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 .
Election/Restrictions
Applicant’s election without traverse of PTEN, RB1, FGRF3, TP53, and ERBB2 from the indicated species elections in the reply filed on April 9th, 2026 is acknowledged.
After further consideration, all species elections are withdrawn. All biomarkers form the relevant tables will be considered for examination.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on July 24th, 2024 and April 16th, 2026 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Summary
Claim 71 has been amended. Claims 1-69 have been canceled. Claims 96-97 have been added. Claims 70-97 are pending. Claims 70-97 are under examination and discussed in this Office action.
Formal Matters
It is noted that an amended specification was filed on September 18th, 2023. For the Applicant’s information, citations to the specification in the rejections below are based on this specification.
Specification
The disclosure is objected to because of the following informalities: in the Examples, there are several instances of superscript numbers as would appear in a scientific publication for labeling of references. However, no references are included. It is suggested to remove these superscript numbers. Appropriate correction is required.
The use of the terms such as PredicineBEACON, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see page 39 of the specification). 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.
Claim Objections
Claim 70 is objected to because of the following informalities:
Claim 70 recites “from said subject at least part” in step (e) of the claim. It appear this is meant to read “from said subject at least in part”, and it is suggested to insert the word “in” as indicated.
Appropriate correction is required.
Claim Rejections - 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 70-97 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.
Claim 70 is indefinite in the recitation “at least about 80x” in line 14 of the claim. The phrase “at least” typically indicates a minimum point; however, the phrase “at least” is controverted by the term “about,” which implies that values above and below the indicated amount are permitted. Therefore, the juxtaposition of these two terms makes it unclear what maximum dimensions are encompassed by the claim. In Amgen, Inc. v. Chugai Pharmaceutical co., 927 F.2d 1200 (CAFC 1991), the CAFC stated, “[t]he district court held claims 4 and 6 of the patent invalid because their specific activity of “at least about 160,000” was indefinite.” After review, the CAFC states “[w]e therefore affirm the district court’s determination on this issue.” Thus, the CAFC found the phrase “at least about” indefinite where the metes and bounds of the term were not defined in the specification. See MPEP 2173.05(b) III. For the purpose of compact prosecution, the limitation “at least about 80x” will be interpreted as “at least 80x”. Claims 71-97 are also rejected here for their dependence on claim 70 and not further clarifying the identified issue.
Claim 71 recites the limitation “[t]he method of claim 70, wherein said first or second biological sample is selected from the group consisting of: a cell-free deoxyribonucleic acid (cfDNA) sample, a cell-free ribonucleic acid (cfRNA) sample, a plasma sample, a serum sample, a buffy coat sample, a peripheral blood mononuclear cell (PBMC) sample, a red blood cell sample, a urine sample, a saliva sample, tissue biopsy, pleural fluid sample, peritoneal fluid sample, amniotic fluid sample, cerebrospinal fluid sample, lymphatic fluid sample, sweat sample, tear sample, semen sample, or any derivative thereof, and any combination thereof.” It is unclear from this recitation if the second biological sample can truly be any of these sample types given the description of the second biological sample in claim 70. Claim 70 recites “sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample”, which could be interpreted to be a cfDNA sample. Therefore, given that a cfDNA sample is separated out as an option from the other options on the list, it is unclear how the second biological sample could be any option other than a cfDNA sample, particularly when it is unclear if the rest of the samples are intended to contain cfDNA. For instance, it is known that a plasma sample may contain cfDNA (see Christensen, Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557); however, again, given that a cfDNA sample is separated out from the list, it is unclear if a plasma sample is intended to have cfDNA in it or not. Therefore the claim is found indefinite. For the purpose of compact prosecution, the above recitation, with respect to the second biological sample, will be interpreted to require a cfDNA sample.
Claim 72 recites the limitation "wherein said first of second biological sample comprises said plasma sample". There is insufficient antecedent basis for this limitation in the claim. Claim 70, from which claim 72 depends, does not introduce “a plasma sample”. Therefore, the claim is found indefinite.
Claim 73 recites the limitation " wherein said first of second biological sample comprises said urine sample ". There is insufficient antecedent basis for this limitation in the claim. Claim 70, from which claim 73 depends, does not introduce “a urine sample”. Therefore, the claim is found indefinite.
Claim 76 is indefinite in the recitation “at least about 1000x” in line 2 of the claim. The phrase “at least” typically indicates a minimum point; however, the phrase “at least” is controverted by the term “about,” which implies that values above and below the indicated amount are permitted. Therefore, the juxtaposition of these two terms makes it unclear what maximum dimensions are encompassed by the claim. See the rejection of claim 70 for relevant case law. For the purpose of compact prosecution, “at least about 1000x” will be interpreted as “at least 1000x”.
Claim 79 recites the limitation "wherein said cancer". There is insufficient antecedent basis for this limitation in the claim. Claim 70, from which claim 79 depends, does not introduce “a cancer”. Therefore, the claim is found indefinite.
Claim 80 recites the limitation "wherein said cancer". There is insufficient antecedent basis for this limitation in the claim. Claim 70, from which claim 80 ultimately depends, does not introduce “a cancer”. Therefore, the claim is found indefinite.
Claim 81 recites the limitation “wherein said biological sample is obtained or derived from said subject after receiving a therapy for said cancer”. It is unclear from this recitation which biological sample is being referenced, the first biological sample or the second biological sample. There is also insufficient antecedent basis for this limitation in the claim. Claim 70, from which claim 81 depends, does not introduce “a biological sample” or “a cancer”. Therefore, the claim is found indefinite. For the purpose of compact prosecution, “wherein said biological sample is obtained or derived from said subject after receiving a therapy for said cancer” will be interpreted as “wherein said second biological sample is obtained or derived from said subject after receiving a therapy for said cancer”.
