DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application was filed on October 26, 2023.
It is noted that there are no claims to domestic or foreign priority in the present application as of January 28, 2026.
Claim Status
Claims 1-10 are currently pending and under examination.
Drawings
The drawings filed on October 26, 2023 are acceptable.
Specification
The use of the terms: “Qiagen”, “RNeasy”, “Invitrogen”, “Direct-Zol”, “Zymo Research”, “Thermo Scientific”, “TaqMan”, “Applied Biosystems”, and “CellTiter-Glo”, 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 21-23 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.
Claim Interpretation
The specification provides special definitions for the following claim terms:
“The term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art… the term “about” is used provides a variation (error range) of 0-10% above or below a given value…” (Specification, page 6). Therefore, the broadest reasonable interpretation of claims reciting “about X”, where X is a recited numerical value encompasses a range of values consisting of 0.9X to 1.1X (i.e. 90% - 110% of the recited value). For example, claim 7 recites “about 300 mg of the PARP1 inhibitor”. Given the broadest reasonable interpretation of this claim term, claim 7 has been understood to encompass a closed interval including the endpoints “270 - 330 mg of the PARP1 inhibitor”. As another example, claim 10 recites “about 2 days to about 2 years”. Given the broadest reasonable interpretation of this claim term, claim 10 has been understood to encompass a closed interval including the endpoints “1.8 days – 2.2 years” (i.e. “43 hours and 12 minutes to 803 days”).
““Subject” refers to an animal, such as a mammal, for example a human… The animal may be… any other vertebrate or invertebrate with a liver.” (Specification, page 6). Therefore, the broadest reasonable interpretation of claims reciting a “subject” encompasses subjects that are “any vertebrate or invertebrate with a liver”.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
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 1-10 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for measuring an mRNA expression level of ADRM1-ΔEx9 in a biological sample that is liver tissue (i.e. normal liver, matched neighboring liver tissue, or HCC primary tumor tissue) in human subjects, comparing the expression level to a reference level of ADRM1-ΔEx9, and treating the HCC in the subject if the expression level of ADRM1-ΔEx9 is significantly higher than the reference level of ADRM1-ΔEx9, does not reasonably provide enablement for embodiments comprising “subjects” that are not humans, biological samples that are not liver tissue, an expression level of ADRM1-ΔEx9 in the biological sample that is significantly lower than the reference level of ADRM1-ΔEx9 and/or expression levels not measured at the level of mRNA. 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 for detecting and treating hepatocellular carcinoma (HCC) in a subject comprising obtaining a biological sample from the subject, measuring “the expression level” of ADRM1-ΔEx9 in the biological sample, comparing the expression level of ADRM1-ΔEx9 with a reference level of ADRM1-ΔEx9 mRNA, and treating the HCC in the subject if the expression level of ADRM1-ΔEx9 in the biological sample is significantly higher or significantly lower than the reference level of ADRM1-ΔEx9.
As broadly claimed, a “subject” is not limited to any particular organism. The specification provides a special limiting definition of this claim term: ““Subject” refers to an animal, such as a mammal, for example a human… The animal may be… any other vertebrate or invertebrate with a liver.” (Specification, page 6). Therefore, the broadest reasonable interpretation of claims reciting a “subject” encompasses subjects that are “any vertebrate or invertebrate with a liver”.
Additionally, as broadly claimed, “a biological sample from the subject” is not limited to any particular type of biological sample (e.g. liver tissue, HCC tissue, blood, plasma, urine, skin, hair, bone, or any other sample that may be collected from the subject). The specification does not provide any special limiting definition of this claim term. Therefore, the broadest reasonable interpretation of claims reciting “a biological sample from the subject” encompasses any type of biological sample that may be collected from the subject.
Furthermore, as broadly claimed, “measuring the expression level of ADRM1-ΔEx9” is not limited to any particular method for measuring the expression level of ADRM1-ΔEx9. The specification does not provide any special limiting definition of this claim term. Therefore, the broadest reasonable interpretation of claims reciting “measuring the expression level…” encompasses method steps comprising measuring a relative or absolute level or amount of nascent RNA, mRNA, or protein in the biological sample.
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).
