DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. The election of species requirement set forth in the Office action of 20 August 2025 is withdrawn.
Claims 1, 4, 7, 10, 12, 15-19, 21-23, 25-27, 29, 31, 35, 39 and 42 are pending and have been examined herein.
It is noted that the listing of claims filed 20 October 2025 omits claim 3. However, claim 3 was cancelled in the amendment filed 27 April 2023. Future listings of the claims should include all claim numbers of previously pending and currently pending claims, including claims that have been canceled.
Claim Interpretation
3. In claim 1 at step (c), the language of “continuing to administer the first cancer therapy” and “beginning to administer a second cancer therapy” are considered to require actively administering the first or second cancer therapy, respectively. Regarding 35 U.S.C. 101, the claims recite the judicial exception of a law of nature of the correlation between the nucleic acid markers and cancer burden, as well as efficacy of the cancer therapy. However, the final administering step in claims 1, 2, 4, 7, 10, 12, 15-19, 21-23, 25-27, 29, 31, 35 and 42 is considered to integrate the recited judicial exceptions into a practical application.
Claim Objections
4. Claim 39 is objected to because of the following informalities:
Claim 39 recites at (b) “from the first group or patients” whereas the claim should recite “from the first group of patients.”
Appropriate correction is required.
Claim Rejections - 35 USC § 101
5. 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 39 is rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. Claim 39 recites the correlation between the nucleic acid marker and cancer burden, as well as the correlation between the nucleic acid marker and efficacy of cancer therapy. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
Herein, claim 39 recites steps of identifying the first dose level as being efficacious or not efficacious based on the results obtained with the nucleic acid marker. In the absence of a clear, liming definition in the specification for “identified” or “identifying” and the absence of clear direction in the claim as what is encompassed by “identified” or “identifying,” this step has been interpreted to include mentally drawing a conclusion regarding the efficacy of the therapy based on the results obtained with the nucleic acid marker. Such “identifying” / “identified” thereby encompasses processes that may be performed mentally through critical thinking processes and thus is an abstract idea.
Claim 39 also requires performing a step of "comparing" the nucleic acid marker at step (b). Neither the specification nor the claims set forth a limiting definition for "comparing" (i.e., “compared to”) and the claims do not set forth how comparing is accomplished. Note that whether the comparing step is recited as an active step or a passive step, the claims still require that a comparison is made between the nucleic acid marker of the patient with that of an earlier measurement or different measurement. The broadest reasonable interpretation of the “comparing” step is that this step may be accomplished by critical thinking processes. Such “comparing” thereby encompasses only an abstract idea / process.
The claims recite “discontinuing" the patient from the trial or “escalating the patient to a second dose level.” Neither the specification nor the claims set forth a limiting definition for “discontinuing” or “escalating” and the claim does not set forth how these steps are accomplished. As broadly recited, “discontinuing” and “escalating” may be accomplished mentally and thus are an abstract step / process. “Discontinuing” and “escalating” may also be accomplished verbally. Such verbal communication is also abstract, having no particular concrete or tangible form. Note that “escalating” does not require actively administering a higher dosage of the first cancer therapy regimen to the patient.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps of measuring the nucleic acid marker is part of the data gathering process necessary to observe the judicial exception. The first administering step is also part of the data gathering process. The first administering step and measuring steps do not practically apply the judicial exception.
As discussed above, claim 39 encompasses the embodiments of discontinuing the patient from the clinical trial or “escalating the patient to a second dose level” and these steps are themselves the judicial exception of an abstract idea and not something “in addition” to the judicial exception(s). The claim is not limited to a method which requires administering a particular therapy to the patient at step (c) so as to integrate the judicial exception into a practical application.
Regarding step (a) of claim 39, Applicant’s attention is directed to M.P.E.P. § 2106.04(d)(2)(c), which states:
“The treatment or prophylaxis limitation must impose meaningful limits on the judicial exception, and cannot be extra-solution activity or a field-of-use. For example, consider a claim that recites (a) administering rabies and feline leukemia vaccines to a first group of domestic cats in accordance with different vaccination schedules, and (b) analyzing information about the vaccination schedules and whether the cats later developed chronic immune-mediated disorders to determine a lowest-risk vaccination schedule. Step (b) falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). While step (a) administers vaccines to the cats, this administration is performed in order to gather data for the mental analysis step, and is a necessary precursor for all uses of the recited exception. It is thus extra-solution activity, and does not integrate the judicial exception into a practical application.”