Claim 82 recites the limitation "detected presence or absence of said cancer". There is insufficient antecedent basis for this limitation in the claim. Claim 70, from which claim 82 depends, does not introduce “a cancer”. Therefore, the claim is found indefinite.
Claims 85-88 and 90 are indefinite for the recitation of Tables 1, 7, 8, 9, and 10, respectively. As stated in MPEP 2173.05(s), claims should be complete to themselves and the reference to tables renders the claims incomplete. Claims which recite figures or tables are only permitted in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into a claim.
Claim 94 recites the limitation "determining a circulating tumor DNA (ctDNA) fraction of said cancer". There is insufficient antecedent basis for this limitation in the claim. Claim 70, from which claim 94 ultimately depends, does not introduce “a cancer”. Therefore, the claim is found indefinite.
Claim 96 is indefinite in the recitation “at least about 10000x” in line 2 of the claim. The phrase “at least” typically indicates a minimum point; however, the phrase “at least” is controverted by the term “about,” which implies that values above and below the indicated amount are permitted. Therefore, the juxtaposition of these two terms makes it unclear what maximum dimensions are encompassed by the claim. See the rejection of claim 70 for relevant case law. For the purpose of compact prosecution, “at least about 10000x” will be interpreted as “at least 10000x”.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
Claims 70-97 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The specification, while being enabling for a human subject, does not reasonably provide enablement for any subject as embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
(A) With respect to the breadth of the claims: Claim 70 as currently drafted encompasses a method for detecting a presence or an absence of minimal residual disease (MRD) in a subject, comprising: (a) assaying deoxyribonucleic acid (DNA) molecules from a first biological sample obtained or derived from said subject at a first time point; (b) detecting a set of biomarkers from said DNA molecules based at least in part on said assaying of (a), wherein said set of biomarkers comprise differentially expressed markers or variants; (c) generating a plurality of probe nucleic acids that are customized for said subject, wherein said probe nucleic acids comprises sequences of at least a subset of said set of biomarkers; (d) using said plurality of probe nucleic acids, sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample obtained or derived from said subject at a second time point to detect the presence or absence of said subset of said set of biomarkers, wherein said sequencing is performed at a depth of at least about 80x; (e) sequencing nucleic acids obtained or derived from said subject at least part by using whole genome sequencing to determine a copy number of at least one region of a genome of a subject; and (f) computer processing said subset of said set of biomarkers and said copy number of said at least one region of a genome to detect said presence or absence of minimal residual disease (MRD) in a subject.
“A subject” and “the subject” does not limit the subject to a human subject and the analysis of human samples as described in the specification. Consequently, the breadth of the claim is expansive since they encompass any kind of subject. Claims 71-97 encompass the same breadth as claim 70 since they do not limit the subject to a human subject, and in fact further limit the biomarkers detected to those associated with bladder cancer in humans (see claims 86-88 and 90, corresponding Tables 7-10 in the instant specification).
(B) The nature of the invention: The invention is in the field of detecting a presence or an absence of minimal residual disease in a subject.
(C), (D), (E) With respect to the state of the prior art, the level of one of ordinary skill and predictability of the art:
Juppner (Functional properties of the PTH/PTHrP receptor, Bone, August 1995, S39-S42) teaches that despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics (Abstract; Pages 39S-40S). This art indicates that there is known functional differences between homologs in different organisms, and therefore inter-species extrapolation would be unpredictable.
The art supports use of specific subjects. However, methods comprising any subject are highly unpredictable.
The invention is drawn to biological molecules, and is therefore in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The level of skill in the art is therefore deemed to be high.
(F), (G) With respect to the amount of direction and working examples provided by the applicant: The Applicant has not provided a general description directed towards subjects. However, the Applicant has provided working examples that are directed only to human subjects. As noted at Page 29, paragraph [00117]-[00118], and in Examples 2 and 3 (see Pages 36-37, paragraph [00142] in particular), the samples used in the working examples are samples from humans. The Applicant has not provided working examples directed towards any other type of subject.
(H) Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its high predictability, and the limited amount of guidance in the form of varied working examples in the specification. A skilled artisan recognizes that a subject very broadly refers to any number of different species and thus applicability of the claimed method to a subject as embraced by the claims remains unpredictable, requiring undue experimentation. For example, an artisan would need to test the method on an expansive number of different biomarkers in different organisms to determine if it is applicable to detecting presence or absence of minimal residual disease in said organisms. This reasonably represents undue experimentation.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC), states that, “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable,” citing Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in the context of the utility requirement, that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion”). The Genentech decision continued, “tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id. at p. 1005.
After applying the Wands factors and analysis to claims 70-97, in view of the applicant’s entire disclosure, and considering the In re Wright, In re Fisher and Genentech decisions discussed above, it is concluded that the practice of the full scope of the invention as claimed would not be enabled by the written disclosure. Therefore, claims 70-97 are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to practice the claimed invention to it the full scope embraced by the claims.
Written Description
Claims 85-88 and 90 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). See MPEP § 2163.
Claim 85 recites the limitation “[t]he method of claim 70, wherein said set of biomarkers comprises one or more members selected from the group consisting of genes listed in Table 1”. Given this claim depends from claim 70, the claim as written embraces a method wherein one or more biomarkers in the claimed table are applicable to minimal residual disease from any cancer. However, there is no further description or definition in the claims to suggest that any combination of biomarkers from Table 1 are applicable to minimal residual disease from any cancer.
