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/Action Summary
This action is in response to the papers filed on July 27, 2026.
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.
Any objections and rejections not reiterated below are hereby withdrawn.
The provisional nonstatutory double patenting rejection over copending application number 18864311 has been withdrawn because the claims of ‘311 are currently limited to methods involving measuring the expression of “TROLL-8”, and the amended claims under examination in the instant application no longer recite “TROLL-8”.
Drawings
This is a new objection necessitated by the papers filed on July 27, 2026.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Interpretation
The present claims are being treated according to their broadest reasonable interpretation (See MPEP 2111).
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.
The relative terms “higher”, “greater”, “increased”, and “decreased” previously rejected as indefinite relative terms as not defining the intended scope of protection by setting forth a standard for ascertaining the requisite degree, or guidance as to what level of difference (i.e. 2x, 4x, Y%, etc.) is meaningful in the context of the claimed method have instead been interpreted broadly by the plain meaning of the words of the claims as requiring only that the expression level differs from the control level (e.g. a level of “5” is greater than a level of “4”). It is noted that the claims do not require any particular threshold or measure of “statistical significance”.
Conditional steps such as: “wherein when a cancer is detected or a tumor grade has increased or a tumor has progressed, the method further comprises administering…” is not required by all embodiments of the claims.
The conditional “administering to the subject an agent that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression” step has been interpreted as broadly encompassing any agent that functions to reduce the amount of any one of the recited genes in a tissue sample. For example, the claim as presently written, given its broadest reasonable interpretation read in light of the specification appears to encompass administering any agent that kills cancer cells which overexpress these genes relative to noncancer control cells.
“wherein… indicates” and equivalent claim terms do not positively recite a method step.
On page 18, the specification describes the breadth of “a subject”: “The subject can be a vertebrate… the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician”.
For example, claim 1 recites “measuring an expression level of a long non-coding RNA for TRAF3IP2-AS1 (TROLL-3) and/or AC122821.1 (TROLL-5), and/or expression level of WDR26 and/or NCOA5 and/or measuring the localization of WDR26 and/or NCOA5, wherein a higher the level of lncRNA for TROLL-3, and/or TROLL-5, and/or a higher the level of WDR26 and/or NCOA5 and/or the more WDR26 and/or NCOA5 localized in the cytoplasm of a cell relative to a control, the greater the severity and/or invasiveness…; or wherein the presence of lncRNA for TROLL-3 and/or TROLL-5 indicates the presence of… ovarian cancer, colon cancer, lung cancer, melanoma, or breast cancer… and wherein when a cancer is detected, or a tumor grade has increased or a tumor has progressed, the method further comprises administering…”.
Under its broadest reasonable interpretation, claim 1 therefore requires the following active steps:
Obtaining a tissue sample from a subject (i.e. any vertebrate) including, for example, any member of any one of the clades: Cyclostomata (jawless vertebrates, e.g., lampreys or hagfishes) or Gnathostomata (jawed vertebrates, e.g., Condrichtyes (cartilaginous fishes), Euteleostomi (bony vertebrates, which includes the class Mammalia)); and,
Measuring an expression level of a lncRNA: TROLL-3, TROLL-5, WDR26, or NCOA5, or
Measuring the localization of WDR26 or NCOA5; and,
(conditional step, not required) - When a cancer is detected or a tumor grade has increased or a tumor has progressed, the method further comprises administering to the subject an agent that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression. (i.e. any agent that functions to reduce the amount of any one of the recited genes in a tissue sample; e.g., any agent that kills cancer cells which overexpress these genes relative to noncancer control cells).
Claims 2 and 6 recite “assessing the efficacy of a… cancer treatment regimen…” and “cancer treatment regimen”, respectively. Claims 2 and 6 further recite conditional treatment steps: “when a treatment regimen is found not to be efficacious, the method further comprises administering” (claim 2), and “the method further comprises changing the treatment regimen when the treatment regimen is not efficacious to a treatment that inhibits…” (claim 6), which are not required by all embodiments of the claims.
