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 present application, filed on July 8, 2022, is a 371 of PCT/US2021/13290, filed on January 13, 2021, and claims priority to U.S. Provisional Patent Application Nos: 62/960,623, filed January 13, 2021 and 62/990,784, filed March 17, 2020.
Election/Restrictions
Applicant's election with traverse of “Group I (Claims 1, 2, 6, 7, 10, 12, and 15-21)” in the reply filed on November 5, 2025 is acknowledged. It appears that the election of this group contains a typographical error, as Claim 15 belongs in Group III, as specified in the requirement for restriction mailed August 5, 2025 and as acknowledged by the response. Therefore, the provisional election made in the response is to “Group I (Claims 1, 2, 6, 7, 10, 12, and 16-21)”. The traversal is on the ground(s) that “the correct standard for determining unity of invention is stated in rule 37 C.F.R. 1.475(a).” This is not found persuasive because the examiner applied this standard in the requirement for restriction of record. 37 C.F.R. 1.475 reads:
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37 C.F.R 1.475 (a) (see above) states that “Where a group of inventions is claimed in an application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.
As was described in the requirement for restriction dated August 5, 2025, the shared technical feature common to the claimed inventions of Groups I, II, and III is not a special technical feature, as it does not make a contribution over the prior art in view of Oliveira-Mateos et al. (see requirement for restriction of record). Because 37 C.F.R. 1.475 states “the requirement of unit of invention shall be fulfilled only when there is a technical relationship among those inventions involving the same or corresponding special technical feature”, and there is no special technical feature shared among the claims, unity does not exist between the inventions of Groups I, II, and III.
The requirement is still deemed proper and is therefore made FINAL.
Claims 8, 15, 22, and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on November 5, 2025.
Claim Status
Claims 1, 2, 6-8, 10, 12, and 15-23 are currently pending. Claims 8, 15, 22, and 23 are withdrawn. Claims 1, 2, 6, 7, 10, 12, and 16-21 are under examination.
Drawings
The drawings are objected to because categorical labels and text throughout the figures are so unclear as to be largely illegible. Corrected, higher quality 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:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that the sequences present in the specification as originally filed are not the same sequences provided in the sequence listing parts of the disclosure. For example, SEQ ID NO: 10 listed on page 49 of the instant specification is 5’-GUAACUGAAACUUACUUAA-3’ (length:19 nt), while in the sequence listing PDF and computer-readable file, SEQ ID NO: 10 is listed as: 5’-GAACGAAAGACAA-3’ (length:13 nt). It appears that the SEQ ID NO:10 provided in the specification has no discernable relationship to the SEQ ID NO: 10 present in the sequence listing. Furthermore, the SEQ ID NO: 10 listed on page 49 of the specification filed on July 8, 2022 is not present anywhere in the sequence listing filed on July 11, 2025 AND the SEQ ID NO: 10 in the sequence disclosure filed on July 11, 2025 is not present anywhere in the specification filed on July 8, 2022.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and a statement that the substitute specification contains no new matter.
Specification
The use of the terms: Trizol, Invitrogen, SuperScript, Applied Biosystems, TaqMan, Addgene, pBluescript, pBabe, Lipofectamine, RNAiMax, Sigma, “Santa Cruz”, Alexa Fluor, Essen BioScience, IncuCyte, Corning, Visiopharm, Dako, Agilent, Roche, Vector Laboratories, Label IT, Mirus, ThermoFisher Scientific, Molecular Devices, Genepix, Pierce, Abcam, Cell Signaling, and a list of trademarked anticancer therapeutics on pages 25-30, which are each a trade name or a mark used in commerce, has been noted in this application. Each term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The listing of references in the specification (on pages 52-66) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The amendment filed on July 11, 2025 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: The nucleotide sequences disclosed in the sequence listing filed on July 11, 2025 do not match the sequences originally disclosed and present in the specification as filed on July 8, 2022 (see nucleotide sequence listing section above). Therefore, the introduction of the new sequences in the July 11, 2025 amendment are new matter.
Applicant is required to cancel the new matter in the reply to this Office Action.
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.
Claims 1, 2, 6, 7, 10, 12, and 16-21 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
Relevant to the lack of particular structural limitations in the rejected claims drawn to a) measuring the expression level of lncRNA for “TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8…”, and b) “wherein the cancer comprises a TAP63 regulated cancer…” MPEP 2163 states:
“The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.” Additionally, at 2163 II A3 (a), the MPEP states:
“describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene “because it is only an indication of what the gene does, rather than what it is.”); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ3d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The present claims are broadly drawn to methods comprising measuring expression levels of at least one of the recited “TROLL” lncRNAs, WDR26, or NCOA5 in any cancer (claims 1,2, 6-7, 10, 16-18, and 20) or wherein the cancer “comprises a TAP63 regulated cancer” (claims 12, 19, and 21).
In the case of the instant claims, the functionality of “TAP 63 regulated” lncRNA or cancer is a critical feature of the claimed methods.
The specification defines “TROLLs” are “TAp63-regulated oncogenic lncRNAs” (page 21) (i.e. are functionally defined as long noncoding RNAs that a) are oncogenic and b) are regulated by p63 isoforms comprising an N-terminal transactivation domain).