Turning to the specification, there is no description that clearly defines or describes that any combination of biomarkers from Table 1 are applicable to minimal residual disease from any cancer. Table 1 is presented on Page 20 of the specification as “List of genes”, with no indication of their relation to specific cancers or how to select a combination of genes for use in the method, particularly considering there are certain genes associated with certain cancers. This is exemplified in Figure 2 of Bailey (Comprehensive Characterization of Cancer Driver Genes and Mutations, Cell, April 2018, 173, 371-385). Bailey presents a comprehensive characterization of driver genes and mutations associated with many cancers, with Figure 2 providing a summary of particular driver genes associated with particular cancers. While the figure also presents a number of genes in the “Multi” section, it is clearly indicated that not every gene present in multiple cancers is present in every cancer. There are still definitive links between particular genes and particular cancers. Therefore, the Applicant does not have possession of the method as claimed because they do not have possession of any combination of the genes of Table 1 to detect minimal residual disease from any cancer.
Claims 86-88 recite variations of the method of claim 70, wherein said set of biomarkers comprises one or more members selected from the group consisting of genes listed in Tables 7, 8, or 9. Claim 90 recites wherein said fixed plurality of probes comprise one or more members selected from the group consisting of genes listed in Table 10. Given these claims ultimately depend from claim 70, the claims as written embrace methods wherein the specific biomarkers in the claimed tables are applicable to minimal residual disease from any cancer. However, there is no further description or definition related to this method in the claims.
Turning to the specification, there is no description that clearly defines or describes that the biomarkers in the claimed tables are applicable to minimal residual disease from any cancer. Tables 7-10 are referenced in the specification with relation to Example 3 (starting on Page 33 of the instant specification), which is directed to muscle-invasive bladder cancer (MIBC). Therefore, the biomarkers of these tables are considered relevant to minimal residual disease associated with MIBC. However, there is no further description indicating that the biomarkers are widely applicable to minimal residual disease associated with any other cancer. Overall, there is no description that clearly defines or describes that the biomarkers of Tables 7-10 are widely applicable to any cancer.
Therefore, the Applicant does not have possession of the methods as claimed. Claims 85-88 and 90 do not present possession of the methods as claimed and do not have supported based on the specification.
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 70-97 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. While the claims are directed to a process, and therefore meet step 1 of the subject matter eligibility test (see MPEP 2106.03), the claims recite the natural correlation between genetic biomarkers and minimal residual disease. Such correlation is a natural phenomenon because it describes a consequence of natural processes in the human body.
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe a natural phenomenon: the natural correlation between genetic biomarkers and minimal residual disease.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B.” The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of assaying deoxyribonucleic acid (DNA) molecules from a first biological sample obtained from a subject at a first time point; detecting a set of biomarkers from said DNA molecules comprising differentially expressed markers or variants; generating a plurality of probe nucleic acids that are customized for said subject, wherein said probe nucleic acids comprises sequences of at least a subset of said set of biomarkers; using said plurality of probe nucleic acids, sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample from said subject at a second time point to detect the presence or absence of said subset of said set of biomarkers, wherein said sequencing is performed at a depth of at least about 80x, or 1000x, or 10000x; sequencing nucleic acids obtained or derived from said subject at least part by using whole genome sequencing or low-pass whole genome sequencing to determine a copy number of at least one region of a genome of a subject; computer processing said subset of said set of biomarkers and said copy number of said at least one region of a genome to detect said presence or absence of minimal residual disease (MRD) in a subject; as well as specific samples types; specific sequencing techniques; comparison of copy number measurements at different time points; specific types of cancer; generic treatments for cancer; specific biomarkers; specific alterations in the biomarkers; determining mutant allele frequency; determining ctDNA fraction; and determining tumor mutational burden, the claims do not improve upon any techniques necessary to accomplish these steps. The claims merely use existing methods for these steps. Note that MPEP 2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While the instant claims recite steps of assaying deoxyribonucleic acid (DNA) molecules from a first biological sample obtained from a subject at a first time point; detecting a set of biomarkers from said DNA molecules comprising differentially expressed markers or variants; generating a plurality of probe nucleic acids that are customized for said subject, wherein said probe nucleic acids comprises sequences of at least a subset of said set of biomarkers; using said plurality of probe nucleic acids, sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample from said subject at a second time point to detect the presence or absence of said subset of said set of biomarkers, wherein said sequencing is performed at a depth of at least about 80x, or 1000x, or 10000x; sequencing nucleic acids obtained or derived from said subject at least part by using whole genome sequencing or low-pass whole genome sequencing to determine a copy number of at least one region of a genome of a subject; computer processing said subset of said set of biomarkers and said copy number of said at least one region of a genome to detect said presence or absence of minimal residual disease (MRD) in a subject; as well as specific samples types; specific sequencing techniques; comparison of copy number measurements at different time points; specific types of cancer; generic treatments for cancer; specific biomarkers; specific alterations in the biomarkers; determining mutant allele frequency; determining ctDNA fraction; and determining tumor mutational burden, no such machines are required by the claim, and certainly no particular machines. Even if some conventional machine were recited in the claims, like a particular sequencing device, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP 2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, sequencing does not transform the DNA or cfDNA of interest into something else during the sequencing process.