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 .
Applicant’s amendments and remarks, filed on 07/08/2025, are acknowledged. Applicant’s arguments have been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn.
Status of Claims
Claims 1-4, 6-8, 10, and 11 are presently under examination.
Claims 5, 9 are cancelled. Claims 10 and 11 are newly added.
Objections
Claim 1 is objected to for the following informalities:
Claim 1 recites “A = number of reads (patient in need thereof sample) - number of reads (limit regression from the MSS control subject(s))”. In this case, the “A” is grammatically incorrect (since there is no “A” in the equation and it appears to refer to the “Δ” symbol in the equation). Correction is requested via amendment.
Claim 1 recites “obtaining the ms.score….and the ms.score for the MSS control subject.” In each case, the term “the ms.score” is grammatically incorrect and should to recite “obtaining an ms.score”. Correction is requested via amendment.
Priority
Applicant’s claim for the benefit of priority under 35 U.S.C. 119(a)-(d) is acknowledged. This application is the National Stage filing under 35 USC 371 of PCT/EP2020/055915 filed on 03/05/2020. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
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 1-4, 6-8, 10, and 11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
The United States Patent and Trademark Office published revised guidance on the application of 35 U.S.C. § 101. USPTO’s 2019 Revised Patent Subject Matter Eligibility Guidance (“Guidance”). Under the Guidance, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes) (Guidance Step 2A, Prong 1); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)) (Guidance Step 2A, Prong 2).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that are not “well-understood, routine and conventional in the field” (see MPEP § 2106.05(d)); or 2019 Revised Patent Subject Matter Eligibility Guidance, 84 Fed. Reg. 50-57 (January 7, 2019).
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.(Guidance Step 2B). See Guidance, 84 Fed. Reg. at 54-56.
Step 1
This part of the eligibility analysis evaluates whether the claim falls within any statutory category. See MPEP 2106.03. In this case, the claimed invention (claim 1 being representative) requires performing a series of process steps. As such, the claims fall into one of the four statutory categories. (Step 1: YES).
A. Guidance Step 2A, Prong 1
The Revised Guidance instructs us first to determine whether any judicial exception to patent eligibility is recited in the claim. The Revised Guidance identifies three judicially-excepted groupings identified by the courts as abstract ideas: (1) mathematical concepts, (2) certain methods of organizing human behavior such as fundamental economic practices, and (3) mental processes. In this case, the following limitations recited in the claims 1 and 17 constitute the abstract idea for the following reasons:
iv) calculating a log 10 transformation of the read counts per locus for said patient and for the MSS control subject, and calculating a limit regression for each repeat obtained from the MSS control subject,
v) obtaining the ms.score for the undiagnosed patient and the ms.score for the MSS control subject by calculating the following formula :
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wherein, N = number maximal of repeat sequenced; n = number of repeat sequences, A = number of reads (undiagnosed patient sample) - number of reads (limit regression from the MSS control subject)….
vi) comparing the ms.score obtained with the undiagnosed patient with the ms.score of the MSS control subject;
vii) concluding that the undiagnosed patient has a CMMRD syndrome or a MSI leukemia/lymphoma when his ms.score is superior than the ms.score of the MSS control subject.
Mental Processes
Regarding steps iv) through vii), under the broadest reasonable interpretation, these steps amount to observing and analyzing data and making a decision based on said analysis. As such, the above steps can be performed by the human mind and fall within the “mental processes” grouping of abstract idea set forth in the 2019 PEG (Section I, 84 Fed. Reg. at 52). Applicant is also reminded that the amount of sophistication in the data analysis (which may tax the human brain) does not take the analysis outside the realm of mental processes. The Office's eligibility guidance does not set limit on the number of calculations that can or cannot be performed mentally. MPEP § 2106.04(a)(2)III. Accordingly, but for the recitation of a programmable processor, the above steps fall within the mental process groupings of abstract ideas because they cover concepts performed in the human mind, including observation, evaluation, judgment, and opinion. See MPEP 2106.04(a)(2), subsection III. [Step 2A, Prong 1: YES]
Mathematical Concept
The above steps also recite a mathematical concept. Regarding step (iv) the claim requires calculating a log 10 transformation and a limit regression, which are interpreted as mathematical calculations based on the knowledge of one of ordinary skill in the art. Regarding step (v), the claim requires obtaining an “ms.score” by using a specific mathematical formula, which also amounts to a mathematical calculation. See MPEP 2106.04(a)(2). Therefore, when read in light of the specification, the claimed predicting step also encompasses a mathematical concept.