Regarding the breadth of “subjects” in the claims, the art, for example, de la Fuente et al., “Alternative splicing across the tree of life” eLife 2024; 13:RP94802 teach a comparative analysis of alternative splicing across 1494 species spanning the entire tree of life and conclude that “alternative splicing is highly variable across lineages” (i.e. in different species) (de la Fuente et al., Abstract). Furthermore, de la Fuente et al. teach that while prior studies have developed databases for alternative splicing analysis, they are not comprehensive because the prior databases focus on model organisms such as human and mouse, primarily focus on conserved splicing events, and rely on orthology- and multiple sequence alignment- based methods that do not address biases in publicly available genome annotations comprising at least differing RNA-Seq read depth, differing computational approaches, sampled tissue diversity, and differing assembly quality (de la Fuente et al., page 3-4). Finally, de la Fuente teach mammals and birds (i.e. exemplar vertebrates with livers) display a greater degree of interspecific heterogeneity in splicing relative to the proportion of coding composing genes (de la Fuente et al., page 8).
Regarding the breadth of “measuring the expression level of ADRM1-ΔEx9”, the art, for example Silva et al., “Quantifying gene expression: the importance of being subtle” Mol Syst Biol. (2016) 12:885 teach that at the genic level, the mRNA concentration of a particular transcript and the concentration of its encoded protein are generally well correlated across tissues within a given organism when taking into account the transcript-specific translation/protein degradation rates (Silva et al., page 1, column 3, paragraph 1-2). However Silva et al. teach important biological examples that are exceptions to this general correlation wherein in different tissues: a) a transcript having similar mRNA concentrations in the two tissues varies by two orders of magnitude in protein concentration and b) a transcript having a ten-fold difference in mRNA concentrations between two tissues exhibit similar protein concentrations (Silva et al., page 2, column 1-2 bridging paragraph).
Regarding the breadth of “biological sample”, the art, for example, Chen et al., “Long-Read RNA sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor-Specific Isoforms” Hepatology, Vol. 70, No. 3, 2019 teach measuring elevated, tumor-specific, expression of an unannotated isoform of ADRM1 with exon 9 skipped (i.e. ADRM1-ΔEx9) in HCC (Chen et al., page 1024, column 1), including in biological samples collected from HCC patients (Chen et al., page 1013, column 1, paragraph 2). Chen et al. further teach measuring the expression of ADRM1-ΔEx9 by “Quantitative RT-PCR” in HCC primary tumors (“T”), normal liver tissues (“NL”), and nontumoral adjacent liver tissue (“NT”). Chen et al. further teach that expression of ADRM1-ΔEx9 in normal livers was “negligible” (Chen et al., page 1019, column 1-2 bridging paragraph and figure 4 D, panel 2; see below).
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Guidance in the specification and Working Examples
The specification provides examples wherein mRNA expression levels of ADRM1-ΔEx9 are quantified in human liver samples adjacent to HCC tumors and samples of primary HCC tumors (Specification, figure 1C and page 2, paragraph 3), wherein expression of ADRM1-ΔEx9 mRNA is higher in HCC tumor samples and increased tumor expression of ADRM1-ΔEx9 mRNA correlates with worse overall survival (Specification, figure 1F).
The specification provides no data or working examples of: a) measuring ADRM1-ΔEx9 mRNA expression in biological samples from subjects that are not humans, b) measuring ADRM1-ΔEx9 mRNA expression in biological samples that are not liver tissues (i.e. not HCC or HCC-adjacent). Likewise, the specification provides no data or working examples of measuring ADRM1-ΔEx9 nascent RNA expression or protein quantitation in biological samples obtained from a subject with HCC. Finally, the specification provides no data or examples of significantly lower expression of ADRM1-ΔEx9 mRNA in a biological sample from a subject with HCC.
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 (i.e. measuring ADRM1-ΔEx9 (at any level of gene expression, nascent RNA, mRNA, protein, etc.) in any subject comprising any vertebrate or invertebrate having a liver, and in any biological sample obtained from the subject).
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 measuring ADRM1-ΔEx9 nascent RNA, mRNA, or protein in any biological sample type collected from any vertebrate or invertebrate having a liver.