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between genetic biomarkers and minimal residual disease in the instant case have to do with assaying deoxyribonucleic acid (DNA) molecules from a first biological sample obtained from a subject at a first time point; detecting a set of biomarkers from said DNA molecules comprising differentially expressed markers or variants; generating a plurality of probe nucleic acids that are customized for said subject, wherein said probe nucleic acids comprises sequences of at least a subset of said set of biomarkers; using said plurality of probe nucleic acids, sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample from said subject at a second time point to detect the presence or absence of said subset of said set of biomarkers, wherein said sequencing is performed at a depth of at least about 80x, or 1000x, or 10000x; sequencing nucleic acids obtained or derived from said subject at least part by using whole genome sequencing or low-pass whole genome sequencing to determine a copy number of at least one region of a genome of a subject; computer processing said subset of said set of biomarkers and said copy number of said at least one region of a genome to detect said presence or absence of minimal residual disease (MRD) in a subject; as well as specific samples types; specific sequencing techniques; comparison of copy number measurements at different time points; specific types of cancer; generic treatments for cancer; specific biomarkers; specific alterations in the biomarkers; determining mutant allele frequency; determining ctDNA fraction; and determining tumor mutational burden. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: “The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” However, as will be discussed below, these limitations do not arrive at an inventive concept. In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. Here, the judicial exception is the natural correlation between genetic biomarkers and minimal residual disease. The additional elements recited in the claims (i.e. assaying deoxyribonucleic acid (DNA) molecules from a first biological sample obtained from a subject at a first time point; detecting a set of biomarkers from said DNA molecules comprising differentially expressed markers or variants; generating a plurality of probe nucleic acids that are customized for said subject, wherein said probe nucleic acids comprises sequences of at least a subset of said set of biomarkers; using said plurality of probe nucleic acids, sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample from said subject at a second time point to detect the presence or absence of said subset of said set of biomarkers, wherein said sequencing is performed at a depth of at least about 80x, or 1000x, or 10000x; sequencing nucleic acids obtained or derived from said subject at least part by using whole genome sequencing or low-pass whole genome sequencing to determine a copy number of at least one region of a genome of a subject; computer processing said subset of said set of biomarkers and said copy number of said at least one region of a genome to detect said presence or absence of minimal residual disease (MRD) in a subject; as well as specific samples types; specific sequencing techniques; comparison of copy number measurements at different time points; specific types of cancer; generic treatments for cancer; specific biomarkers; specific alterations in the biomarkers; determining mutant allele frequency; determining ctDNA fraction; and determining tumor mutational burden) does amount to mere instructions to apply the correlation, since the additional elements serve as mere conventional steps taken for the purpose of gathering data about minimal residual disease, which any practical use of the natural correlation would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra - solution activity. Likewise, MPEP 2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This aligns closely with the instant claims, where the additional elements of the claims amount to sequencing, generating probes, specific sample types, particular cancers, and generic treatment.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the method being for detecting a presence or an absence of minimal residual disease in a subject is considered a “field of use”. However, as MPEP 2106.05(h) indications, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was routine and conventional in the prior art to detecting a presence or absence of minimal residual disease using biomarkers and sequencing, determine copy numbers and relate them to minimal residual disease, sequence using a fixed plurality of probes, determining ctDNA fraction based on mutant allele frequencies, determine TMB based on mutant allele frequencies, and sequence using methylation based methods.
For example, Christensen (Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557) teaches a method for detecting a presence or an absence of minimal residual disease (MRD) in a subject (Page 1552, column 1, paragraph 2), comprising: (a) assaying deoxyribonucleic acid (DNA) molecules from a first biological sample obtained or derived from said subject at a first time point (Page 1548, column 1, paragraph 6 to column 2, paragraph 1; Page 1548, column 2, paragraph 4; Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4; Appendix A, Page 2, paragraphs 2-3); (b) detecting a set of biomarkers from said DNA molecules based at least in part on said assaying of (a), wherein said set of biomarkers comprise differentially expressed markers or variants (Page 1548, column 2, paragraph 2; Page 1549, column 1 to column 2, paragraph 1; Appendix 1, Page 3, paragraph 2); (c) generating a plurality of primer nucleic acids that are customized for said subject, wherein said primer nucleic acids comprises sequences of at least a subset of said set of biomarkers (Page 1548, column 2, paragraph 2; Page 1549, column 1 to column 2, paragraph 1; Appendix 1, Page 3, paragraph 2); (d) using said plurality of primer nucleic acids, sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample obtained or derived from said subject at a second time point to detect the presence or absence of said subset of said set of biomarkers, wherein said sequencing is performed at a depth of at least about 80x, 1000x, or 10000x (Page 1548, column 2, paragraph 2; Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4; Appendix 1, Page 3, paragraph 2); and (f) computer processing said subset of said set of biomarkers to detect said presence or absence of minimal residual disease (MRD) in a subject (Page 1548, column 2, paragraph 3; Page 1549, column 1 to column 2, paragraph 1; Figure 2). Christensen teaches on the claimed sample types (Page 1548, column 1, paragraph 2; Page 1548, column 2, paragraph 2; Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4). Christensen teaches on whole exome sequencing (Page 1548, column 1, paragraph 6 to column 2, paragraph 1; Page 1548, column 2, paragraph 4; Appendix A, Page 2, paragraphs 2-3). Christensen teaches on bladder cancer (Page 1547, Introduction, MIBC = muscle invasive bladder cancer; Page 1548, column 1, paragraph 5). Christensen teaches on treatments for cancer (Page 1554, Discussion; Appendix 1, Page 19, Figure A7). Christensen teaches on specific biomarkers, and alterations in those biomarkers (Figure 1C). Christensen teaches on determining mutant allele frequency (Page 1552, column 2, paragraph 3; Figure 4C).
Honoré (Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact, Cancers, October 2021, 13, 1-25) teaches on custom panels specific to a patient’s tumor employing hybridization-based capture using specific probes to detect minimal residual disease in ctDNA (e.g. cfDNA) (Page 6, paragraph 5).