It is noted that the “TROLL” nomenclature utilized to identify the recited long noncoding RNAs are not used in the prior art and appear to be particular to the present applicants. The specification teaches corresponding gene names for “TROLLs” that are present in the prior art (page 48, table 1, reproduced in part below).
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No complete sequences of the TROLLs are provided in the disclosure. Therefore, the nucleotide sequences (i.e. structures) of the TROLLs are described/defined only by their concordance with previously published sequences referenced in table 1. Specifically, TROLL-2 is described as RPSAP52, TROLL-3 is described as TRAF3IP2-AS1, TROLL-2 is described as NCBI accession NR_015410, TROLL-5 is described as LINC00514, TROLL-6 is described as RP11-13811.3, TROLL-7 is described as MALAT1, and TROLL-8 is described as AL161668.12.
“RP11-98G7.1” appears to refer to multiple GTEx transcripts mapped to the cytogenetic map clone “RP11-98G7” placed on hg38 overlapping with the MIR9-1HG gene (see below). It is unclear whether “RP11-98G7.1” refers to MIR9-1HG, one (or all of) the transcript models in the “RP11-98G7.1” cytogenetic map clone, or something else entirely. Furthermore, there is no sequence provided for “TROLL-1” in the present disclosure.
It is additionally noted that nucleotide sequences are not provided for the primers in Table 1 that were used for qRT-PCR of the recited lncRNAs and genes.
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Similarly, TROLL-8 (i.e. “AL161668.12”) is a cytogenetic map clone consisting of 147,393 base pairs comprising several full gene models (NDRG2, MIR6716, RNASE13, TPPP2, ENSG00000255472, RNASE 7, RNASE8, ENSG00000299988, ARGEF40, ZNF219, ENSG00000178107, AND RNU6-252P) and there is no indication as to which gene model “AL161668.12” refers. There is no sequence provided for “TROLL-8” in the present disclosure.
The specification additionally teaches “Tap63 regulated cancer such as breast cancer (but not limited to triple negative breast cancer, lung cancer (including, but not limited to adenocarcinomas and squamous cell carcinomas), ovarian (including, but not limited to serous and non-serous adenocarcinomas), liver cancer, colon cancer, or melanoma)” (e.g., page 24) OR “any disease where uncontrolled cellular proliferation occurs such as cancers. A representative but non-limiting list of cancers that the disclosed compositions can be used to treat is the following: lymphoma, B cell lymphoma, T cell lymphoma, mycosis fungoides, Hodgkin's Disease, myeloid leukemia, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, squamous cell carcinoma of head and neck, lung cancers such as small cell lung cancer and non-small cell lung cancer, neuroblastoma/glioblastoma, ovarian cancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas of the mouth, throat, larynx, and lung, cervical cancer, cervical carcinoma, breast cancer, and epithelial cancer, renal cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, large bowel cancer, hematopoietic cancers; testicular cancer; colon cancer, rectal cancer, prostatic cancer, or pancreatic cancer. For example, the cancer can be a Tap63 regulated cancer such as breast cancer (but not limited to triple negative breast cancer), lung cancer (including, but not limited to adenocarcinomas and squamous cell carcinomas), ovarian (including, but not limited to serous and non-serous adenocarcinomas), liver cancer, colon cancer, or melanoma. In some instances the cancer comprises a p53 mutation.” (page 25). Furthermore, the specification defines: “The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, feline…, guinea pig, rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient.” (page 18).
The specification teaches only “identification of TROLLs” in: human breast cancer (page 35-40, paragraph 1) and mouse models of human breast cancer (page 45, paragraph 3). The specification teaches overexpression of only TROLL-2 and TROLL-3 in ovarian, colon, melanoma, and breast cancer (page 40, paragraph 2- page 41)
Therefore, the “cancer” recited by the claims encompasses an effectively unlimited genus encompassing any cancer in any organism, and the “Tap63 regulated cancer” recited by the claims encompasses a functionally defined genus of any cancer that is regulated by Tap63 (i.e. is in any way influenced by the over-, under- expression, or function of Tap63).
The specification does not teach the structure of the recited “TROLLs” or the actual breadth of the genera “cancer” (in any organism) or “Tap63 regulated cancer”, or which cancers may or may not fall into this subgenus.
The claims encompass genera of structurally undefined “TROLLs” and “Tap63 regulated cancers”.
For claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F. 3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615.
Further, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
An adequate written description of a DNA, such as the cDNA of the recombinant plasmids and microorganisms of the '525 patent, "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
Thus considering the breadth of the compounds/genera required by the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
Claims 1, 2, 6, 7, 10, 12, and 16-21 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for detecting the presence of, assessing tumor grade and/or progression, and/or metastasis, assessing the efficacy of a treatment regimen, or treating an ovarian cancer, a colon cancer, a melanoma, or a breast cancer in human or mouse subjects comprising measuring expression of TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or WDR26 and/or NCOA5, does not reasonably provide enablement detecting the presence of any cancer in any organism comprising measuring expression of TROLL-1 or TROLL-8. 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112(a) have been described by the court in In re Wands, 8 USPQ2d 1400 (CAFC 1988). Wands states at page 1404, “Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability of the art, and (8) the breadth of the claims.”