On page 20, the specification provides the breadth of “treatment”: “The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment… In addition, this term includes palliative treatment, that is treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition or disorder; preventative treatment… and supportive treatment, that is treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.” Accordingly, the term “cancer treatment regimen” appears to encompass “palliative treatment” which is “treatment designed for the relief of symptoms” and not “curing of the disease…”
Because the treatment steps are conditionally recited, claims 2 and 6 only require method steps: i) obtaining a tissue sample, ii) measuring the expression level… and iii) comparing the expression level(s) to a control.
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 claims contain 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.
This rejection has been updated as necessitated by the amendments to the claims.
Relevant to the lack of particular structural limitations in the rejected claims drawn to a) measuring the expression level of lncRNA for “TROLL-3 and/or TROLL-5…”, 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 “TAP63 regulated cancer” (claims 1,2, 6-7, 10, 16-18, and 20) or wherein the cancer “comprises triple negative breast 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-3 is described as TRAF3IP2-AS1, or “the longest transcript… NR_034110.1” (specification, page 38) and TROLL-5 is described as LINC00514. It is noted that in the revised claim, TROLL-5 appears to be identified as “AC122821.1”, which is a mouse draft chromosome assembly comprising more than 200,000 nucleotides (see GenBank AC122821.1) (also see table 1, specification page 48). NR_034110.1 corresponds to a 2195 nucleotide sequence annotated “Homo sapiens TRAF3IP2 antisense RNA 1 (TRAF3IP2-AS1), transcript variant 3, antisense RNA” in GenBank NR_034110.1.
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). As described in the claim interpretation above, “subject” therefore encompasses any vertebrate (e.g., hagfish, lamprey, birds, or mammals).
A search of known nucleotide sequences disclosed to the U.S. NIH National Library of Medicine’s National Center for Biotechnology Information “NCBI” (entire nonredundant nucleotide database):
TROLL-3 (also see “NCBI Blast_NR_034110_Homo sapiens TRAF3IP2 antisense”):
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AC122821.1:
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Or (nonredundant nucleotide database excluding the taxa Simiiformes (taxid:314293) and Mus taxid:10088):
TROLL-3 (see also “NCBI Blast_NR_034110_Homo sapiens TRAF3IP2 antisense_notSimiiformesnotMus”) :
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AC122821.1:
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demonstrates that the nucleotide sequence of TRAF3IP2-AS1 “TROLL-3” (NR_034110.1) or AC122821.1 “TROLL-5” do not appear to be conserved across species representative of the broadly claimed genus “vertebrate”.
Furthermore, a sequence alignment using the megablast algorithm for highly similar sequences between the sequences described in the specification as human “TROLL-5” (LINC00514, NR_033861.1) and mouse “TROLL-5” (AC122821.1) does not identify any significant matching sequences. Using the relaxed “discontinuous megablast” for more dissimilar sequences “intended for cross-species comparisons” demonstrates the mouse and human TROLL-5 do not appear to be well conserved at the nucleotide sequence level (see below).
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The most “blastn” algorithm for somewhat similar sequences similarly identifies a lack of sequence conservation between the mouse and human TROLL-5:
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Therefore, it is not clear how one having skill in the art would begin to identify lncRNAs having the required functionality: “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) from genomic sequences known for the broadly recited genus of “subjects” (i.e. any vertebrate).
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.
Response to arguments
The response states:
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The rejection of record has been updated as necessitated by the amendments to the claims. It is particularly noted that the breadth of the claims encompasses detecting the presence of TAP63 regulated ovarian cancer, colon cancer, lung cancer, melanoma, or breast cancer in in subject (i.e. any vertebrate) comprising measuring an expression level of TROLL-3, identified by the human gene symbol “TRAF3IP2-AS1” and “the longest transcript… NR_034110.1”, specification page 38, or TROLL-5, identified by the mouse sequence “AC122821.1”, which is a draft chromosome assembly of unordered contigs totaling more than 200,000 bp.
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. 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).
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). As described in the claim interpretation above, “subject” therefore encompasses any vertebrate (e.g., hagfish, lamprey, birds, or mammals).
