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 .
Claim Status
Claims 1-8 are cancelled by Applicant.
Claims 9-16 are newly added by Applicant.
Claims 9-16 are currently pending and are herein under examination.
Claims 9-16 are rejected.
Claims 9-11 and 15-16 are objected.
Priority
The instant application claims domestic benefit as a 317 filing of international application PCT/EP2022/052080, filed 01/28/2022, which claims foreign priority to European Application No. EP21305121.2, filed 01/29/2021. The claims to domestic benefit and foreign priority are acknowledged. As such, the effective filing date for claims 9-16 is 01/29/2021.
Information Disclosure Statement
The IDS filed 07/21/2023 follows the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of the list of references cited from the IDS is included with this Office Action.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(u)(1) because all the figures recite “FIGURE” instead of “FIG.” Change the figure labeling to “FIG. 1”, FIG. 2”, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) 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. 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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on specification pg. 16, line 28, and pg. 35, line 18. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Abstract
The abstract of the disclosure is objected to for the following reasons. Line 1 should spell out MSI before using the abbreviation. Line 2 should recite “operating” not “operate”. Line 3 should spell out MNRs before using the abbreviation. The abbreviation “(WES)” in line 6 should be deleted since it is not used later on. Line 8 should recite “named” or “called” instead of “namely”. 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 Interpretation
MPEP 2111.04(II) recites “[t]he broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.”
The broadest reasonable interpretation of steps iii-vii in claim 9 includes them being contingent limitations. Step iii is contingent upon the normal sample being available. When the normal sample is not available, step iii is not performed. Step iv-vii are being interpreted as contingent upon step iii. Thus, steps iv-vii are not required when step iii is not required.
Claim Objections
Claims 9-11 and 15-16 are objected to because of the following informalities:
Claims 9-11 and 15 should separate each individual step by a line indentation. See MPEP 608.01(i)(i).
Claim 9, line 1, should spell out “MSI” first before using the abbreviation.
Claim 9, line 2, should recite “and, if available, from a normal”.
Claim 9, line 3, should recite “mononucleotide repeats (MRN) sequences” instead of “mononucleotide - MRN - sequences”.
Claim 9, line 5, should recite “patient, or”.
Claim 9, lines 5-6, should recite “a number N of MNRs
Claim 9, line 6, should recite “sample
Claim 9, step iii, recites “depending if” which should recite either “if” or “depending on if”.
Claim 9, step iv, should recite “tumor purity (TP)” instead of “tumor purity - TP -“.
Claim 9, step iv, should recite “tumoral sample” to maintain consistent terminology.
Claim 9, lines 10-11, should recite “MNR, and vii)” instead of “MNR and, vii)”.
Claims 9-10, step vi, and claim 11, step viii, should recite determining, calculating, computing or another similar word rather than “doing”.
Claims 9-10, step vi, and claim 11, step viii, should recite “the ratio of … [[on]] to ...”
Claims 9-10, step vii, and claim 11, step ix, should recite “greater” rather than “superior”.
Claim 10, line 2, should recite “from [[a]] tumor and normal samples”.
Claim 10, line 3, and claim 11, line 3, should recite “a number of MNRs” instead of “a number N of mononucleotide repeats - MNR -“ because the abbreviation has already been provided in claim 9.
Claim 10, step iv, and claim 11, step vi, should recite “the TP” instead of “the tumor purity - TP -“ because claim 9 already provided the abbreviation.
Claim 11, step ii, should recite “sequencing a number N …
Claim 11, line 6, should recite “MNR, v)” instead of “MNR; v)”.
Claim 11, line 10, should recite “MNR, and ix)” instead of “MNR and, ix)”.
Claim 15, line 1, should recite either “a mononucleotide repeat (MNR)” or “in [[a]] mononucleotide repeats (MNR)”.
Claim 15, line 2, should recite “from [[a]] tumor and normal samples”.
Claim 15, line 3, should recite “a number N of MNR sequences” instead of “a number N of mononucleotide repeats - MNR - sequences” because the abbreviation is already recited.
Claim 15, step vi, should recite “adjusted, and vi)”.
Claim 15, step vi, should recite “the ΔRatio [[-]]adjusted”.
Claim 15, step iv, should recite “<50% and concluding that”.
Claim 16, line 1, should spell out “MSI” first before using the abbreviation.
Claim 16, line 1, should recite “identified [[has]] as having”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC 112(b)
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 9-16 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.
Claims dependent from a rejected claim are also rejected, unless otherwise noted.
Claim 9, step ii, recites “the corresponding normal sample”. It is unclear if this refers to “a normal sample” in line 2, or refers to another normal sample that corresponds to the tumoral sample. For examination, the former interpretation is being used. Clarify what the phrase refers to.
