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 .
Status of Claims
Applicant' s amendment filed 01/27/2026 is acknowledged. Claim 9 has been amended. Claims 1-8 and 10-47 have been cancelled. Claim 9 is pending in the instant application and the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejection
Status of Prior Rejections/Objections:
The 101 rejection of claim 9 is maintained and modified to address amendments.
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(a)
Claim 9 is 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
Regarding claim 9, the amended claim now recites “(e) categorizing the human subject as having an miRNA signature classifier (MSC) High profile and MSC High lung cancer when at least 14 miRNA pair expression ratios are assigned a positive score; and (f) administering a lung cancer treatment that eliminates or reduces in severity a sign or symptom of lung cancer to the … subject classified as having the MSC High lung cancer”.
First, the claim now encompasses categorizing the human subject as having MSC High lung cancer when at least 14 miRNA pair ratios are assigned a positive score out of 27 claimed pairs. Just considering the events with exactly 14 pair ratios in step (d) for exemplary purposes, there would be nCr = n!/((n-r)!r!) = 27!/(13!14!) = 20,058,300 possible combinations that could result in a positive categorization. Thus, the claims encompass a high degree of breath due to the number of possible combinations encompassed by the categorization scheme.
Second, the working example provides categorization of lung cancer for “MSC High”, “MSC Intermediate”, and “MSC Low”. In contrast, while the claims call the classifier a “MSC High” profile and lung cancer, the set of miRNAs belongs to the RD set of Table 9, which is described in the disclosure as part of the “Intermediate risk” profile. This “Intermediate” profile defines RD positive as a minimum of 10/27 ratios exceeding the cut-off values of Table 9 as positive (para [000157]; see also para [000155]) and sets forth the “Intermediate risk” as the union of RD positive with the intersections of the PD positive, RAD negative, and PAD negative categories (para [000157]). While 10 or more encompasses 14 or more, one of skill in the art would not understand from the disclosure whether this threshold difference would meaningfully change the performance or what difference a removal of the intersection of the three categories would have on the performance of the prediction of lung cancer compared to the RD positive category alone.
Utilizing the data that is provided, however, in Table 11 for the MSC Intermediate category comprising the miRNA ratios of the invention, there are 29 individuals identified as having lung cancer and 130 individuals without lung cancer. This results in a positive predictive value (see formula in para [00093]) MSC Intermediate 29/(29+130) = 18% in the MILD population sampled.
Third, the art teaches unpredictability of the class of miRNAs used in categorization. Hicks (Hicks SD, Middleton FA. A Comparative Review of microRNA Expression Patterns in Autism Spectrum Disorder. Front Psychiatry. 2016 Nov 4;7:176) teaches miRNAs as candidate biomarkers for autism spectrum disorder (Abstract) teaches differential regulation at least of miR-15b, mir-16, mir-19b, mir-451a (i.e., mir-451), and mir-92a or the mature products thereof in serum (Table 2) and that there was no single miRNA identified in all 12 studies (pg. 3, Overlapping miRNAs in ASD, para 2).
Thus, the skilled artisan would recognize the unpredictability in applying the instant method of categorization to any human subject who may have such comorbid diseases/conditions, wherein confounding effects of the comorbid disease/condition may lead to directional effects that oppose that of lung cancer. Further, as described by Hicks, the field of miRNA research frequently has low reproducibility, as demonstrated by the lack of miRNAs shared across studies, further adding to the unpredictability.
As amended, the claims encompass categorizing a subject as having a type of lung cancer when at least 14 miRNA pair ratios are assigned a positive score and administering a treatment for lung cancer. Under the assumption that the MILD population is representative of a lung cancer patient population, the claim requires diagnosing and treating an individual that is expected to have an about 18% chance of actually having lung cancer. In the alternative, the artisan, wishing to practice such an invention would be required to perform an undue amount of experimentation in order to supplement the diagnostic capabilities of the claimed invention so as to confidently diagnose and treat patients—be that redoing the work to determine ratios for the present invention that increase confidence, determining a threshold of miRNA pairs that produces a higher predictive value, adding additional diagnostic steps (e.g., additional miRNAs, genes, etc.), etc.
Taken together, there is a high degree of uncertainty and experimentation due to the breadth of the claims; the minimal direction provided by the inventor for categorizing a subject as having a type of lung cancer based on the claimed set of miRNA ratios in the working examples; the teachings of the art regarding lack of reproducibility and potentially confounding effects of comorbid conditions; and the low predictive power of the class that encompasses the claimed invention in the working examples. Balanced only against the high level of skill in the art, it is held that the level of experimentation to utilize the full scope of the invention claimed would be undue.
For this reason, the claims do not comply with the 112(a) enablement requirements.