Together, the specification and the art teach that the genera “subject”, “biological sample”, and “expression level” recited by the claims are very broad and diverse categories comprising all organisms within “vertebrates or invertebrates having a liver” (i.e. humans, mice, fish, birds, “Alitta virens”/ “Nereis virens” (i.e. sandworm)), all possible types of biological samples (i.e. any tissue or secretion or fluid that can be collected from an organism), and measurements of discrete biopolymers having different mechanisms of production, regulation, and degradation within different cells (i.e. nascent RNA, mRNA, protein).
Furthermore, the specification and art teach there are very many unpredictable variables comprising at least: a) presence of the alternatively spliced transcript ADRM1-ΔEx9 in each particular subject organism encompassed by the claims (i.e. is the ADRM1-ΔEx9 transcript present in all subjects encompassed by the claims?), b) presence of the alternatively spliced transcript ADRM1-ΔEx9 in each liver cancer (HCC) of the particular subject organisms encompassed by the claims (i.e. are the molecular mechanisms underlying ADRM1-ΔEx9 overexpression specifically in HCC tissue conserved in all subjects encompassed by the claims?), c) detectable differences in all possible molecular levels of gene expression (i.e. nascent RNA, mRNA, protein) for each possible HCC-equivalent liver cancer in each subject organism (i.e. is ADRM1-ΔEx9 overexpression detectable when measuring nascent RNA, mRNA, and protein expression in all subjects, cancers, and tissues encompassed by the claims?).
This would require significant inventive effort including generating large datasets comprising nascent RNA, mRNA, and protein expression levels of the ADRM1-ΔEx9 splice variant in all possible biological samples collected from all possible subjects encompassed by the claims, 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 of the preferred embodiments: Measuring an mRNA expression level of ADRM1-ΔEx9 in a biological sample that is liver tissue (i.e. normal liver, matched neighboring liver tissue, or HCC primary tumor tissue) in human subjects, comparing the expression level of ADRM1-ΔEx9 mRNA with a reference level of ADRM1-ΔEx9 mRNA, wherein the expression level of ADRM1-ΔEx9 mRNA is significantly higher than the reference level of ADRM1-ΔEx9 mRNA, and treating the HCC in the subject. Given these factors, 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)-Indefiniteness
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 1-10 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 "the expression level of ADRM1-ΔEx9" in line 4. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether the claim requires measuring an mRNA expression level, protein expression level, nascent RNA expression level, or something else.
Claim 1 recites the limitation “a reference level of ADRM1-ΔEx9” in line 5. It is unclear whether the “reference level” is required to be measured in the same biological sample from a subject with HCC, a different sample from the same subject with HCC, a different sample from a different subject not having HCC, or a predetermined numerical cutoff relative to a previously determined reference level of ADRM1-ΔEx9 in a subject or in a population of subjects, or something else entirely.
Claim 1 recites “treating the HCC in the subject” as a conditional method step. Therefore, claim 1 does not require this step in all embodiments encompassed by the broadest reasonable interpretation of the claim. However, dependent claims 6-10 limit the “treating the HCC in the subject” step. It is not clear if this step, and consequently, claims further limiting this step, are intended to be required by the claims.
The terms “significantly higher” and “significantly lower” in claims 1 and 4 are relative terms which renders the claim indefinite. The terms 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. It is unclear whether the claims require that the expression level of ADRM1-ΔEx9 measured in the biological sample from the subject with HCC must: simply differ from the reference level (i.e. is not equivalent to the reference level), differ from the reference level by a particular absolute amount, differ from the reference level by a particular relative amount (e.g. 2-fold different, 3.8842-fold different, etc.), or differ from the reference level by an amount that is deemed “significant” based upon a statistical test to be selected by the process user. It is unclear what threshold or statistical test is required to be applied to the comparison to constitute a “significantly higher” or “significantly lower” expression level as presently recited by the claims.
Claims 2-10 are additionally indefinite because they depend from, and thus include the indefinite limitation(s) of, the claim(s) rejected as indefinite above.
Claim Rejections - 35 USC § 101
Claims 1-10 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. 2016, 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.
