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 .
Election/Restrictions
Applicant’s election without traverse of Group I, species hsa-miR-18b-3p in the reply filed on 1/9/2026 is acknowledged.
Any rejection or objection not reiterated or updated or otherwise addressed in this Office action was overcome by amendment to the claims.
Improper Markush Grouping Rejection
Claims 21-23 are rejected on the basis that it contains 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 § 2117.
The Markush grouping of different miRNA listed in the alternative 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:
The miRNAs do not all share the same structure, namely each has a unique nucleotide sequence. The mere fact that they are all miRNA does not explain their common utility because not all miRNA would be expected to function in the claimed methods. There is no expectation from the prior art that they would all function in the same way.
Furthermore, with regard to common function, the specification does not provide data to support that all of these miRNA would function predictively in the claimed method in the same way, that is with similar or the same predictive relationship.
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.
Response to Remarks
Claim 21-23 have not been amended to overcome the rejection and remains rejected for the reasons of record. No substantive argument was presented against the rejection.
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, 5, 6, 7, 8, 9 10, 11 and 21-24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to law of nature and an abstract idea without significantly more. The claim(s) recite(s) identifying a change in the expression of miRNA in a before and after sample, which is an abstract idea that is a mathematical process. The claims all further set forth that the change indicates mucositis which is a naturally occurring correlation.
This judicial exception is not integrated into a practical application because although claim 1 recites three options for treatment, the treatments are not specific to mucositis, for example “varying the dosage of the antitumor therapy” includes increasing or decreasing dosage which will not treat mucositis. The treatment step in claim 21 does not integrate the judicial exception because it occurs during a data gathering step and does not apply or use the judicial exception in any way. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exception are routine data gathering steps recited at an extremely high level of generality with regard to technique and sample used. For example, Kahraman et al. (cited herein) teaches detecting microRNA expression in liquid biopsies using commercially available microarrays.
Response to Remarks
Applicant argues that the treatments recited in claim 1 add meaningful limitation that is not routine nor conventional. However, as noted in the rejection, the treatments are not specific to mucositis, and in all embodiments would not even be expected to reduce or prevent further mucositis. Therefore, they do not integrate the recited judicial exceptions or provide significantly more than the judicial exception.
No substantive argument is provided for claims 21-23.
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, 5, 6, 7, 8, 9 10, 11 and 21-24 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims recite a method for diagnosis and treatment of mucositis in a cancer patient undergoing cancer treatment and include identifying a change in the expression of has-miR-18b-3p (consonant with the election) as an indicator of mucositis, and claims 1, 2, 5, 6, 7, 8, 9 10, 11 and 24 further require subsequent treatment of the patient.
However, the specification does not provide any data to support that a change, either upregulation or downregulation, in the expression of the miR is indicative of mucositis.
The specification shows in the examples that the miR differentially expressed in response to neoplastic agents, specifically the miR was upregulated relative to control, irrespective of the type of treatment (p. 24, line 6). However, the disclosure does not provide any data to demonstrate that this upregulation is related to the development of mucositis or if it occurs in all patients regardless of whether or not mucositis develops.
The specification additionally shows that in three out of only four patients tested, an increase in the levels of circulating hsa-miR-18b-3p was detected (p. 25, line 5). The specification hypothesizes that "the interpatient differences in expression levels might in some way be linked to the patient's susceptibility to developing oral mucositis and/or the degree or severity thereof." The disclosure does not provide any technical support and/or evidence of an association between the levels of the specific miRNA has-miR-18b-3p and the presence or diagnosis of mucositis of a cancer patient. Not all cancer patients undergoing antitumor therapy develop mucositis. Whether the disreguation of the elected miRNA inevitably results in oral or intestinal mucositis, or predicts which treated patients will develop one of these, is unpredictable based on the evidence of record.
Gutierrez-Camino (2018; IDS 6/15/23) teaches that 206 miRNA were screened to determine a predictive marker of mucositis in pediatric acute lymphoblastic leukemia (ALL) patients. Of the 206 potential markers tested, only three were potential hits as being predictive of mucositis. Gutierrez-Camino (2017; IDS 6/15/23) demonstrates unpredictability of identifying diagnostic biomarkers. The reference attempted to validate the results of a prior study connecting polymorphisms in miRNA to the development of mucositis in pediatric acute lymphoblastic leukemia (ALL) patients. Of five previously identified markers, only one was able to be confirmed as a potential diagnostic marker. These references together demonstrate that it is highly unpredictable whether any putative marker will itself be a diagnostic marker for mucositis, and that such a predictive relationship must be determined empirically using appropriate case-controlled studies.
Given the level of unpredictability in the art, and the lack of evidence to support the assertion that the expression of the miR is associated with mucositis, the practice of the claimed invention would require carrying out appropriate case-controlled studies covering a variety of types of cancer, treatments and types of mucositis (oral versus GI). It is unpredictable which of these studies would result in finding a predictive relationship between expression levels of the miR before and after treatment. This experimentation, considering the number of variables concerned would require an enormous amount of work, where it is highly unpredictable if the outcome will be successful.
Thus, having carefully considered the data provided in the disclosure, the high level unpredictability in the art, and the amoung of experimentation required to practice the invention, it is concluded that it would require undue experimentation to practice the claimed invention.
Response to Remarks
Applicant points to paragraphs 57-59 and 78-79 of the specification which show that the required miRNA was overregulated in circulating serum of patients affected by advanced stage head and neck cancer.
Applicant further argues that an interrogation of the TOGA public database showed that miR-18b-3p levels are low in tumor tissue and shows no difference of expression between healthy and tumor tissue. Applicant argues that this “confirmed specificity” or the miRNA as a biomarker of the mucositis inflammatory process.
However, there is not a nexus between the showing that the miRNA is upregulated after cancer treatment and that it is an indicator of mucositis. As noted in the rejection, very few miRNA are expected to be markers of developing mucositis. There is no evidence in the specification that the increase in the miR recognized in the specification is correlated specifically to the development of mucositis and not simply a marker that the individuals had been treated for cancer.
For example, the specification does not show a difference in the level of the miR in patients that develop mucositis after treatment and patients that do not, and therefore the specific does not show that the change in expression observed is a predictor of developing mucositis.
The rejection is maintained.
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.
Claim(s) 21, 22, and 23 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kahraman et al. (Scientific Reports | (2018) 8:11584 | DOI:10.1038/s41598-018-29917-2; 11 pages, and supplemental table 1).
The reference teaches measuring in a blood sample (a liquid biopsy) the expression of miR-18b-3p, subjecting the subject to treatment with paclitaxel (an antimitotic chemotherapy), obtaining a second measurement in blood of the expression of the miRNA, and determining whether a change has occurred. See p.2, study set up, patient characteristics and p. 3, miRNA measurement on microarrays. Evidence that miR-18b-3p expression was measured is in the supplemental table attached to the paper, which reports data for this miR on the 16th page of the table.
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The claim recites that the change indicates mucositis. However, this states an inherent property of the change, but does not require any further action.
Response to Remarks
The response argues that the amendment overcomes the rejection since Kahraman is entirely silent regarding mucositis. However, this limitation is addressed in the rejection. Namely, the newly added limitation does not require any further action, it merely states an inherent property of “the change”. The language is sufficiently broad to encompass detecting a change that is upregulation or down regulation or detecting no change. The amendment describes what the change means, but does not require action. Furthermore “indicates mucositis” is broad in and of itself and encompasses indicating the presence or absence of the condition, especially considering that the claim encompasses that any change indicates mucositis.
The rejection is maintained.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
