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 .
Priority
This application is a national stage entry of PCT/US2018/025680 filed on April 20, 2018 which claims priority from U.S. Provisional Application No. 62/479,759, filed on March 31, 2017.
Response to Amendment
Applicant’s amendment filed on July 29, 2025, amending claims 2-4 and cancelling claim 12 has been entered. Claims 1, 5, 10, 13-15 and 18 were previously cancelled. Claims 2-4, 6-9, 11, 16, 17 and 19 are currently pending and presented for examination.
Response to Arguments
Applicant's arguments filed on July 29, 2025 have been fully considered but they are not persuasive.
With respect to the rejection under 35 USC 101, Applicant argues that it can be seen that the independent claims (claims 2-4) are being amended to recite six specific cancers in response to the office Action which states “[t]he combination of steps recited in the claims...are not sufficient to qualify as a patent-eligible practical application as the claim covers every substantial practical application of the correlation.” Applicant argues that the noted limitation of the independent claims should establish that the invention being recited in the amended claim set does not pre-empt the noted correlation from “every substantial practical application of the correlation”. Applicant argues that in conjunction with the previous amendments to the claims and corresponding arguments from the Applicant the claims as amended should now be found to qualify as a patent-eligible practical application of the invention.
These arguments are found not persuasive because amending the claims to recite a method for predicting overall survival (OS) and progression free survival (PFS) for a period of over at least 12 months of a subject having cancer, wherein the cancer is breast cancer, prostate cancer, lung cancer, pancreatic cancer, kidney cancer or esophageal cancer, does not overcome the rejection of record because the claims are still only drawn to the natural correlation between the size of circulating cells in a biological sample which is blood from a cancer patient having certain types of cancer and overall survival and progression free survival for a period of time, and the claims do not require any further steps that integrate the recited judicial exceptions into a practical application of the exception. The newly added limitation merely recites that the cancer is breast cancer, prostate cancer, lung cancer, pancreatic cancer, kidney cancer or esophageal cancer, however the claims remain drawn to a naturally occurring correlation between the size of circulating cells and overall or progression free survival without significantly more. The claims as originally filed already contained the limitation that the cancer is breast cancer, prostate cancer, lung cancer, pancreatic cancer, kidney cancer or esophageal cancer (original claim 12). Thus, the claims are still drawn to a naturally occurring correlation between survival of cancer and the size of circulating cells in blood from a subject having cancer. The combination of steps recited in the claims taken as a whole, including the steps of determining the size of circulating cells in blood from a subject having cancer to predict overall survival (OS) and progression free survival (PFS) of a subject having cancer, are not sufficient to qualify as a patent-eligible practical application because even though Applicant has discovered the correlation between predicting overall survival (OS) and progression free survival (PFS) of a subject having cancer and the size of circulating cells in blood from a subject having cancer, and thus takes a human action to trigger the manifestation of the correlation and the measurement of the circulating cells, the correlation exists in principle apart from any human action. In other words, no human action is required to obtain circulating cells of any particular size or to obtain overall or progression free survival. These aspects are naturally occurring and do not involve human action and thus are not patent eligible subject matter. Thus, the size of circulating cells in blood from a subject having cancer is a natural phenomenon or a naturally occurring correlation.
Therefore, since Applicant’s amendments are not sufficient to overcome the rejection of record, the previous rejection under 35 USC 101 is hereby maintained and reproduced below.
With respect to the rejection under 35 USC 103, Applicant argues that while Adams teaches CAMLs might serve as a “cellular biomarker” of “cancer aggressiveness” (page 3514, right column), the teachings of Adams are insufficient to make obvious the specific methods recited in claims 2-4. Applicant argues that independent claims 2-4 are directed to “method[s] for predicting overall survival (OS) and progression free survival (PFS) of a subject having cancer.” Both OS and PFS are art-recognized terms that have specific meanings. Applicant argues that Adams fails to teach or suggest a method for predicting OS and PFS, let alone even mention the concepts of OS and PFS with respect to CAMLs and as such, the cited art fails to teach or suggest each and every element of the claims. Thus Applicant argues that because the cited art fails to teach or suggest a method for predicting OS or PFS, it cannot be said to make obvious the amended claim set present herein.