Independent claim 1 is directed to “A method for treating hepatocellular carcinoma (HCC) in a subject… comprising (a) obtaining a biological sample from the subject; (b) measuring the expression level of ADRM1-ΔEx9 in the biological sample; (c) comparing the expression level… with a reference level of ADRM1-ΔEx9 mRNA; and (d) treating the HCC in the subject if the expression level… in the sample is significantly [higher or lower] than the reference level…”
Claim 1 is directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation of the expression level of ADRM1-ΔEx9 and the presence of HCC in a subject) and an abstract idea (i.e. a comparison to a control). It is noted that the treatment step is conditional upon the comparison to control, and thus is not required by all embodiments encompassed by the claim (i.e. if the ADRM1-ΔEx9 level is not significantly higher or lower than the control). The specification explicitly teaches that in the cohort of HCC patients (i.e. subjects) for which supporting data was reported, “ADRM1-ΔEx9 is overexpressed in 63.9% of HCC patients” (Specification page 13). Therefore, the claims encompass measuring ADRM1-ΔEx9 expression in HCC patients, wherein the level of ADRM1-ΔEx9 is not significantly higher or lower than the reference level of ADRM1-ΔEx9, and no treatment is administered to the subject because the recited treatment step (d) in claim 1 is conditional upon the ADRM1-ΔEx9 expression level being significantly different from control ADRM1-ΔEx9 expression.
Claim 2 recites that the biological sample is “tissue of a primary HCC tumor of the subject”.
Claim 3 recites the expression level of ADRM1-ΔEx9 is measured by any one of several diverse molecular techniques (i.e. “northern blotting, a nuclease protection assay, in situ hybridization, or quantitative reverse transcriptase polymerase chain reaction (RT-qPCR)”).
Claim 4 further requires treating the HCC in the subject if the expression level of ADRM1-ΔEx9 is significantly higher than the reference level of ADRM1-ΔEx9.
Claim 5 further recites “wherein the expression level of ADRM1-ΔEx9 in the biological sample is at least 3.8842 fold greater than the reference level of ADRM1-ΔEx9.”
Claim 6 further recites that the treatment comprises administering a PARP1 inhibitor.
Claim 7 further recites a dose of PARP1 inhibitor of about 300 mg.
Claim 8 further requires that the PARP1 inhibitor is administered at least two times per day.
Claim 9 further requires that the PARP1 inhibitor is Olaparib, Rucaparib, Niraparib, Talazoparib, or any combination thereof.
Claim 10 further requires that the administration recited by claim 8 occurs for about 2 days to about two years.
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 level or amount of expression of ADRM1-ΔEx9 and the presence of Hepatocellular Carcinoma (HCC) is a law of nature/natural phenomenon. The “measuring” and “comparing” steps recited by the claims are data gathering necessary to perform the method, and a recitation of an abstract idea (see above), respectively. Furthermore, as described above, the conditional treatment step not encompassing all embodiments of the claims does not require the process user to do anything in light of the natural correlation and comparison to control, because the claims do not require this step for all subjects. Therefore, the positively recited method steps amount to no more than an “instruction to apply the natural law”. Even if the steps require 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. 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”.
Step 2A Prong II
The judicial exceptions are not integrated into a practical application of the exceptions. The claims do not recite any additional elements that integrate the exceptions into a practical application of the exceptions.
While claims 1 and 3 recite “measuring the expression level of ADRM1-ΔEx9” (claim 1) comprising “northern blotting, a nuclease protection assay, in situ hybridization, or… RT-qPCR” (claim 3), these steps are not integrations into a practical application of the exceptions. Rather, these steps are extra-solution data gathering methods necessary to perform the method.
Claims 1, 4 and 5 recite “treating the HCC in the subject if the expression level of ADRM1-ΔEx9 is…”: a) “significantly higher… or lower than the reference level of ADRM1-ΔEx9” (claim 1); b) “…significantly higher than the reference level…”; or c) “at least 3.8842 fold greater than the reference level…”. These steps are not integrations of the exceptions into a practical application of the exceptions at least because: i) the treatment step is recited as a conditional step and is therefore not required by the claim under the broadest reasonable interpretation of the scope of the claims as presently recited and ii) the recited step of “treating the HCC” is extremely generic and encompasses any conceivable treatment known in the art including, for example, surgical resection, any chemotherapy, any immunotherapy, any radiotherapy, etc. Therefore, the “treating the HCC” step recited by claims 1, 4, and 5 does not require any particular therapy.