Further, regarding the final step of “discontinuing the patient from the early stage clinical trial or escalating the patient to a second dose level of the first cancer therapy,”
Applicant’s attention is directed to MPEP 2106.04(d)(2):
Examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. An example of such a limitation is a step of "administering amazonic acid to a patient" or a step of "administering a course of plasmapheresis to a patient." If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. For example, a step of "prescribing a topical steroid to a patient with eczema" is not a positive limitation because it does not require that the steroid actually be used by or on the patient, and a recitation that a claimed product is a "pharmaceutical composition" or that a "feed dispenser is operable to dispense a mineral supplement" are not affirmative limitations because they are merely indicating how the claimed invention might be used.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited measuring steps are recited at a high degree of generality and measuring any nucleic acid marker of tumor burden was well-known, routine and conventional in the prior art. This finding is evidenced by the specification at para [0053] (para numbering herein is with respect to the published application), which states “Methods of measuring respective nucleic acid markers are not particularly limited and are known in the art.”
See also MPEP 2106.05(d) II which states that:
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. 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., 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.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
6. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, 7, 10, 12, 15-19, 21-23, 25-27, 29, 31, 35, 39 and 42 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 1, 4, 7, 10, 12, 15-19, 21-23, 25-27, 29, 31, 35, 39 and 42 are indefinite over the recitation of “retaining the patient receiving the second cancer therapy regimen in the first group of patients.” Since the patients receiving the second cancer therapy regimen are receiving a cancer therapy that is different from the other patients in the first group, it is unclear as to what is meant by retaining the patients receiving the second cancer therapy regimen in the first group. For instance, it is unclear as to whether this is intended to encompass merely keeping a record of the names of the patients who subsequently receive the second cancer therapy regimen as part of the original first group, or if this requires keeping the patients in the clinical trial and continuing to monito the efficacy of the second cancer therapy regimen, and/or if this requires that the patients receiving the second cancer therapy regimen are not considered to be distinct from those patients receiving the first cancer therapy regimen and the outcome of all patients in the first group are considered together, irregardless of whether they receive the first or the second cancer therapy regimen. Accordingly, the metes and bounds of what is encompassed by “retaining” the patients receiving the second cancer therapy regimen in the first group is not clear.
Claim Rejections - 35 USC § 103
7. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kurzrock, R. (U.S. 20170251973) in view of Melnikova et al (U.S. 20180087114).
Kurzrock et al teaches methods for performing an early stage clinical trial comprising the steps of:(a) administering a first dose level of a first cancer therapy regimen to a first group of patients;(b) determining the therapeutic efficacy of the first dose level for patients in the first group of patients by measuring a nucleic acid marker of cancer burden in a biological sample from the first group or patients, wherein the first dose level is identified as being efficacious in a patient in the first group of patients when the nucleic acid marker indicates a lower cancer burden as compared to a measurement made at baseline or at an earlier time point after onset of the first cancer therapy regimen; and wherein the dose level is identified as not being efficacious in a patient when the nucleic acid marker indicates a higher cancer burden as compared to a measurement of the nucleic acid marker taken at baseline or at an earlier time point after onset of the cancer therapy regimen; and(c) continuing to administer the first dose level to the patient when the first cancer therapy regimen is identified as being efficacious in the patient, and discontinuing the patient from the early stage clinical trial if the first dose level is identified as not being efficacious (e.g., claims 10 and 11; para [0010], [0012], [0019], [0022], [0025] and [0029]).
Kurzrock (para [0010]) states:
Therefore, there is a need in the art to rapidly measure the effectiveness of a cancer treatment drug or drug regimen (multiple drugs administered during a single course of therapy) in order to measure patient benefit quickly in view of the multitude of serious side effects that cancer treatment entails. This need is not only for the patient treatment situation but also for clinical trials of therapies wherein subgroups can be identified early in a treatment cycle to provide approvable criteria to determine which patients are appropriate for subgroup criteria that are within the label indications of an approved therapeutic or therapeutic combination.