Claim Rejections - 35 USC § 101
Claim 9 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) abstract ideas and natural phenomena. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter?
Yes, the claim is directed to a process.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
The claim now recites “A method comprising:” the following steps: “(a) determining the expression ratio …”; “(b) comparing the expression ratio …”; “(c) assigning a positive score…or assigning a non-positive score …”; “repeating steps (a) through (c)”; “(d) categorizing the subject”. The steps encompass the abstract ideas of a mental process, e.g., performing observations, evaluations, making judgements, and/or performing mathematic calculations (including those capable of being performed in the human mind). Thus, the claims both recite and are directed to abstract ideas.
The claim also recites the natural phenomenon of miRNA expression ratios being correlated with a lung cancer treatment status.
Step 2A, prong 2. Is the judicial exception integrated into a practical application?
Steps (a)-(d) require only abstract idea and therefore do not integrate the claim into a practical application.
As amended, the claim now recites the step of “(f) administering a lung cancer treatment that eliminates or reduces in severity a sign or symptom of lung cancer to the human subject classified as having the MSC High lung cancer” that is assigned when “at least 14 miRNA pair expression ratios are assigned a positive score”.
MPEP 2106.04(d)(2) discusses factors relevant to integrating a judicial exception with a treatment or prophylaxis including (a) the particularity or generality of the treatment/prophylaxis and (b) whether the limitations have more than a nominal or insignificant relationship to the exceptions.
The treatment in the amended claim comprises any lung cancer treatment that eliminates or reduces in severity a sign or symptom of lung cancer. This set of treatments, interpreted under the broadest reasonable interpretation according to MPEP 2111, includes any reasonable treatment that reduces in severity or eliminates a sign or symptom of lung cancer.
The set of symptoms associated with lung cancer is notably broad. Collins (Collins LG, et al. Lung cancer: diagnosis and management. Am Fam Physician. 2007 Jan 1;75(1):56-63.) teaches that patients may present with non-specific systematic symptoms of fatigue, anorexia, and weight loss (pg. 57, Clinical Presentation) and that symptoms such as cough, dyspnea [shortness of breath], and hemoptysis are common manifestations of a primary [lung] tumor (pg. 57, Primary Tumor). Collins teaches that acute bronchitis is the most common cause of hemoptysis (pg. 57, Primary Tumor, spanning pg. 58), and the UCHealth teaches cough and shortness of breath are likewise to upper respiratory infections (Upper respiratory infection (URI) [Internet]. UCHealth; 2024 [cited 2026 Feb 17]. Available from: https://www.uchealth.org/diseases-conditions/upper-respiratory-infections/). See Collins Table 2 for additional symptoms, including confusion, headache, nausea and vomiting, seizures, and weakness, wherein Collins further states that weakness and weight loss are among the non-specific symptoms of the extrathoracic spread stage of disease (pg. 58, Extrathoracic Spread).
Williams (Williams AC, et al. Dyspnea Management in Early Stage Lung Cancer: A Palliative Perspective. J Hosp Palliat Nurs. 2012 Jul;14(5):341-342) teaches a differential for causes of the symptom dyspnea in early stage lung cancer and interventions for each cause (Table 1). While there are direct causes associated with the tumor noted (e.g., tumor, lymph invasion, obstruction/restriction), other causes may originate from the treatments of the lung cancer instead (e.g., post operative pain, loss of lung tissue from surgery, chemotherapy-induced vomiting) or potentially unrelated to the cancer (e.g., anxiety, panic, a sedentary lifestyle) (Table 1), wherein it is noted that psychological disorders and a sedentary lifestyle may be comorbid with lung cancer. It is further noted that such treatments of this symptom of lung cancer are not restricted to, for example, chemotherapeutic drugs or other forms of medical management (Table 1; Quality of Life Related to Dyspnea in Early-Stage Lung Cancer; Nursing Management of Dyspenea in Early-Stage Lung Cancer).
Because the treatments encompass treatments that address symptoms of lung cancer, wherein such symptoms encompass non-specific symptoms that may originate from a comorbid condition, the limitation fails to require more than a nominal or insignificant relationship to the exceptions. Subjects may be on a variety of therapeutics unrelated to any potential lung cancer diagnosis that overlap with the symptomology of lung cancer (e.g., taking aspirin for blood thinning though it may also reduce in severity pain associated with a lung cancer). Further, such palliative medications, while potentially improving quality of life, fail to meaningfully treat the cancer itself.