Claim 2 further requires that the biological sample is tissue of a primary HCC tumor of the subject. This claim does not integrate the exceptions into a practical application of the exceptions. Rather, this claim instruct the artisan to sample a particular tissue type in the “obtaining a biological sample” step, i.e. constitute necessary data gathering to perform the method and merely recite a tissue type in which the law of nature may be observed.
Claims 6-10 require that the “treating the HCC” step recited by claim 1 comprises “administering a PARP1 inhibitor” (claim 6), administering about 300 mg of a PARP 1 inhibitor (claim 7), administering the PARP 1 inhibitor at least two times per day (claim 8), the PARP1 inhibitor is Olaparib, Rucaparib, Niraparib, Talazoparib, or any combination thereof (claim 9), or the PARP1 inhibitor is administered for about 2 days to about two years (claim 10). These dependent claims do not integrate the exceptions into a practical application at least because the “treating the HCC” step recited by claim 1 is not required by the claims.
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 ADRM1-ΔEx9 in the biological sample” are mere data gathering steps that amount to extra solution activity to the judicial exception. Claim 3 recites measuring said expression level by “northern blotting, a nuclease protection assay, in situ hybridization, or… RT-qPCR”.
However, determining the expression level of genes including ADRM1-ΔEx9 in HCC samples was well known in the art at the time the invention was made. The prior art, for example Chen et al., “Long-Read RNA sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor-Specific Isoforms” Hepatology, Vol. 70, No. 3, 2019 teach measuring elevated, tumor-specific, expression of an unannotated isoform of ADRM1 with exon 9 skipped (i.e. ADRM1-ΔEx9) in HCC (Chen et al., page 1024, column 1). Chen et al. further teach measuring the expression of ADRM1-ΔEx9 by “Quantitative RT-PCR” in HCC, normal liver tissues, and nontumoral adjacent liver tissue (Chen et al., Figure 4 and page 1017, column 1). Furthermore, the instant specification teaches “measuring the expression level of ADRM1-ΔEx9 in a sample taken from the subject can be determined using conventional methods, such as, for example, northern blotting, nuclease protection assays, in situ hybridization, or … quantitative reverse transcriptase polymerase chain reaction (RT-qPCR).” Therefore, the instant specification acknowledges that the methods for measuring the expression level of ADRM1-ΔEx9 recited by claim 3 are conventional in the art.
Steps directed to “treating the HCC”… “compris[ing] administering a PARP1 inhibitor to the subject” 1) are not required by the claims as presently recited and 2) are likewise well-known, routine, and conventional in the art.
The prior art, for example, Wang et al., “Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors” PNAS Vol. 117, No. 42, 26356-26365 (published October 20, 2020) teach treating Hepatocellular carcinoma with PARP1 inhibitors including the “inhibitors Olaparib, Rucaparib, and Niraparib have been approved by the Food and Drug Administration” (Wang et al., page 26364, column 2, paragraph 3) and that “combination therapy of Olaparib and NU7441 is an effective method for treating HCC” (i.e. a treatment comprising a PARP1 inhibitor; Olaparib) (Wang et al., page 26365, column 1, paragraph 1).
Another example in the prior art, Xu et al., “Inducing Synergistic DNA Damage by TRIP13 and PARP1 Inhibitors Provides a Potential Treatment for Hepatocellular Carcinoma” Journal of Cancer, 2022; 13(7): 2226-2237 (published April 11, 2022) teaches treating HCC with Olaparib and DCZ0415 (i.e. a treatment comprising a PARP1 inhibitor; Olaparib).
A review in the prior art, Paturel et al., “Poly(ADP-Ribose) Polymerase Inhibition as a Promising Approach for Hepatocellular Carcinoma Therapy” Cancers 2022, 14, 3806 (published August 5, 2022) teaches PARP1 inhibitors are widely used for the treatment of HCC (Paturel et al., Abstract), such as the PARP1 inhibitors Talazoparib, Niraparib, Olaparib, and Rucaparib (Paturel et al., page 5, paragraph 1).