It is disclosed that measurement of response to treatment in clinical trials may be made by the method set forth in claims 10 and 11 of Kurzrock:
10. A process for determining whether a patient would benefit for cancer treatment with a particular therapeutic, comprising (a) conducting a baseline measurement of the level of circulating tumor DNA (ctDNA) for specific oncogene mutations/alterations from a response biomarker specific for a tumor to identify early patient response to drug therapy, wherein the response biomarker is selected from the group consisting of the response biomarkers in Tables 1A and 1B, (b) providing a single potentially effective dose of a therapeutic to the patient, (c) conducting a second measurement of the level of circulating tumor DNA (ctDNA) for specific oncogene mutations/alterations from a response biomarker specific for a tumor, wherein the response biomarker is selected from the group consisting of the response biomarkers in Tables 1A and 1B, wherein the second or serial measurement(s) are conducted 1-14 days following the dose of the therapeutic, and (d) comparing the results of the first measurement to the second measurement to determine if at least a 1% reduction indicates that the patient would benefit to continue to treat the tumor with the therapeutic.
11. The process for determining whether a patient would benefit for cancer treatment with a particular therapeutic of claim 10, wherein the second or serial measurement(s) are conducted from 1-10 days after completion of a first dose of a therapeutic to the patient.
Kurzrock teaches that ctDNA levels in plasma or urine are indicative of tumor burden and that “(t)he relative measurement of ctDNA can be used to determine effectiveness of a cancer therapy and has been demonstrated for numerous metastatic cancers including breast, lung and colorectal cancer” (para [0030]). It is stated that a reduction in the level of biomarker by 1% indicates that the patient is responsive to the treatment (e.g., claim 10 and para [0019]). The reference teaches that early response to treatment can be measured using either ctDNA biomarkers or PET FDG at baseline and days 1 to 14 (para [0033]). It is stated that “The present method is able to determine treatment effectiveness at a much earlier time in order to change ineffective treatments earlier or to determine which patients should continue on a clinical study” (para [0028]).
Kurzrock does not specifically teach that the first dose level is identified as being efficacious in those instances when the nucleic acid marker indicates a stable cancer burden.
However, Melnikova teaches methods for detecting nucleic acid biomarkers in bodily fluids, such as serum or urine samples, as indicative of the efficacy of cancer therapy in a patient and recommending that the therapy be continued if a favorable response is detected or recommending discontinuation of the therapy and administering a new treatment if the response is unfavorable (e.g., para [0004-0007] and [0072]). It is disclosed that the quantity of circulating tumor DNA (ctDNA) is tumor-burden dependent “with greater amounts present as tumor volume and subsequent cellular turnover increase” (para [0097]).
Melnikova (para [0051]) further teaches that the measurement of mutant ctDNA in body fluids, such as serum or plasma, can be used to determine if a higher dosage of a cancer therapy is need in a clinical trial. It is stated that:
“The determination of levels of the cancer mutation early in a treatment can assist in the determination of a proper dosage level of a medication. An early response that is less than expected based on historical data or comparison with control and standard samples with known responses may indicate that a higher dosage is needed. In this way, a dose can be titrated for each individual. This information is particularly useful when the medication is in clinical trials, since efficacious dosage ranges can be established much more quickly than without the ability to quickly assess efficacy that these methods enable.”
Melnikova teaches that an anti-cancer therapy is considered to be effective if the measured marker indicates that the patient has a complete response (CR), partial response (PR) or stable disease (SD) - e.g., para [0053]). For instance, Melnikova (para [0098]) teaches that response to Osimertinib is monitored by measuring EGFR-activating mutations (L858R, exon 19 deletions) and the resistant mutation T790M in urine from patients with metastatic NSCLC and that patients with CR, PR and stable disease (SD) were all considered to have clinical benefit from the Osimertinib treatment. See also para [0116-0117].
In view of the teachings of Melnikova, 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 Kurzrock so as to have also identified the first dose of cancer therapy as effective in those patients in which the measurement of the nucleic acid biomarker (i.e., ctDNA) was indicative of stable disease. One would have been motivated to have done so because Melnikova discloses that patients with stable disease are also positively responding to the therapy and such a modification would have ensured that such patients continued to be treated with the effective dose of the therapy.