These arguments are found not persuasive because a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
In the instant case, Adams et al. specifically teaches that there are highly differentiated giant circulating (macrophage-like) cells isolated from the peripheral blood of patients with breast, prostate, or pancreatic cancer (page 3514). Adams teaches that these cells were isolated using a low-pressure filtration system equipped with precision microfilters, allowing histological identification of cellular morphology (page 3514). Adams teaches that these cells are termed circulating cancer-associated macrophage-like cells (CAML) (page 3514).
Adams specifically states that this cell population is not detected in healthy individuals and thus serves as an immune response to cancer presence and of cancer aggressiveness (page 314). Adams teaches that the CAMLs were identified as a single cell with an enlarged nuclear profile (14-64 m in diameter) (page 3518). Adams further teaches that the average diameter of a CAML is 51.3 m and the average number of CAMLs per sample is 13.3 (page 3518). Thus, Adams specifically teaches determining the size of circulating cells in a biological sample from a subject having cancer wherein the average diameter being 51.3 m which overlaps with the claimed size of 50 m or more. Therefore, Adams teaches identifying enlarged 50 m or more circulating cells in patients with cancer by the same procedure as claimed, wherein the presence of these cells indicates cancer aggressiveness.
Adams further teaches that the circulating cells were determined to be on average 29 per 7.5 ml sample (page 3516). Therefore, Adams specifically teaches identifying 6 or more cells per 7.5 ml of sample, as claimed, wherein the presence of these circulating cells indicates cancer aggressiveness. Adams further teaches analysis of HER-2 by FISH Probe on circulating cells, which will allow visualization of CEP17 dots associated with HER-2 (page 3518). Figure S3 of Adams teaches that these CAMLs which indicate cancer aggressiveness were found to contain 19 CEP17 signals. Therefore, Adams specifically teaches determining the number of CEP17 dots in circulating cells from a biological sample from a subject having cancer wherein the circulating cell has 10 or more CEP17 dots wherein the presence of these circulating cells indicates cancer aggressiveness.
Adams further teaches that the detection of these cells in the peripheral blood of patients with advanced cancer may serve as an independent prognostic indicator of cancer progression (page 3515). Adams further specifically teaches that CAMLs provide a robust indicator of invasive cancer (page 3517).
Thus, one of ordinary skill in the art might reasonably infer from the teachings of Adams, as detailed above that the circulating cancer-associated macrophage-like cells (CAMLs) that are not detected in healthy individuals and serves as an immune response to cancer presence and of cancer aggressiveness, would predict overall survival and progression free survival. Since Adams teaches that the presence of these circulating cells indicates cancer aggressiveness, and provide a robust indicator of invasive cancer, one would expect OS and PFS of a subject with these cells to be lower than a subject not having these circulating cells with the claimed properties, because the cancer would be expected to be more aggressive and invasive and harder to control. Therefore, since aggressive and invasive cancers are usually more difficult to treat, one would expect the presence of these cells to predict OS and PFS as claimed in the instant claims. With respect to the limitation that the OS and/or PFS is over a period of at least 12 months, one would reasonably expect patients lacking these CAMLs to have less aggressive and less invasive cancer that is treatable resulting in a greater OS and PFS for an indefinite period of time. Therefore, in the absence of secondary considerations such as a demonstration of criticality, the time period as claimed, i.e. at least 12 months or at least 24 months is rendered obvious in view of the cited prior art teachings.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Thus, for these reasons and for the reasons of record, the previous rejection under 35 USC 103 is hereby maintained and reproduced below.
This action is final.
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 2-4, 6-9, 11, 16, 17 and 19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a natural phenomenowithout significantly more.
The claims recite a method for predicting overall survival (OS) and progression free survival (PFS) of a subject having cancer, said method comprising determining the size of circulating cells in a blood sample from a subject having cancer, wherein when at least one cell in said sample is about 50 mm or more in size, the OS and PFS of the subject is predicted to be less than a subject having cancer where none of the cells is more than about 50 mm in size, wherein circulating cells are isolated from the blood samples using size exclusion methodology that comprises using a microfilter, wherein the microfilter has a pore size ranging from about 5 microns to about 20 microns, and wherein said OS and/or PFS is over a period of at least 12 months.