The nature and breadth of the claims
The claims are drawn to methods of detecting the presence of any cancer in any organism comprising measuring the expression of TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, TROLL-8, WDR26, and/or NCOA5 in a tissue sample from the organism compared to a control, wherein the presence or higher expression relative to the control of the recited lncRNAs or protein-coding genes indicates the presence of the cancer.
As broadly claimed, “a subject” is not limited to any particular organism. Furthermore, “a cancer” is not limited to any particular type of cancer and may be interpreted as encompassing any cancer.
Claims 12, 19, and 21 further require that the cancer is a “TAP63 regulated cancer”.
The unpredictability of the art and the state of the prior art
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The art does not appear to teach an unambiguous sequence for “TROLL1” or “TROLL-8”. The art, for example, Rodriguez-Enriquez et al., “Multi-Biomarker Pattern for Tumor Identification and Prognosis” Journal of Cellular Biochemistry 112:2703-2715 (2011) teaches that “Because it is well known that several pathways and processes are altered in tumor cells, the concept of ‘‘single marker’’ in cancer results [is] incorrect.” (Rodriguez-Enriquez et al., abstract). Rodriguez-Enriquez et al. teach that biomarkers of particular cancers require extensive data for validation based on large randomized clinical trials, meta-analyses that include patients with both high and low levels of the biomarker and that said validation requires establishment of a strong correlation between presence/absence or changes in the biomarker and a treatment and that evaluation of baselines and biomarker value has to be carried out rigorously in parallel for normal adjacent cells as well as for suspected cancer cells. Rodriguez-Enriquez et al. further teach that many such markers have been developed using subjective criteria and convenient choice of cut-off points that add confusion rather than clarification on the real value of established or new marker and on understanding of clinical outcomes (Rodriguez-Enriquez et al., page 2704). Finally, Rodriguez-Enriquez et al. teach “the traditional approach of selecting individual proteins (Ki67, cyclins, HIF-1a, and HIF-1a targets) operating in a common or in different pathway (proliferation, angiogenesis, apoptosis, or glycolysis) results incorrect because there is no single biomarker for any cancer type. In fact, unsuccessful clinic outcomes emerge when treatment against individual biomarker is performed (Table I). Therefore, efforts must be oriented to the use of a cancer biomarker pattern, that is, a combination of several biomarkers from different altered pathways (proliferation + angiogenesis + hypoxia + glycolysis), to reach a better understanding of cancer progression and to achieve prognostic significance in solid cancers. (Rodriguez-Enriquez et al., page 2711, column 2).
Guidance in the Specification and Working Examples
The specification provides examples wherein expression of the recited TROLLs are different between human or mouse controls and cancer cells, but only silencing of TROLL-2 decreased cell proliferation (page 36). The specification demonstrates TROLL-2 and TROLL-3 expression levels positively correlate with progression of human breast cancer, but does not provide such examples for the other recited lncRNAs. Finally, the specification states “In conclusion… we have identified novel biomarkers associated with cancer progression: two TAp63-regulated oncogenic lncRNAs or “TROLLs”” [TROLL-2 and TROLL-3] “and one of their common interacting proteins, WDR26.” (page 46).
It is noted that the specification does not unambiguously provide structural description of TROLL-1 or TROLL-8 because there is no identification of these unique gene identifiers by a synonymous gene symbol known in the art and there is no complete nucleotide sequence provided for these lncRNAs in the disclosure.
The guidance in the specification demonstrates a working example for at least one species of TAp63-regulated cancer (i.e. human breast cancer) within the genus “cancer” or “TAp63-regulated cancer” for two of the recited lncRNAs (i.e. TROLL-2 and TROLL-3) and their associated protein (i.e. WDR26). This guidance amounts to an invitation for the skilled artisan to try and follow the disclosed instructions to make and use the claimed invention as broadly claimed ( measuring the expression of any one of the recited lncRNAs or protein coding genes for any cancer in any organism).
Quantity of Experimentation
The quantity of experimentation in this area is extremely large since there are a significant number of parameters which would have to be studied to use the invention for any cancer in any organism or any cancer in a human comprising measuring only any one of the recited genes. For example, as described by Rodriguez-Enriquez et al., biomarkers of particular cancers require extensive data for validation based on large randomized clinical trials, meta-analyses that include patients with both high and low levels of the biomarker and that said validation requires establishment of a strong correlation between presence/absence or changes in the biomarker and a treatment and that evaluation of baselines and biomarker value has to be carried out rigorously in parallel for normal adjacent cells as well as for suspected cancer cells. Further, many such markers have been developed using subjective criteria and convenient choice of cut-off points that add confusion rather than clarification on the real value of established or new marker and on understanding of clinical outcomes (Rodriguez-Enriquez et al., page 2704). Finally, Rodriguez-Enriquez et al. teach “the traditional approach of selecting individual proteins (Ki67, cyclins, HIF-1a, and HIF-1a targets) operating in a common or in different pathway (proliferation, angiogenesis, apoptosis, or glycolysis) results incorrect because there is no single biomarker for any cancer type. In fact, unsuccessful clinic outcomes emerge when treatment against individual biomarker is performed (Rodriguez-Enriquez et al., Table I).