Claim 9, step iii, recites “the ΔRatio” which lacks antecedent basis. To overcome this rejection, amend to “a ΔRatio”.
Claim 9, step iv, recites “the tumor purity” which lacks antecedent basis. To overcome this rejection, amend to “a tumor purity”.
Claim 9, step v, recites “the ΔRatio adjusted” which lacks antecedent basis. To overcome this rejection, amend to “a ΔRatio adjusted”.
Claim 9, step vi, recites “the number of MNR with a ΔRatio adjusted mutated”. It is unclear what this means. Does it mean that each MNR has an adjusted ΔRatio, wherein a portion of the adjusted ΔRatios contain mutated MNRs, or is there some other interpretation conferred by the verb mutated? Clarify the meaning of this recitation.
Claim 9, step vi, recites “the total number of ΔRatio of the MNR”. It is unclear if this recitation means a total number of ΔRatios for all the MNRs, or if it means a final value ΔRatio for a particular MNR. Clarify the meaning of this recitation. For examination, the former interpretation is being used.
Claim 10, line 5, recites “said patients”. Claims 9-10 recite “said patient” but there is no mention of “patients”. Provide antecedent basis or clarify what the recitation refers to.
Claim 10, step iv, recites “the tumor sample”. It is unclear if this refers to the tumoral sample in claim 9, step i, or a specific tumoral sample from the tumoral samples in claim 10, step i. Clarify which tumoral sample is being referenced.
Claim 10, step vi, recites “the number of MNR with a ΔRatio adjusted mutated” and “the total number of ΔRatio of the MNR”. It is unclear if these recitations refer to the same data recited in claim 9, step vi, or if they refer to distinct data derived from claim 10, steps i-v. For examination, the latter interpretation is being used. Clarify what the recitations in claim 10, step vi, refer to.
Claim 10, step vii, recites “the MSICare score obtained at the step vi)”. It is unclear if this refers to the MSICare score obtained in claim 9, step vi, or claim 10, step vi. For examination, it refers to claim 10, step vi. Clarify which MSICare score and which step iv is being referenced.
Claim 11, steps ii, iv, v and vi, recites “the tumoral sample” and “the tumor sample”. It is unclear which tumor sample is being referenced because both claim 9, step i, and claim 10, step i, recite a tumoral sample. Clarify which tumor sample is being referenced.
Claim 11, step ii, recites “the corresponding normal sample”. It is unclear if this refers to “the corresponding normal sample” recited in claim 9, step ii, or refers to a different normal sample that corresponds to the tumor sample in claim 11, step i. For examination, the latter interpretation is used. Clarify the meaning of the phrase.
Claim 11, step iii, recites “the normal polymorphic zones for the MNR” which lacks antecedent basis. Provide antecedent basis for the recitation.
Claim 11, step iii, recites “the MNR”. It is unclear which MNRs are being referenced because both claim 9, step ii, and claim 11, step ii, recite a number N of MNR. Clarify which MNRs are being referenced.
Claim 11, step iv, recites “the mutated MNR” which lacks antecedent basis. There is no prior mention of this phrase in either claim 9 or 11. Provide antecedent basis or clarify what it refers to.
Claim 11, step viii, recites “the number of MNR with a ΔRatio adjusted mutated” and “the total number of ΔRatio of the MNR”. It is unclear if these recitations refer to the same data recited in claim 9, step vi, or if they refer to distinct data derived from claim 11, steps i-vii. For examination, the latter interpretation is being used. Clarify what these recitations refer to.
Claim 14 recites “the result” which lacks antecedent basis. There is no mention of “a result” in claim 9. Provide antecedent basis or clarify what the phrase refers to.
Claim 14 recites “wherein a further step of communicating the result to the patient is added.” The limiting effect of this wherein clause is unclear. It is unclear whether an active step of communicating is required, or if it recites an intended use of communicating the result as indicated by “is added”. To clarify that claim 14 recites an active step, Applicant can amend to “further comprising a step of communicating a result to the patient”. For examination, claim 14 recites an active step.
Claim 15, line 5, recites “the DNA of the tumoral samples of said patients” which lacks antecedent basis. Claim 15, step i, recites “tumor … samples obtained from said patient”, but does not recite tumoral samples from a plurality of patients. To overcome this rejection, amend the phrase to “the DNA of the [[tumoral]] tumor samples of said [[patients]] patient”.
Claim 15, step iii, recites “the ΔRatio” which lacks antecedent basis. Amend to “a ΔRatio”.
Claim 15, step iv, recites “the tumor purity” which lacks antecedent basis. Amend to “a tumor purity”.
