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 .
The claims dated 5/28/2024 are under consideration.
Election/Restrictions
Applicant’s election of Group IV, claims 103, 107, 110 and 112, in the reply filed on 5/7/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
However, upon search and consideration of Group IV, the restriction requirements between Groups I-V are withdrawn.
Applicant’s election of SEQ ID NO: 1 (miR-2115-3p) as the species in the reply filed on 5/7/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 112 is withdrawn as the claim requires determining the expression of more than the single elected miRNA.
Priority
The present application is a 371 national stage entry of PCT/EP2022/059970 (filed 4/13/2022), and claims priority to foreign applications EPO 21174970.0 (filed 5/20/2021) and EPO 21196432.5 (filed 9/13/2021).
Priority is recognized.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the specification 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 or on a submitted IDS, they have not been considered.
Drawings
The drawings are objected to because the replacement sheets filed 5/28/2024 include color in Fig. 10A-10D. It is unclear if applicant intends the application to include color figures.
If applicant does not intend the application to include colored drawings, it is suggested applicant files a grayscale or black and white copy of the drawings.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that SEQ ID NO: 45 is not part of the XML as the XML only lists 44 sequences. Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The abstract of the disclosure is objected to because it recites “prevent invention” rather than “present invention". A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 82 is objected to because of the following informalities: the claim recites “thereby identifying the patient as patient who will respond to lung cancer immunotherapy” rather than “thereby identifying the patient as a patient who will respond to lung cancer immunotherapy”. Appropriate correction is required.
Claim 119 is objected to because of the following informalities: the claim recites “thereby identifying the patient as patient who will benefit from immunochemotherapy or immunotherapy” rather than “thereby identifying the patient as a patient who will benefit from immunochemotherapy or immunotherapy”. Appropriate correction is required.
Claim Interpretation
Claim 1 is drawn to a “method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer”; however, the method does not explicitly require active method steps directed towards using miRNA levels or making a prediction regarding the patient. MPEP 2111.02 states:
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction.
Accordingly, the claim language of “method of predicting a response to lung cancer immunotherapy of a patient suffering from lung cancer” merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims. The claims are given the broadest reasonable interpretation as requiring a single active step of: in a blood sample of a patient suffering from lung cancer, determining the level of at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 44, a fragment thereof, and a sequence having at least 80% sequence identity thereto.
Claim 23 is drawn to a “method of providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy”; however, the method does not explicitly require active method steps directed towards using miRNA levels or providing information regarding the patient. MPEP 2111.02 states:
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction.
Accordingly, the claim language of “providing a survival prognosis to a patient suffering from lung cancer who is eligible to immunotherapy” merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims. The claims are given the broadest reasonable interpretation as requiring a single active step of: in a blood sample of a patient suffering from lung cancer, determining the level of at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 44, a fragment thereof, and a sequence having at least 80% sequence identity thereto.
Claim 103 is drawn to a “method of selecting a patient suffering from lung cancer to benefit from immunochemotherapy or immunotherapy”; however, the method does not explicitly require active method steps directed towards using miRNA levels or the selecting of the patient. MPEP 2111.02 states:
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction.
Accordingly, the claim language of “selecting a patient suffering from lung cancer to benefit from immunochemotherapy or immunotherapy” merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims. The claims are given the broadest reasonable interpretation as requiring a single active step of: in a blood sample of a patient suffering from lung cancer, determining the level of at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 44, a fragment thereof, and a sequence having at least 80% sequence identity thereto.
Claim 103 includes language that is “optional”, regarding a TPS of the patient. Claim scope is not limited by claim language that makes optional but does not require steps to be performed. MPEP 2111.04.
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, 4, 9, 14, 15, 22, 23, 24, 26, 31, 34, 38, 41, 42, 49, 82, 83, 103, 107, 110, 112 and 119 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more.