Together, the specification and the art teach that the genera “cancer in a subject” and “TAp63-regulated cancer” are very broad and diverse categories comprising dozens to hundreds of different species for each “subject” species (i.e. human vs mouse vs. canine., etc.). Furthermore, the specification and the art teach there are many unpredictable variables comprising at least: a) the requirement for large clinical trial datasets to validate each individual marker or combination of markers for each subject type and for each cancer type b) requirement for meta-analyses of expression levels of each marker or combination of markers in different subjects, c) intra-tumor heterogeneity of gene expression, and d) evaluation of meaningful baseline expression values and cutoffs. Furthermore, the prior art teaches negative results using single biomarkers for detection of cancer. “many such markers have been developed using subjective criteria and convenient choice of cut-off points that add confusion rather than clarification on the real value of established or new marker and on understanding of clinical outcomes (Rodriguez-Enriquez et al., page 2704). Finally, Rodriguez-Enriquez et al. teach “the traditional approach of selecting individual proteins (Ki67, cyclins, HIF-1a, and HIF-1a targets) operating in a common or in different pathway (proliferation, angiogenesis, apoptosis, or glycolysis) results incorrect because there is no single biomarker for any cancer type. In fact, unsuccessful clinic outcomes emerge when treatment against individual biomarker is performed (Rodriguez-Enriquez et al., Table I).”.
This would require significant inventive effort including generating large clinical trials spanning the genera “subject” (i.e. all organisms), “cancer” (i.e. all cancers), “TAp63-regulated cancer” (i.e. all or a representative number of species encompassing the total variation within the genus), for each single biomarker (e.g. “TROLL-2”) and/or each combination of biomarkers (e.g. “TROLL-1 and TROLL-2 and WDR26”), with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the successive steps.
Level of Skill in the Art
The level of skill in the art is deemed to be high.
Conclusion
In the instant case, given the extremely broad claims in a highly unpredictable art, the large quantity of experimentation required to define and resolve these unpredictable variables, the lack of guidance provided in the specification and art commensurate with the scope of the claims, and lack of working examples outside TROLL-2 and TROLL-3 expression with WDR26 localization in human breast cancer, balanced only against the high level of skill in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claims as broadly written.
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.
Claims 1, 2, 6, 7, 10, 12, and 16-21 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recites the limitation "measuring the expression level of the long non-coding RNA for…" in line 3. There is insufficient antecedent basis for this limitation in the claim. Furthermore, it is unclear to which long non-coding RNA the claim refers, as at least some of the recited genes are expressed as multiple transcripts/isoforms (i.e. different long non-coding RNAs for a single gene) (for example, see specification page 38 “the longest transcript of TROLL-3…”).
Claim 1 recites the limitation "…wherein the higher the level of…NCOA5 and/or the more WDR26 and/or NCOA5 localized in the cytoplasm of a cell…" in lines 6-7. There is insufficient antecedent basis for this limitation in the claim. Claim 1 recites only steps of “obtaining a tissue sample from a subject” and “measuring the expression level of the long non-coding RNA for TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8 and/or expression level of WDR26”. The claim does not recite an active step of measuring NCOA5 expression OR of measuring the localization of WDR26 and/or NCOA5.
Claim 1 is also rendered indefinite because it is unclear how the preamble is intended to breathe life and meaning into the claim. The preamble of claim 1 is directed to “A method of assessing tumor grade and/or progression of a cancer and/or metastasis or detecting the presence of a cancer in a subject…” However, the claim only requires active, positively recited method steps of “obtaining a tissue sample from a subject” and “measuring the expression level of the long non-coding RNA for TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8 and/or expression level of WDR26”. Thus, it is not clear if applicant intends to cover any method for measuring an expression level of any one (or any combination) of the recited genes in a tissue sample from a subject, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If the claim requires something more, it is unclear what additional active process step the method requires and it appears that the claims are incomplete. The claims fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims.
The terms “higher”, “greater”, “increased” and “decreased” in claims 1, 2, and 6 are relative terms which render the claim indefinite. The terms “higher” and “greater” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The relative terms render the “expression level” parameter of the claims indefinite because the claims and the specification provide no guidance as to what level of difference (i.e. 2x, 4x, Y%, etc.) is meaningful in the context of the claimed method.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The terms “TROLL” in claim 1, 2, 6-7, 10, 16, 18, and 20 is used by the claim to mean “TAP63-regulated oncogenic long non-coding RNA” (specification, page 21). This gene nomenclature appears to be unique to the present applicants. The specification does provide conventional identifiers for the recited “TROLL” genes in Table 2: TROLL-1 (RP11-98G7.1), TROLL-2 (RPSAP52), TROLL-3(TRAF3IP2-AS1), TROLL-5 (LINC00514), TROLL-7 (MALAT1), and TROLL-8(AL161668.12). No additional identifiers or nucleotide sequences comprising the recited TROLL genes are provided. RPSAP52, TRAF3IP2-AS1, LINC00514, and MALAT1 are all gene symbols used in the art. “RP11-98G7.1” appears to refer to multiple GTEx transcripts mapped to the cytogenetic map clone “RP11-98G7” placed on hg38 overlapping with the MIR9-1HG gene (see below). It is unclear whether “RP11-98G7.1” refers to MIR9-1HG, one (or all of) the transcript models in the “RP11-98G7.1” cytogenetic map clone, or something else entirely. Furthermore, there is no sequence provided for “TROLL-1” in the present disclosure.