Landau (US 20210002728 A1) teaches sequencing nucleic acids obtained or derived from said subject at least part by using whole genome sequencing to determine a copy number of at least one region of a genome of a subject (Pages 2-3, paragraphs [0014]-[0015]); and computer processing said copy number of said at least one region of a genome to detect said presence or absence of minimal residual disease (MRD) in a subject (Pages 2-3, paragraphs [0014]-[0015]). Landau teaches wherein said sequencing of (e) further comprises sequencing nucleic acids of a sample taken at said first time point, and sequencing nucleic acids of a sample taken at a second time point (Pages 2-3, paragraph [0014]; Page 5, paragraph [0028]). Landau teaches comparing results of said sequencing of nucleic acids of said sample taken at said first time point and said sequencing of said nucleic acids of said sample taken at said second time point to determine said copy number of at least one region of a genome of a subject (Pages 2-3, paragraph [0014]; Page 5, paragraph [0028]). Landau teaches the method further comprising, based at least in part on said sequencing of (e), detecting a copy number variation (Pages 2-3, paragraph [0014]).
Hovelson (Rapid, ultra-low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy, Oncotarget, September 2017, 8, 89849-89866) teaches on low-pass whole genome sequencing for copy number profiling in cfDNA (Page 89849, column 2, paragraph 2 to Page 89850, column 1, paragraph 1).
Chauhan (Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study, PLOS Medicine, August 2021, 18, 1-30, and supplemental table) teaches on sequencing using a fixed plurality of probes (Page 7, paragraph 5 through Page 8, paragraph 1; Page 10, paragraph 6 through Page 12, paragraphs 1 and 2; Figure 1A; Table S2).
Oxnard (US20250019770A1, effectively filed November 12th, 2021) teaches determining a circulating tumor DNA (ctDNA) fraction of said cancer of said subject, based at least in part on said set of mutant allele frequencies (Page 4, paragraph [0031]).
Chaudhary (US 20200075122 A1) teaches that TMB can be determining based at least in part on a set of mutant allele frequencies (Page 1, paragraph [0003]).
Li (DNA Methylation Detection: Bisulfite Genomic Sequencing Analysis, Epigenetics Protocols, January 2011, 11-21) teaches on bisulfite genomic sequencing for detection DNA methylation (Page 12, paragraph 2), which is pertinent to step (a).
Having considered the factors discussed in MPEP 2106.04(c)(II) and MPEP 2106.05 (a)-(c) and (e)-(h), as well as the prior art of Christensen, Honoré, Landau, Hovelson, Chauhan, Oxnard, Chaudhary, and Li, it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exception into a practical application of that exception in such a way as to provide meaningful limits on the use of the judicial exception. Therefore, claims 70-97 are rejected here under 35 U.S.C. 101.
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 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 70-74, 76-88, 91-93, and 96 are rejected under 35 U.S.C. 103 as being unpatentable over Christensen (Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557), in view of Honoré (Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact, Cancers, October 2021, 13, 1-25) and Landau (US 20210002728 A1).
Regarding instant claim 70, Christensen teaches a method for detecting a presence or an absence of minimal residual disease (MRD) in a subject (Page 1552, column 1, paragraph 2), comprising: (a) assaying deoxyribonucleic acid (DNA) molecules from a first biological sample obtained or derived from said subject at a first time point (Page 1548, column 1, paragraph 6 to column 2, paragraph 1; Page 1548, column 2, paragraph 4; Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4; Appendix A, Page 2, paragraphs 2-3); (b) detecting a set of biomarkers from said DNA molecules based at least in part on said assaying of (a), wherein said set of biomarkers comprise differentially expressed markers or variants (Page 1548, column 2, paragraph 2; Page 1549, column 1 to column 2, paragraph 1; Appendix 1, Page 3, paragraph 2); (c) generating a plurality of primer nucleic acids that are customized for said subject, wherein said primer nucleic acids comprises sequences of at least a subset of said set of biomarkers (Page 1548, column 2, paragraph 2; Page 1549, column 1 to column 2, paragraph 1; Appendix 1, Page 3, paragraph 2); (d) using said plurality of primer nucleic acids, sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample obtained or derived from said subject at a second time point to detect the presence or absence of said subset of said set of biomarkers, wherein said sequencing is performed at a depth of at least about 80x (Page 1548, column 2, paragraph 2; Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4; Appendix 1, Page 3, paragraph 2; see 112(b) interpretation); and (f) computer processing said subset of said set of biomarkers to detect said presence or absence of minimal residual disease (MRD) in a subject (Page 1548, column 2, paragraph 3; Page 1549, column 1 to column 2, paragraph 1; Figure 2).
Christensen does not teach on using probe nucleic acids.
Honoré, in the same field of endeavor, teaches on custom panels specific to a patient’s tumor employing hybridization-based capture using specific probes to detect minimal residual disease in ctDNA (e.g. cfDNA) (Page 6, paragraph 5).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Christensen with the probes of Honoré. Since both Christensen and Honoré are in the same field of endeavor (e.g. detecting minimal residual disease with cfDNA using custom panels), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because probes allow for enrichment of regions of interest for sequencing (Honoré, Page 6, paragraph 5).
Neither reference teaches sequencing nucleic acids obtained or derived from said subject at least part by using whole genome sequencing to determine a copy number of at least one region of a genome of a subject; and computer processing said copy number of said at least one region of a genome to detect said presence or absence of minimal residual disease (MRD) in a subject.