A search of known nucleotide sequences disclosed to the U.S. NIH National Library of Medicine’s National Center for Biotechnology Information “NCBI” (entire nonredundant nucleotide database):
TROLL-3 (also see “NCBI Blast_NR_034110_Homo sapiens TRAF3IP2 antisense”):
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Or (nonredundant nucleotide database excluding the taxa Simiiformes (taxid:314293) and Mus taxid:10088):
TROLL-3 (see also “NCBI Blast_NR_034110_Homo sapiens TRAF3IP2 antisense_notSimiiformesnotMus”) :
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AC122821.1:
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demonstrates that the nucleotide sequence of TRAF3IP2-AS1 “TROLL-3” (NR_034110.1) or AC122821.1 “TROLL-5” do not appear to be conserved across species representative of the broadly claimed genus “vertebrate”.
Furthermore, a sequence alignment using the megablast algorithm for highly similar sequences between the sequences described in the specification as human “TROLL-5” (LINC00514, NR_033861.1) and mouse “TROLL-5” (AC122821.1) does not identify any significant matching sequences. Using the relaxed “discontinuous megablast” for more dissimilar sequences “intended for cross-species comparisons” demonstrates the mouse and human TROLL-5 do not appear to be well conserved at the nucleotide sequence level (see below).
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The most “blastn” algorithm for somewhat similar sequences similarly identifies a lack of sequence conservation between the mouse and human TROLL-5:
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Therefore, it is not clear how one having skill in the art would begin to identify lncRNAs having the required functionality: “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) from genomic sequences known for the broadly recited genus of “subjects” (i.e. any vertebrate).
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).
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.
Response to arguments
The response states:
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It is noted that the breadth of the claims as amended encompasses embodiments previously identified as not within the enabled scope of the disclosure (i.e. a “subject” is not limited to human (TROLL-3, TRAF3IP2-AS1, NR_034110.1) or mouse(TROLL-5, AC122821.1)). Therefore, the claims are/remain rejected.
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.
This is a new grounds of rejection necessitated by the amendments to the claims.
Claims 1 and 2 as amended identifies “TROLL-5” as “AC122821.1”. As noted above, AC122821.1 is a GenBank accession identifier that refers to a draft mouse chromosome sequence comprising 41 unordered contigs having a total length of more than 200,000 nucleotides. It is unclear which portion of AC122821.1 corresponds to “TROLL-5”.
Claims 2 and 6 recite methods of “assessing the efficacy of”, or “treating a subject… with” a cancer treatment regimen for a TAP63-regulated ovarian cancer, colon cancer, lung cancer, melanoma, or breast cancer wherein if a treatment regimen is found not to be efficacious, the “method further comprises administering to the subject an agent that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression” (claim 2) or “changing the treatment regimen… to a treatment that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression”. The claims and the specification do not provide any particular treatment targeted to inhibit the expression of any of the recited genes. Rather, the claims appear broadly directed to administering any anti-cancer agent or immunotherapy known in the art that happens to be efficacious against the TAP63 regulated cancer in question. Therefore, the scope of protection sought by the claims is unclear.
Claims 1, 2, and 6 recite conditional treatment steps (i.e. these steps are not required by all embodiments of the claims). In embodiments wherein the recited conditions are not met, the claim does not require treating the subject. Therefore, the broadest interpretation of the claims encompasses only the steps of i) obtaining a sample, ii) measuring the expression of any one of the recited genes, and iii) comparing the expression level measured in (ii) with a control sample or value. It is unclear whether the claims are intended to encompass any method of measuring an expression level of at least any one of the recited genes in a subject having one of the recited cancers relative to a control sample, or is somehow intended to require more.
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.
This is a new grounds of rejection necessitated by the amendments to the claims.
