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 Group I, a method comprising assaying from a sample from an individual, in the reply filed on 11/13/25 is acknowledged.
Claims 3-17, 22-23, 25, 31-32, 34-36, 40-44, 46-53 are cancelled.
Claims 1-2, 18-21, 24, 26-30, 33, 37-39, and 45 are pending.
Claims 2 and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Elections were made without traverse in the reply filed on 11/13/25.
Claims 1, 18-21, 26-30, 33, 37-39, and 45 are currently under examination.
Priority
The instant application 18/009,945 filed on 12/12/22 is a 371 US national phase of PCT/GB2021/051536 filed on 6/17/21, and claims foreign priority to GB2107412.5 filed on 5/25/21 and GB2009224.3 filed on 6/17/20. Receipt is acknowledged of GB2107412.5 and GB2009224.3 certified copies of papers required by 37 CFR 1.55. Priority Documents were electronically retrieved by USPTO from participating IP office on 12/12/22. The priority date is determined to be 6/17/20.
Information Disclosure Statement
The information disclosure statement filed 3/15/23 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. No copies of NPL citations 15, 19, and 41 have been provided.
Objections to the Specification
The disclosure is objected to because pages 371-375 contain an embedded hyperlink and/or other form of browser-executable code. 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
Claims 1, 21, 26, 29-30, 33, 39, and 45 are objected to because of the following informalities:
claims 1, 21, 26, 29-30, 33, 39, and 45 contain periods, and per MPEP 608.01(m):
“Periods may not be used elsewhere in the claims except for abbreviations.” It is recommended to use parentheses instead (e.g., claim 1 i) one or more…);
claim 21 may contain typographical errors of “[[CG]]”, wherein it is not clear if applicant intends for those limitations to be removed from a. – j.; and
claim 33 should indent the “v. a test for cell-free…” to maintain current format.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Scope of Enablement
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.
Claim 28 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for “administering one or more therapeutic… treatments to the individual based on the assessment” (Specification page 25, lines 21-22), does not reasonably provide enablement for “preventative treatments to the individual based on the assessment” (Specification page 25, lines 21-22).
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.
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the amount of direction or guidance present,
5. the presence or absence of working examples,
6. the breadth of the claims,
7. the quantity of experimentation needed, and
8. the level of the skill in the art.
The nature of the invention (1) and breadth of the claims (6)
The nature of the invention and breadth of Claim 28 is a method of treating or preventing cancer in an individual. Page 389-392 of the specification include examples of cancer treatments that are administered “in an amount sufficient to prevent, treat, cure, alleviate or partially arrest cancer or one or more of its symptoms.” Therefore, the breadth of claim 28 encompasses aspects of administration of a therapeutic agent (like the embodied cytotoxic chemotherapeutics) for prevention of cancer.
The state of the prior art (2) and the predictability or lack thereof in the art (3)
Regarding cervical intraepithelial neoplasia grade 3 (CIN3), Sladic et al. (2022; “Cervical Intraepithelial Neoplasia Grade 3 in a HPV-Vaccinated Patient: A Case Report”; Medicina 2022, 58, 339. https://doi.org/10.3390/medicina58030339) Abstract teaches that “Although HPV [human papillomavirus] immunization has shown to be extremely effective in preventing a high proportion of cervical precancerous lesions and cervical cancers, HPV vaccines do not protect against all oncogenic high-risk HPV genotypes.”
Therefore, it appears that some cervical cancer prevention is achieved through vaccinations, and not prevented through administration of the embodied cytotoxic chemotherapeutics.
The amount of direction or guidance present (4) and the presence or absence of working examples (5)
Beginning on page 389 of the Specification, applicant provides guidance with respect to the administration of cancer treatments to individuals, but does not provide data with respect to the claimed prevention of cancer.
Said cancer is known in the art to not be entirely vaccine preventable as explained above and applicant has not provided an explanation of the cancer expected to be prevented via the administration of the treatments.
The quantity of experimentation needed (7)
The quantity of experimentation needed is extremely difficult, novel, and undue experimentation; the ability of the claimed method to therapeutically prevent the onset of a cancer of which we do not fully understand the pathogenesis or in which prevention therapy is dubious, and not enabled by the experiments disclosed in the specifications of instant application and the status of art at the time of filing.