Similarly, TROLL-8 (i.e. “AL161668.12”) is an indefinite term because AL161668 is a cytogenetic map clone consisting of 147,393 base pairs comprising several full gene models (NDRG2, MIR6716, RNASE13, TPPP2, ENSG00000255472, RNASE 7, RNASE8, ENSG00000299988, ARGEF40, ZNF219, ENSG00000178107, AND RNU6-252P) and there is no indication as to which gene model “AL161668.12” refers. There is no sequence provided for “TROLL-8” in the present disclosure.
The term is indefinite because the specification does not clearly define or redefine the term.
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Claims 2, 10, 12, and 16-21 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Regarding claims 2, 10, 12, and 16-21 the phrases "preferably" and “most preferably” render the claims indefinite because it is unclear whether the limitations following these phrases are part of the claimed invention. See MPEP § 2173.05. Furthermore, the broad recitation of multiple alternatives followed by a narrow recitation or recitations of “preferably” and/or “most preferably” raises a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 10, 16, 18, and 20 are additionally indefinite because they recite the phrase “wherein the primers used in the PCR reaction or the primers of Table 3 or Table 5.” It is unclear whether there are more primers intended to be recited in the claim by the use of the word “or” emphasized in bold above, or if this is a typographical error for the verb “are”.
Claims 12, 17, 19, and 21 recite the phrase “the cancer comprises breast cancer, liver cancer, lung cancer, ovarian, colon, or melanoma; most preferably… triple negative breast cancer”. This claim term is indefinite because it is unclear whether the claim is meant to require that the particular cancer is a cancer selected from the Markush group, or that “the cancer comprises” more than one form of cancer. Furthermore, the recitation of “ovarian” and “colon” in the Markush group while the other alternatives are recited as [location cancer] (e.g. lung cancer) raises doubt as to whether “ovarian” and “colon” refer to cancers having primary tumors in the ovary or colon or are something else (e.g. any sample from ovary or colon; any cancer having established a secondary tumor at the ovary or colon).
Claims 10, 16, 18, and 20 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of MPEP 2173.05(s): “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing of table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
In the instant case, the claims recite “the primers of Table 3 or Table 5” rather than the particular sequences or particular combinations of polynucleotide SEQ ID NOs for amplifying particular target sequences. Furthermore, the primers of Table 3 are designed to amplify “Tap63 binding sites” and intergenic “non-specific” sequences annotated as hundreds to thousands of nucleotides “upstream” of the transcription start site of the recited genes. Therefore, these primers do not hybridize to the genes to be measured and therefore are not PCR primers capable of being “used in the PCR reaction” to measure the expression level of the recited genes. Furthermore, the primers of Table 5 are only directed to TROLL-2 and TROLL-3. Therefore, no particular primers are recited by the claim(s) for measuring the expression of TROLL-1, TROLL-5, TROLL-7, TROLL-8, WDR26, or NCOA5, further casting doubt upon the scope of the claims as presently recited.
Claim Interpretation
The present claims are being treated according to their broadest reasonable interpretation (See MPEP 2111). Therefore, all of the “and/or” terms recited by the claims have been interpreted as encompassing “or” embodiments wherein the broadest reasonable interpretation of the claim only requires any one of the recited alternatives. Furthermore, all of the “preferably” and “most preferably” claim terms followed by narrower limitations within the same claim as a broad claim limitation have been interpreted as merely exemplary of the broadest reasonable interpretation of the claim. Thus the limitations following the term “preferably” are not required by the broadest reasonable interpretation of the claims. It is further noted that the “wherein… indicates” and equivalent claim terms do not positively recite a method step.
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 1, 2, 6, 7, 10, 12, and 16-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63,67 (1972); see also M.P.E.P. 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exceptions, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to processes that involve a natural principle and judicial exceptions.
Step 2A Prong I
The claims are taken to be directed to natural phenomena and abstract ideas.
Step 2A Prong II
Independent claim 1 is directed to “A method of assessing tumor grade and/or progression of a cancer and/or metastasis or detecting the presence of a cancer in a subject comprising” the following method steps: a) obtaining a tissue sample from a subject, b) measuring an expression level of a long non-coding RNA for TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8 and/or an expression level of WDR26. Claim 1 further recites that the severity, invasiveness, or presence of a tumor or cancer is indicated by higher expression of the recited gene(s) relative to a control. Claim 1 therefore appears to require a comparison to a control in order to accomplish the goal set forth in the preamble of the claim.
