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 and Action Summary
This action is in response to the papers filed on May 4, 2026.
Claims 2-6 were canceled by applicant.
Claims 1 and 7-10 are currently pending and under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
The scope of enablement rejection under USC 112(a) has been withdrawn in view of the amendments to the claims.
The rejections of record under USC 112(b) have been withdrawn in view of the amendments to the claims. The rejections under 112(b) below are new grounds of rejection necessitated by the amendments to the claims.
Drawings
The drawings filed on October 26, 2023 are acceptable.
Specification
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 1 recites “about 3.8842 times the reference level”. Given the broadest reasonable interpretation of this claim term, claim 1 has been understood to encompass a closed interval including the endpoints “3.49578 to 4.27262 time the reference level”. 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 Objections
Claim 1 is objected to because of the following informalities: “ADRM1-ΔEx9 mRNAin non-tumor…” at line 12. It appears that a space has been omitted between “mRNA” and “in”. Appropriate correction is required.
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 and 7-10 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.
This is a new grounds of rejection necessitated by the amendments to the claims.
Claim 1 recites the limitation "the biological sample" in line 5. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 is rejected under 35 U.S.C. 112(b) because it is not clear what method steps are required by the claim. First, the step “administering… only if…[condition]” is a conditional treatment step and is therefore not required in all embodiments of the method as presently claimed. Second, the condition “the subject is determined to have…[biomarker expression level limitations relative to a reference]… the determination being made by: [method steps (a)-(c).” likewise does not appear to be required by all embodiments of the method, because it is not clear whether “if the subject is determined” requires performing the determining steps or merely states that determination steps may be performed.
Claim 1 is rejected under 35 U.S.C. 112(b), as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. Claim 1 recites a step of “(a) obtaining a biological sample”, a step “(b) measuring an mRNA expression level of ADRM1-ΔEx9 in the biological sample”, and a step “(c) comparing the mRNA expression level obtained in step (b) with a reference level of ADRM1-ΔEx9 mRNA in non-tumor liver tissue that is adjacent to liver tumor tissue in the subject”. Step (c) requires a comparison between “an mRNA expression level of ADRM1-ΔEx9 measured in the biological sample” and “a reference level of ADRM1-ΔEx9 mRNA in non-tumor liver tissue that is adjacent to liver tumor tissue in the subject”. Therefore, the sample collection and data gathering steps related to the “non-tumor liver tissue that is adjacent to liver tumor tissue in the subject” and “measuring… [a reference level]…” appear to be essential to the invention. However, the claim does not recite steps of obtaining such a “non-tumor liver tissue that is adjacent to liver tissue in the subject” nor “measuring an mRNA expression level of ADRM1-ΔEx9 in” [the non-tumor liver tissue that is adjacent to liver tissue in the subject].
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “wherein the biological sample is a liver tissue”, and the claim also recites “wherein the biological sample is tissue of a primary HCC tumor of the subject” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 1 recites the limitation “Wherein the reference level (i.e. singular) … is measured in separate wells (i.e. plural) of the RT-qPCR reaction (i.e. singular)”. It is unclear whether this step requires that the separate reverse transcriptase quantitative polymerase chain reactions (RT-qPCR) comprising template RNA extracted from “non-tumor liver tissue that is adjacent to liver tumor tissue in the subject” (i.e. “reference tissue”) are carried out in separate wells of an unspecified plate (such as the 384-well PCR plates referenced on page 13 of the specification) in which tumor RNA is measured, that the reference tissue RNA is measured in duplicate (or triplicate, etc.) in parallel RT-qPCR reactions, or something else.
Claim 1 recites a wherein clause: “wherein the increased expression level of ADRM1-ΔEx9 results in enhanced anti-tumor efficacy of PARP1 in the subject”. First, it is unclear whether applicant intends to recite “anti-tumor efficacy of PARP1” (a protein produced by cells recited elsewhere as a drug target) or “anti-tumor efficacy of [the pharmaceutical composition comprising a PARP1 inhibitor]” (as is recited elsewhere in the claims). Second, it is unclear how this clause is meant to meaningfully limit the recited method steps as it neither positively recites a new step nor limits a preceding step. It appears that this wherein clause is a statement of an intended result and/or the natural correlation between ADRM1-ΔEx9 mRNA expression level in tumor tissue and the susceptibility of the tumor to PARP1 [inhibitors].