8. Claim(s) 1, 4, 7, 10, 12, 15-17, 29, 31, 35, and 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kurzrock, R. (U.S. 20170251973) in view of Melnikova et al (U.S. 20180087114), and further in view of Zhang et al (Chin Clin Oncol. 2014. 5(4), p. 1-20).
The teachings of Kurzrock and Melnikova are presented above.
As discussed above, Kurzrock teaches continuing to administer a first cancer therapy regimen to the patient when the first cancer therapy regimen is identified as being efficacious in the patient, and discontinuing the first cancer therapy regimen and beginning to administer a second cancer therapy regimen to the patient when the first cancer therapy regimen is identified as not being efficacious in the patient (e.g., para [0012], [0022], [0025], and [0031]). For instance, Kurzrock (para [0025]) states:
“the early selection of responders for clinical trials such that a greater percentage of drugs will achieve statistical significance for efficacy and subsequent commercial approval with labeling requiring/suggesting that the presently disclosed procedure be conducted after a single treatment dose in order to determine who stays on the treatment and who gets moved to a different treatment. This is important because drugs that produce definitive responses, but in only small subsets of patients, may not be approvable in unselected patient populations. Yet these drugs can be successful once there is the ability to select the subgroup of responders within days of the first dose of drug.”
The combined references do not disclose “retaining the patient receiving the second cancer therapy regimen in the first group of patients.”
However, Zhang teaches “adaptive clinical trials” in which the patients in a clinical trial are evaluated at early stages to determine their responsiveness to a therapeutic regimen and changes are made if the patient is determined to not be responsive to the therapeutic regimen (e.g., abstract and p. 1 and 2). Zhang teaches that the adaptive clinical trial can utilize biomarkers to evaluate response to therapies (p. 10 “Biomarker-guided adaptive design”). Two clinical trials are discussed that “have implemented adaptive randomization schemes to assign patients to the more efficacious treatments based on their biomarker-guided profiles, and use interim analyses to monitor the efficacy outcomes during the trial” (p. 10-11). Zhang (p. 2) states:
“In general, an adaptive design may allow for adaptive dose escalation/de-escalation; early stopping of the trial for toxicity, efficacy or futility; dropping or adding new treatment arms; using a seamless phase transition; adjusting an adaptive randomization scheme based on patient response or covariates; sample size re-estimation; and biomarker-guided treatment allocation. The purpose of the adaptive design is to give the investigator the flexibility to identify the best clinical benefit of the treatment as the trial progresses and then use that information to provide the best treatment to patients newly enrolling in the trial without undermining the scientific validity and integrity of the intended trial.”
As shown in the examples and discussion provided by Zhang, in the adaptive clinical trials, patients remain in the trial - i.e., are retained in a “group 1” - after they are identified as being non-responsive to a cancer therapy regimen and are subsequently administered a second, different cancer therapy regimen or a higher dosage of a first cancer therapy regimen.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Kurzrock so as to have retained the patients identified as not having an efficacious response to the first cancer therapy regimen and who were then administered a second, different cancer therapy regimen in the clinical trial and thereby to have retained such patients in “group 1.” One would have been motivated to have done so for the advantages set forth by Zhang of allowing for the continual monitoring of the efficacy of the second cancer therapy and the overall outcomes of the patients so that the best therapy could be selected for those patients and also to aid in the design of future clinical trials.
Regarding claim 4, Kurzrock teaches that samples are collected from the patients before and at multiple times after the initiation of treatment and at least within 14 of the initiation of treatment (e.g., para [0032]). Thus, Kurzrock teaches that the sample is obtained from the patients within 5 weeks after onset of the first cancer therapy regimen.
