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 .
Claims Status
The amendments and remarks filed 01/08/2026 are acknowledged.
Claims 1-4, 7-13, and 16-19 are pending.
Claims 1, 4, 10, and 13 are amended.
Claims 5-6 and 14-15 are cancelled.
Applicant’s election without traverse of the following species in the reply filed 01/08/2026 is acknowledged: ADAM10, CD59, and TSPAN9 for the target proteins, plasma for the biological sample, and chemotherapy for the anti-cancer treatment.
Claims 1-4, 7-13, and 16-19 are under examination.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Taiwan on 11/15/2022. It is noted, however, that applicant has not filed a certified copy of the TW111143627 application as required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/20/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites
an acronym (i.e. ADAM10, CD59, and TSPAN9). The first time an acronym is used, it must be accompanied by the definition of the abbreviation. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: Claim 10 recites “(d) administering to the subject having CRC with an anti-cancer treatment.” To reflect more conventional claim language, the Examiner recommends amending the claim to recite “(d) administering to the subject having CRC with a therapeutically effective amount of an anti-cancer treatment.” Appropriate correction is required.
Claim 18 is objected to because of the following informalities: Claim 18 recites “a thermotherapy therapy”. The additional “therapy” is redundant and the Examiner recommends amending the claim to recite “a thermotherapy.” Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 7-13, and 16-19 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the claimed inventions are directed to at least one judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claims 1-4, 7-13, and 16-19 are determined to be directed to subject matter that is a natural phenomenon and an abstract idea. The rationale for this determination is explained below.
Step 1: It must first be determined if the claim is to a statutory category, and, if so proceed to step 2A prong 1. Independent claim 1 is directed to a method of determining whether a subject has or is at risk of developing colorectal cancer (CRC) and independent claim 10 is directed to a method for diagnosing and treating CRC in a subject, and therefore, these claims fall within the statutory category of a method.
Step 2A, prong 1: Prong 1 requires the Examiner to evaluate whether the claim
recites a judicial exception and, if so, proceed to prong 2. In this case, claims 1 and 10 are drawn to the judicial exception “(c) determining whether the subject has CRC based on the calculated risk score of step (b), wherein the subject does not have CRC if the calculated risk score of step (b) is lower than a predetermined risk score, and the subject has CRC if the calculated risk score of step (b) is the same or above the predetermined risk score.” Step (a-6) recites “dividing”, step (a-7) recites “determining the concentration”, and step (b) recites “calculating a risk score”, and thus, the steps describe a natural phenomenon, i.e. the relationship between markers and the risk of disease, and comprise concept(s) relating to data comparisons that can be performed mentally or are analogous to human mental work, being an abstract idea or an idea “of itself” as per MPEP 2106.04(a)(2)(III)(A). The remaining claims all depend from claims 1 and 10, respectively, and so, recite the same judicial exception.
Step 2A, prong 2: Prong 2 requires the Examiner to evaluate whether the claim
recites additional elements that integrate the exception into a practical application of
that exception and, if not, proceed to step 2B. In order to integrate the recited judicial
exception into a practical application, the claim will apply, rely on, or use the judicial
exception that imposes a meaningful limit such that the claim is more than a drafting
effort to monopolize the judicial exception. Examiners evaluate integration by identifying
additional elements in the claim beyond the judicial exception and evaluating those
elements individually and in combination to determine whether they integrate the
exception into a practical application. Examples that have been found by the Courts in which the exception was not integrated into a practical application include:
Mere instructions to implement an abstract idea on a computer
Adding generic instructions that the judicial exception should be used (“apply
it”)
Adding insignificant extrasolution activity to the exception (“mere data
gathering”)
Generally linking the use of the exception to a particular technological
environment or field of use
The remaining elements of claims 1 and 10 are:
(a-1) selecting three surrogate peptides corresponding to the three target proteins, wherein the surrogate peptides are ADAM10 surrogate peptide, CD59 surrogate peptide, and TSPAN9 surrogate peptide, wherein the ADAM10 surrogate peptide comprises the amino acid sequence of SEQ ID NO: 1; the CD59 surrogate peptide comprises the amino acid sequence of SEQ ID NO: 6; and the TSPAN9 surrogate peptide comprises the amino acid sequence of SEQ ID NO: 12;