Claim 15, step iv, recites “the tumor sample”. It is unclear which tumor sample is being referenced because steps i and ii recite tumoral samples. Clarify which tumoral sample is being referenced.
Claim 15, step v, recites “the ΔRatio adjusted” which lacks antecedent basis. Amend to “a ΔRatio adjusted”.
Claim 15, lines 7 and 8, recite “the MNR”. It is unclear which MNR is being referenced because step ii recites a number N of MNR sequences. Clarify which MNR is being referenced.
Claim 16, recites “according to a method for diagnosing a MSI cancer according to claim 9”. It is unclear if this recitation refers to parts of claim 9 or refers to the entirety of claim 9. For examination purposes, this recitation is being interpreted as “according to [[a]] the method for diagnosing [[a]] the MSI cancer in claim 9”.
Claim 16, line 3, recites “said patient”. It is unclear if said patient refers to “a patient” in claim 16, line 1, or the patient recited in claim 9. For examination, the former interpretation is used. Clarify which patient is being referenced.
35 USC 112(d)
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 12 and 16 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.
Claim 12 fails to further limit claim 9 because cancer is already inherently metastatic or not metastatic.
Claim 16 fails to include all the limitations of claim 9. Claim 16 depends on claim 9 but does not require the limitations of claim 9. MPEP 608.01(n)(III) recites “if claim 1 recites a method of making a specified product, a claim to the product set forth in claim 1 would not be a proper dependent claim if the product can be made by a method other than that recited in the base method claim, and thus, does not include the limitations of the base claim.” This is because claim 16 recites “a cancer in a patient identified as having a MSI cancer according to a method for diagnosing a MSI cancer according to claim 9”. The word identified indicates that the cancer patient with a MSI cancer is a product by process. The product is the cancer patient with a MSI cancer, and the process previously performed is the method of claim 9. However, a cancer patient can be diagnosed as having an MSI cancer using a method different than claim 9 because the product is the same regardless of the process used. See MPEP 2113.I regarding product by process limitations.
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 § 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 9-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
Step 1:
Step 1 asks whether the claims recite statutory subject matter. In the instant application, claims 9-14 recite a method and claim 15 recites a method. As such, these claims recite statutory subject matter (Step 1: YES).
Step 2A, Prong 1:
Claims that recite statutory subject matter are analyzed under Step 2A, Prong 1 to determine if they recite any concepts that equate to an abstract idea, law of nature or natural phenomena. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claim 9 recites “iii) calculating the ARatio for each MNR depending if the normal sample is available or not, iv) calculating the tumor purity - TP - for the tumor sample, v) calculating the ARatio adjusted, vi) obtaining a MSICare score by doing the ratio of the number of MNR with a ARatio adjusted mutated on the total number of ARatio of the MNR and, vii) concluding that the patient in need thereof has a MSI cancer when the MSICare score obtained at the step vi) is superior than a calculated threshold value.”
Claim 10 recites “iii) calculating the ARatio for each MNR, iv) calculating the tumor purity - TP - for the tumor sample, v) calculating the ARatio adjusted, vi) obtaining a MSICare score by doing the ratio of the number of MNR with a ARatio adjusted mutated on the total number of ARatio of the MNR and, vii) concluding that the patient in need thereof has a MSI cancer when the MSICare score obtained at the step vi) is superior than a calculated threshold value.”
Claim 11 recites “iii) evaluating the normal polymorphic zones for the MNR, iv) evaluating the mutated MNR appearing in the tumor sample only outside the normal polymorphic zone of each MNR; v) calculating the ARatio for each MNR obtained from the tumoral sample; vi) calculating the tumor purity - TP - for the tumor sample, vii) calculating the ARatio adjusted, viii) obtaining a MSICare score by doing the ratio of the number of MNR with a ARatio adjusted mutated on the total number of ARatio of the MNR and, ix) concluding that the patient in need thereof has a MSI cancer when the MSICare score obtained at the step viii) is superior than a calculated threshold value.”
Claim 14 recites “wherein a further step of communicating the result to the patient is added.”
Claim 15 recites “iii) calculating the ARatio for each MNR, iv) calculating the tumor purity - TP - for the tumor sample, v) calculating the ARatio adjusted and vi) concluding that the MNR is wild type when the ARatio -adjusted is < 50% concluding that the MNR is mutated when the ARatio adjusted is >50%.”
Limitations reciting a mental process.
Claims 9-11 and 15 contain limitations recited at such a high level of generality that they equate to a mental process because they are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as concepts that can be practically performed in the human mind. The paragraphs below discuss the broadest reasonable interpretation (BRI) of the limitations in these claims that recite a mental process.