The level of the skill in the art (8)
The level of skill in the art is high with respect to preventative therapeutic research. However, even a highly skilled artisan would not expect that administration of a treatment could prevent the cancer currently known to not be wholly preventable and lacking a known therapeutic regimen for prevention.
Claim Rejections - 35 USC § 112 – Indefiniteness
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 21, 26-27, 29, 30, 33, 39, and 45 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 21, 26, 29, 30, 33, 39, and 45 recite the phrase “particularly” and/or “preferably”. These phrases render the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. For purposes of compact prosecution, the limitations following the phrases are interpreted as not required by the invention.
Claim 27 depends upon canceled claim 9. For purposes of compact prosecution, claim 27 is interpreted as depending on claim 1.
Claims 29-30 and 33 depend upon claim 27 and are similarly indefinite.
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.
Claim 27 is rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claim is directed to the statutory category of a process.
Step 2A, prong one: The claim recites a judicial exception.
Claim 27 recites “a step of stratifying the individual”. This limitation is an abstract mental process (see MPEP 2106.04(a)(2)(III)).
Step 2A, prong two: The judicial exception is not integrated into a practical application.
Claim 1 recites extra-solution and data-gathering limitations at high levels of generality. Claim 27 ends with the judicial exception.
Step 2B: The claim does not provide an inventive concept.
MPEP 2106.05(d)):
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S.
at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health
Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir.
2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs.
Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir.
2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115
USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78,
115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123
USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v.
Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic
variants, Genetic Techs. Ltd., 818 F.3d at 1377, 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119
USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah
Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d
1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d
at 1247.
The claim ends with the judicial exception. Additionally, methods of determining risks of having cancer are not inventive (Zhang et al.; 2016; WO 2016/115530 A1).
For the reasons set forth above, claim 27 is not directed to patent eligible subject matter.
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.
Claims 1, 18-21, 26-28, 37-38, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (2016; WO 2016/115530 A1).
Relevant to claims 1 and 18-21, Zhang et al. Abstract teaches that "Disclosed herein are methods, systems, platforms, non-transitory computer-readable medium, services, and kits for determining a cancer type in an individual. Also described herein include methods, systems, platforms, non-transitory computer-readable medium, and compositions for generating a CpG methylation profile database."
Further relevant to claims 1 and 18-21, the below excerpt demonstrates that the elected SEQ ID NOs 67 and 503 align to the GYPC gene and contain cg15975865.
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531
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Greyscale
Further relevant to claims 1 and 18-21, Zhang et al. teaches "In some embodiments, the methylation profile comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 biomarkers selected from the group consisting of Table 15" (paragraph 0009). Zhang et al. page 216 teaches cg15975865 within Table 15.
Relevant to claim 26, Zhang et al. teaches "Suitable next generation sequencing technologies are widely available. Examples include… Illumina's Genome Analyzer, GoldenGate Methylation Assay, or Infinium Methylation Assays, i.e., Infinium HumanMethylation 27K BeadArray or VeraCode GoldenGate methylation array…" (paragraph 0199).
Relevant to claim 27, Zhang et al. teaches "In specific embodiments, provided herein include methods for determining the risk of developing cancer in a patient. Biomarker methylation percentages, amounts or patterns are characteristic of various risk states, e.g., high, medium or low" (paragraph 0243).
Relevant to claim 28, Zhang et al. teaches "In other embodiments, described herein include methods, systems, platform, non-transitory computer-readable medium, services, and kits for determining the prognosis of a cancer in an individual in need thereof, prediction of a treatment response, and treatment response monitoring" (paragraph 0004).
Further relevant to claim 28, Zhang et al. teaches "In some embodiments, the method further comprises implementing a treatment regimen based on the diagnosed cancer type" (paragraph 0029).
Relevant to claims 37-38, Zhang et al. teaches "In one embodiment, provided herein include methods for determining the course of cancer in a patient, cancer course refers to changes in cancer status over time, including cancer progression (worsening) and cancer regression (improvement). Over time, the amount or relative amount ( e.g., the pattern) of methylation of the biomarkers changes. For example, hypermethylation or hypomethylation of biomarker "X" and "Y" are increased in some instances with cancer. Therefore, the trend of these biomarkers, either increased or decreased methylation over time toward cancer or non-cancer indicates the course of the disease. Accordingly, this method involves measuring the methylation level or status of one or more biomarkers in a patient at least two different time points, e.g., a first time and a second time, and comparing the change, if any. The course of cancer is determined based on these comparisons" (paragraph 0249).