Natural Correlation
Additionally, claim(s) 1 is also directed to a natural correlation for the following reasons. In particular, the instant claims require extracting DNA from a sample from a patient and mathematically correlating this information with a score that is associated with a particular disease (CMMRD or MSI). Therefore, the discriminating step further recites a law of nature because it describes the naturally occurring relationship between a subject’s biomarkers and disease. See MPEP 2106.04(b). It is noted that even if a claim does recite a law of nature or natural phenomenon, it may still be eligible. For example, claims reciting a naturally occurring relationship between a patient’s genotype and the risk of QTc prolongation (a law of nature) were held eligible as not “directed to” that relationship because they also recited a step of treating the patient with an amount of a particular medication that was tailored to the patient’s genotype. Vanda Pharms., 887 F.3d at 1134-36, 126 USPQ2d at 1279-81. This particular treatment step applied the natural relationship in a manner that integrated it into a practical application. The court’s analysis in Vanda is equivalent to a finding of eligibility at Step 2A Prong Two (Pathway B).
B. Guidance Step 2A, Prong 2
This part of the eligibility analysis evaluates whether the claim includes any additional steps/elements that integrate the recited judicial exception into a practical application of the exception. In this case, the additional steps/elements that are not part of the abstract idea are as follows:
i) extracting DNA from a sample obtained from said patient
ii) sequencing a number (N) of repeat sequences having a length of between 8 and 30 nucleic acids from the mononucleotides microsatellites DNA of said patient, iii) repeating the steps i) and ii) for at least one control subject having stable microsatellite cancer (MSS control subject)
With regards to the additionally recited steps i) through iii), these steps are not limited to any particular techniques or devices and generally require obtaining data for use by the abstract idea. Accordingly, these steps amount to insignificant extra-solution activity and are not indicative of an integration into a practical application. See MPEP 2106.05(g). With regards to the claimed processors, this imitation is recited at high level of generality and reads on a generic computer. Accordingly, this feature is merely being used as a tool to perform generic computer functions or the abstract idea, and therefore amounts to no more than mere instructions to apply the exception using a generic computer. See MPEP 2106.05(f). Even when viewed in combination, these additional elements do not integrate the recited judicial exception into a practical application. [Step 2A, Prong 2: NO]. Accordingly, the claims as a whole do not integrate the recited judicial exception into a practical application and the claims are directed to the judicial exception. [Step 2A, Prong 2: NO]
C. Guidance Step 2B:
Under the 2019 PEG, a conclusion that an additional element is insignificant extra-solution activity in Step 2A should be re-evaluated in Step 2B. In this case, the claims do not include additional steps and/or elements appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception(s) for the following reasons:
As discussed above, the non-abstract steps/elements amount to nothing more than insignificant extra-solution activity. A review of the specification teaches examples of conventional sequencing methods for performing all of the aforementioned data acquisition steps [see at least page 9]. In addition, Salipante et al. (Clinical Chemistry 2014, 60:9, pp.1192–1199), teaches that methods for sequencing mononucleotide microsatellite loci using next-generation sequencing methods in cancer diagnosis were routine and conventional in the art [see entire]. Accordingly, it is the examiner’s position that there is nothing unconventional with regards to how the DNA is being extracted or sequenced. See MPEP 2106.05(d)(Part II). Thus, the independent claims as a whole do not amount to significantly more than the exception itself. Therefore, the claim(s) is/are not patent eligible.