Landau, in the same field of endeavor, teaches sequencing nucleic acids obtained or derived from said subject at least part by using whole genome sequencing to determine a copy number of at least one region of a genome of a subject (Pages 2-3, paragraphs [0014]-[0015]); and computer processing said copy number of said at least one region of a genome to detect said presence or absence of minimal residual disease (MRD) in a subject (Pages 2-3, paragraphs [0014]-[0015]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Christensen with the copy number detection of Landau. Since both Christensen and Landau are in the same field of endeavor (e.g. detection of residual disease via sequencing), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because the method of Landau can “determine the presence or absence of residual tumor, prognosticate the likelihood of having such disease, and also develop therapeutic or prophylactic interventions for such diseases” (Landau, Page 16, paragraph [0125]).
Regarding instant claim 71, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches wherein said second biological sample is a cell-free deoxyribonucleic acid (cfDNA) sample (Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4; see 112(b) interpretation).
Regarding instant claim 72, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches wherein said first or second biological sample comprises said plasma sample (Page 1548, column 2, paragraph 2; Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4).
Regarding instant claim 73, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen’s experimentation used plasma samples (Page 1548, column 2, paragraph 2; Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4). However, Christensen teaches that circulating tumor DNA (e.g. cfDNA) is detectable in urine from those with bladder cancer (Page 1548, column 1, paragraph 2). Therefore, it would be obvious to use a urine sample in the method as claimed. One of ordinary skill in the art would be motivation to do so because it amounts to simple substitution of one known element for another (see MPEP 2141(III)).
Regarding instant claim 74, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches wherein at least one of said DNA molecules are assayed using whole exome sequencing to produce nucleic acid sequencing reads (Page 1548, column 1, paragraph 6 to column 2, paragraph 1; Page 1548, column 2, paragraph 4; Appendix A, Page 2, paragraphs 2-3).
Regarding instant claim 76, Christensen, in view of Honoré and Landau, teaches The method of claim 70. Christensen further teaches wherein said sequencing of (d) is performed at a depth of at least about 1,000x (Page 1549, column 1 to column 2, paragraph 1; see 112(b) interpretation).
Regarding instant claim 77, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Landau further teaches wherein said sequencing of (e) further comprises sequencing nucleic acids of a sample taken at said first time point, and sequencing nucleic acids of a sample taken at a second time point (Pages 2-3, paragraph [0014]; Page 5, paragraph [0028]).
Regarding instant claim 78, Christensen, in view of Honoré and Landau, teaches the method of claim 77. Landau further teaches the method further comprising comparing results of said sequencing of nucleic acids of said sample taken at said first time point and said sequencing of said nucleic acids of said sample taken at said second time point to determine said copy number of at least one region of a genome of a subject (Pages 2-3, paragraph [0014]; Page 5, paragraph [0028]).
Regarding instant claims 79 and 80, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches wherein said cancer is bladder cancer (Page 1547, Introduction, MIBC = muscle invasive bladder cancer; Page 1548, column 1, paragraph 5).
Regarding instant claim 81, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches wherein said biological sample is obtained or derived from said subject after receiving a therapy for said cancer (Page 1549, columns 1 and 2 to Page 1552, column 1, paragraphs 1-4; see 112(b) interpretation).
Regarding instant claim 82, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches the method further comprising identifying a clinical intervention to treat said MRD in said subject, based at least in part on said detected presence or said absence of said cancer (Page 1554, Discussion; Appendix 1, Page 19, Figure A7).
Regarding instant claim 83, Christensen, in view of Honoré and Landau, teaches the method of claim 82. Christensen further teaches wherein said clinical intervention is chemotherapy or immunotherapy (Appendix 1, Page 19, Figure A7).
Regarding instant claim 84, Christensen, in view of Honoré and Landau, teaches the method of claim 82. Christensen further teaches the method further comprising administering said clinical intervention to said subject thereby treating said MRD in said subject (Appendix 1, Page 19, Figure A7).
Regarding instant claim 85-88, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches wherein said set of biomarkers comprises TP53 (Figure 1C), which is found in Tables 1 and 7-9 of the instant specification.
Regarding instant claim 91, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches wherein said set of biomarkers comprises tumor-associated alterations consisting of insertions or deletions (indels) (Figure 1C).
Regarding instant claim 92, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Landau further teaches the method further comprising, based at least in part on said sequencing of (e), detecting a copy number variation (Pages 2-3, paragraph [0014]).
Regarding instant claim 93, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches the method further comprising determining, among said set of biomarkers, a mutant allele frequency of a set of somatic mutations (Page 1552, column 2, paragraph 3; Figure 4C).
Regarding instant claim 96, Christensen, in view of Honoré and Landau, teaches the method of claim 70. Christensen further teaches wherein said sequencing of (d) is performed at a depth of at least about 10,000x (Page 1549, column 1 to column 2, paragraph 1; see 112(b) interpretation).
Claim 75 is rejected under 35 U.S.C. 103 as being unpatentable over Christensen (Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557), Honoré (Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact, Cancers, October 2021, 13, 1-25) and Landau (US 20210002728 A1), as applied to claims 70-74, 76-88, 91-93, and 96, and further in view of Hovelson (Rapid, ultra-low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy, Oncotarget, September 2017, 8, 89849-89866).
Regarding instant claim 75, Christensen, in view of Honoré and Landau, teaches the method of claim 70.
None of these references teach wherein said whole genome sequencing of (e) further comprises low-pass whole genome sequencing.