Claims 10, 16, 18, and 20 are indefinite because they recite the “wherein the primers used in the PCR reaction are [SEQ ID NO: 44, 45, 52, 53 or 98-141]”. As presently recited, the claim requires only the use of any one of the recited SEQ ID NOs. Furthermore, the claim encompasses any and all combinations of the recited PCR primers. It is noted that SEQ ID NO: 44, 45, 52, and 53 are annotated as amplifying TAp63 binding sites upstream of the transcription start site as described in table 3 of the specification (i.e. these primers do not amplify the lncRNA). Furthermore, it is unclear how combinations of primers annealing upstream of TROLL-5 (e.g. SEQ ID NO: 52 or 53) are intended to be used in combination with primers annealing to overlapping regions of the transcribed region of TROLL-3 (see table 5, specification). Finally, considering the tiling primer sets of table 5 directed towards TROLL-3, it is unclear whether and how all combinations (i.e. all of the recited primers together) are intended to meaningfully report on the expression level of TROLL-3, as overlapping amplicons of different lengths would be simultaneously produced and would likely interfere with each other during PCR co-amplification.
Claims 12, 17, 19, and 21 recite the phrase “the cancer comprises triple negative breast cancer”. This claim term is indefinite because it is unclear whether the claim is meant to require that the cancer is limited to triple negative breast cancer or is intended to encompass embodiments wherein “the cancer comprises” more than one form of cancer, so long as one of the constituent forms is triple negative breast cancer.
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.
This rejection has been updated as necessitated by the amendments to the claims.
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 TRAF3IP2-AS1 (TROLL-3), AC122821.1 (TROLL-5), or an expression level or localization of WDR26 NCOA5. 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 further recites a conditional step of “when a cancer is detected or a tumor grade has increased or a tumor has progressed, the method further comprises administering to the subject an agent that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression”.
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). As written, “when a cancer is detected or a tumor grade has increased or a tumor has progressed, the method further comprises administering…” does not require the process user to do anything based on the comparison to the control. “administering…” 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).
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-3, TROLL-5, or the expression level of WDR26 or NCOA5 or the intracellular localization of WDR26 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. Claim 2 further recites a conditional step “when a treatment regimen is found not to be efficacious, the method further comprises administering to the subject an agent that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression”.
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). As written, “when a treatment regimen is found not to be efficacious, the method further comprises administering…” does not require the process user to do anything based on the comparison to the control. “administering…” 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).
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-3, TROLL-5 or the expression level of WDR26 or NCOA5 or the intracellular localization of WDR26 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 conditional method step c) “changing the treatment regimen when the treatment regimen is not efficacious to a treatment that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression.”
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).
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-3 or TROLL-5 and c) administering to a subject positive for TROLL-3 or TROLL-5 expression an anti-cancer agent and/or immunotherapy that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression.
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, wherein the primers used in the PCR reaction are SEQ ID 44, 45, 52, 53, or 98-141.
Claims 12, 17, 19, and 21 require that the cancer comprises a 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-3, TROLL-5 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 “administering” or “changing the treatment” steps recited by claims 1,2, 6, and 7 are conditional steps not required by all embodiments of the claims. 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 claims 1, 2, 6 and 7 as amended now recite conditional steps of “administering to the subject an agent that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression” (Claims 1-2), “a treatment that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression” (Claim 6), or “an anti-cancer agent or immunotherapy that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression” (Claim 7), these conditional treatment steps do not integrate the exception into a practical application of the exception because these conditional steps are not required by all embodiments of the claims and for the following additional reasons.
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. Furthermore, there is no indication or limitation as to what “agent” or “agents” have the recited function “inhibit[s] TROLL-3, TROLL-5, WDR26, or NCOA5 expression”. Therefore, it appears that the claim (in embodiments wherein the treatment step is administered), does not provide any particular therapy or prophylaxis that amounts to more than a referral of the process user to the relevant field (oncology) and encompasses any treatment that kills cancer cells (e.g., cells that overexpress the recited markers).
While claim 6 recites “changing the treatment regimen when the treatment regimen is not efficacious to a treatment that inhibits TROLL-3, TROLL-5, WDR26, or NCOA5 expression”, this is also not an integration of the exception into a practical application. 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. As previously described, there is no indication or limitation as to what “agent” or “agents” have the recited function “inhibit[s] TROLL-3, TROLL-5, WDR26, or NCOA5 expression”. Therefore, it appears that the claim (in embodiments wherein the treatment step is administered), does not provide any particular therapy or prophylaxis that amounts to more than a referral of the process user to the relevant field (oncology) and encompasses any treatment that kills cancer cells (e.g., cells that overexpress the recited markers).