(a-2) labeling the three surrogate peptides of step (a-1) by isotopes;
(a-3) digesting the ex vivo biological sample by means of a proteolytic process to produce a digest wherein the digest comprises target peptides respectively corresponding to the three target proteins;
(a-4) adding a predetermined concentration of the isotope-labeled surrogate peptides of step (a-2) to the digest of step (a-3);
(a-5) determining the amounts of the target peptides and the isotope labeled
surrogate peptides in the mixture of step (a-4) by mass spectrometry;
and in claim 10:
(a-7) (d) administering to the subject having CRC with an anti-cancer treatment
In this case, the remaining elements of steps (a-1) to (a-5) are directed to a method of measuring (i.e. “selecting”, “adding”, “determining”, “dividing”) the natural phenomenon, and step (a-7)(d) of claim 10 is directed to instructions of “apply it” in administering an anti-cancer treatment. The claimed elements directed to a method of measuring are necessary steps in order to observe the natural phenomenon (i.e. mere data gathering steps) and therefore, do not integrate the judicial exception. The claimed elements of “apply it” are instructions on how the judicial exception should be used. The anti-cancer treatment is not specific to the target proteins or CRC. Therefore, this does not integrate the judicial exception because it is a generic treatment for cancer (i.e. any anti-cancer treatment). The “apply it” is more akin to general instructions to treat someone with cancer, rather than an integration of the judicial exception. Thus, for the purpose of Step 2A, prong 2, these elements do not integrate the judicial exception.
Claims 2-3 and 11-12 are concept(s) relating to data comparisons that can be performed mentally or are analogous to human mental work, being an abstract idea or an idea “of itself”, which as discussed herein and previously, are both necessary to utilize the judicial exception as well as insignificant extrasolution activity.
Claims 4, 7-8, 13, and 16-17 only further describe the judicial exception, they cannot add additional elements to the judicial exception, and thus are ineligible for the same reasons.
Claims 9 and 19 describe the subject (i.e. where the phenomenon is observed) and therefore, are directed to the judicial exception itself, and thus, are ineligible for the same reasons.
Claim 18 is directed to instructions of “apply it” and how the judicial exception should be used. The chemotherapy is not specific to the target proteins or CRC. Therefore, this does not integrate the judicial exception because it is a generic anti-cancer treatment (i.e. any chemotherapy, as Applicant elected in the election of species requirement).
Step 2B: Where a claim does not integrate the exception, a claim may
nevertheless be patent eligible, for example where additional elements are “significantly
more” than the exception such that the additional elements were unconventional in
combination. Considerations include whether or not the claim adds a specific limitation
or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; or simply appends well-understood, routine, conventional activities previously known to the
industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may be present. In this case, the discovery is in the correlation between the target proteins (ADAM10, CD59, and TSPAN9) and CRC. The limitations of (a-1) to (a-5) are directed to routine, conventional, and well-understood activities known in the industry at the time of the invention, specified as a high level of generality, and step (a-7) in claim 10 only adds generic instructions that the judicial exception should be used or “apply it”, and therefore, these steps are not enough to qualify as “significantly more” when recited with the judicial exception in the claims. This is equally true when considering the steps individually and as an order combination. Regarding claims 1 and 10, obtaining a sample and measuring proteins in the sample is conventional wisdom in the art. The claims are drawn to the necessary data gathering steps. In support of the routine of steps (a-1) to (a-5), this method was described in the art at least as far back as 2005 as an absolute quantification (AQUA) method. Kirkpatrick et al., 2005 (instant PTO-892) teaches each of the steps of (a-1) to (a-5) [see Methods, pages 267-272; Figure 1, page 268]. This method has also been commercialized as a kit or service, for example, in Thermo Scientific, 2014 (instant PTO-892).
Further, regarding claims 10 and 18, anti-cancer treatment is conventional wisdom in the art. The claims are drawn to the application (“apply it”) of treating a subject that has CRC with an anti-cancer treatment, specifically a chemotherapy (as elected and set forth in instant claim 18). It is well known and routine to administer a chemotherapy to subjects with CRC in order to treat the CRC.