Dependent Claims
Dependent claims 2-4, 6-8, 10, and 11 have also been considered under the two-part analysis but do not include additional steps/elements appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception(s) for the following reasons. Regarding claim(s) claims 2-4, 6-8, 10, and 11, these claims recite limitations that further limit the type of sequencing or the nature of the data being used by the abstract idea. Therefore, these claims amount to insignificant extra-solution activity and are not indicative of an integration into a practical application (Step 2A, prong 2 and Step 2B analysis). Regarding claim(s) 10, this claim comprises administering a therapeutically effective amount of radiotherapy, chemotherapy, and/or immunotherapy when a patient is diagnosed as having CMMRD or MSI (by the method of claim 1). In this case, although the claim recites administering a therapeutically effective amount of radiotherapy, chemotherapy, and/or immunotherapy, these are all generically recited and do not impose any meaningful constraints on the claimed administering, e.g. particular types, amounts, and/or durations of treatment. See MPEP 2106.04(d)(2). As such, this limitation may thus be understood as no more than an attempt to generally link the judicial exception to a field of use. See MPEP 2106.05(h). Therefore, this claim fails to meaningfully limit the claim because it does not require any particular application of the abstract idea and therefore amounts only to a generic instruction to “apply” the exception or to a mere indication of the field of use or technological environment in which the abstract idea is performed.
Therefore, based on the two-part analysis, the instantly rejected claims as a whole are not drawn to eligible subject matter as they are directed to an abstract idea (and/or natural correlation) without significantly more.
Response to Arguments
Applicant’s arguments, filed 07/08/2025, have been fully considered but are not persuasive for the following reasons.
Applicant argues that the invention is patent eligible because steps (i)-(iii) are not directed to insignificant extra-solution activity. In response, as set forth in the Step 2A (prong 2) analysis, steps i) through iii) are not limited to any particular sequencies or sequencing techniques and generally require obtaining data for use by the abstract idea. Accordingly, absent any evidence to the contrary, the examiner maintains that these steps amount to insignificant extra-solution activity and are not indicative of an integration into a practical application. See MPEP 2106.05(g). In addition, as set forth above in the Step 2B analysis, a review of the specification teaches examples of conventional sequencing methods for performing all of the aforementioned data acquisition steps [see at least page 9]. Moreover, Salipante et al. (Clinical Chemistry 2014, 60:9, pp.1192–1199), teaches that methods for sequencing mononucleotide microsatellite loci using next-generation sequencing methods in cancer diagnosis were routine and conventional in the art [see entire]. Accordingly, it is the examiner’s position that there is nothing unconventional with regards to how the DNA is being extracted or sequenced. See MPEP 2106.05(d)(Part II). Thus, the independent claims as a whole do not amount to significantly more than the exception itself.
Applicant additionally argues that the claimed invention provides an improvement to the technology, namely by taking advantage of current next-generation sequencing methods that enable fast and sensitive results compared to other approaches. In response, it is first noted that the instant claims are not limited to next-generation sequencing technology. Therefore, applicant is arguing asserted improvements that are not even part of the claims, as required. See MPEP 2106.04(d)(1). That being said, the improvement analysis at Step 2A Prong Two differs in some respects from the improvements analysis at Step 2B. Specifically, the “improvements” analysis in Step 2A determines whether the claim pertains to an improvement to the functioning of a computer or to another technology without reference to what is well-understood, routine, conventional activity. In this case, for reasons discussed above, it is the examiner’s position that steps (i) through (iii) do not result in an improvement to the functioning of a computer or another technology as there is nothing unconventional with regards to how the DNA is being extracted or sequenced. In addition, there is also case law supporting the determination that claims that merely provide efficiency or accuracy increases over mental calculations do not recite eligible subject matter. See Bancorp Servs., L.L.C. v. Sun Life Assurance Co. of Can. (US.), 687 F.3d 1266, 1279 (Fed. Cir. 2012) ("Using a computer to accelerate an ineligible mental process does not make that process patent-eligible.").
Applicant additionally argues that steps (iv)-(vii) are no longer directed to an abstract idea because the claims have been amended to recite the use of a programmable processor. In response, as set forth above (Step 2A analysis), the recitation of a processor does not negate the mental nature of these limitations because the claim merely uses it as a tool to perform the otherwise mental processes. Applicant does not contend that it invented any of the processor components or their basic function or that processor was unknown in the art as of time of the invention. Accordingly, the claimed processor has been reasonably interpreted as conventional computer elements and using a computer as a tool to perform an abstract idea. Accordingly, the examiner maintains that the claimed invention merely manipulates existing information to generate additional information, which, without more, is not patent eligible. See Digitech Image Techs., LLC v. Elecs. For Imaging, Inc., 758 F.3d 1344, 1351 (Fed. Cir. 2014) (“Without additional limitations, a process that employs mathematical algorithms to manipulate existing information to generate additional information is not patent eligible.”); see also CyberSource, 654 F.3d at 1375 (“The mere manipulation or reorganization of data . . . does not satisfy the transformation prong.”).