Regarding claims 9-11 and 15, calculating a ΔRatio includes performing on pen and paper the calculations described on specification pg. 4, lines 31-33. Calculating tumor purity includes performing on pen and paper the calculations described on specification pg. 5, lines 7-13. Calculating ΔRatio adjusted includes performing on pen and paper the calculations described on specification pg. 5, lines 21-25. Obtaining a MSICare score includes performing on pen and paper the calculations described on specification pg. 5, lines 26-28. Concluding that a patient has MSI cancer by comparing a numerical score to a threshold includes mental analysis and mental determination. Concluding that MNR is a wild type includes comparing a number to threshold, which is a mental process.
Claim 11, step iii, includes counting how many repeats are normal for a normal sample. Claim 11, step iv, includes evaluating mutated MNRs outside the normal polymorphic zone includes only detecting MNRs when there is a repeat count outside the normal repeat bounds of a normal sample.
Limitations reciting a mathematical concept.
Claims 9-11 and 15 recite limitations that equate to a mathematical concept because they are similar to the concepts of organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)), which the courts have identified as mathematical concepts. The paragraphs below discuss the broadest reasonable interpretation (BRI) of the limitations in these claims that recite a mathematical concept.
Regarding claims 9-11 and 15, calculating a ΔRatio includes performing calculations described on specification pg. 4, lines 31-33. Calculating tumor purity includes performing calculations described on specification pg. 5, lines 7-13. Calculating ΔRatio adjusted includes performing calculations described on specification pg. 5, lines 21-25. Obtaining a MSICare score includes performing calculations described on specification pg. 5, lines 26-28.
Limitations reciting a natural phenomenon.
Claims 9-11 and 15 recite limitations that are similar to the concept of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017), which the courts have established as a natural phenomenon. Claims 9-11 correlate mutated mononucleotide repeats (MNR) to a microsatellite instability (MSI) cancer, wherein the mutated status of MNRs has a natural correlation to a MSI cancer. Claim 15 determines whether a MNR is wild type or mutated based on a natural correlation between repeat counts from MNRs in tumor and normal samples.
Limitations reciting organizing human activity.
Claim 14 equate to organizing human activity because it is similar to managing personal behavior or relationships or interactions between people (See MPEP 210604(a)(2).II.C). The broadest reasonable interpretation of claim 14 includes a doctor communicating verbally to a patient their MSI cancer status.
As such, claims 9-15 recite an abstract idea and a natural phenomenon (Step 2A, Prong 1: YES).
Additional Elements:
Once limitations have been identified that recite a judicial exception, the claims are evaluated for additional elements. The additional elements are then analyzed under Step 2A, Prong 2 then Step 2B. The instant claims recite the following additional elements:
Claim 9 recites “i) extracting DNA from a tumoral sample and if available from a normal sample obtained from said patient, ii) sequencing a number N of mononucleotide repeats - MNR - sequences having a length of at least 12 nucleic acids in the DNA of the normal sample of said patient and the corresponding MNR in the DNA of the tumoral sample of said patient or sequencing a number N of mononucleotide repeats in the tumoral sample and having a length of at least 12 nucleic acids in the corresponding normal sample”
Claim 10 recites “i) extracting DNA from a tumoral and normal samples obtained from said patient, ii) sequencing a number N of mononucleotide repeats - MNR - sequences having a length of at least 12 nucleic acids in the DNA of the normal samples of said patient and the corresponding MNR in the DNA of the tumoral samples of said patients,”
Claim 11 recites “i) extracting DNA from a tumoral sample obtained from said patient, ii) sequencing a number N of mononucleotide repeats - MNR - in the tumoral sample and having a length of at least 12 nucleic acids in the corresponding normal sample,”
Claim 12 recites “wherein the cancer is metastatic or not.”
Claim 13 recites “wherein the cancer is a colorectal cancer, a gastric cancer or an endometrial cancer.”
Claim 15 recites “i) extracting DNA from a tumor and normal samples obtained from said patient, ii) sequencing a number N of mononucleotide repeats - MNR - sequences having a length of at least 12 nucleic acids in the DNA of the normal samples of said patient and the corresponding MNR in the DNA of the tumoral samples of said patients,”
These above recited additional elements are analyzed below under both Step 2A, Prong 2 and Step 2B:
Step 2A, Prong 2:
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflect an improvement to a computer, technology, or technical field (MPEP § 2106.04(d)(1) and 2106.5(a)), require a particular treatment or prophylaxis for a disease or medical condition (MPEP § 2106.04(d)(2)), implement the recited judicial exception with a particular machine that is integral to the claim (MPEP § 2106.05(b)), effect a transformation or reduction of a particular article to a different state or thing (MPEP § 2106.05(c)), nor provide some other meaningful limitation (MPEP § 2106.05(e)). Rather, the claims include limitations that equate to insignificant extra-solution activity (MPEP § 2106.05(g)) and field of use limitations (MPEP § 2106.05(h)). The paragraphs below discuss the additional elements recited above in the instant claims.