Hovelson, in a reasonably pertinent field, teaches on low-pass whole genome sequencing for copy number profiling in cfDNA (Page 89849, column 2, paragraph 2 to Page 89850, column 1, paragraph 1).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Christensen, in view of Honoré and Landau, with the low-pass whole genome sequencing of Hovelson. Since Hovelson teaches on copy number profiling of cfDNA for oncology screening, which is reasonably pertinent to the method of Christensen, in view of Honoré and Landau, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because low-pass whole genome sequencing can “recapitulate known whole-genome copy number profiles in cell lines and advanced prostate, colon, lung, and breast cancer patient samples, while retaining the ability to identify both focal and broad CNAs with megabase-level resolution” (Hovelson, Page 89849, column 2, paragraph 2).
Claims 89 and 90 are rejected under 35 U.S.C. 103 as being unpatentable over Christensen (Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557), in view of Honoré (Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact, Cancers, October 2021, 13, 1-25) and Landau (US 20210002728 A1), as applied to claims 70-74, 76-88, 91-93, and 96, and further in view of Chauhan (Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study, PLOS Medicine, August 2021, 18, 1-30, and supplemental table).
Regarding instant claim 89, Christensen, in view of Honoré and Landau, teaches the method of claim 70.
None of these references teach wherein (d) further comprises sequencing using a fixed plurality of probes, wherein said probes of said fixed plurality of probes comprise probes that do not comprise sequences of said subset of said set of biomarkers.
Chauhan, in the same field of endeavor, teaches on sequencing using a fixed plurality of probes (Page 7, paragraph 5 through Page 8, paragraph 1; Page 10, paragraph 6 through Page 12, paragraphs 1 and 2; Figure 1A; Table S2). Chauhan teaches on gene options that are different from those taught by Christensen (Table S2), making it obvious that the fixed plurality of probes can comprise probes that do not comprise sequences of the prior claimed subset.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Christensen, in view of Honoré and Landau, with the fixed probe panel of Chauhan. Since both Christensen and Chauhan are in the same field of endeavor (e.g. detecting minimal residual disease in bladder cancer), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because Chauhan’s panel represents 49 consensus driver genes frequently mutated in bladder cancer (Chauhan, Page 12, paragraph 1).
Regarding instant claim 90, Christensen, in view of Honoré, Landau, and Chauhan, teaches the method of claim 89. Chauhan further teaches wherein said fixed plurality of probes comprise ERBB2 (Table S2).
Claim 94 is rejected under 35 U.S.C. 103 as being unpatentable over Christensen (Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557), in view of Honoré (Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact, Cancers, October 2021, 13, 1-25) and Landau (US 20210002728 A1), as applied to claims 70-74, 76-88, 91-93, and 96, and further in view Oxnard (US20250019770A1, effectively filed November 12th, 2021).
Regarding instant claim 94, Christensen, in view of Honoré and Landau, teaches the method of claim 93.
None of these references teach the method further comprising determining a circulating tumor DNA (ctDNA) fraction of said cancer of said subject, based at least in part on said set of mutant allele frequencies.
Oxnard, in a reasonably pertinent field, teaches determining a circulating tumor DNA (ctDNA) fraction of said cancer of said subject, based at least in part on said set of mutant allele frequencies (Page 4, paragraph [0031]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Christensen, in view of Honoré and Landau, with the ctDNA fraction determination of Oxnard. Since Oxnard teaches on detecting tumor genomic content, which is reasonably pertinent to the cancer detection of Christensen, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because “[t]umor fraction can be used to monitor a patient at risk for cancer (with or without current diagnosis); as a factor used in diagnosing cancer; or to determine if a current treatment regimen is having an effect, e.g., a beneficial effect (Oxnard, Pages 14-15, paragraph [0114]).
Claim 95 is rejected under 35 U.S.C. 103 as being unpatentable over Christensen (Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557), in view of Honoré (Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact, Cancers, October 2021, 13, 1-25) and Landau (US 20210002728 A1), as applied to claims 70-74, 76-88, 91-93, and 96, and further in view of Chaudhary (US 20200075122 A1).
Regarding instant claim 95, Christensen, in view of Honoré and Landau, teaches the method of claim 93.
None of these references teach the method further comprising determining a tumor mutational burden (TMB) of said cancer of said subject, based at least in part on said set of mutant allele frequencies.
Chaudhary, in a reasonably pertinent field, teaches that TMB can be determined based at least in part on a set of mutant allele frequencies (Page 1, paragraph [0003]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Christensen, in view of Honoré and Landau, with the TMB determination of Chaudhary. Since Chaudhary teaches on detecting mutation load in a tumor sample, which is reasonably pertinent to the cancer detection of Christensen, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because tumor mutation load (e.g. TMB) is a sensitive marker that can help predict response to certain anticancer immunotherapies, further related to bladder cancer (Chaudhary, Page 3, paragraph [0037]).
Claim 97 is rejected under 35 U.S.C. 103 as being unpatentable over Christensen (Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557), in view of Honoré (Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact, Cancers, October 2021, 13, 1-25) and Landau (US 20210002728 A1), as applied to claims 70-74, 76-88, 91-93, and 96, and further in view of Li (DNA Methylation Detection: Bisulfite Genomic Sequencing Analysis, Epigenetics Protocols, January 2011, 11-21).
Regarding instant claim 97, Christensen, in view of Honoré and Landau, teaches the method of claim 70.
None of these references teach wherein (a) or (d) comprises methylation-aware sequencing, enzymatic methylation sequencing, or bisulfite methylation sequencing.