The claim(s) recite(s):
“determining the level of at least one miRNA in a blood sample of a patient suffering from lung cancer” (claim 1);
“the level of the at least one miRNA is compared to a reference level of said at least one miRNA” (claim 4);
“the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 28 to SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39 to SEQ ID NO: 42, SEQID NO: 44, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient will respond to said lung cancer immunotherapy” (claim 4);
“the level of the at least one miRNA is compared to an empirically determined cut-off score” (claim 9);
“allows to classify the patient as patient who will respond to lung cancer immunotherapy or as a patient who will not respond to lung cancer immunotherapy” (claim 9);
“the cut- off score is determined by the weighted sum of one or more miRNAs selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 13, SEQ ID NO: 34,SEQ ID NO: 39, a fragment thereof, and a sequence having at least 80% sequence identity thereto” (claim 9);
“the level of the at least one miRNA is compared to a reference level of said at least one miRNA, wherein the reference level is the level of the at least one miRNA determined by measuring a number of reference blood samples from subjects suffering from lung cancer having a known poor survival prognosis” (claim 26);
“the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 26, SEQID NO: 28 to SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39 to SEQ ID NO: 42, SEQID NO: 44, a fragment thereof, and a sequence having at least 80% sequence identity thereto below the reference level indicates that the patient has a good survival prognosis” (claim 26);
“the level of the at least one miRNA having a nucleotide sequence selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 27, SEQ ID NO: 36, SEQ ID NO 38, SEQ ID NO: 43, a fragment thereof, and a sequence having at least 80% sequence identity thereto above the reference level indicates that the patient has a good survival prognosis” (claim 26);
“the level of the at least one miRNA is compared to an empirically determined cut-off score, which allows to classify the patient as having a good or poor survival prognosis” (claim 31);
“the cut-off score is determined by the weighted sum of one or more miRNAs selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 13,SEQ ID NO: 34, SEQ ID NO: 39, a fragment thereof, and a sequence having at least 80% sequence identity thereto” (claim 31);
“carrying out the method of any one of claim 1” (claim 82);
“assigning the patient to (said) the lung cancer immunotherapy” (claim 82);
“determining the level of at least one miRNA in a blood sample of a patient suffering from lung cancer” (claim 103);
“the level of the at least one miRNA is compared to a (miRisk) cut-off score” (claim 110);
“the level of the at least one miRNA above the (miRisk) cut-off score indicates that the patient will benefit from immunochemotherapy” (claim 110); and
“the level of the at least one miRNA below or equal to the (miRisk) cut-off score indicates that the patient will benefit from immunochemotherapy or immunotherapy” (claim 110); and
“carrying out the method of claim 103” (claim 119).
Element A sets forth an abstract idea that encompasses mathematical concepts and the mental consideration of data. The specification states that levels may be determined as “scaled, normalized, or scaled and normalized amounts or values (e.g. RPM)” (p. 21). Thus, the step broadly encompasses the processing of raw data in “determining the level of at least one miRNA in a blood sample”.
Element B sets forth an abstract idea that encompasses comparing two pieces of data, which can be performed mentally.
Element C sets forth a natural correlation that is the relationship between the expression of miRNA and phenotype of a patient.
Element D sets forth an abstract idea that encompasses comparing two pieces of data.
Element E is based upon the natural correlation between the expression of miRNA and phenotype of a patient.
Element F sets forth a mathematical principle regarding a value that is to be calculated.
Element G sets forth an abstract idea that encompasses comparing two pieces of data, which can be performed in a purely mental manner.
Element H sets forth a natural correlation that is the relationship between the expression of miRNA and phenotype of a patient.
Element I sets forth a natural correlation that is the relationship between the expression of miRNA and phenotype of a patient.
Element J is based upon the natural correlation between the expression of miRNA and phenotype of a patient.
Element K sets forth a mathematical principle regarding a value that is to be calculated.
Element L involves the performing of the method of claim 1. As noted above in Element A, the method of claim 1 involves abstract ideas.
Element M sets forth an abstract idea that encompasses mentally thinking about data to reach a conclusion.
Element N sets forth an abstract idea that encompasses mathematical concepts and the mental consideration of data. The specification states that levels may be determined as “scaled, normalized, or scaled and normalized amounts or values (e.g. RPM)” (p. 21). Thus, the step broadly encompasses the processing of raw data in “determining the level of at least one miRNA in a blood sample”.
Element O sets forth an abstract idea encompassing comparing two pieces of data, which may be done in a purely mental manner.
Element P is based upon the natural correlation between the expression of miRNA and phenotype of a patient.
Element Q is based upon the natural correlation between the expression of miRNA and phenotype of a patient.
Element R involves the performing of the method of claim 1. As noted above in Element A, the method of claim 103 involves abstract ideas.
The judicial exceptions are not integrated into a practical application because the claims do not involve:
improvements to the functioning of a computer or to any other technology or technical field;
applying or using the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition;
applying the judicial exception with, or by use of, a particular machine; or
effecting a transformation or reduction of a particular article to a different state or thing.