Finally, regarding claims directed to requirements for dosing of a PARP1 inhibitor, the prior art, Reference ID: 4326612, Lynparza U.S. Food and Drug Administration Medication Guide (September 2018) teaches routine and well known guidelines for dosage and administration of Lynparza (Olaparib) capsules at 300 mg, twice daily, continuing until disease progression or unacceptable toxicity (4326612, page 1, “Dosage and Administration”) and teaches patient populations that underwent therapy with Lynparza for a duration that varied from less than 6 months to more than 2 years (4326612, page 3, section 5.1, paragraph 1).
The claims do not require the use of any particular non-conventional reagents.
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.
Claims 1-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al., “Long-Read RNA sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor-Specific Isoforms” Hepatology, Vol. 70, No. 3, 2019.
Regarding claim 1, Chen et al. teach measuring elevated, tumor-specific, expression of an unannotated isoform of ADRM1 with exon 9 skipped (i.e. ADRM1-ΔEx9) in HCC (Chen et al., page 1024, column 1), including in biological samples collected from HCC patients (Chen et al., page 1013, column 1, paragraph 2). Chen et al. further teach measuring the expression of ADRM1-ΔEx9 by “Quantitative RT-PCR” in HCC, normal liver tissues, and nontumoral adjacent liver tissue. Chen et al. further teach comparing the expression level of ADRM1-ΔEx9 to a reference level of ADRM1-ΔEx9 (Chen et al., Figure 4 and page 1017, column 1).
It is noted that as presently recited, step (d): “treating the HCC in the subject if the expression level of ADRM1-ΔEx9 in the biological sample is significantly higher or significantly lower than the reference level of ADRM1-ΔEx9” is conditional upon the comparison between the biological sample and the reference and thus is not required by the broadest reasonable interpretation of the claim.
Therefore, Chen et al. anticipates claim 1 as presently recited because Chen et al. teach methods comprising all of the positively recited method steps required by claim 1 as presently written.
Regarding claim 2, Chen et al. teaches the biological sample is tissue of a primary HCC tumor of a subject (Chen et al., page 1018, column 1, paragraph 2).
Regarding claim 3, Chen et al. teach measuring an ADRM1-ΔEx9 expression level by RT-qPCR (Chen et al., Figure 4 and page 1017, column 1).
Regarding claim 4, Chen et al. teach ADRM1-ΔEx9 expression in the biological sample (i.e. the primary HCC tumor) is significantly (p<0.05, paired t test) overexpressed relative to the reference level (i.e. ADRM1-ΔEx9 expression in nontumoral liver) (Chen et al., page 1019, column 1, paragraph 2 and figure 4D).
Regarding claim 5, Chen et al. teach median ADRM1-ΔEx9 expression in the biological sample is 8.33-fold higher (i.e. at least 3.8842 fold greater) than in the reference and more than 10-fold up regulation could be readily detected in ~50% of cases, with few cases reaching as high as 100-fold (Chen et al., page 1019, column 1, paragraph 2).
Regarding claims 6-10, as described above, the treatment step recited in claim 1 is recited as a conditional step and is thus not required. Claims 6-10 depend from and further limit the conditional treatment step recited by claim 1. Therefore, claims 6-10 are likewise anticipated by Chen et al. because the treatment step is not required by the claims.
Claims 1-4 and 6-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sun et al., “Abstract 3959: Novel spliced isoform of the proteasome subunit ADRM1/Rpn13 promotes hepatocellular carcinoma (HCC) development through selective degradation of tumor suppressor p53” Cancer Res (2023) 83(7_Supplement):3953 (published April 4, 2023). It is noted that the Sun et al. reference was previously cited on the IDS filed June 5, 2025 as NPL Cite No. 1. Therefore, a new copy of this document has not been added to the application file
It is noted that the authorship of the Sun et al. reference is distinct from the inventorship of the instant application and that this rejection may be overcome by the filing of a 132 Katz-type declaration or a declaration under 37 C.F.R. 1.130(a) (see MPEP 717.01(a)(1)(B) “Where the authorship of the prior art disclosure includes the inventor or a joint inventor named in the application, an “unequivocal” statement from the inventor or a joint inventor that he/she (or some specific combination of named joint inventors) invented the subject matter of the disclosure, accompanied by a reasonable explanation of the presence of additional authors, may be acceptable in the absence of evidence to the contrary.”