Li, in a reasonably pertinent field, teaches on bisulfite genomic sequencing for detection DNA methylation (Page 12, paragraph 2), which is pertinent to step (a).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified Christensen, in view of Honoré and Landau, with the bisulfite sequencing of Li. Since Li teaches on sequencing of DNA, which is reasonably pertinent to the sequencing of Christensen, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because “[b]isulfite genomic sequencing is regarded as a gold-standard technology for the detection of DNA methylation because it pro vides a qualitative, quantitative, and efficient approach to identify 5-methylcytosine (5mC) at single base-pair resolution” (Li, Page 12, paragraph 2).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 70-97 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68-87 of copending Application No. 19297727, in view of Christensen (Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma, Journal of Clinical Oncology, May 2019, 37, 1547-1557), Honoré (Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact, Cancers, October 2021, 13, 1-25), Landau (US 20210002728 A1), Hovelson (Rapid, ultra-low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy, Oncotarget, September 2017, 8, 89849-89866), Chaudhary (US 20200075122 A1), and Li (DNA Methylation Detection: Bisulfite Genomic Sequencing Analysis, Epigenetics Protocols, January 2011, 11-21).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘727 reference application and the instant application claim a method for detecting a presence or an absence of minimal residual disease (MRD) in a subject, comprising: (a) assaying deoxyribonucleic acid (DNA) molecules from a first biological sample obtained or derived from said subject at a first time point; (b) detecting a set of biomarkers from said DNA molecules based at least in part on said assaying of (a), wherein said set of biomarkers comprise differentially expressed markers or variants; (c) generating a plurality of probe nucleic acids that are customized for said subject, wherein said probe nucleic acids comprises sequences of at least a subset of said set of biomarkers; (d) using said plurality of probe nucleic acids, sequencing cell free deoxynucleic acids (cfDNA) from a second biological sample obtained or derived from said subject at a second time point to detect the presence or absence of said subset of said set of biomarkers, wherein said sequencing is performed at a depth of at least about 80x, wherein said second biological sample comprises a blood sample, a urine sample, or a urine cell pellet sample; and (f) computer processing said subset of said set of biomarkers to detect said presence or absence of minimal residual disease (MRD) in a subject (instant claim 70, 72, and 73; reference claim 68).
The ‘727 reference application and the instant application both further claim wherein said first or second biological sample is selected from the group consisting of: a cell-free deoxyribonucleic acid (cfDNA) sample, a cell-free ribonucleic acid (cfRNA) sample, a plasma sample, a serum sample, a buffy coat sample, a peripheral blood mononuclear cell (PBMC) sample, a red blood cell sample, a urine sample, a saliva sample, tissue biopsy, pleural fluid sample, peritoneal fluid sample, amniotic fluid sample, cerebrospinal fluid sample, lymphatic fluid sample, sweat sample, tear sample, semen sample, or any derivative thereof, and any combination thereof (instant claim 71; reference claim 69); wherein said first or second biological sample comprises said plasma sample (instant claim 72; reference claim 70); wherein said sequencing of (d) is performed at a depth of at least about 10,000x (instant claim 96; reference claim 72); wherein said sequencing of (e) further comprises sequencing nucleic acids of a sample taken at said first time point, and sequencing nucleic acids of a sample taken at a second time point (instant claim 77; reference claim 73); wherein said cancer is selected from the group consisting of: genitourinary cancer, prostate cancer, bladder cancer, and any combination thereof (instant claim 79; reference claim 74); further comprising identifying a clinical intervention for said subject, based at least in part on said detected presence or said absence of said cancer (instant claim 82; reference claim 79); wherein said clinical intervention is selected from the group consisting of: surgical resection, chemotherapy, radiotherapy, immunotherapy, adjuvant therapy, neoadjuvant therapy, androgen deprivation therapy, and a combination thereof (instant claim 83; reference claim 80); wherein (d) further comprises sequencing using a fixed plurality of probes, wherein said probes of said fixed plurality of probes comprise probes that do not comprise sequences of said subset of said set of biomarkers (instant claim 89; reference claim 82); wherein said set of biomarkers comprises tumor-associated alterations selected from the group consisting of: single nucleotide variants (SNVs), insertions or deletions (indels), and rearrangements (instant claim 91; reference claim 84); further comprising determining, among said set of biomarkers, a mutant allele frequency of a set of somatic mutations (instant claim 93; reference claim 85); and further comprising determining a circulating tumor DNA (ctDNA) fraction of said cancer of said subject, based at least in part on said set of mutant allele frequencies (instant claim 94; reference claim 86).
The ‘727 reference application and the instant application both claim tables of biomarkers, with the tables described in the specification. Upon review of the ‘727 specification, it is found that both the ‘727 reference application and instant application claim wherein said set of biomarkers related to customized biomarkers comprises one or more members selected from a group consisting of overlapping genes (instant claims 85-88; reference claim 81). The ‘727 reference application and instant application claim wherein said fixed plurality of probes comprise one or more members selected from a group consisting of overlapping genes (instant claim 90; reference claim 83).
The ‘727 claims do not require sequencing nucleic acids to determine a copy number of at least one region of a genome of the subject; whole exome sequencing; low-pass whole genome sequencing; sequencing to a depth of at least about 1000x; comparing results of sequencing at a first and second time point to determine a copy number of at least one region of a genome of a subject; a biological sample is obtained or derived from a subject after receiving a therapy for a cancer; detecting a copy number variation or a copy number loss; determining a tumor mutation burden based at least in part on mutant allele frequencies; or methylation sequencing techniques. However, Christensen, Honoré, Landau, Hovelson, Chaudhary, and Li teach the claimed limitations as discussed in the above 103 rejections, obviating these variations to the claims of the ‘727 application. Any additional limitations of the claims of copending Application No. 19297727 are encompassed by the open claim language "comprising" found in the instant claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
All claims stand rejected.
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/ALLISON E SCHLOOP/Examiner, Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
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