It is noted that Applicant has not challenged the examiner’s position that the claims recite a mathematical concept as well as a natural correlation. Accordingly, these positions are maintained for reasons set forth above. For at least these reasons, the rejection is maintained.
Claim rejections - 35 USC § 112 – Lack of Enablement
The following is a quotation of 35 U.S.C. 112(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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
This enablement rejection has been modified in view of applicant’s amendments.
Claims 1-4, 6-8, 10, and 11 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 would require undue experimentation have been summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986) and reiterated by the Court of Appeals in In re Wands, 8 USPQ2d 1400 at 1404 (CAFC 1988). These factors include, but are not limited to: A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See also MPEP § 2164.01(a). While all of these factors are considered, a sufficient amount for a prima facie case are discussed below which leads to the determination that the above claim lacks enablement due to undue experimentation being required to make and use the invention.
The nature of the invention; the level of one of ordinary skill in the art:
Claim 1, as best understood, is directed to a method of diagnosing a CMMRD cancer or a MSI leukemia/lymphoma in a patient which has been summarized above (see rejection under 35 USC 101). Therefore, the nature of the invention, as claimed, is complex in that it requires specific knowledge of DNA sequence data, numbers of repeats, and mathematically derived (patient/control) scores for making a predictive diagnosis of CMMRD cancer or MSI leukemia.
The breadth of the claims; the amount of direction or guidance presented; the presence or absence of working examples:
Regarding claim(s) 1, the claimed invention is broad in that it is not limited to any particular DNA information (e.g. markers/sequences associated with particular cancer), particular type of cancer (see also rejection under 35 USC 112b), particular age range of patient, or particular (patient/control) range of scores that are predictive of diagnosing the full scope of cancers embraced by the claims.
With regards steps i) through iii), the claimed invention purports to be able to diagnose any type of CMMRD syndrome simply by extracting and sequencing DNA from a patient and control without regard for any particular genetic marker information or particular sequence repeat information. The specification does not provide any evidence that applicants have actually identified specific biomarkers/sequencies associated with the full scope of cancers encompassed by the claims. The instant specification suggests that “CMMRD cancer” is caused by mutations in the Mismatch Repair (MMR) genes: MLH1, MSH2, MSH6, PMS2 [page 4] and teaches an embodiment wherein CMMRD is colorectal cancer [page 7]. However, such limitations are not recited in the present claims and it is improper to import narrowing limitations into the claims. MPEP 2111.01. At best, the specification provides a limited example for practicing the claimed invention [pages 20-25] that only covers a limited study population of patients with specific mutations in one of the 4 major MMR genes and with specific clinical scores. Moreover, applicant’s own specification explicitly states that CMMRD is difficult to diagnose for several reasons, e.g. because the broad spectrum of tumors seen in this rare cancer syndrome and the lack of clear, disease-specific clinical features [page 1]. With regards to genetic markers for “MSI cancer”, the specification generically states that this is a cancer having microsatellite instablity [page 4]. However, this also does not provide sufficient guidance on what genetic markers are required to practice the claimed invention. Without knowledge of what generic markers (i.e. DNA information) is associated with a particular type of cancer, one of skill in the art would not know how to make and use the claimed method for the full scope of cancers encompassed by the claims without undue experimentation.
Regarding claim(s) 1, steps iv) through vii), the instantly claimed invention purports to be able to mathematical analyze arbitrary “numbers of reads” between patient/controls and generate arbitrary “ms.scores” for a patient/control and make a diagnostic prediction based on a generic comparison of said “ms.scores”. However, the specification does not provide any evidence that applicants have actually identified a sufficient number of “repeats” and “ms.scores” for patients/controls that are associated with (and thus predictive) of the full scope of cancers encompassed by the claims (i.e. CMMRD syndrome or MSI leukemia). Such information is not trivial. The specification also doesn't provide any guidance as to what type of "differences" in the repeat counts or threshold values should be used for practicing the claimed invention to determine a patient’s likelihood for the full scope of cancers embraced by the claims. Disease likelihood is inherently associated with the probability that an event occurs (i.e. predictions). However, the claims don't recite any limitations that indicate the use of a predictive model. At best, the specification provides a minimal discussion of repeat counts associated with cancer and limited discussion of a mathematical model for calculating “ms.scores” based on read count. As such, the specification fails to provide sufficient teaching of genetic markers/sequencies, and “ms.scores” and threshold values necessary to practice the claimed invention for the full scope of what is being claimed. For these reasons, it is unclear how one skilled in the art would be able to “conclude” that a patient has CMMRD cancer or MSI leukemia, as claimed, simply by looking at the differences between “ms.scores” for patient and controls. Without knowledge of such information, one of skill in the art would not know how to make and use the claimed method for the full scope of (patient and control) scores encompassed by the claims without undue experimentation.