Regarding claim 1, Sun et al. teach “ADRM1-ΔEx9 is more frequently upregulated (i.e. relative to reference” in HCC tumors than the canonical full-length counterpart.” (Sun et al., Abstract). Therefore, Sun et al. teach methods comprising (a) obtaining a biological sample from an HCC tumor; (b) measuring an expression level of ADRM1-ΔEx9 in the biological sample; and (c) comparing the expression level of ADRM1-ΔEx9 with a reference level (i.e. a reference against which ADRM1-ΔEx9 expression in the HCC tumors is determined to be “overexpressed”).
It is noted that as presently recited, step (d): “treating the HCC in the subject if the expression level of ADRM1-ΔEx9 in the biological sample is significantly higher or significantly lower than the reference level of ADRM1-ΔEx9” is conditional upon the comparison between the biological sample and the reference and thus is not required by the broadest reasonable interpretation of the claim.
Therefore, Sun et al. anticipates claim 1 as presently recited because Sun et al. teach methods comprising all of the positively recited method steps required by claim 1 as presently written.
Regarding claim 2, Sun et al. teach the biological sample is tissue from human hepatocellular carcinoma (i.e. a primary HCC tumor of the subject) (Sun et al., Abstract).
Regarding claim 3, Sun et al. teach the expression level of ADRM1-ΔEx9 is measured by “junction-specific Taqman PCR assay” (i.e. qualitative reverse transcriptase polymerase chain reaction) (Sun et al., Abstract).
Regarding claim 4, Sun et al. teach ADRM1-ΔEx9 overexpression significantly correlated with inferior patient survival (i.e. ADRM1-ΔEx9 is significantly overexpressed relative to the reference level of ADRM1-ΔEx9) (Sun et al., Abstract).
Regarding claim 6-10, as described above, the treatment step recited in claim 1 is recited as a conditional step and is thus not required. Claims 6-10 depend from and further limit the conditional treatment step recited by claim 1. Therefore, claims 6-10 are likewise anticipated by Sun et al. because the treatment step is not required by the claims.
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.
As was discussed in the 102 rejections above, it is noted that as presently recited in claim 1, step (d): “treating the HCC in the subject if the expression level of ADRM1-ΔEx9 in the biological sample is significantly higher or significantly lower than the reference level of ADRM1-ΔEx9” is conditional upon the comparison between the biological sample and the reference and thus is not required by the broadest reasonable interpretation of the claim.
In the interest of compact prosecution, the following obviousness rejections address the conditional treatment step recited by claim 1.
Claims 1-6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al., “Long-Read RNA sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor-Specific Isoforms” Hepatology, Vol. 70, No. 3, 2019 in view of Wang et al., “Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors” PNAS Vol. 117, No. 42, 26356-26365 (published October 20, 2020).
Regarding claim 1, Chen et al. teach measuring elevated, tumor-specific, expression of an unannotated isoform of ADRM1 with exon 9 skipped (i.e. ADRM1-ΔEx9) in HCC, which was “negligible in normal livers but markedly overexpressed in HCC” (Chen et al., page 1024, column 1), including in biological samples collected from HCC patients (Chen et al., page 1013, column 1, paragraph 2). Chen et al. further teach measuring the expression of ADRM1-ΔEx9 by “Quantitative RT-PCR” in HCC, normal liver tissues, and nontumoral adjacent liver tissue. Chen et al. further teach comparing the expression level of ADRM1-ΔEx9 to a reference level of ADRM1-ΔEx9 (Chen et al., Figure 4 and page 1017, column 1). Finally, Chen et al. teach “the strong up-regulation of [ADRM1-ΔEx9] is highly suggestive of its potential as a biomarker for HCC.” (Chen et al., page 1024, column 1).
Chen et al. does not teach treating the HCC in subjects having significantly higher or lower expression of ADRM1-ΔEx9 relative to a reference level of ADRM1-ΔEx9.