Regarding claim 7, Kurzrock does not specifically state that the steps of measuring the biomarkers, identifying the therapy as efficacious or not efficacious in the patients, and continuing to administer the therapy or discontinuing the therapy and administering a second therapy are repeated daily or every other day or every third day or twice a week or weekly. However, Kurzrock teaches repeating the steps of measuring the level of the nucleic acid biomarker and evaluating the response of the patient at multiple time points after the initiation of the first cancer therapy regimen and states that “the second or serial measurement(s) are conducted 1-14 days following the dose of the therapeutic” (e.g., para [0022] and [0031] and claim 11). Further, Melnikova teaches obtaining samples and measuring the nucleic acid biomarkers in the sample daily for seven days after the beginning of treatment to determine ctDNA levels as indicative of changes tumor burden (e.g., claims 1 and 3, and para [0044]). In Figure 14, Melnikova shows the changes in ctDNA EGFR mutation levels at daily intervals (para [0023]). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the method of Kurzrock by performing the measuring, identifying and continuing to administer or discontinuing the administering steps at frequent intervals, including daily or every other day or twice a week or weekly as taught by Kurzrock and Melnikova to provide the benefit of closely monitoring any changes or lack of changes in tumor burden in response to the cancer therapy regimen so that the most suitable cancer therapy regimen could be administered to the patient.
Regarding claim 10, as discussed above, Kurzrock and Melnikova both teach serial analysis of the nucleic acid biomarkers from the patients at multiple time points following the initiation of the first cancer therapy regimen and thereby teach identifying the first cancer therapy as being efficacious or not efficacious is based on a trend or a change in trend of two or more measurements of the nucleic acid marker.
Regarding claim 12, in the method of Kurzrock, the first cancer therapy regimen is identified as not being efficacious when cancer progression occurs in the patient, as shown by a greater tumor burden (e.g., para [0030]).
Regarding claims 15-17, as discussed above, Kurzrock teaches that the nucleic acid marker that is detected is circulating tumor DNA (ctDNA; e.g., para [0022] and [0030] and claims 10-11).
Regarding claims 29 and 31, Kurzrock does not teach that the clinical trial further comprises administering a third cancer therapy regimen to a control group which is a standard of care therapy regimen.
However, Zhang teaches two-arm clinical trials in which an experimental cancer therapy regimen is compared to a standard treatment (e.g., Figure 2; p. 4: “For a two-arm trial in which an experimental treatment is compared with a standard treatment to assess the therapeutic effect” and p. 8 “a randomized phase III trial is conducted to compare the experimental therapy with the standard therapy”).
In view of the teachings of Zhang, 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 Kurzrock so as to have included a control group receiving a third therapy that is a standard of care cancer therapy regimen in order to have provided the benefit set forth by Zhang of using the clinical trial to access if the efficacy of a new treatment is better than that of the standard treatment in a matched patient population.
Regarding claim 35, Kurzrock does not teach that the first group of patients and the control group of patients had the same result on a pre-trial companion diagnostic test, wherein the pre-trial companion diagnostic test is given to the patients prior to the patient receiving therapy in order to predict a benefit of the first cancer therapy.
However, Zhang teaches that “The clinical application of a targeted therapy requires the identification of biomarkers that can be used to identify patients who are likely to be sensitive to the targeted therapy” (p. 10). It is disclosed that patients are stratified based on biomarkers prior to initiating therapy to identify patients likely to respond to a targeted drug (p. 10). Zhang provides the example of the BATTLE clinical trial and states (p. 11):
“The BATTLE trial enrolled patients with stage IV recurrent non-small cell lung cancer. The primary endpoint was the eight-week disease control rate, which was recorded as a binary outcome. The four biomarker profiles used in the trial were EGFR mutation/amplification, KRAS and BRAF mutation, VEGF and VEGFR expressions, and Cyclin D1/RXR expressions. Four targeted therapies, erlotinib, vandetanib, erlotinib plus
bexarotene, and sorafenib, were evaluated, with one therapy targeting each one of the four biomarker profiles. The goals of the trial were to test the treatment efficacy and biomarker effect, and to evaluate their predictive roles in providing better treatment to patients in the trial based on their biomarker profiles.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the clinical trial with a first group of patients and a control group of patients that had the same result on a pre-trial companion diagnostic test prior to receiving the therapy so that the first group receiving a targeted therapy and the control group were well matched, thereby ensuring the accuracy of a trial comparing the efficacy of a new target cancer therapy regimen with a standard of care cancer therapy regimen.