Relevant to claim 45, Zhang et al. teaches "To identify a cancer-type specific signature, methylation differences between a particular cancer type and its surrounding normal tissue, differences between different cancer types, as well as differences between two normal tissues in a pair-wise fashion were compared" (paragraph 0361).
Zhang et al. does not teach a specific embodiment having all the claimed elements. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. AG. Pro, 425 U.S. 273, 282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is... a person of ordinary creativity, not an automaton." Id. At 1742.
Consistent with this reasoning, it would have been prima facie obvious to have
selected various combinations of various disclosed elements — including methylation markers, stratification, and multiple time points — for a method comprising assaying from a sample from an individual the methylation status of a panel, to arrive at compositions "yielding no more than one would expect from such an arrangement."
Claims 29-30, 33, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (2016; WO 2016/115530 A1), as applied to claims 1, 18-21, 26-28, 37-38, and 45 above, and further in view of Alcazar et al. (2014; "The Role of Ultrasound in the Assessment of Uterine Cervical Cancer"; J Obstet Gynecol India 64, 311-316 (2014). https://doi.org/10.1007/s13224-014-0622-4).
The teachings of Zhang et al. are applied to instantly rejected claims 29-30, 33, and 39 as they were previously applied to claims 1, 18-21, 26-28, 37-38, and 45 as rendering obvious a method comprising assaying from a sample from an individual the methylation status of a panel. Zhang et al. is silent to specifics regarding transvaginal ultrasounds as treatments. However, these limitations were known in the prior art and taught by Alcazar et al.
Relevant to claims 29-30, 33, and 39, Alcazar et al. teaches “Studies evaluating the role of transvaginal/transrectal ultrasound for staging cervical cancer were reported in early 90s” (first sentence of “Transvaginal/Transrectal Ultrasound for Local Staging of Cervical Cancer” Section). Alcazar et al. Figures 1-7 depict transvaginal ultrasound images successfully identifying cervical cancers.
Although Zhang et al. is silent to the Alcazar et al. transvaginal ultrasounds, this limitation would have been prima facie obvious to the skilled artisan. It is noted that Zhang et al. and Alcazar et al. are analogous disclosures to the instant cancer field.
The skilled artisan would have been motivated to combine the analogous art. Alcazar et al. teaches that transvaginal ultrasounds have been used since the early 90s, and the Figures demonstrate success in imaging cervical cancers. Thus, the skilled artisan would have been motivated to use this common and well-known technique to treat individuals.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Zhang et al., and further in view of Alcazar et al., as discussed in the preceding paragraphs.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 18-21, 26-29, 37-38, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-19, 24-26, 48-49, and 52-55 of copending Application No. 18/009,957 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are drawn to A method comprising assaying from a sample from an individual the methylation status of a panel of: i. one or more CpGs selected from a panel of CpGs identified in SEQ ID NOs 1 to 500 wherein the CpGs are identified at nucleotide positions 61 to 62; and/or ii. one or more CpGs selected from within a panel of one or more Differentially Methylated Regions (DMRs) defined by SEQ ID NOs 501 to 808, wherein the CpGs are denoted by CG.
The copending claims are drawn to “A method comprising assaying from a sample from an individual the methylation status of a panel of: i. one or more CpGs selected from a panel of CpGs identified in SEQ ID NOs 1 to 5000 wherein the CpGs are identified at nucleotide positions 61 to 62; and/or ii. one or more CpGs selected from within a panel of one or more Differentially Methylated Regions (DMRs) defined by SEQ ID NOs 5001 to 5418, wherein the CpGs are denoted by CG.”
Although the elected species of SEQ ID NOs are not identical to copending application SEQ ID NOs, the skilled artisan would find this difference prima facie obvious. Both inventions contain identical assay steps and methodologies to assay methylation status, and both inventions pertain to the same cancer (CIN3). It is noted that both the instant and copending SEQ ID NOs correspond to characterized methylation regions, as denoted by the cg-number designation. The skilled artisan would recognize that the instant and copending regions would be assayed within commercially available methylation arrays (e.g., Illumina), and would thus find the instant and copending inventions as obvious variants.
The copending claims are required to perform the instant methods. Thus, they are obvious variants. Dependent claims are rejected as they are coextensive in scope.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682