The claimed limitations add insignificant extra-solution activity to the judicial exceptions. The additional elements are data gathering steps.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims encompass the use well-known and conventional assays, such PCR, RT-PCR, qRT-PCR, next generation sequencing, etc. as described on p. 21 of the instant specification.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4, 9, 14, 15, 22, 23, 24, 26, 31, 34, 38, 41, 42, 49, 82, 83, 103, 107, 110, 112 and 119 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 2, 4, 9, 14, 15, 22, 23, 24, 26, 31, 34, 38, 41, 42, 49, 82, 83, 103, 107, 110, 112 and 119 each involve determining the level of at least one miRNA in a blood sample, where a nucleotide sequence of the miRNA is selected from the sequences of SEQ ID NO: 1 to 44 and further includes “a fragment thereof and a sequence having at least 80% identity thereto”.
The full-length sequences of SEQ ID NOs: 1 to 44 have lengths that vary between 20 to 25 nucleotides. In terms of the full-length sequences, this results in between 424,996 and 14,000,116 potential sequences, depending on the length of the sequence. The before mentioned numbers do not take into consideration insertions and/or deletion variants. The calculations do not also consider sequences “having at least 80% identity” with a “fragment” of one of SEQ ID NOs: 1 to 44. All together this results in a genus of possible miRNA sequences the claims encompass determining the levels of in a blood sample from patients suffering from lung cancer having species that numbers in the tens of millions of miRNA sequences.
SEQ ID NOs: 1 to 44 were identified in the instant specification through the sequencing of small RNAs obtained from blood samples of stage IV lung cancer patients (p. 82), advanced NSCLC (p. 86) and stage IV NSCLC (p. 95).
There is no guidance as to whether any of the potential miRNA sequences encompassed by the claim, outside of SEQ ID NOs: 1 to 44 are actually found in a blood sample of a lung cancer patient, including patients with lung cancer other than NSCLC. There is no indication which of the potential miRNA sequences have the same property of SEQ ID NOs: 1 to 44, which is being differentially expressed within the blood of stage IV lung cancer patients, advanced NSCLC patients and stage IV NSCLC patients. The specification provides no core structure or sequence that is relevant to using a sequence variant of SEQ ID NOs: 1 to 44 in the claimed methods.
The limited species number of relevant miRNA sequences disclosed as being detected in the blood of NSCLC patients (i.e., one sequence for each miRNA identified) does not adequately support the entire genus of tens of millions of miRNA sequences and miRNA fragments sequences encompassed by the claim. Thus, the specification does not adequately describe in the entire genus of the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4, 9, 14, 15, 22, 23, 24, 26, 31, 34, 38, 41, 42, 49, 82, 83, 103, 107, 110, 112 and 119 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
The specification, while being enabling for detecting the full length sequence of one of SEQ ID NOs: 1 to 44 and making predictions regarding stage IV NSCLC patients, does not reasonably provide enablement for using any variant or fragment of SEQ ID NOs: 1 to 44 to make any prediction regarding any lung cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The claims broadly encompass embodiments in which miRNA levels are actively used to “predict” a response: to “lung cancer immunotherapy”; to “predict” a “survival prognosis”; to “provide” a “survival prognosis”; in “assigning the patient to the lung cancer immunotherapy”; or to “select” a patient “suffering from lung cancer to benefit from immunochemotherapy or immunotherapy”.
The scope of “lung cancers” includes NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma), small cell lung cancer, carcinoid tumors, mesothelioma, etc. The scope of “immunotherapy” includes PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, bispecific antibodies and T-cell engagers, cancer vaccines, adoptive T cell therapy, etc.
The instant specification only studied stage IV NSCLC patients treated with nivolumab or pembrolizumab, which are PD-1 inhibitors.
The state of the art demonstrates that miRNA levels vary between different types and stages of lung cancer and differentially expressed miRNAs are able to be used to identify different types of lung cancer. See, e.g., Raponi (Cancer Res. 2009. 69(14):5779-5783); Bishop (Clin Cancer Res. 2010. 16(2):610-619); Du (Journal of Experimental & Clinical Cancer Research. 2010. 29:75, 12 pages); Hu (Oncotarget. 2017. 8(43):74554-74566); Yanaihara (Cancer Cell. 2006. 9:189-198); and Mairinger (Modern Pathology. 2014. 27:1632-1640). Based on the variation in miRNA expression levels between different types of lung cancers, it is unpredictable whether the miRNA expression levels observed in stage IV NSCLC patients can be reasonably extrapolated to all other types of lung cancer. Differences in miRNA expression levels may reflect the type or stage of lung cancer as opposed to the responsiveness to an immunotherapy or a prognosis of survival.