See for example:
Gill et al., 2003 (instant PTO-892)
Lawes et al., 2005 (instant PTO-892)
McQuade et al., 2017 (instant PTO-892)
This list is not exhaustive, but illustrates that at the time of or before the instant invention, administering chemotherapies (i.e. anti-cancer treatment) to a subject with colorectal cancer in order to treat the colorectal cancer was already publicly known.
Gill teaches that 5-fluorouracil (5-FU) remains the most widely used chemotherapeutic agent for the treatment of colorectal cancer [page 683, right column, second paragraph] and that newer agents, including capecitabine, irinotecan, and oxaliplatin have significantly expanded the options for management of patients with advanced colorectal cancer [see Abstract], supporting that the claimed method of administering a chemotherapy to the subject having CRC at the time of the invention was well-known, routine, and conventional.
Lawes teaches that the combination of irinotecan or oxaliplatin with 5-FU based chemotherapy regimens for advanced CRC demonstrated better response rated compared with 5-FU and folinic acid (FA) and adjuvant chemotherapy in stage III CRC has been established to improved long-term survival [see Abstract], further supporting that the claimed method of administering a chemotherapy to the subject having CRC at the time of the invention was well-known, routine, and conventional.
McQuade teaches that chemotherapeutic intervention coupled with surgery is the backbone of metastatic CRC treatment and the only means of enhanced survival, the combinational of several chemotherapeutic agents have been incorporated into routine clinical practice [for the treatment of CRC], and combination regimens incorporating irinotecan, oxaliplatin, and capecitabine, are now all established options for use as first-line, second-line, and sequential treatment of CRC [see Abstract], further supporting that the claimed method of administering a chemotherapy to the subject having CRC at the time of the invention was well-known, routine, and conventional.
Regarding claims 2-3 and 11-12, the claims further define how the risk scores are calculated, however, since said “calculating” is itself a judicial exception, then further details of it cannot be considered “significantly more”, and are thus, patent ineligible.
Regarding claims 4 and 13, the claims define the predetermined risk score, which is a recitation of the judicial exception, specifically, relating the natural correlation between the target proteins and CRC, which represents a natural phenomenon as per MPEP 2106.04(b)(I), and therefore cannot be seen as adding “significantly more” and are thus, patent ineligible.
Claims 7-8 and 16-17 define the biological sample, however, such samples were routine and conventional samples for quantitative proteomics. Holcar et al., 2020 (instant PTO-892) teaches that plasma EVs can be used for reliable quantification as biomarkers of disease [see Abstract].
Claims 9 and 19 describe the subject (i.e. where the phenomenon is observed) and therefore, are directed to the judicial exception itself, and thus, are ineligible for the same reasons.
The Court in Ameritox v Millennium 88 F.Supp.3d 885 (2015) determined that while the decision in Mayo tied the notion of well-understood and conventional steps to
"activity already engaged in by the scientific community”, the Court when deciding
Myriad v Ambry couched the question as "techniques that a scientist would have
thought” to use. Thus, the relevant question when determining whether or not
a technique was routine and conventional is not necessarily that the steps were strictly practiced in the art prior to the invention as in Mayo, but whether the techniques are
those that would have been thought of by the artisan given the relevant information.
This conclusion is supported not only by the Ameritox case, but also by the decision in
Ariosa v Sequenom, where the sample was clearly unconventional (maternal plasma
had routinely been disregarded as medical waste) but when provided with information
regarding the natural relationship between cffDNA in maternal plasma and a diagnosis,
the remaining portion of the claim was drawn to no more than "known laboratory
techniques". This is also supported by the decision in Myriad v Ambry, where the probes
for BRCA7 were previously unknown, but represented no more than a standard
technique for detection; "any scientist engaged in obtaining the sequence of a gene in a
patient sample would rely on these techniques”.
As a whole, considering every step of the most recent guidelines for a proper
§101 analysis, claims 2-4, 7-9, 11-13, and 16-19 do not provide significantly more than the recitation of the judicial exception and are thus not patent eligible.