Claim 1 is directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation between the level or amount of expression of one or more gene products and the severity, invasiveness, or presence of a cancer in a human) and an abstract idea (i.e. a comparison to a control).
Independent claim 2 is directed to “A method of assessing the efficacy of a cancer treatment regimen administered to a subject comprising” the following method steps: a) obtaining a tissue sample from a subject, b) measuring the expression level of the lncRNA for TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8, and/or the expression level of WDR26 and/or NCOA5 and/or the intracellular localization of WDR26 and/or NCOA5 relative to a control. Claim 2 further recites that non-efficacious treatment regimen is indicated by expression levels higher than a negative control or equivalent to a positive control OR by WDR and/or NCOA5 cytoplasmic localization greater than a negative control and/or equivalent to a positive control. Alternatively, “preferably”, claim 2 recites that the positive control is a reference gene or pretreatment sample from the same subject.
Claim 2 is directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation between the level or amount of expression of one or more gene products and the presence or relative abundance of a cancer in a human) and an abstract idea (i.e. a comparison to a control).
Independent claim 6 is directed to “A method of treating a cancer in a subject comprising” the following method steps: a) obtaining a tissue sample from a subject receiving a cancer treatment regimen, b) measuring the expression level of the lncRNA for TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8, and/or the expression level of WDR26 and/or NCOA5 and/or the intracellular localization of WDR26 and/or NCOA5 relative to a control. Claim 6 further recites that non-efficacious treatment regimen is indicated by expression levels higher than a negative control or equivalent to a positive control OR by WDR and/or NCOA5 cytoplasmic localization greater than a negative control and/or equivalent to a positive control. Claim 6 further recites the method step c) “changing the treatment regimen when the treatment regimen is not efficacious”.
Claim 6 is directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation between the level or amount of expression of one or more gene products and the presence or relative abundance of a cancer in a human) and an abstract idea (i.e. a comparison to a control). Claim 6 further requires changing the treatment regimen when the presence or relative abundance of the cancer is increasing or stable during treatment. As written, “changing the treatment regimen when the treatment regimen is not efficacious” does not require the process user to do anything based on the comparison to the control. “changing the treatment regimen” is only required for those subjects with stable or increasing expression levels of the gene product(s) (i.e. the claim encompasses embodiments wherein this step is not required) AND “changing the treatment regimen” encompasses all possible changes to the existing regimen, including cessation of treatment.
Independent claim 7 is directed to “A method of treating a cancer in a subject” comprising the method steps: a) obtaining a tissue sample from the subject, b) measuring the expression level of the lncRNA for TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8, and c) administering to a subject positive for TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8 expression an anti-cancer agent and/or immunotherapy.
Claim 7 is directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation between the level or amount of expression of one or more gene products and the presence of a cancer in a human). As written, “administering to a subject positive for” one or more gene products does not require the process user to do anything. The conditional “administering” step is only required for those subjects expressing the gene product(s) (i.e. the claim encompasses embodiments wherein this step is not required).
Claims 10, 16, 18, and 20 require that the expression levels recited by the independent claims are measured by: in situ hybridization, PCR, quantitative PCR, real-time PCR, quantitative, real-time PCR, reverse transcriptase PCR, Western blot, northern blot, and/or microarray. Alternatively, “preferably”, the expression levels are measured by any one of the PCR methods using PCR primers of Table 3 or Table 5.
Claims 12, 17, 19, and 21 require that the cancer comprises a TAP63 regulated cancer; alternatively, “preferably” breast cancer, liver cancer, lung cancer, ovarian, color, or melanoma; alternatively “most preferably” triple negative breast cancer.
A comparison to a control is an abstract idea. (See MPEP 2106.04(a)(III)(A); claims to “comparing BRCA sequences and determining the existence of alterations,” wherein the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014).
A correlation that preexists in the human is an unpatentable phenomenon. The association between the expression of lncRNA encoded by the TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, TROLL-8, or expression level or localization of WDR26 or NCOA5 and the presence or severity or invasiveness of a tumor or cancer is a law of nature/natural phenomenon. The “assessing” and “detecting the presence” steps recited by the claims amount to no more than an “instruction to apply the natural law”. These “assessing” and “detecting the presence” steps amount to no more than a mental step. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the natural law to a new and useful end. Furthermore, the “changing the treatment regimen” step recited by claim 6 encompasses cessation of the treatment regimen. Therefore, these steps do not require the process user to do anything in light of the correlation. These steps fail to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself”.
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception.
While claim 2 recites “a cancer treatment regimen administered to a subject”, this is not an integration of the exception into a practical application. Instead, the treatment step, conducted prior to the observation of the natural phenomenon, is extra-solution activity.
While claim 6 recites “changing the treatment regimen when the treatment regimen is not efficacious”, this is also not an integration of the exception into a practical application. Because this element encompasses cessation of treatment, it does not require the process user to do anything in light of the observation of the natural phenomenon. Furthermore, even in embodiments encompassed by the claim wherein the treatment regimen is changed, the claim does not provide for any particular therapy that integrates the judicial exception into a practical application.