The additional elements in claims 9-11 and 15 equate to insignificant extra-solution activity of necessary data gathering. These claims gather data necessary to perform the subsequent steps in the respective claims that recite a judicial exception.
Claims 12-13 equate to field of use limitations because they further limit the type of cancer being sequenced, which is used to perform the judicial exception in claim 9.
As such, claims 9-15 are directed to an abstract idea and a natural phenomenon (Step 2A, Prong 2: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). These claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims recite additional elements that equate to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The paragraphs below discuss the additional elements recited above in the instant claims.
When the additional elements of claims 9-13 and 15 are viewed alone and in combination, they equate to WURC limitations as taught by Johansen et al. (“Johansen”; NPL ref. 34 on IDS filed 07/21/2023; BMC cancer 19, no. 1 (2019): 971) and Zhu et al. (“Zhu”; The Journal of Molecular Diagnostics, 20(2), 225-231).
Johansen collects matched tumor and germline DNA (pg. 2, col. 1, last para.) then sequences the tumor and germline DNA (pg. 2, col. 2, last para.). MSIsensor was used to detect microsatellite loci in the NGS data, where sites are only microsatellites if the homopolymer is at most five bases long and repeated at least three times (pg. 3, col. 1, para. 2).
Zhu teaches “DNA was extracted from paired tumor-normal tissue for MSI detection by NGS” (pg. 226, col. 2, para. 1). 90 microsatellite loci with homopolymers were sequenced in both tumor and normal samples, and only 23 loci were selected for use in MIS-ColonCore as shown in Table 1 (pg. 228, col. 2, para. 3). Zhu teaches “[t]he scanned loci were restricted to mononucleotide repeats because those were reported as the most sensitive and specific for MSI detection” (pg. 226, col. 1, para. 3). Table 1 shows the loci used and shows loci MS-BR1 with a 14 repeat length homopolymer.
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they are WURC limitations as taught by Johansen and Zhu. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 9-15 are not patent eligible.
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.
Claim 9 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhu et al. (“Zhu”; The Journal of Molecular Diagnostics 20, no. 2 (2018): 225-231).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 9:
A method of diagnosing an MSI cancer in a patient in need thereof comprising
Zhu discloses a method called MSI-ColonCore that detects MSI in colorectal cancer by next generation sequencing (abstract).
i) extracting DNA from a tumoral sample and if available from a normal sample obtained from said patient,
Zhu teaches “DNA was extracted from paired tumor-normal tissue for MSI detection by NGS” (pg. 226, col. 2, para. 1).
ii) sequencing a number N of mononucleotide repeats - MNR - sequences having a length of at least 12 nucleic acids in the DNA of the normal sample of said patient and the corresponding MNR in the DNA of the tumoral sample of said patient or sequencing a number N of mononucleotide repeats in the tumoral sample and having a length of at least 12 nucleic acids in the corresponding normal sample,
Zhu teaches “[t]he scanned loci were restricted to mononucleotide repeats because those were reported as the most sensitive and specific for MSI detection” (pg. 226, col. 1, para. 3). Table 1 shows the loci used and shows as an example loci MS-BR1 with a 14 repeat length homopolymer. The same loci were sequenced for both tumor and normal samples (pg. 227, col. 1, para. 1-2) (pg. 227, col. 2, para. 1). 90 microsatellite loci with homopolymers were sequenced in both tumor and normal samples, and only 23 loci were selected for use in MIS-ColonCore as shown in Table 1 (pg. 228, col. 2, para. 3).
iii) calculating the ΔRatio for each MNR depending if the normal sample is available or not, iv) calculating the tumor purity - TP - for the tumor sample, v) calculating the ΔRatio adjusted, vi) obtaining a MSICare score by doing the ratio of the number of MNR with a ΔRatio adjusted mutated on the total number of ΔRatio of the MNR and, vii) concluding that the patient in need thereof has a MSI cancer when the MSICare score obtained at the step vi) is superior than a calculated threshold value.
As discussed in Claim Interpretation, the broadest reasonable interpretation of claim 9 includes steps iii-vii being contingent limitations. They are contingent upon a normal sample being available in step iii. In the instance a normal sample is not available, steps iii-vii are not performed. Therefore, steps iii-vii are not required in claim 9 under its broadest reasonable interpretation.