The instant claims follow the pattern of Julitis (May 2016 guidance) claim 2,
which is ineligible. This is also similar to the fact pattern of the claims at issue in Mayo,
where a drug was administered, the natural metabolites were measured, and a
conclusion was made about treatment efficacy; this was deemed ineligible by the
Supreme Court.
In Mayo, a level of the metabolite "less than about 230 pmol per 8x 10° red blood
cells [indicated] a need to increase the amount of said drug”. Such claim limitations
were found to be a description of the correlation itself and not “significantly more”. It was
also found that steps prior to this constituted routine data gathering, instructing the artisan to engage in conventional, well-known practices and then "warning" the user of
the implications of the data; this was not eligible in Mayo. Applicant has not invented nor
improved any technology but the claims are directed to the discovery of a natural
phenomenon (the correlation described above) and instructs others to gather the
necessary data using known techniques and then informs others of the implications of
that data.
Claims 2-4, 7-9, 11-13, and 16-19 are directed to the judicial exception itself. Additional elements are deficient because these claims merely describe additional steps to the gathering method or further describe the judicial exception and what it indicates with generic instructions that the judicial exception should be used or “apply it”,
In summary, the above analysis conducted in line with all current guidance
issued by the USPTO sets forth the rationale and evidence for deeming the above
claims patent ineligible. It is appreciated that all inventions at some level embody, use,
reflect, rest upon, or apply a law of nature, natural phenomenon, or abstract idea.
However, the instant claims do not improve another technology, apply the judicial
exception with any specific machine, transform the gathered data into a different state
or thing, include any limitations which use or apply the exception, add a limitation that is
anything more than what is well-understood, conventional, or routine in the field, or any
other meaningful limitation beyond generally linking the use of the exception to a
particular technological environment. In other words, the claims as a whole instruct a
user to observe the target proteins and surrogate peptides of ADAM10, CD59, and TSPAN9 in a particular context using conventional samples and a known methodology to calculate a risk score (i.e. a ratio) because the levels of the target proteins and surrogate peptides inform the relevant audience about a correlation that exists between the gathered data and colorectal cancer. The added steps of measuring (i.e. determining and dividing) and calculating are necessary data gathering steps and administering a chemotherapy (anti-cancer treatment) “based on” the gathered data is no more than instructions to “apply it”.
Therefore, claims 1-4, 7-13, and 16-19 are not patent eligible.
Claim Rejections - 35 USC § 103
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.
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 1-4 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Dash et al., 2022 (02/20/2023 IDS).
Regarding claims 1, 7-8, Dash teaches selecting 13 target proteins and CD9, which comprise ADAM10, CD59, and TSPAN9, and then quantifying the selected targets in plasma derived EVs by synthesizing 14 surrogate peptides representing the selected proteins [page 15, fourth paragraph; Table 1].
The sequences for the surrogate peptides for ADAM10, CD59, and TSPAN9 as set forth in Table 1 of Dash have 100% sequence identity to SEQ ID NOs: 1, 6, and 12 of the instant claim, respectively.
Dash teaches that the surrogate peptides were labeled with stable isotopes (SIS) [page 8, fourth paragraph], EV samples (ex-vivo biological samples) were digested with trypsin (proteolytic digestion) and the 14 SIS (i.e. 13 target proteins plus CD9) peptides were suspended in each EV sample [page 9, second paragraph] and performing MS/MS analysis on each targeted precursor and the generated product ions [page 9, third paragraph], and measuring the concentration of the target peptide in samples by calculating the ratio of the peak area to known concentrations of SIS peptides [page 9, fourth paragraph]. Dash also teaches that quantitative analyses revealed significant increases in ADAM10, CD59, and TSPAN9 levels in plasma EVs from CRC patients compared to healthy controls, indicating high diagnostic ability in early-stage CRC patients [see Abstract; page 17, first-second paragraphs]. Dash further teaches calculating a risk score based on CD59 and TSPAN9 as a cutoff to distinguish between healthy control and CRC patients [page 18, first paragraph].
