical condition by the administration of polynucleotide SEQ ID NO 1 or conjugated with RUNX1.
Predictability and state of the art: The state of the art with respect to using polynucleotide SEQ ID NO 1 or conjugated with RUNX1 for treating a medical condition a disease, disorder, or condition associated reduced levels of PU.1 is under developed and unpredictable, the function of PU.1 is still controversial. Trinh et al. (Blood, 2021) teaches that lncRNA LOUP coordinates with RUNX1 to induce PU.1 long range transcription, conferring myeloid differentiation and inhibiting cell growth (e.g., abstract; Fig. 4). Kim et al. (Oncotarget , 2015) teaches PU.1-induced differentiation
of monocytic leukemia cells into macrophages is important for the development of hematological cancers and IL-32θ suppresses the differentiation of monocytes to macrophages by decreasing PU.1 expression. Gerlach et al. (J. Crohns Colitis. 2022) teaches that PU.1+ Th9 cells accumulate in experimental colorectal tumors. Absence of IL-9 in T cells or deactivation of PU.1 resulted in damaged tumor growth, implying a pro-tumor role for PU.1+ Th9 cells. Xu et al. (Oncol Lett. 2018) teaches Transcription factor PU.1 is involved in the progression of glioma. Yuki et al. (Blood, 2013) teaches PU.1 is an effective tumor inhibitor in classical Hodgkin's lymphoma cells and upregulation of PU.1 expression is a recommended option for treating Hodgkin's lymphoma patients. Liu et al. (Medical Oncology, 2023) teaches that PU.1 negatively regulates tumorigenesis in non‑small‑cell lung cancer.
Thus, the teachings of the post-filing art are consistent with the prior art demonstrating the underdeveloped and unpredictable nature of the invention.
Neither the specification nor prior art teaches about treating a medical condition by administering polynucleotide SEQ ID 1 or conjugated with RUNX1, neither teaches the implications and long-term effects of continuous administration of the polynucleotide in normal tissues.
Amount of experimentation necessary: In light of the breadth of the “treating a medical condition”, the absence of examples, and the lack of guidance undue experimentation would be required to make use of polynucleotide SEQ ID NO 1 or conjugated with RUNX1 for treatment of disease or cancer associated with PU.1. Treating a disease requires an understanding of the disease etiology. The specification is silent as to how one of ordinary skill in the art would determining the timing, dosage of the administration to the disease. Absent of such guidance, undue experimentation would be required to practice the full scope of the claimed method.
In view as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 204-206 are not considered to be enabled by the instant disclosure. the claims are not enabled commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 204-207 are rejected under 35 U.S.C. 103 as being unpatentable over Trinh et al. (“Trinh”, Blood, 2018) in view of Murray et al. (“Murray”, WO-0055373-A2) and Tyner et al. (Tyner”, WO 2020/023921 A1).
Trinh teaches that Long Noncoding RNA Loup interacts with Runx1 and regulates Long-Range Transcription of PU.1 in Acute Myeloid Leukemia (e.g., Title). Trinh teaches RNA-seq analysis of human AML samples retrieved from the Cancer Genome Atlas (TCGA) showed that LOUP expression is reduced in samples belonging to acute promyelocytic leukemia (APL) subtype. Provide a molecular explanation for cell type-specific expression of PU.1 and point to the possibility of modulating local chromatin structure by noncoding RNAs as a therapeutic approach to restore proper PU.1 expression in AML cells (e.g., abstract).
Trinh does not teach the SEQ ID NO 1 as required by the of the instant claims. Trinh does not teach the method of treating AML as required by the instant claims. However, this is cured by Murray and Tyner.
Murray teaches that the mononuclear phagocytic system consists of
circulating monocytes in the blood and macrophages in the tissues. During hematopoiesis in the bone marrow, myeloid progenitor cells differentiate into promonocytes, which leave the bone marrow and enter the blood, where they differentiate further into monocytes (e.g., paragraph 0002). Murray teaches identification of nucleic acids and expression profiles involved in destructive macrophage (DM) development, and to the use of such expression profiles and nucleic acids in methods for identifying candidate agents which modulate this development (e.g., abstract). Murray teaches SEQ ID NO 49 that has 100% homology with SEQ ID NO 1 of the instant claims (e.g., Fig. 49).
Tyner teaches methods of treatment for Acute Myeloid Leukemia in a human, wherein mutations are present in the genes frequently associated in AML, including mutations in one or more genes
selected from the group of NPMl, ASXL1, DNMT3A, NRAS, CBF~.MYH11, IDH1, IDH2, FLT3, FLT3-ITD, MLLT3-KMT2A, MYC, CEBPA, PDSSB, SRSF2, BCOR, RUNX1 (e.g., paragraph 2nd, page 2). Tyner teaches methods of treatment for the mutated conditions above, each generally comprising the steps of: a) obtaining a biological sample from a living human subject or patient with Acute Myeloid Leukemia; detecting whether a particular mutation described herein is present or absent in the biological sample by contacting the biological sample with a probe that binds to the particular mutation; detecting binding between the probe and the protein or gene in question; and, in the presence of binding associated with a particular mutation, administering to the human in need thereof a pharmaceutically or therapeutically effective amount of a specified drug or drugs referenced for the mutation herein (e.g., paragraph 3rd, page 2).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use the SEQ ID NO 49 taught by Murray as the long noncoding RNA Loup that interacts with Runx1 and regulates the transcription of PU.1 in Acute Myeloid Leukemia taught by Trinh and integrate in the method of treatment for Acute Myeloid Leukemia in a human taught by Tyner, for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a method comprising inducing the expression of PU.1 by administering the polynucleotide SEQ ID 49 for the treatment of AML.
One of ordinary skill in the art before the effective filing date of the invention would have been motivated to do so in order to develop a method for treatment of Acute Myeloid Leukemia comprising inducing the expression of PU.1 by administering the polynucleotide SEQ ID 49.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/J. E. ANGELL, Ph.D./Primary Examiner, Art Unit 1637