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. Furthermore, there is no indication or limitation as to what “agent” or “agents” have the recited function “inhibit[s] TROLL-3, TROLL-5, WDR26, or NCOA5 expression”. Therefore, it appears that the claim (in embodiments wherein the treatment step is administered), does not provide any particular therapy or prophylaxis that amounts to more than a referral of the process user to the relevant field (oncology) and encompasses any treatment that kills cancer cells (e.g., cells that overexpress the recited markers).
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 triple negative breast cancer, this is also not an integration of the exception into an application of the exception. Rather, these limitations recite types 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 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).
Even more, Ye Y et al., “Upregulated WDR26 serves as a scaffold to coordinate PI3K/AKT pathway-driven breast cancer cell growth, migration, and invasion” Oncotarget, Vol. 7, No. 14, pp 17854-17869 teach measuring WDR26 in human breast cancer samples, including triple negative breast cancers and that “WDR26 may be an important regulator or prognostic marker of breast cancer progression” (Ye Y et al., page 17855, column 2, paragraph 2).
Similarly, Ye XH et al., “NCOA5 is correlated with progression and prognosis in luminal breast cancer” Biochemical and Biophysical Research Communications 482 (2017) 253-256 teach NCOA5 over-expression is significantly correlated with progression and prognosis in breast cancer (Ye XH et al., page 254, column 2, paragraph 4).
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.
Response to arguments
The response asserts:
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This argument in support of the amended claims has been thoroughly reviewed and is not persuasive. As is addressed in the updated rejection above, the recitation of a generic “administration” or “treatment” step does not necessarily integrate the judicial exception into a practical application when there is no particularity between the treatment and the recited judicial exception. As described above, the breadth of the recited “treatments” having the function of “inhibit[ing] the expression of [at least one of the recited markers]” encompasses any and all treatments in the field of oncology that are capable of killing cancer cells including surgical resection of a tumor. Furthermore, there is no recitation of any particular treatment or agent that accomplishes the goal of “inhibiting the expression…”. In contrast, in the case cited in the arguments (Vanda), the claims integrated recited judicial exceptions into a particular treatment. As is discussed above, the present claims instead generically refer to conditional treatment steps that are not particular to the recited judicial exceptions but rather refer to any cancer treatment having a function encompassing removing or killing cancer cells.
Therefore for these reasons and the reasons already of record, the claims are/remain rejected.
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.
The following 102 rejections are new grounds of rejection necessitated by the amendments to the claims.
Claims 1, 10, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ye Y et al., “Upregulated WDR26 serves as a scaffold to coordinate PI3K/AKT pathway-driven breast cancer cell growth, migration, and invasion” Oncotarget, Vol. 7, No. 14, pp 17854-17869.
Regarding claim 1, Ye Y. et al. teach measuring WDR26 in human breast cancer samples, including triple negative breast cancers and that “WDR26 may be an important regulator or prognostic marker of breast cancer progression” (Ye Y et al., page 17855, column 2, paragraph 2). Ye Y. et al. further teach targeting WDR26 may also represent a novel approach for the treatment of both primary and metastatic tumors (Ye Y. et al., page 17866, column 1).
Regarding claim 10, Ye Y. et al. teach the expression level of WDR26 is measured by immunohistochemistry, Western blot (Ye Y. et al., figure 2), and microarray (Ye Y. et al., page 17866, column 2, paragraph 1).
Regarding claim 12, Ye Y. et al. teach the breast cancer comprises triple negative breast cancer (Ye Y. et al., page 17866, column 1).
Claims 1 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ye XH et al., “NCOA5 is correlated with progression and prognosis in luminal breast cancer” Biochemical and Biophysical Research Communications 482 (2017) 253-256 teach NCOA5 over-expression is significantly correlated with progression and prognosis in breast cancer (Ye XH et al., page 254, column 2, paragraph 4).