Regarding claim(s) 10, directed to administering a therapeutically effective amount of radiotherapy, chemotherapy, and/or immunotherapy when a patient is diagnosed as having CMMRD or MSI (by the method of claim 1), the specification also does not provide any evidence that applicants have actually identified what specific therapies (or combinations thereof) are suitable for “treating” the full scope of cancers encompassed by the claims. Such information is not trivial. The specification provides a laundry list of drugs [pages 12-15]. However, this is not sufficient given the highly variable nature of how different types of cancers respond to different types and combinations of drugs. Without knowledge of such information, one of skill in the art would not know how to make and use the claimed method for the full scope of drugs encompassed by the claims without undue experimentation. For the above reasons, the claims are unpredictable in view of the teachings of the specification.
The state of the prior art; the quantity of experimentation needed:
Given the deficiencies of the specification, as discussed above, the skilled practitioner would turn to the prior art for guidance. However, the Examiner refers to the following prior art references:
Salipante et al. (Clinical Chemistry 2014, 60:9, pp.1192–1199), teaches methods for detecting microsatellite instability using next-generation sequencing [see entire]. Unlike the instant claims, Salipante teaches identifying and using select microsatellite markers in panels for detecting MSI [page 1194 and Table 1]. Salipante additionally teaches that MSI tumors may result from mutations in one or more genes, including MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1),4 DNA mismatch repair protein Msh2 (MSH2), mutS homolog 6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), and epithelial cell adhesion molecule (EPCAM), such as occurs in patients with Lynch syndrome [page 1192, col. 2].
Abedalthagafi et al. (Oncotarget, 2018, Vol. 9, No. 83, pp: 35458-35469) teaches current problems associated with CMMRD syndrome. In particular, they teach that CMMRD syndrome greatly increases the risk of children or young adults developing one or more types of cancer (i.e. it is age related). They also teach that CMMRD is associated with a broad spectrum of cancers which complicates diagnosis due to the lack of clear disease-specific clinical features that combine the full spectrum of CMMRD related tumors (page 35460). Abedalthagafi also teaches that information on optimal therapeutic strategies are limited and current knowledge of treatment regimens and their outcomes are limited to individual case reports, often with variable disease phenotypes (page 35462, col. 2). Therefore, one of skill in the art would not know how to make and use the claimed method for the full scope patient age ranges, drug treatments, and cancers encompassed by the claims without undue experimentation.
Gallon et al. (Human Mutation, 2019, Volume 40, Issue 5, pp. 497-655) teaches a method for diagnosing CMMRD. In particular, unlike the instant claims, their method is limited to specific gene panel with specific genetic variants [Figure 1 and Table S3]. In addition, Gallon teaches that diagnosing CMMRD is unpredictable due to the diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, and that current diagnostic techniques are laborious or of limited sensitivity [Abstract]. As such, this provides evidence that additional experimentation would be needed to practice the claimed invention for the full scope of what is being claimed.
Wang et al. (WO 2016/127067; IDS filed 08/27/2021) teaches methods and compositions for determining prognosis in individual with endometrial cancer. Unlike the instant claims, Wang teaches a well-defined and validated cluster prediction model that was developed based on a large clinical data set and prognostic indicators of recurrence in low-stage endometrioid tumors [0007, 0076, 00137-00158, Table 1]. Their method is also limited to endometrial cancer and requires testing samples for a mutation in particular genes (ESR1, CSDE1) [ref. claims 1, 27, par 00103-106).