Claim Rejections - 35 USC § 101
Claims 1 and 7-10 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 claim amendments.
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 administering a pharmaceutical composition comprising a PARP1 inhibitor… only if the subject is determined to have an increased expression level of ADRM1-ΔEx9… greater than about 3.8842 times the reference level… the determination being made by: (a) obtaining a biological sample from the subject; (b) measuring an mRNA expression level of ADRM1-ΔEx9 in the biological sample; (c) comparing the mRNA expression level… with a reference level of ADRM1-ΔEx9 mRNA; wherein the subject is a human, the subject has HCC, the biological sample is tissue of a primary HCC tumor of the subject [or?] liver tissue, wherein the measuring… includes… qRT-PCR… in separate wells of the reaction…”
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 or an inherent property of a HCC in a subject [sensitivity to PARP1 inhibitors]) 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, the “determination” is recited as conditional upon an unspecified condition (i.e. “if the subject is determined…”) and thus this/these step(s) is/are 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, and/or if the determination is not performed). The newly added “wherein” clause “wherein the increased expression of ADRM1-ΔEx9 results in enhanced anti-tumor efficacy of PARP1 in the subject” (assuming the claim is intended to require “…efficacy of a/the PARP1 inhibitor…”) does not recite any additional method steps, limit any preceding method steps, or add/limit any structural elements of the claim. Therefore, this clause appears to be an additional recitation/statement of the natural correlation (i.e. law of nature/natural phenomenon).
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 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) or a naturally occurring property of a HCC (i.e. susceptibility to a class of anti-tumor pharmaceuticals) 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 and determin[ing] steps not encompassing all embodiments of the claims do 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 claim 1 recites “measuring the expression level of ADRM1-ΔEx9 mRNA” (claim 1) including a “RT-qPCR”, 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.
Claim 1 recites “administering [a PARP1 inhibitor] to the subject… only if the subject is determined to have an increased expression level of ADRM1-ΔEx9 [mRNA]… about 3.8842 times than the reference level of ADRM1-ΔEx9”. These steps are not integrations of the exceptions into a practical application of the exceptions at least because: i) the administering (and determin[ing]) steps are recited as conditional steps and are therefore not required by the claim under the broadest reasonable interpretation of the scope of the claims as presently recited.
The requirements that the subject is a human, the subject has HCC, biological sample is tissue of a primary HCC tumor of the subject, [or] liver tissue likewise do not integrate the exceptions into a practical application of the exceptions. Rather, these claim elements instruct the artisan to sample one (or two? – see 112(b) above) tissue type(s) from a particular subject 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 7-10 require that the “administering… a pharmaceutical composition comprising a PARP1 inhibitor…” step recited by claim 1 comprises 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 “administering” and “determine[ing] steps recited by claim 1 are 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 an mRNA expression level of ADRM1-ΔEx9 in the biological sample… includ[ing] a quantitative reverse transcriptase polymerase chain reaction (RT-qPCR)” are mere data gathering steps that amount to extra solution activity to the judicial exception.
Furthermore, determining the mRNA 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 required by the claims are conventional in the art.
Steps directed to “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.
Response to arguments
The response asserts that the claims are directed to a method of using a PARP1 inhibitor to treat HCC rather than to judicial exceptions and that any recited judicial exception is integrated into a practical application because the response asserts that the claims “require a doctor to administer PARP1 in an effective amount to a subject with HCC to reduce the progression of the HCC, which is a specific method of treatment for specific patients, using a specific compound at effective doses, for a specific outcome” and that “the treatment is not optional”. These arguments and assertions have been thoroughly reviewed and are not persuasive. Regarding these arguments/claim elements, which are further addressed in the updated rejection under 35 U.S.C. 101 above, the claim language as presently amended recites both the administration and determination steps as conditional steps “administering… only if the subject is determined…”. This ambiguity is further addressed in the rejections under 35 U.S.C. 112(b) above.
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 and 7-10 remain/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.
This rejection has been updated as necessitated by the amendments to the claims.
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, the step “administering to the subject a pharmaceutical composition comprising a PARP1 inhibitor in an amount effective to reduce the progression of the HCC, only if the subject is determined to have an increased expression level of ADRM1-ΔEx9 in the biological sample having a fold change greater than about 3.8842 times 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.