However, Wang et al. teach treating Hepatocellular carcinoma with PARP1 inhibitors including the “inhibitors Olaparib, Rucaparib, and Niraparib [that] have been approved by the Food and Drug Administration” (Wang et al., page 26364, column 2, paragraph 3) and that “combination therapy of Olaparib and NU7441 is an effective method for treating HCC” (i.e. a treatment comprising a PARP1 inhibitor; Olaparib) (Wang et al., page 26365, column 1, paragraph 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 combined the method for detecting tumor-specific overexpression of ADRM1-ΔEx9 in HCC relative to reference samples, taught by Chen et al. with the methods for treating HCC taught by Wang et al. comprising administering therapies comprising a PARP1 inhibitor such as Olaparib, Rucaparib, or Niraparib. The ordinary artisan would have been motivated to treat subjects overexpressing ADRM1-ΔEx9 for HCC with a therapy comprising PARP1 inhibitors such as Olaparib, Rucaparib, or Niraparib because of the teaching of Wang et al. that the “combination therapy of Olaparib and NU7441 is an effective method for treating HCC” (i.e. a treatment comprising a PARP1 inhibitor; Olaparib) (Wang et al., page 26365, column 1, paragraph 1).
Regarding claim 2, Chen et al. teaches the biological sample is tissue of a primary HCC tumor of a subject (Chen et al., page 1018, column 1, paragraph 2).
Regarding claim 3, Chen et al. teach measuring an ADRM1-ΔEx9 expression level by RT-qPCR (Chen et al., Figure 4 and page 1017, column 1).
Regarding claim 4, Chen et al. teach ADRM1-ΔEx9 expression in the biological sample (i.e. the primary HCC tumor) is significantly (p<0.05, paired t test) overexpressed relative to the reference level (i.e. ADRM1-ΔEx9 expression in nontumoral liver) (Chen et al., page 1019, column 1, paragraph 2 and figure 4D).
Regarding claim 5, Chen et al. teach median ADRM1-ΔEx9 expression in the biological sample is 8.33-fold higher (i.e. at least 3.8842 fold greater) than in the reference and more than 10-fold up regulation could be readily detected in ~50% of cases, with few cases reaching as high as 100-fold (Chen et al., page 1019, column 1, paragraph 2).
Regarding claim 6, Wang et al. teach treating HCC comprises administering a PARP1 inhibitor to the subject (Wang et al., page 26364, column 2, paragraph 3).
Regarding claim 9, Wang et al. teach the PARP1 inhibitor is “Olaparib, Rucaparib, and Niraparib” (Wang et al., page 26364, column 2, paragraph 3).
Claims 7, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al., “Long-Read RNA sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor-Specific Isoforms” Hepatology, Vol. 70, No. 3, 2019 in view of Wang et al., “Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors” PNAS Vol. 117, No. 42, 26356-26365 (published October 20, 2020) as applied to claims 1-6 and 9 above, and further in view of Reference ID: 4326612, Lynparza U.S. Food and Drug Administration Medication Guide (September 2018)
Regarding claims 7, 8 and 10, the methods taught by Chen et al. in view of Wang et al. do not teach specific dosing regimens comprising administering “about 300 mg of the PARP1 inhibitor” to the subject (as required by claim 7), or administering the PARP1 inhibitor “at least two times per day”, (as required by claim 8) “wherein the PARP1 inhibitor is administered for about two days to about 2 years”(as required by claim 10).
However, FDA reference “4326612” is the U.S. Food and Drug Administration Medication Guide for “Lynparza (Olaparib) capsules, for oral use, as updated in September 2018. 4326612 teaches dosage and administration of Lynparza (Olaparib) capsules at 300 mg, twice daily, continuing until disease progression or unacceptable toxicity (4326612, page 1, “Dosage and Administration”) and teaches patient populations that underwent therapy with Lynparza for a duration that varied from less than 6 months to more than 2 years (4326612, page 3, section 5.1, paragraph 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 combined the methods taught by Chen et al. in view of Wang et al. comprising treating HCC patients (i.e. overexpressing ADRM1-ΔEx9) for HCC by administering a PARP1 inhibitor such as Olaparib to the patients with the teachings of 4326612 describing recommended dosing guidelines approved by the U.S. FDA for Lynparza (i.e. Olaparib). The ordinary artisan would have been motivated to follow the Olaparib dosing guidelines approved by the U.S. FDA because these dosages were shown to be effective with an acceptable safety profile in clinical trials and Wang et al. teach that treatments comprising Olaparib are effective treatments for HCC (Wang et al., page 26365, column 1, paragraph 1).
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