Accordingly, the prior art supports the unpredictability of the claimed invention, since the “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. In re Marzocchi, 439 F.2d 220, 223-24, 169 USPQ 367, 369-70 (CCPA 1971). Finally, said practitioner would turn to trial and error experimentation to determine what generic markers are suitable for the specific type of cancer, develop and validate a predictive model based on all the relevant sequence data and clinical parameters, and identifying (patient/control) scores that are predictive of the intended disease. Due to the unpredictability of the invention, as discussed above, coupled to the lack of guidance in either the prior art or instant specification, it would require undue experimentation to perform the method/system of the claim as broadly written.
For the above reasons, the instantly rejected claims do not comply with the enablement requirement of 35 U.S.C 112(a) since to practice the claimed invention, a person of ordinary skill in the art would have to engage in undue experimentation with no reasonable expectation of success. Applicant is reminded that while the claims are to be interpreted in light of the specification, it does not follow that limitations from the specification may be read into the claims. On the contrary, claims must be interpreted as broadly as their terms reasonably allow. See MPEP 904.01 and Ex parte Oetiker, 23 USPQ2d 1641 (BPAI, 1992).
Response to Arguments
Applicant’s arguments, filed 07/08/2025, have been fully considered but are not persuasive for the following reasons.
Applicant argues that the very nature of the diseases to be treated is the reason why this method does not rely on the use of a single specific "biomarker"(such as a mutation), asserting that the cited documents Wang et al., Zhang et al, Gallo, et al., and Abedalthagafi et al., are not relevant to the present invention. In response, it is again noted that the claimed invention is not limited to any particular microsatellite markers or any particular type of sequencing methodology. In addition, Salipante et al. (Clinical Chemistry 2014, 60:9, pp.1192–1199) has been cited as a teaching of methods for detecting microsatellite instability using next-generation sequencing [see entire]. Unlike the instant claims, Salipante teaches identifying and using select microsatellite markers in panels for detecting MSI [page 1194 and Table 1]. Salipante additionally teaches that MSI tumors may result from mutations in one or more genes, including MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1),4 DNA mismatch repair protein Msh2 (MSH2), mutS homolog 6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), and epithelial cell adhesion molecule (EPCAM), such as occurs in patients with Lynch syndrome [page 1192, col. 2]. Accordingly, absent any evidence to the contrary, the examiner maintains that the instant specification does not provide a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. At best, the specification provides a limited example for practicing the claimed invention [pages 20-25] that only covers a limited study population of patients with specific mutations in one of the 4 major MMR genes and with specific clinical scores. Therefore, for reasons discussed above, the examiner also maintains that the cited prior art supports the unpredictability of the claimed invention, since the “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. In re Marzocchi, 439 F.2d 220, 223-24, 169 USPQ 367, 369-70 (CCPA 1971).
Applicant argues that it is possible to conclude that the patient has a CMMRD syndrome or a MSI leukemia/lymphoma when their ms.score is superior than the ms.score of a control (e.g., a subject without microsatellite instability), and that the ms.score that would be associated with CMMRD syndrome or a MSI leukemia/lymphoma already recapitulates the measured reads counts per locus that are dependent upon microsatellites instability. In response, as set forth above, the specification does not provide any evidence that applicants have actually identified a sufficient number of “repeats” and “ms.scores” for patients/controls that are associated with (and thus predictive) of the full scope of cancers encompassed by the claims (i.e. CMMRD syndrome or MSI leukemia). The specification also doesn't provide any guidance as to what type of "differences" in the repeat counts or threshold values should be used for practicing the claimed invention to determine a patient’s likelihood for the full scope of cancers embraced by the claims. In applications directed to inventions in arts where the results are unpredictable, e.g. biological and chemical arts, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In reSoll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). At best, the specification provides a minimal discussion of repeat counts associated with cancer and limited discussion of a mathematical model for calculating “ms.scores” based on read count. Therefore, absent any evidence to the contrary, the examiner maintains that the specification fails to provide sufficient teaching of genetic markers/sequencies, and “ms.scores” and threshold values necessary to practice the claimed invention for the full scope of what is being claimed. For these reasons, it is unclear how one skilled in the art would be able to “conclude” that a patient has CMMRD cancer or MSI leukemia, as claimed, simply by looking at the differences between “ms.scores” for patient and controls. Without knowledge of such information, one of skill in the art would not know how to make and use the claimed method for the full scope of (patient and control) scores encompassed by the claims without undue experimentation. For at least these reasons, the rejection is maintained.