Claim 16 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Marcus et al. (“Marcus”; Clinical Cancer Research 25, no. 13 (2019): 3753-3758).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 16:
A method for treating a cancer in a patient identified has having a MSI cancer according to a method for diagnosing a MSI cancer according to claim 9, comprising
As discussed above in 35 USC 112(d), the patient diagnosed with an MSI cancer is a product and the method of claim 9 is the method previously performed to obtain the product. A reference that discloses the same product, even if produced by a different method than claim 9, will read on the patient diagnosed with a MSI cancer.
Marcus discloses the product of the patient diagnosed with an MSI cancer by treating patients with microsatellite instability-high solid tumors (abstract).
administering to said patient a therapeutically effective amount of radiotherapy, chemotherapy, immunotherapy or a combination thereof.
Marcus shows in Table 1 clinical trials where the immunotherapy was administered to cancer patients with MSI-H/dMMR (pg. 3754, col. 2, last para.).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 9 and 11-14 are rejected under 35 USC 103 for being unpatentable over Johansen et al. (“Johansen”; NPL ref. 34 on IDS filed 07/21/2023; BMC cancer 19, no. 1 (2019): 971) in view of Cai et al. (“Cai”; The Journal of Molecular Diagnostics 22, no. 7 (2020): 860-870).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 9:
A method of diagnosing an MSI cancer in a patient in need thereof
Johansen uses MSIsensor to determine MSI status using next generation sequencing (abstract).
i) extracting DNA from a tumoral sample and if available from a normal sample obtained from said patient, ii) sequencing a number N of mononucleotide repeats - MNR - sequences having a length of at least 12 nucleic acids in the DNA of the normal sample of said patient and the corresponding MNR in the DNA of the tumoral sample of said patient
Johansen collects and sequences DNA from paired tumor and normal samples (pg. 2, col. 1, last para.) (pg. 2, col. 2, last para.). Johansen teaches “MSIsensor identifies somatically mutated microsatellite loci in NGS data using a two-step process, which first involves scanning the reference genome for microsatellite sites. Sites are considered as microsatellites only if the sequence motif is at most five bases long and repeated at least three times. Microsatellite sites with less than 20 mapped reads in tumor or germline are not considered” (pg. 3, col. 1, para. 1). The sequence motif can be a homopolymer (mononucleotide repeats) (pg. 3, col. 1, para. 1).
iii) calculating the ΔRatio for each MNR depending if the normal sample is available or not, iv) calculating the tumor purity - TP - for the tumor sample, v) calculating the ΔRatio adjusted,
Johansen recites “[t]he second part of the analysis uses a χ2 test to identify mutated microsatellites by comparing the distributions of homopolymer lengths in the tumor and normal samples at the sites identified in the first step” (pg. 3, col. 1, para. 2). MSIsensor calculates a delta value because χ2 necessarily subtracts expected frequencies (normal count distribution) from observed frequencies (tumor count distribution) for each loci (ΔRatio for each MNR). Additionally, in a χ2, the denominator is the expected frequency which scales the squared difference between observed and expected values (ΔRatio adjusted).
However, Johansen does not calculate tumor purity.
Cai detects MSI from circulating tumor DNA by targeted deep sequencing (title). In order to determine tumor coverage distributions of microsatellite loci, tumor reads were normalized by tumor purity (pg. 863, col. 1, step 1-2). Cai recites “the sequencing reads corresponding to the proportion of normal cells within the tumor samples were subtracted from the reads derived from the tumor samples” (pg. 863, col. 2, para. 1). Normalization was performed using equation 1.
It would have been prima facie obvious to have modified the tumor reads covering a microsatellite locus in Johansen by normalizing for tumor purity as taught by Cai. Motivation is taught by Cai who recites “[t]umor samples are often composed of malignant cells admixed with normal cell population, such as epithelial, stromal, or lymphoid cells” (pg. 863, col. 1, last para.). One of skill would thus want to normalize for tumor purity to obtain accurate estimates of tumor coverage for microsatellites. There would have been a reasonable expectation of success because Cai teaches that the normalization requires paired tumor and normal tissues sequencing reads (pg. 863, col. 2, para. 2), which Johansen also discloses. Also, the normalization method is used for detecting MSI, which is the objective of Johansen.
vi) obtaining a MSICare score by doing the ratio of the number of MNR with a ΔRatio adjusted mutated on the total number of ΔRatio of the MNR and, -vii) concluding that the patient in need thereof has a MSI cancer when the MSICare score obtained at the step vi) is superior than a calculated threshold value.
Johansen teaches “[t]he resulting MSIsensor score is a value between 0 and 100 that corresponds to the percentage of mutated microsatellite loci. The tumors were classified as MSI if the score was greater than or equal to 3.5 and MSS if less than 3.5, which is the suggested cut-off for exome sequenced samples in the original MSIsensor publication” (pg. 3, col. 1, para. 2).