Regarding claim 1, Ye XH. et al. teach Nuclear receptor coactivator 5 (NCOA5) is up-regulated in luminal breast cancer relative to adjacent non-cancerous tissues, and that high NCOA5 is associated with significantly lower overall survival (Ye XH. et al., Abstract). Ye XH et al. further teach luminal breast cancers are routinely treated with endocrine therapy (antiestrogens or aromatase inhibitors) (i.e. an agent that kills cancer cells, therefore inhibits NCOA5 expression) (Ye XH. et al., page 254, column 2, paragraph 5).
Regarding claim 10, Ye XH. et al. teach NCOA5 expression is measured by quantitative reverse transcriptase PCR (Ye XH. et al., figure 1).
Claims 1 and 10 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Alt et al., US 2019/0078092 A1 (filed Nov. 26, 2018 and published March 14, 2019)
Regarding claim 1, Alt et al. teach methods of treating breast cancer tumors comprising measuring the expression of TRAF3IP2 and silencing the expression of TRAF3IP2 (Alt et al., Abstract).
Alt et al. teach alternative transcripts of TRAF3IP2 include an antisense transcript that, when overexpressed, has been shown to reduce expression of the protein-coding transcripts produced from the TRAF3IP2 gene (Alt et al., paragraph 0025) (i.e. TRAF3IP2-AS1 (TROLL-3). Finally, Alt et al. teach treating a breast cancer comprising administering a pharmaceutical composition (i.e. an agent) comprising a silencing sequence for TRAF3IP2 (i.e. an agent that inhibits TROLL-3 expression).
Regarding claim 10, Alt et al. teach expression levels are measured by PCR (Alt et al., paragraph 0072).
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The following 103 rejections are new grounds of rejection necessitated by the amendments to the claims.
The following 103 rejections apply to the enabled scope of the claims identified in the 112(a) rejection above.
The following rejections are directed to the human long non-coding RNA “LINC00514”, annotated as “TROLL-5” on page 48 of the specification.
Claims 1, 7, 10, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al., “Silencing of lncRNA LINC00514 inhibits the malignant behaviors of papillary thyroid cancer through miR-20403p/CDC23 axis” Biochemical and Biophysical Research Communications 508 (2019) 1145-1148 in view of Guo et al., “MiR-204-3p Inhibited the Proliferation of Bladder Cancer Cells via Modulating Lactate Dehydrogenase-Mediated Glycolysis” Frontiers in Oncology 9:1242 (2019).
This rejection is directed to the human long non-coding RNA “LINC00514”, annotated as “TROLL-5” on page 48 of the specification.
Furthermore, as was described in the 112(b) rejection above, it is noted that the claimed primers corresponding to “TROLL-5” (SEQ ID NO: 52 and 53) are described in the specification as binding to, and amplifying, a TAp63-binding site “TROLL-5cuNcoos15J” located at “-2320 to -2297” relative to the transcription start site of TROLL-5 (i.e. these primers do not amplify the lncRNA) and it is unclear how they are intended to measure an expression level of TROLL-5.
Regarding claims 1 and 7, Li et al. teach LINC00514 (i.e. TROLL-5) expression is significantly upregulated in papillary thyroid cancer (PTC) cells and tissues through quantitative reverse transcriptase PCR (Li et al., abstract and page 1145, column 2-page 1146). Li et al. teach the molecular mechanism by which TROLL-5 “promotes proliferation, migration and invasion of PTC” comprises sequestration and degradation “sponging” of miR-204-3p, which is a negative regulator of CDC23, which has been previously demonstrated to be overexpressed in various cancers and promotes cell growth and division (Li et al., page 1148, column 2). Li et al. further suggests targeting LINC00514 (i.e. inhibiting the expression of TROLL-5) might be a promising therapeutic target for PTC treatment.
Li et al. does not explicitly teach that LINC00514 (i.e. TROLL-5) overexpression is indicative of the presence of breast cancer.