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).
Chen et al. teach measuring an ADRM1-ΔEx9 expression level by RT-qPCR (Chen et al., Figure 4 and page 1017, column 1).
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).
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 claims 7-10, as described above, the treatment step recited in claim 1 is recited as a conditional step and is thus not required. Claims 7-10 depend from and further limit the conditional treatment step recited by claim 1. Therefore, claims 7-10 are likewise anticipated by Chen et al. because the treatment step is not required by the claims.
Claims 1 and 7-10 remain/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).
This rejection has been updated as necessitated by the amendments to the claims.
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.
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).
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).
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 the limitation “only if the subject is determined to have an increased expression level… having a fold change greater than above 3.8842 times the reference level…”, as noted in the 112(b) and 101 rejections above, this limitation as presently recited appears to be conditional upon some unspecified condition or previous determination or selection step not included in the present claims.
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 7-10, 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.
Response to arguments
The response asserts that the treatment step in amended claim 1 is not optional and thus Chen et al. or Sun et al. do not teach all of the limitations of the claims as amended. This assertion has been thoroughly reviewed and has been addressed in the updated rejections under 35 U.S.C. 112(b), 101 and 102 above. Briefly, amended claim 1 recites “administering… only if the subject is determined”. As such, the administering (and determin[ing]) steps are not required by the claim as presently recited.
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 112(b), 101, and 102 rejections above, it is noted that as presently recited in amended claim 1: “administering… only if the subject is determined to have an increased expression level of ADRM1-ΔEx9 in the biological sample… greater than about 3.8842 times the reference level…” 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 “administering” step recited by amended claim 1.
Claims 1 and 9 remain/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).
This rejection has been updated as necessitated by the amendments to the claims.
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. teaches the biological sample is tissue of a primary HCC tumor of a subject (Chen et al., page 1018, column 1, paragraph 2).
Chen et al. teach measuring an ADRM1-ΔEx9 expression level by RT-qPCR (Chen et al., Figure 4 and page 1017, column 1).
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).
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).
Chen et al. do not teach administering a PARP1 inhibitor to the subjects having an ADRM1-ΔEx9 mRNA expression level greater than about 3.8842 times 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 9, Wang et al. teach the PARP1 inhibitor is “Olaparib, Rucaparib, and Niraparib” (Wang et al., page 26364, column 2, paragraph 3).
Response to arguments
The response asserts that “the combination of Chen and Wang fails to teach or suggest the methods for treating HCC… of amended claim 1… wherein the increased expression level of ADRM1-ΔEx9 results in enhanced anti-tumor efficacy of PARP1 [inhibitor(s)?] in the subject” (emphasis in quotation).
This argument has been thoroughly reviewed and is not persuasive.
First, as discussed in the 112(b), 101, 102, and updated 103 rejections above, the “administering” (i.e. treatment) step is not required by the claims.
Furthermore, the emphasized “wherein” clause appears to be a statement of an intended result and/or a statement of the natural correlation between ADRM1-ΔEx9 mRNA expression level in tumor tissue and the susceptibility of the tumor to PARP1 [inhibitors]. It is noted that “wherein” clauses that simply express the intended result of a process step positively recited are not given patentable weight (See MPEP 2111.04 (I), (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Finally, it is noted that, in supporting a prima facie case of obviousness under 35 U.S.C. 103, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant (See MPEP 2144 (IV)). In this case, as described in the 103 rejection above, the ordinary artisan would have been motivated to administer a pharmaceutical composition comprising a PARP1 inhibitor to a human subject having HCC (taught by Wang et al.), diagnosed by the overexpression of ADRM1-ΔEx9 mRNA (as taught by Chen et al.), 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).
Claims 7, 8, and 10 remain/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)
This rejection has been updated as necessitated by the amendments to the claims.
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).
Response to arguments
The response asserts that the combination of Chen and Wang does not teach or suggest the claimed method for treating HCC of claim 1. This assertion has been thoroughly reviewed and is not persuasive as addressed in the response to arguments against the 103 rejection of claims 1 and 9 over Chen and Wang above. The response does not provide further arguments or assertions against the combination of references cited in the rejections of claims 7, 8, and 10 in addition to those addressed above.
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.
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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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