While claim 7 recites “administering to a subject positive for TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, and/or TROLL-8 an anti-cancer agent and/or immunotherapy”, this step does not integrate the exception into a practical application of the exception because it does not provide for any particular therapy. An “anti-cancer agent” generically encompasses any chemotherapy, immunotherapy, radiotherapy, cryotherapy, etc. and cannot be interpreted as a particular treatment, but is rather an instruction to apply the exception in a generic way.
While claims 10, 16, 18, and 20 require that the expression levels recited by the independent claims are measured by: in situ hybridization, PCR, quantitative PCR, real-time PCR, quantitative, real-time PCR, reverse transcriptase PCR, Western blot, northern blot, and/or microarray, this is not an integration of the judicial exception into a particular application of the exception. Rather, these limitations instruct the artisan to measure the expression levels of the recited genes by any method known in the art at any stage of expression (e.g. in situ hybridization or Northern blot for measuring RNA directly, reverse-transcriptase PCR for measuring relative abundance of RNA after cDNA synthesis, or western blot for measuring relative protein abundance between samples). Furthermore, these generic molecular biology techniques are recited as steps required to gather data necessary to perform the claimed method.
While claims 12, 17, 19, and 21 require that the cancer comprises a TAP63 regulated cancer; alternatively, “preferably” breast cancer, liver cancer, lung cancer, ovarian, color, or melanoma; alternatively “most preferably” triple negative breast cancer, this is also not an integration of the exception into an application of the exception. Rather, these limitations recite broad genera of cancers in which the law of nature may be observed.
Step 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non-patent eligible elements, are sufficient to “transform the nature of the claims into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct at 1297).
The claims are not sufficiently defined to provide a method which is significantly more than a statement of a natural principle for at least these reasons:
The claims do not add a specific limitation other than what is well-understood, routine, and conventional in the field.
Steps directed to measuring the expression level of TROLL-1, TROLL-2, TROLL-3, TROLL-5, TROLL-7, TROLL-8, WDR26, or NCOA5 are mere data gathering steps that amount to extra solution activity to the judicial exception. Claims 10, 16, 18, and 20 recite measuring said expression levels by in situ hybridization, PCR, quantitative PCR, real-time PCR, quantitative, real-time PCR, reverse transcriptase PCR, Western blot, northern blot, and/or microarray. Claims 12, 17, 19, and 21 require that the cancer comprises a TAP63 regulated cancer; alternatively, “preferably” breast cancer, liver cancer, lung cancer, ovarian, color, or melanoma; alternatively “most preferably” triple negative breast cancer.
However, determining the expression level of the recited lncRNAs and protein coding genes in breast cancer was well known in the art at the time the invention was made. The prior art, for example, Oliveira-Mateos et al., “The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition”, Nat. Commun. 2019 Sep 4; 10(1):3979, published September 4, 2019 teaches measuring elevated expression of TROLL-2 (i.e. RPSAP52; NR_026825.2) in tumor samples from patients was associated with worse prognoses in sarcomas (Oliveira-Mateos et al., Abstract and figure 1) including in breast cancer. Furthermore, Bamodu et al., “Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of has-miR-448” BMC Cancer (2016)16:160, published February 25, 2016, teach that overexpression of MALAT1 (i.e. TROLL-7), measured by quantitative, real-time PCR, is associated with increased severity/invasiveness (i.e. malignant/metastatic phenotype) in triple negative breast cancer (Bamodu et al., page 11).
The claims do not require the use of any particular non-conventional reagents.
Furthermore, the courts have recognized the following laboratory techniques as well-understood, routine, and conventional activity in the life-science arts when they are claimed in a merely generic manner or as insignificant extra-solution activity:
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015)
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
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.
(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.
Claims 1, 10, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Oliveira-Mateos et al., “The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition”, Nat. Commun. 2019 Sep 4; 10(1):3979, published September 4, 2019.
Regarding claim 1, the present specification teaches that TROLL-2 is also known in the art as “RPSAP52” (specification, table 2) and the “only reported transcript of TROLL-2 [is] NR_026825.2” (specification, page 38). Oliveira-Mateos et al. teach RPSAP52 transcript NR_026852.2 (page 15, column 1, paragraph 2) (i.e. TROLL-2) expression is elevated in tumor samples from patients and was associated with worse prognoses in sarcomas (Oliveira-Mateos et al., Abstract and figure 1) including in breast cancer (Oliveira-Mateos et al., page 2, column 1, paragraph 3). Therefore, Oliveira-Mateos et al. teach obtaining a sample from a subject and measuring an expression level of TROLL-2 (i.e. all of the positively recited method steps in claim 1). In addition, Oliveira-Mateos et al. teach that overexpression of TROLL-2 relative to a control is indicative of the presence of a cancer in the sample and that the overexpression of TROLL-2 is associated with a worse prognosis (i.e. greater severity and/or invasiveness) (Oliveira-Mateos et al., abstract and Figure 7c, see below).