However, Guo et al. teach MiR-204-3p distinguishes the progression of malignant gastric cancer and breast cancer, wherein miR-204-3p overexpression significantly suppresses the proliferation and induced apoptosis of cancer cells (Guo et al., page 8, column 1).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the methods taught by Li et al. comprising treating cancers by inhibiting the expression of TROLL-5 with the teachings of Guo et al. that breast cancers are negatively regulated by expression of miR-204-3p to arrive at the claimed method wherein when TROLL-5 overexpression is detected in a tumor, the tumor is treated with an agent that inhibits TROLL-5 expression. The ordinary artisan would have been motivated to modify the methods of Li et al. with the teachings of Guo et al. because of the teachings of Guo et al. that: a) breast cancer is suppressed by expression of miR-204-3p, b) overexpression of miR-204-3p leads to apoptosis of cancer cells (Guo et al., page 9, column 1) and because of the teachings of Li et al. that TROLL-5 inhibits miR-204-3p expression to drive tumor growth and progression (Li et al., page 1148, column 1).
Regarding claims 10 and 20, Li et al. teach measuring TROLL-5 expression by quantitative reverse-transcriptase PCR (Li et al., page 1146, column 1, paragraph 3)
Claims 12 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. in view of Guo et al. as applied to claims 1, 7, 10 and 20 above, and further in view of Li et al. 2013, “Differential Distribution of microRNAs in Breast Cancer Grouped by Clinicopathological Subtypes” Asian Pacific J Cancer Prev, 14(5), 3197-3203 (2013).
Regarding claims 12 and 21, Li et al. 2017 in view of Guo et al. do not teach that the breast cancer comprises triple negative breast cancer.
However, Li et al. 2013, teaches that miR-204-3p is differentially expressed (down regulated) in triple negative breast cancer cells relative to controls (Li et al., page 3200, column 5).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have tried applying the methods for measuring TROLL-5 expression as a marker for the presence or progression of breast cancers due to downregulation of the tumor suppressor miR-204-3p caused by the “sponging” activity of TROLL-5 towards miR-204-3p to triple negative breast cancer because of the teachings of Li et al. 2013 that mir-204-3p is significantly down regulated in triple negative breast cancers relative to controls.
Claims 2, 6, 16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al., “Silencing of lncRNA LINC00514 inhibits the malignant behaviors of papillary thyroid cancer through miR-20403p/CDC23 axis” Biochemical and Biophysical Research Communications 508 (2019) 1145-1148 in view of Guo et al., “MiR-204-3p Inhibited the Proliferation of Bladder Cancer Cells via Modulating Lactate Dehydrogenase-Mediated Glycolysis” Frontiers in Oncology 9:1242 (2019) and Safe et al., US 2013/0267575 A1 (published October 10, 2013).
Regarding claims 2 and 6, Li et al. teach LINC00514 (i.e. TROLL-5) expression is significantly upregulated in papillary thyroid cancer (PTC) cells and tissues through quantitative reverse transcriptase PCR (Li et al., abstract and page 1145, column 2-page 1146). Li et al. teach the molecular mechanism by which TROLL-5 “promotes proliferation, migration and invasion of PTC” comprises sequestration and degradation “sponging” of miR-204-3p, which is a negative regulator of CDC23, which has been previously demonstrated to be overexpressed in various cancers and promotes cell growth and division (Li et al., page 1148, column 2) (i.e. LINC00514 “TROLL-5” is a pro-oncogenic lncRNA that acts by decreasing the expression of a tumor-suppressor target gene (miR-204-3p)). Li et al. further suggests targeting LINC00514 (i.e. inhibiting the expression of TROLL-5) might be a promising therapeutic target for PTC treatment.
Li et al. does not explicitly teach that LINC00514 (i.e. TROLL-5) overexpression is indicative of the presence of breast cancer.
However, Guo et al. teach MiR-204-3p distinguishes the progression of malignant gastric cancer and breast cancer, wherein miR-204-3p overexpression significantly suppresses the proliferation and induced apoptosis of cancer cells (Guo et al., page 8, column 1).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the methods taught by Li et al. comprising treating cancers by inhibiting the expression of TROLL-5 with the teachings of Guo et al. that breast cancers are negatively regulated by expression of miR-204-3p to arrive at the claimed method wherein when TROLL-5 overexpression is detected in a tumor, the tumor is treated with a subject that inhibits TROLL-5 expression. The ordinary artisan would have been motivated to modify the methods of Li et al. with the teachings of Guo et al. because of the teachings of Guo et al. that: a) breast cancer is suppressed by expression of miR-204-3p, b) overexpression of miR-204-3p leads to apoptosis of cancer cells (Guo et al., page 9, column 1) and because of the teachings of Li et al. that TROLL-5 inhibits miR-204-3p expression to drive tumor growth and progression (Li et al., page 1148, column 1).