Regarding claim 42, as discussed above, Kurzrock teaches that the ctDNA biomarker contains a mutation associated with cancer and thereby the DNA marker comprises DNA sequence information (e.g., para [0016], [0019], [0022] and [0031-0032]).9. Claim(s) 18, 19 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kurzrock, R. (U.S. 20170251973) in view of Melnikova et al (U.S. 20180087114), and Zhang et al (Chin Clin Oncol. 2014. 5(4), p. 1-20) and further in view of Zimmermann et al (U.S. 20190316184).
The teachings of Kurzrock, Melnikova and Zhang are presented above.
Regarding claim 18, the combined references do not teach that the DNA marker is evaluated for its methylation status.
However, Zimmermann teaches methods for monitoring response of cancer patients to therapy and/or selecting a particular therapy or treatment regimen that is likely to be effective in the subject by assaying for the methylation status of particular DNAs in a sample from a patient (e.g., para [0311]). Zimmermann (para [0745]) teaches:
“In some embodiments, the fraction of tumor DNA out of total DNA (such as fraction of tumor cfDNA out of total cfDNA or fraction of tumor cfDNA with a particular mutation out of total cfDNA) is determined. In some embodiments, the fraction of tumor DNA may be determined for a plurality of mutations, where the mutations can be single nucleotide variants, copy number variants, differential methylation, or combinations thereof.”
Zimmermann (para [0838]) also teaches that “plasma ctDNA levels have been shown to correlate with changes in tumor burden, thereby providing an earlier measure of treatment response, and to discriminate patients with and without eventual clinical recurrence post-surgery.”
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 Kurzrock so as to have determined the efficacy of the first cancer therapy regimen in the patients by detecting ctDNA methylation status, in addition to or in place of measuring the ctDNA mutation biomarkers. One would have been motivated to have done so because Zimmermann teaches that ctDNA methylation status can also be used to determine tumor burden, particularly following cancer therapy. Thereby, such a modification of the method of Kurzrock would have provided an additional and effective means for identifying those patients in which the first cancer therapy regimen was efficacious and those patients in which the first cancer therapy regimen was not efficacious.
Regarding claims 19 and 21, Kurzrock does not teach that the DNA marker comprises size distribution of the DNA marker (claim 19) or that the DNA marker does not comprise DNA sequence information (claim 21).
However, Zimmermann teaches that cell-free DNA (cfDNA) is fragmented and that the size distribution of the fragments varies from 150-350 bp to >10000 bp. Circulating tumor DNA (ctDNA) in plasma is shorter in size, with ctDNA from hepatocellular carcinoma patients having a size range of 100-220 bp in length, and “the highest tumor DNA concentration in fragments of 150-180 bp in length (para [0226]). Zimmermann (para [0735]) states that “(i)n some embodiments, there is a change to the integrity of RNA or DNA (such as a change in the size of fragmented cfRNA or cfDNA or a change in nucleosome composition) that is associated with a disease or disorder such as cancer, or an increased risk for a disease or disorder such as cancer.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention so as to have additionally used the biomarker of size distribution of the cell-free DNA to determine changes in the quantity of ctDNA in plasma or urine samples of the patients in order to have provided an additional measure of the quantity of ctDNA in the samples as indicative of the efficacy or lack of efficacy of the first cancer therapy regimen.10. Claim(s) 19 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kurzrock, R. (U.S. 20170251973) in view of Melnikova et al (U.S. 20180087114), and Zhang et al (Chin Clin Oncol. 2014. 5(4), p. 1-20) and further in view of Lapin et al (J Transl Med. 2018. 16: 300, p. 1-10).
The teachings of Kurzrock, Melnikova and Zhang are presented above.
Regarding claims 19 and 21, Kurzrock does not teach that the DNA marker comprises size distribution of the DNA marker (claim 19) or that the DNA marker does not comprise DNA sequence information (claim 21).