Claim 11:
The rejection applied above to claim 9 is applied to claim 11. Claim 11 differs from claim 9 by requiring step iii) evaluating the normal polymorphic zones for the MNR and iv) evaluating the mutated MNR appearing in the tumor sample only outside the normal polymorphic zone of each MNR. Johansen discloses these limitations. The BRI of claim 11, step iii, includes determining normal read count distributions in microsatellites of normal samples. Johansen determines homopolymer length distributions in normal samples at microsatellites (pg. 3, col. 1, para. 2). The BRI of claim 11, step iv, includes only determining a microsatellite as mutated in a tumor sample when the distribution does not fall within the distribution of the same microsatellite in a normal sample. Johansen discloses this limitation by teaching that χ2 identifies mutated microsatellites by comparing distributions of homopolymer lengths in tumor and normal samples (pg. 3, col. 1, para. 1). This necessitates that a microsatellite be identified as mutated when the tumor distribution does not fall within the normal distribution.
Claims 12-13:
Johansen use colorectal cancer samples that are not said to be metastatic (abstract).
Claim 14:
Johansen teaches “MSIsensor provide a cost-efficient method to facilitate the analysis of CRC patients, which can be integrated in routinely genetic testing of patients” (pg. 6, col. 2, para. 1). However, Johansen does not communicate results to a patient. It would have been prima facie obvious over the teachings of Johansen to communicate the results of MSIsensor to a patient so that the patient can understand prognosis. MSI status is important for assessment of prognosis (pg. 5, col. 1, para. 2). There would have been a reasonable expectation of success to communicate lab results as this is standard medical practice.
Claim 10 is rejected under 35 USC 103 for being unpatentable over Johansen et al. (“Johansen”; NPL ref. 34 on IDS filed 07/21/2023; BMC cancer 19, no. 1 (2019): 971) in view of Cai et al. (“Cai”; The Journal of Molecular Diagnostics 22, no. 7 (2020): 860-870), as applied above to claim 9, and in further view of Licorbio (Include both biological and technical replicates in your experiments; published online 18 Feb 2020).
The limitations of claim 9 have been taught in the rejection above by Johansen and Cai.
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 10:
Claim 10 differs from claim 9 by requiring the normal sample in steps i and iii and requiring multiple tumor and normal samples from a subject. In claim 10 steps iii-vii are required. Because claim 9 has been examined as if it required steps iii-vii, claim 10 is rejected for the same reasons applied above to claim 9 over Johansen and Cai.
However, Johansen and Cai do not collect tumor samples and normal samples from a single subject.
Licorbio discloses technical replicates (pg. 1, para. 1). The broadest reasonable interpretation of multiple tumor and normal samples includes technical replicates because the samples have not been limited to be distinct samples or not a sample that is divided into replicates. It would have been prima facie obvious to take technical replicates of the paired tumor and normal samples of Johansen and Cai as taught by Licorbio because Licorbio states that technical replicates demonstrate variability of protocol and generate more accurate and reliable results (pg. 1, para. 1-2). There would have been a reasonable expectation of success because the technical replicates of the paired tumor and normal samples would produce sequencing reads that would undergo the same pipeline taught in Johansen and Cai.
Claim 15 is rejected under 35 USC 103 for being unpatentable over Johansen et al. (“Johansen”; NPL ref. 34 on IDS filed 07/21/2023; BMC cancer 19, no. 1 (2019): 971) in view of Cai et al. (“Cai”; The Journal of Molecular Diagnostics 22, no. 7 (2020): 860-870) and Licorbio (Include both biological and technical replicates in your experiments; published online 18 Feb 2020).
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 15:
A method of diagnosing a mutation in a MNR in a patient in need thereof comprising
Johansen uses MSIsensor to determine microsatellite instability status using next generation sequencing (abstract).
i) extracting DNA from a tumor and normal samples obtained from said patient, ii) sequencing a number N of mononucleotide repeats - MNR - sequences having a length of at least 12 nucleic acids in the DNA of the normal samples of said patient and the corresponding MNR in the DNA of the tumoral samples of said patients
Johansen collects and sequences DNA from paired tumor and normal samples (pg. 2, col. 1, last para.) (pg. 2, col. 2, last para.). Johansen teaches “MSIsensor identifies somatically mutated microsatellite loci in NGS data using a two-step process, which first involves scanning the reference genome for microsatellite sites. Sites are considered as microsatellites only if the sequence motif is at most five bases long and repeated at least three times. Microsatellite sites with less than 20 mapped reads in tumor or germline are not considered” (pg. 3, col. 1, para. 1). The sequence motif can be a homopolymer (mononucleotide repeats) (pg. 3, col. 1, para. 1).