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Regarding claim 10, Oliveira-Mateos et al. teach the expression level of TROLL-2 is measured by RT-PCR (Oliveira-Mateos et al., Figure 1) and RT-qPCR (Real-time, Reverse Transcriptase, quantitative PCR) (Oliviera-Mateos et al., Figure 4 and page 15, column 1, paragraph 3)
Regarding claim 12, Oliveira-Mateos et al. teach TROLL-2 overexpression in breast cancer (Oliveira-Mateos et al., page 2, column 1).
Claims 1, 10 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bamodu et al., “Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of has-miR-448” BMC Cancer (2016)16:160, published February 25, 2016.
Regarding claim 1, the present specification teaches that TROLL-7 is also known in the art as “MALAT-1” (specification, page 35 and Table 1, page 48). Bamodu et al. teach methods of detecting the presence of a cancer comprising obtaining a sample from a subject and measuring MALAT-1 overexpression in “highly metastatic” Triple Negative breast cancer cells (Bamodu et al., Abstract).
Regarding claim 10, Bamodu et al. teach measuring MALAT-1 (i.e. TROLL-7) expression by quantitative, reverse transcriptase, realtime PCR (Bamodu et al., page 4, column 1, paragraph 2).
Regarding claim 12, Bamodu et al. teach the cancer is triple negative breast cancer (i.e. a TAP63 regulated cancer, a breast cancer, triple negative breast cancer) (Bamodu et al., abstract).
Claims 1, 2, 6, 7, 10, 12, and 16-21 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Safe et al., US 2013/0267575 A1, published October 10, 2013.
Regarding claim 1, the present specification teaches that TROLL-7 is also known in the art as “MALAT-1” (specification, page 35 and Table 1, page 48). Safe et al. teach methods of assessing prognosis (i.e. tumor grade and/or progression and/or metastasis or detecting the presence), wherein overexpression of MALAT-1 is correlated with poor prognosis (survival/recurrent/metastasis) in squamous cell carcinoma of the lung (i.e. lung cancer), hepatocellular carcinoma (liver cancer), bladder, and colorectal cancer (i.e. colon cancer) (Safe et al., paragraph 0198) (i.e. obtaining a sample from a subject and measuring the expression level of TROLL-7 relative to a control.
Regarding claims 2, 6 and 7, the present specification teaches that TROLL-7 is also known in the art as “MALAT-1” (specification, page 35 and Table 1, page 48). Safe et al. teach methods of monitoring the efficacy of a cancer treatment regimen and methods of treating cancer (Safe et al., paragraph 0016) comprising determining the expression level of at least one specificity protein (Sp) regulated non-coding RNA in a sample obtained from a subject, administering a treatment, and determining the expression level in a second sample obtained from the subject after treatment administration (Safe et al., paragraph 0016). Safe et al. further teach the treatment is determined to be effective when the expression of the Sp up-regulated ncRNA is lower in the second sample than in the first sample. Safe et al. teach that MALAT-1 (i.e. TROLL-7) is an SP-regulated ncRNA that is overexpressed in cancer relative to controls (Safe et al., paragraphs 0009-0010). Finally, Safe et al. teach administering a treatment regimen comprising “Sp transcription factor agents” “that downregulate Sp transcription factors” after administration of radiation, chemotherapy agents, or vaccine therapies to decrease expression of resistance genes and enhance drug- and drug-radiation therapies (Safe et al., paragraph 0113). Therefore, Safe et al. teach methods comprising steps of: i) obtaining a tissue sample from a subject after administration of a cancer treatment regimen and ii) measuring the expression level of TROLL-7 (i.e. MALAT-1), wherein decreased expression of TROLL-7 relative to controls including a pre-treatment sample from the subject indicates that the treatment is effective; and i) obtaining a sample from a subject receiving a cancer treatment regimen (e.g. drug- or drug-radiation therapy), ii) measuring the expression level of TROLL-7, and iii) adding an Sp transcription factor agent to a treatment comprising another therapeutic agent (i.e. changing the treatment regimen) to decrease resistance and enhance drug therapy effectiveness.
Regarding claims 10, 16, 18, and 20, Safe et al. teach measuring the expression of MALAT-1 (i.e. TROLL-7) by realtime PCR (Safe et al., paragraph 0029).
Regarding claims 12, 17, 19, and 21, Safe et al. teach that the cancer is squamous cell carcinoma of the lung (i.e. lung cancer), hepatocellular carcinoma (liver cancer), bladder, and colorectal cancer (i.e. colon cancer) (Safe et al., paragraph 0198).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18864311 (herein referred to as ‘311). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘311 anticipate the present claims.
Claim 1 of ‘311 recites “A method of assessing tumor grade and/or progression of a cancer and/or metastasis in a subject comprising obtaining a tissue sample from a subject and measuring the expression level of the long non-coding RNA for TROLL-8; wherein the higher the level of lncRNA for TROLL-8, the greater the severity and/or invasiveness of the tumor is indicated. Therefore, claim 1 of ‘311 recites all of the presently claimed method steps of claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claim 1 is provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claim 1 of copending Application No. 18277760 (herein referred to as ‘760). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Claim 1 of ‘760 reads:
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Claim 1 of the present application reads:
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Conclusion
No claim is allowed.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682