MPEP 2106.04(d)(2)(b) discusses the difference between a treatment for ketoacidosis and aspirin in a method of detecting blood glucose. Despite abdominal pain being a symptom of diabetic ketoacidosis (Diabetic ketoacidosis [Internet]. Mayo Foundation for Medical Education and Research; 2026 [cited 2026 Feb 17]. Available from: https://www.mayoclinic.org/diseases-conditions/diabetic-ketoacidosis/symptoms-causes/syc-20371551) and the ability of aspirin to relieve pain, it is noted that the guidance states aspirin is not known in the art as a treatment for ketoacidosis. Given current guidance, treating incidental symptoms of a disease is not sufficient to overcome the requirement that limitations have more than a nominal or insignificant relationship to the exception.
Thus, the limitation fails to require more than a nominal or insignificant relationship to the judicial exception of the abstract idea(s) and/or natural phenomenon, and the claim as a whole is not integrated into a practical application.
Step 2B. Does the claim amount to significantly more?
As discussed above in Step 2A, the claims amount to a recitation of abstract ideas and a generically recited treatment step. As MPEP 2106.05 makes clear: “An inventive concept ‘cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself.’… Instead, an "inventive concept" is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself.”
As each step of the claim encompasses an abstract idea aside from step (f), the inventive concept must be born from step (f). As discussed in the Remarks dated 1/27/06, pg. 5 para 2, treatments for lung cancer were well known before the effective filing date of the claimed invention and the administration remains generically recited. For this reason and those previously discussed, this treatment fails to amount to than instructions to apply the limitation and merely appends well-understood, routine, and conventional activity specified at a high level of generality. Thus, the claims as a whole fail to amount to significantly more.
Response to Arguments
Applicant's arguments filed 01/27/2026 have been fully considered but they are not persuasive.
Applicant argues that at the time of the claimed invention, the ordinarily skilled artisan would have immediately recognized the particular lung cancer treatments as recited in the amended claim, citing the Lung Cancer Research Foundation’s list of 35 FDA approved lung cancer treatments (provided in the IDS dated 01/27/2026). Applicant alleges that the lung cancer treatment claimed is therefore in a format similar to Vanda rather than Examples 43 and 49 of the Guidance. Applicant further argues that requiring less than 14 miRNA pairs does not impact subject matter eligibility.
Regarding the argument that the artisan would have recognized the lung treatments as particular, the MPEP outlines the requirements for the broadest reasonable interpretation in section 2111. The claims are not limited to FDA approved therapies, nor does the specification define the treatments to such therapies.
Indeed, as discussed in the 101 above, many treatments exist beyond those in the FDA-approved lists in the document cited that “reduce in severity a sign or symptom of lung cancer”. Williams, as discussed above in the 101 rejection, teaches the treatments for such symptoms beyond FDA chemotherapeutics for dyspnea (Table 1). And, more broadly, the claimed treatments are not limited to those that treat or control cancer itself but also those that provide palliative relief from the symptoms associated with cancer. As discussed in the 101 rejection, the guidance in the MPEP regarding whether limitations have more than a nominal or significant relationship to the exception directs that insulin is particular to the detection of a high blood glucose level while aspirin is not because it is not known as a treatment for ketoacidosis or diabetes. As such, aspirin would have at best a nominal connection to the law of nature because it does not treat or prevent ketoacidosis. As cited in the 101 rejection, ketoacidosis includes symptoms of pain.
The currently amended lung cancer treatments continue to include palliative treatments. Yet, these treatments, following the logic of the guidance provided, fail to treat the disease of cancer itself in more than a nominal or insignificant way.
Accordingly, given the broadest reasonable interpretation, the claim continues to lack the specificity of Vanda in the treatment/prophylaxis. Therefore, it is not integrated into a practical application according to the Alice/Mayo framework, as discussed in greater detail above. As the remainder of the claim is directed to abstract ideas, the claim as a whole is neither integrated into a practical application nor represents significantly more.
Regarding the argument of less than 14 miRNA pairs, this argument is moot as the preamble as the preamble has been amended and this aspect of the rejection has not been reiterated.
Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Adai (WO 2013/063519 A1; published 05/02/2013) teaches measuring up to 9 “diff pairs” of miRNAs, wherein two “diff pair miRNAs” may be evaluated by dividing values representing the expression levels [i.e., generating ratios of pairs of miRNAs] (para [0018]). Adai teaches various “diff pair miRNA” ratios (claims 62-68); determining a treatment based on the “diff pair” value [e.g., a ratio] of at least one miRNA (e.g., claim 73) or a calculated diagnostic score (claim 74); and administering a chemotherapy to the patient (claim 76). However, Adai fails to teach the specific miRNA pairs of the ratios in the instant claims.
Conclusion
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 Emma R Hoppe whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571) 272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/EMMA R HOPPE/ Examiner, Art Unit 1683
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683