However, Johansen and Cai do not collect tumor samples and normal samples from a single subject.
Licorbio discloses technical replicates (pg. 1, para. 1). The broadest reasonable interpretation of multiple tumor and normal samples includes technical replicates because the samples have not been limited to be distinct samples or not a sample that is divided into replicates. It would have been prima facie obvious to take technical replicates of the paired tumor and normal samples of Johansen and Cai as taught by Licorbio because Licorbio states that technical replicates demonstrate variability of protocol and generate more accurate and reliable results (pg. 1, para. 1-2). There would have been a reasonable expectation of success because the technical replicates of the paired tumor and normal samples would produce sequencing reads that would undergo the same pipeline taught in Johansen and Cai.
iii) calculating the ΔRatio for each MNR, iv) calculating the tumor purity - TP - for the tumor sample, v) calculating the ΔRatio adjusted,
Johansen recites “[t]he second part of the analysis uses a χ2 test to identify mutated microsatellites by comparing the distributions of homopolymer lengths in the tumor and normal samples at the sites identified in the first step” (pg. 3, col. 1, para. 2). MSIsensor calculates a delta value because χ2 necessarily subtracts expected frequencies (normal count distribution) from observed frequencies (tumor count distribution) for each loci (ΔRatio for each MNR). Additionally, in a χ2, the denominator is the expected frequency which scales the squared difference between observed and expected values (ΔRatio adjusted).
However, Johansen does not calculate tumor purity.
Cai detects MSI from circulating tumor DNA by targeted deep sequencing (title). In order to determine tumor coverage distributions of microsatellite loci, tumor reads were normalized by tumor purity (pg. 863, col. 1, step 1-2). Cai recites “the sequencing reads corresponding to the proportion of normal cells within the tumor samples were subtracted from the reads derived from the tumor samples” (pg. 863, col. 2, para. 1). Normalization was performed using equation 1.
It would have been prima facie obvious to have modified the tumor reads covering a microsatellite locus in Johansen by normalizing for tumor purity as taught by Cai. Motivation is taught by Cai who recites “[t]umor samples are often composed of malignant cells admixed with normal cell population, such as epithelial, stromal, or lymphoid cells” (pg. 863, col. 1, last para.). One of skill would thus want to normalize for tumor purity to obtain accurate estimates of tumor coverage for microsatellites. There would have been a reasonable expectation of success because Cai teaches that the normalization requires paired tumor and normal tissues sequencing reads (pg. 863, col. 2, para. 2), which Johansen also discloses. Also, the normalization method is used for detecting MSI, which is the objective of Johansen.
vi) concluding that the MNR is wild type when the ΔRatio -adjusted is < 50% concluding that the MNR is mutated when the ΔRatio adjusted is >50%.
Johansen teaches “[t]he resulting MSIsensor score is a value between 0 and 100 that corresponds to the percentage of mutated microsatellite loci. The tumors were classified as MSI if the score was greater than or equal to 3.5 and MSS if less than 3.5, which is the suggested cut-off for exome sequenced samples in the original MSIsensor publication” (MNR is wild type when the Ratio adjusted is < 50%) (pg. 3, col. 1, para. 2).
Conclusion
No claims are allowed.
Claim 16 is patent eligible under 35 USC 101 because it recites only an additional element.
Notable, but not relied upon, prior art includes: Yamamoto et al. (In Seminars in oncology, vol. 46, no. 3, pp. 261-270. WB Saunders, 2019) reviews MSI in next generation sequencing and shows in Table 1 a list of MSI detection software including MANTIS, MSIsensor, and ColonCore. Kautto et al. (NPL ref. 32 on IDS filed 07/21/2023; Oncotarget 8, no. 5 (2016): 7452) subtracts normalized normal reads from normalized tumor reads to calculate a stepwise difference between tumor and normal distributions at each microsatellite loci, then averages the score of each locus (pg. 7469, col. 2, para. 2-3). Trabucco et al (The Journal of Molecular Diagnostics 21, no. 6 (2019): 1053-1066) teaches that PCA-based MSI scores correlate with tumor purity (Figure 3). Zhao et al. (Oncology Letters 20, no. 2 (2020): 1982-1988) discloses NovoPM-MSI to detect MSI from NGS data using Mann-Whitney U Test between normal and tumor normalized read counts from each locus (Figure 1). Lozac'hmeur et al. (US 2021/0098078 A1) MSI detection in liquid biopsy. Yan (Nature communications 10, no. 1 (2019): 1670) sequences 5 tumor regions per patient with adjacent matched normal tissue and PBMS.
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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