However, Lapin teaches that the size of cfDNA that originates from tumor cells is shorter than cfDNA fragments that originate from normal, non-malignant cells (e.g., abstract and p. 1 final para to p. 2 first para). Figure 1 of Lapin shows the differences in size distribution of cfDNA and cfDNA level in plasma from healthy controls (a) and from a patient with pancreatic cancer (b). Lapin measured cfDNA levels in blood samples from patients following chemotherapy. Lapin (see abstract) concludes that:
“This study demonstrates that cfDNA fragment size and cfDNA levels can be used to predict disease outcome in patients with advanced pancreatic cancer. The described approach, using a rapid, economic and simple test to reveal prognostic information, has potential for future treatment stratification and monitoring.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention so as to have additionally used the biomarker of size distribution of the cell-free DNA to determine changes in the quantity of ctDNA in plasma samples of the patients in order to have provided an additional measure of the quantity of ctDNA in the samples as indicative of the efficacy or lack of efficacy of the first cancer therapy regimen. One would have been motivated to have done so because Lapin teaches that the size distribution of cfDNA fragments provides a rapid, economic and simple assay for monitoring a patient’s response to cancer therapy.
11. Claim(s) 18, 21, 22, 23, 25, 26 and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kurzrock, R. (U.S. 20170251973) in view of Melnikova et al (U.S. 20180087114), and Zhang et al (Chin Clin Oncol. 2014. 5(4), p. 1-20) and further in view of Sina (Nature Communications. 2018. 9: 4915, p. 1-13; cited in the IDS).
The teachings of Kurzrock, Melnikova, and Zhang are presented above. The combined references do not teach that the DNA marker is methylation status and that the methylation status is measured using a gold electrode and the DNA marker is measured by electrochemistry, particularly comprising differential voltammetry.
However, Sina (p. 1) teaches that there are “fundamental differences in DNA solvation and DNA-gold affinity between cancerous and normal genomes” due to differences in methylation between cancerous and normal genomes. Sina (P. 2, col. 1) teaches:
“Epigenetic reprogramming in cancer represents a unique methylation landscape involving the net loss of global DNA methylation together with a concomitant increase in the levels of methylcytosines at regions often involved in regulatory roles (e.g., promoter regions), wherein CpG sites are abundant and clustered within a short span3. Given
the versatile nature of cancer leaving different biomarkers for different cancer types, epigenetically reprogrammed methylation landscape (i.e., Methylscape) is found to be a common feature exhibited by most cancer types and therefore can serve as a
universal cancer biomarker. “
It is further disclosed that the Methylscape can be used for cancer diagnosis and prognosis as well as to determine responses to therapy (p. 2, col. 1).
Sina discloses methods to detect the Methylscape biomarker using a solid gold electrode and differential voltammetry (p. 11, col. 2).
Sina (p. 4, col. 1) states:
“The electrochemical assay involved the direct adsorption of 5 µL of purified DNA (10 ng/µL concentration in SSC5X buffer at neutral pH) onto gold electrodes for 10
min. Subsequently, the adsorption competence was measured by Differential Pulse Voltammetry (DPV) in presence of the [Fe (CN)6]3-/4- redox system (Fig. 2a, see methods section for details). Upon adsorption of DNA on gold electrodes, [Fe(CN)6]3-/4-redox system generates a Faradaic current signal, which is proportionally lower than the bare electrode signals25–27 (i.e., the greater the DNA adsorption is, the larger the relative current signal difference, %ir, with respect to the original baseline.”
Sina exemplifies methods wherein cfDNA from colorectal cancer patients has a higher gold adsorption as compared to normal cfDNA plasma samples (p. 6, col. 2 and p. 8, col. 2).
Sina further teaches that the methylation biomarker assay disclosed therein provides the benefit that it “can effectively identify the Methylscape biomarker from cancer genomes without extensive sample preparation (e.g., bisulphite or enzyme treatment and PCR amplification) and sensor surface modification― a laborious process for most bio-sensing techniques” (p. 10, col. 1). The assay is also non-invasive since it uses plasma as a source of the cfDNA and provides “excellent specificity” (p. 11, col. 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 Kurzrock so as to have assayed for the DNA marker of methylation status of the DNA marker, and particularly the Methylscape using the assay of Sina which uses a gold electrode and differential voltammetry. One would have been motivated to have done so because Sina teaches that the Methylscape biomarker provides an effective means for detecting cancer and for can be used to determine response to cancer therapy and the Methylscape assay provides the advantages that it can be performed without extensive sample preparation or laborious sensor surface modification and provides excellent specificity.
Regarding claim 21, the Methylscape biomarker is considered to not require sequence information because the global methylation status can be determined without detecting methylation at specific nucleotides of known identity.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682