The state of the art demonstrates that different types and stages of lung cancer are treated with different types of immunotherapies. See, e.g., Wang (BMC Med. 2022. 20:426, 11 pages); and Patel (European Journal of Cardio-Thoracic Surgery. 2023. 64(2): 8 pages). Based on the different responses to different immunotherapies, it is unpredictable whether the responsiveness in one type/stage of lung cancer can reasonably extrapolated to other types of types/stages of lung cancer.
Furthermore, multiple studies have analyzed the relationship between miRNA expression and immunotherapy responsiveness. The studies have identified different sets of miRNA. See, e.g., Rajakumar (npj Precision Oncology. 2022. 6:19); Fan (Genomics. 2020. 112:2063-2071); Rajakumar (medRxiv Preprint. "A blood-based miRNA signature predicts immunotherapy efficacy in advanced stage non-small cell lung cancer". 11/1/2021)and Grenda (Frontiers in Oncology. 2021. 10: Article 583613). Thus, it is further unpredictable that the panel of miRNAs described in the specification can broadly be extrapolated across all other types of lung cancer and immunotherapies.
It would require undue experiment to determine which miRNAs are relevant in lung cancers other than stage IV NSCLC and to which immunotherapies. Given the differences discussed above between lung cancers, immunotherapy responsiveness and miRNA panel identification, it is unpredictable whether the identified panel as universal applicability to lung cancer and immunotherapies.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 38, 82 and 119 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 38, the claim refers to “a patient to whom a lung cancer immunotherapy will be administered”. It is unclear what patients are and are not encompassed by the claim. It is unclear if at the time of performing the active method step of claim 38 a patient is not scheduled to be administered an immunotherapy, but subsequently after carrying out the method step of claim 38 is administered an immunotherapy, such a patient is within the scope of the claim.
Regarding claim 82, the claim states “thereby identifying the patient as patient who will respond to lung cancer immunotherapy”. The claim is incomplete as claim 1 as required by claim 82 does require any active method step of “identifying” the patient.
Regarding claim 119, the claim recites “said therapy” in the last line. The recitation lacks proper antecedent basis as the claim previously sets forth “immunochemotherapy or immunotherapy”.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14, 15, 38, 41 and 42 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claims 14 and 15, the claims do not further limit how the active method step of claim 1 is carried out. The claims do not recite any additional elements that further limit the scope of the active method step. The claim fails further limit claim 1.
Regarding claims 38, 41 and 42, the claims do not further limit how the active method step of claim 23 is carried out. The claims do not recite any additional elements that further limit the scope of the active method step. The claim fails further limit claim 23.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 1, 2, 14, 15, 22, 23, 24, 38, 41, 42, 49, 103 and 107 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fehlmann (JAMA Oncol. 2020. 6(5):714-723 and Supplementary Online Content; published online 3/5/2020) as evidenced by miRBase hsa-miR-2115-3p (retrieved on 6/4/2026 from the internet: www.mirbase.org/mature/MIMAT0011159).
Claims 1, 23 and 103 are given the broadest reasonable interpretation as described above.
Regarding claims 1, 2, 23, 24 and 103, Fehlmann teaches determining the expression level of miRNA in blood samples from lung cancer patients (p. 717, RNA Extraction and Quality Control and Arrays).
The data of Fehlmann demonstrates the level of elected hsa-miR-2115-3p was determined (p. 111, 142, 173, 216, 235, 264 and 298 of 307).
PNG
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249
332
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Greyscale
miRBase demonstrates that the sequence of hsa-miR-2115-3p is identical to elected SEQ ID NO: 1. The known sequence of hsa-miR-2115-3p is provided below:
Regarding claims 14 and 15, the claim does not require any additional active methods steps or further limit how the step of determining the expression level of miRNA in blood samples from lung cancer patients is carried out.
Fehlmann anticipates claims 14 and 15 for the same reason as claim 1.
Regarding 22, Fehlmann teaches the lung cancer is NSCLC (p. 715, Participants).
Regarding claims 38, 41 and 42, the claims do not limit the scope of the patient at the time of performing the active method step of claim 23. The claims do not require any additional active methods steps or further limit how the step of determining the expression level of miRNA in blood samples from lung cancer patients is carried out.
Fehlmann anticipates claims 38, 41 and 42 for the same reason as claim 23.
Regarding 49, Fehlmann teaches the lung cancer is NSCLC (p. 715, Participants).
Regarding 107, Fehlmann teaches the lung cancer is NSCLC (p. 715, Participants).
Claim(s) 1, 2, 4, 14, 15, 22, 23, 24, 26, 38, 41, 42, 49, 82, 83, 103, 107, 110, and 119 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fan (Genomics. 2020. 112:2063-2071) as evidenced by miRBase hsa-miR-145-5p (retrieved on 6/10/2026 from the internet: www.mirbase.org/mature/MIMAT0000437).