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 1-4, 6-8, 10, and 11 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 pre-AIA the applicant regards as the invention. Claims that depend directly or indirectly from claim(s) 1 is/are also rejected due to said dependency.
Claim 1 recites “MSI leukemia/lymphoma”. In each case, it is unclear as to the metes and bounds of these terms such that the artisan would recognize the boundaries of what is being claimed, i.e. what type of cancers or leukemia are encompassed by this term. With regards to “MSI leukemia”, a review of the specification also fails to provide any limiting definition for this term. The specification teaches that “MSI cancer” denotes that an instability is detected in at least 2 microsatellite markers [page 4]. However, this is not a limiting definition and does not serve to clarify the scope of leukemia encompassed by the claim. Clarification is requested via amendment.
Claim 1 recites a “calculating a log 10 transformation of a read counts per locus for said patient and for the MSS control subject”. It is unclear what is meant by “a read counts per locus”. This phrase appears to be grammatically incorrect (and should simply recite “read counts per locus”). Correction is requested via amendment.
Claim 1 recites “calculating a limit regression for each repeat obtained from the MSS control subject.” It is unclear as to the metes and bounds of the term “limit regression”. A review of the specification does not provide any limiting definition for this term or describe any algorithms, equations, or prose equivalent that correspond to the claimed function. One of ordinary skill in the art would recognize that regression analysis is performed in order to determine a mathematical correlation between variables, e.g. dependent and one or more independent variables, and that there are many types of regression, e.g. linear, logistic, polynomial, and quantile regression. In this case, however, this is not what is being claimed (i.e. Step iv) does not provide any model/equation or any specific variables that would be used in a correlation and does not result in determining a correlation between anything). As a result, it is unclear what computational operation is actually required. Clarification is again requested as applicant has not provided any illuminating arguments or clarifying amendments.
Claim 1 recites v) calculating the ms.score…by calculating the following formula :
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wherein, N = number maximal of repeat sequenced; n = number of repeat sequences, A= number of reads (undiagnosed patient sample) - number of reads (limit regression from the MSS control subject). In particular, this limitation is problematic for the following reasons. It is unclear what is meant by “N = number maximal of repeat sequenced” and “number of reads (patient in need thereof sample)”. These limitations appear to be erroneous (and grammatically incorrect) translations into English from a foreign document. Moreover, these parameters have not been previously obtained by the claim (as there is no previous step for determining the number of reads). In fact, the above mathematical expression does not even appear to use the log 10 transformation from step (iv). As such, there is lack of antecedent basis for these features. For these reasons, it is unclear as to the metes and bounds of the above step such that the artisan would recognize what computation/calculation is actually being performed. Clarification is again requested as applicant has not provided any illuminating arguments or clarifying amendments.
Claim 1 recites “vii) concluding that the patient in need thereof has a CMMRD cancer or a MSI leukemia/lymphoma when his ms.score is superior than the ms.score of the MSS control subject”. It remains unclear what is meant by the term “superior”. This limitation appears to be a literal translation into English from a foreign document and is both grammatically and idiomatically erroneous. Clarification is again requested as applicant has not provided any illuminating arguments or clarifying amendments. For purposes of examination, this term is interpreted as “greater than”.
Claim 10 recites “administering a therapeutically effective amount of radiotherapy, chemotherapy, and/or immunotherapy when a patient is diagnosed…by the method of claim 1.” It is unclear what limiting effect is intended by the phrase “by the method of claim 1”. This appears to be a shorthand reference back to claim 1 and/or a product-by-process type limitation (where the information generated by the method of claim 1 is broadly construed as the product). However, Applicant is reminded that in product-by-process limitations directed to the nature of the data (i.e. how the patient was identified or diagnosed) has no limiting effect on the method as claimed. Clarification is again requested as applicant has not provided any illuminating arguments or clarifying amendments. To obviate this rejection, applicant is encouraged to cancel this claim and amend claim 1 to include an “administering” step.
Conclusion
No claims are 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PABLO S WHALEY whose telephone number is (571)272-4425. The examiner can normally be reached between 1pm-9pm EST.
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/PABLO S WHALEY/Primary Examiner, Art Unit 3619