However, Dash does not specifically teach that the risk score includes ADAM10.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have also included ADAM10 in the calculated risk score to determine if a subject has (i.e. diagnosing a subject with) CRC because Dash teaches that there were significant increases in ADAM10, CD59, and TSPAN9 levels in plasma EVs from CRC patients compared to healthy controls, indicating high diagnostic ability in early-stage CRC patients. There would be a reasonable expectation of success of calculating a risk score based on ADAM10, CD59, and TSPAN9 in order to determine if a subject has (i.e. diagnosing a subject with) CRC because Dash teaches that a risk score can be calculated based on concentrations of target proteins and surrogate peptides in order to distinguish between healthy state and CRC state of a subject.
Claims 2 and 3 are included in this rejection because Dash teaches that the equation for probability in risk evaluation was generated by logistic regression [see Figure 6(C)]. Further, these claims are directed to determining a ratio. Ratios are just a way of presenting data, and therefore, the limitation of this claim does not change the outcome of the independent claim.
Claim 4 is included in this rejection because the claim is directed to determining a specific risk score based on a ratio. Ratios are just a way of presenting data, and therefore, the limitation of this claim does not change the outcome of the independent claim.
Claim 9 is included in this rejection because Dash teaches that peripheral blood samples (ex vivo biological samples) were collected from healthy donors and CRC patients [page 4, second paragraph] and that cells for culture came from human CRC cell lines [page 4, third paragraph]. Thus, the ex vivo biological sample was necessarily from a human subject.
Claims 1-4, 7-13, and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Dash et al., 2022 (02/20/2023 IDS), as applied to claims 1-4 and 7-9 above, and further in view of McQuade et al., 2017 (instant PTO-892).
The teachings of Dash are above.
However, Dash does not specifically teach administering to the subject having (i.e. diagnosed with) CRC with a chemotherapy (anti-cancer treatment) in order to treat the cancer.
Regarding claims 10 and 18, McQuade teaches that chemotherapeutic intervention coupled with surgery is the backbone of metastatic CRC treatment and the only means of enhanced survival, the combinational of several chemotherapeutic agents have been incorporated into routine clinical practice [for the treatment of CRC], and combination regimens incorporating irinotecan, oxaliplatin, and capecitabine, are now all established options for use as first-line, second-line, and sequential treatment of CRC [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered a chemotherapy to treat CRC, as taught by McQuade, to a subject that has (i.e. diagnosed with) CRC of Dash. One would have been motivated to have administered a chemotherapy to treat CRC in a subject that has CRC because McQuade teaches that chemotherapeutic intervention coupled with surgery is the backbone of metastatic CRC treatment and the only means of enhanced survival, the combinational of several chemotherapeutic agents have been incorporated into routine clinical practice, and combination regimens incorporating irinotecan, oxaliplatin, and capecitabine, are now all established options for use as first-line, second-line, and sequential treatment of CRC.
Regarding claims 11 and 12, Dash teaches that the equation for probability in risk evaluation was generated by logistic regression [see Figure 6(C)]. Further, these claims are directed to determining a ratio. Ratios are just a way of presenting data, and therefore, the limitation of this claim does not change the outcome of the independent claim.
Claim 13 is included in this rejection because the claim is directed to determining a specific risk score based on a ratio. Ratios are just a way of presenting data, and therefore, the limitation of this claim does not change the outcome of the independent claim. Further, even if the specific risk score did change the outcome of the independent claim, since it would have been obvious to have calculated a risk score based on the concentrations of the target proteins and surrogate peptides of ADAM10, CD59, and TSPAN9, then one of ordinary skill in the art could have reasonably expected to arrive at the claimed risk score based on the data and a logistic regression calculation, as taught by Dash, since the target proteins and surrogate peptides of Dash are 100% identical to those instantly claimed and the risk score (i.e. ratio) is only a way to present data.
Claims 16 and 17 are included in this rejection because Dash teaches selecting 13 target proteins and CD9, comprising ADAM10, CD59, and TSPAN9, and quantifying the selected targets in plasma derived EVs by synthesizing 14 surrogate peptides representing the selected proteins [page 15, fourth paragraph; Table 1].
Claim 19 is included in this rejection because Dash teaches that peripheral blood samples (ex vivo biological samples) were collected from healthy donors and CRC patients [page 4, second paragraph] and that cells for culture came from human CRC cell lines [page 4, third paragraph]. Thus, the ex vivo biological sample was necessarily from a human subject.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
Prosecution Insights