Similarly, Li et al. do not expressly teach measuring LINC00514 “TROLL-5” expression in the context of methods for assessing the efficacy of a cancer treatment regimen comprising administering treatments/agents that inhibit the expression of TROLL-5 when said treatment regimen is not efficacious.
However, Safe et al. teach methods of monitoring the efficacy of a cancer treatment and methods of treating cancer (Safe et al., paragraph 0016) comprising determining the presence or progression of a cancer by measuring the elevated expression level (relative to controls) of lncRNAs that function to decrease the expression level of tumor suppressor genes (Safe et al., paragraphs 0009-0010, and 0016) and administering a treatment that downregulates the expression of the pro-oncogenic lncRNAs to decrease resistance and enhance drug therapy effectiveness (Safe et al., paragraph 0113).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the methods taught by Li et al. comprising treating cancers by inhibiting the expression of TROLL-5 with the teachings of Guo et al. that breast cancers are negatively regulated by expression of miR-204-3p and the teachings of Safe et al. that overexpression of lncRNAs relative to controls that decrease the expression level of tumor suppressor genes indicates the presence of a cancer, that a pre-existing treatment is not efficacious for the cancer, and changing the regimen to a treatment that inhibits the expression of the pro-oncogenic lncRNAs to arrive at the claimed method wherein when TROLL-5 overexpression is detected in a tumor and the tumor is treated with an agent that inhibits TROLL-5 expression. The ordinary artisan would have been motivated to modify the methods of Li et al. with the teachings of Guo et al. and the teachings of Safe et al. because of the teachings of Guo et al. that: a) breast cancer is suppressed by expression of miR-204-3p, b) overexpression of miR-204-3p leads to apoptosis of cancer cells (Guo et al., page 9, column 1) and because of the teachings of Li et al. that TROLL-5 inhibits miR-204-3p expression to drive tumor growth and progression (Li et al., page 1148, column 1) and further because of the teachings of Safe et al. that addition of a therapeutic agent that decreases the expression level of the pro-oncogenic lncRNA decreases resistance to chemotherapeutic agents and enhances the efficacy of drug therapy (Safe et al., paragraph 0113).
Regarding claims 16 and 18, Li et al. teach measuring TROLL-5 expression by quantitative reverse-transcriptase PCR (Li et al., page 1146, column 1, paragraph 3).
Claims 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. in view of Guo et al. and Safe et al. as applied to claims 2, 6, 16, and 18 above, and further in view of Li et al. 2013, “Differential Distribution of microRNAs in Breast Cancer Grouped by Clinicopathological Subtypes” Asian Pacific J Cancer Prev, 14(5), 3197-3203 (2013).
Regarding claims 17 and 19, Li et al. 2017 in view of Guo et al. and Safe et al. do not teach that the breast cancer comprises triple negative breast cancer.
However, Li et al. 2013, teaches that miR-204-3p is differentially expressed (down regulated) in triple negative breast cancer cells relative to controls (Li et al., page 3200, column 5).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have tried applying the methods for measuring TROLL-5 expression as a marker for the presence or progression of breast cancers due to downregulation of the tumor suppressor miR-204-3p caused by the “sponging” activity of TROLL-5 towards miR-204-3p to triple negative breast cancer because of the teachings of Li et al. 2013 that mir-204-3p is significantly down regulated in triple negative breast cancers relative to controls.
Double Patenting
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.
This rejection has been updated as necessitated by the amendment to the instant claims and the claims in ‘760 (claim set dated of June 15, 2026).
Amended 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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY MARK TURPIN whose telephone number is (703)756-5917. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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