The following rejections are over an unelected species.
Claims 1, 23 and 103 are given the broadest reasonable interpretation as described above.
Regarding claims 1, 2, 23 and 103, Fan teaches determining the expression levels of miRNA in the serum of a blood sample of lung cancer patients (p. 2064, 2.1 Patient data, 2.2. Serum RNA isolation, 2.3. MiRNA expression profiling), including hsa-miR-145-5p (Fig. 1).
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miRBase demonstrates that the sequence of hsa-miR-145-5p is identical to elected SEQ ID NO: 23. The known sequence of hsa-miR-145-5p is provided below:
Regarding claims 2 and 24, hsa-miR-145-5p includes a fragment that has 100% identity with a fragment with SEQ ID NO: 8, i.e., GGAA.
Regarding claims 4 and 26, Fan further teaches comparing miRNA levels in patients that are non-responders to a lung cancer immunotherapy as encompassed by claims 4 and 26.
Regarding claims 14 and 15, the claims do not require any additional active methods steps or further limit how the step of determining the expression level of miRNA in blood samples from lung cancer patients is carried out.
Regarding 22, Fan teaches the lung cancer is NSCLC (p. 2065, 3.1 Patient demographics).
Regarding claims 38, 41 and 42, the claims do not limit the scope of the patient at the time of performing the active method step of claim 23. The claim does not require any additional active methods steps or further limit how the step of determining the expression level of miRNA in blood samples from lung cancer patients is carried out.
Fan anticipates claims 38, 41 and 42 for the same reason as claim 23.
Regarding 49, Fan teaches the lung cancer is NSCLC (p. 2065, 3.1 Patient demographics).
Regarding claim 82, Fan teaches the method of claim 1. Fan further teaches assigning the patient to lung cancer immunotherapy (p. 2069).
Regarding claim 83, Fan teaches the lung cancer is NSCLC (p. 2065, 3.1 Patient demographics).
Regarding claim 107, Fan teaches the lung cancer is NSCLC (p. 2065, 3.1 Patient demographics).
Regarding claim 110, Fan further teaches comparing miRNA levels in patients that are non-responders to a lung cancer immunotherapy as a “(miRisk) cut-off score”.
Regarding claim 119, Fan teaches the method of claim 103. Fan further teaches treating a patient with the therapy anti-PD1 (p. 2064, 2.1. Patient data).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 9, 31 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fan (Genomics. 2020. 112:2063-2071) as evidenced by miRBase hsa-miR-145-5p (retrieved on 6/10/2026 from the internet: www.mirbase.org/mature/MIMAT0000437) in view of Bishop (Clin Cancer Res. 2010. 6(2):610-619).
The following rejections are over an unelected species.
Regarding claim 9, 31 and 34, Fan teaches determining the expression levels of miRNA in the serum of a blood sample of lung cancer patients (p. 2064, 2.1 Patient data, 2.2. Serum RNA isolation, 2.3. MiRNA expression profiling), including hsa-miR-145-5p (Fig. 1).
miRBase demonstrates that the sequence of hsa-miR-145-5p is identical to elected SEQ ID NO: 23. The known sequence of hsa-miR-145-5p is provided above.
While Fan teaches comparing miRNA levels, Fan does not teach the additional elements specific to claims 9, 31 and 34.
However, it was within the skill of the ordinary artisan to develop other methods of comparing miRNA levels, such as to threshold values as demonstrated by Bishops. The claims are rendered obvious as resulting from a simple substitution of comparing methods that are functionally equivalent to each other.
Improper Markush Group
Claims 1, 2, 4, 9, 14, 15, 22, 23, 24, 26, 31, 34, 38, 41, 42, 49, 82, 83, 103, 107, 110, 112 and 119 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The claims recite the following Markush grouping: at least one miRNA selected from the group consisting of SEQ ID NOs: 1-44, a fragment thereof, and a sequence having at least 80% sequence identity thereto. The Markush group is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 706.03(y) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 706.03(y)IIA).
Here, the recited alternative species do not share a single structural similarity, as each miRNA has a different chemical structure in that it consists of a different nucleotide sequence. The only structural similarity present is that all of the miRNA comprise nucleotides. The fact that the miRNA comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides alone is not essential to the asserted common activity of being correlated with lung cancer. Accordingly, while the different miRNA are asserted to have the property of being correlated with lung cancer, they do not share a substantial structural similarity essential to this activity.
Further, the recited miRNA do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that miRNA behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited miRNA possess the common property of being correlated with lung cancer.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
No claims allowed.
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/JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682
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