This judicial exception is not integrated into a practical application because the claims of the instant application are directed to non-statutory subject matter because it is not a patent-eligible practical application of a law of nature. The claims are directed to a naturally occurring correlation between overall survival and progression free survival of a subject with cancer for over a period of at least 12 months and the size of circulating cells in a blood sample. The combination of steps recited in the claims taken as a whole, including the steps of determining the size of circulating cells in a blood sample from a subject having cancer to predict overall survival (OS) and progression free survival (PFS) of a subject having cancer for over a period of at least 12 months, are not sufficient to qualify as a patent-eligible practical application as the claim covers every substantial practical application of the correlation. Even though Applicant has discovered the correlation between predicting overall survival (OS) and progression free survival (PFS) of a subject having cancer over a period of at least 12 months and the size of circulating cells in a blood sample from a subject having cancer, and thus takes a human action to trigger the manifestation of the correlation, the correlation exists in principle apart from any human action. Thus, the size of circulating cells in a biological sample from a subject having cancer is a natural phenomenon or a naturally occurring correlation.
A natural principle is the handiwork of nature and occurs without the hand of man. For example, the disinfecting property of sunlight is a natural principle. The relationship between blood glucose levels and diabetes is a natural principle. A correlation that occurs naturally when a man-made product, such as a drug, interacts with a naturally occurring substance, such as blood, is also considered a natural principle because, while it takes a human action to trigger a manifestation of the correlation, the correlation exists in principle apart from any human action. These are illustrative examples and are not intended to be limiting or exclusive.
PNG
media_image1.png
18
19
media_image1.png
Greyscale
For this analysis, the claims focus on a natural principle since the natural principle is a limiting element or step. Thus, the claims are not directed to a practical application of the natural principle that amounts to substantially more than the natural principle itself.
Eligibility Step 2B: Whether a claim amounts to significantly more.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not include additional elements/steps or a combination of elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied to ensure that the claims amount to significantly more than the natural principle itself.
A claim that focuses on the use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71-72, 101 USPQ2d 1961, 1966 (2012)). To show integration, the additional elements or steps must relate to the natural principle in a significant way to impose a meaningful limit on the claim scope. The analysis turns on whether the claim has added enough to show a practical application. See id. at 1968. In other words, the claim cannot cover the natural principle itself such that it is effectively standing alone. A bare statement of a naturally occurring correlation, albeit a newly discovered natural correlation or very narrowly confined correlation, is not sufficient. See id. at 1965, 1971.
PNG
media_image1.png
18
19
media_image1.png
Greyscale
A claim with steps that add something of significance to the natural laws themselves would be eligible because it would confine its reach to particular patent-eligible applications of those laws, such as a typical patent on a new drug (including associated method claims) or a new way of using an existing drug. See id. at 1971; see also 35 U.S.C. 100(b). In other words, the claim must be limited so that it does not preempt the natural principle being recited by covering every substantial practical application of that principle. The process must have additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself. See id. at 1968.
In the instant case, the claims are only drawn to the natural correlation between the size of circulating cells in a blood sample from a cancer patient and overall survival and progression free survival over a period of at least 12 months and the claims do not require any further steps that integrate the recited judicial exceptions into a practical application of the exception.
For these reasons, when the claims are considered as a whole, the claims do not recite anything significantly more than a judicial exception and therefore are not directed to patent eligible subject matter.
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 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.
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 2-4, 6-9, 11, 16, 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Adams et al. (PNAS, 2014, vol. 111, no. 9, pages 3514-3519).
Claims 2-4, 6-9, 11, 16, 17 and 19 of the instant application claim a method for predicting overall survival (OS) and progression free survival (PFS) of a subject having cancer, said method comprising determining the size of circulating cells in a blood sample from a subject having cancer, wherein when at least one cell in said sample is about 50 mm or more in size, the OS and PFS of the subject is predicted to be less than a subject having cancer where none of the cells is more than about 50 mm in size, wherein circulating cells are isolated from the blood samples using size exclusion methodology that comprises using a microfilter, wherein the microfilter has a pore size ranging from about 5 microns to about 20 microns, and wherein said OS and/or PFS is over a period of at least 12 months.
Adams et al. teaches that there are highly differentiated giant circulating (macrophage-like) cells isolated from the peripheral blood of patients with breast, prostate, or pancreatic cancer (page 3514). Adams teaches that these cells were isolated using a low-pressure filtration system equipped with precision microfilters, allowing histological identification of cellular morphology (page 3514). Adams teaches that these cells are termed circulating cancer-associated macrophage-like cells (CAML) (page 3514). Adams teaches that this cell population is not detected in healthy individuals and thus serves as an immune response to cancer presence and of cancer aggressiveness (page 314).
Adams teaches that giant fused macrophages are CAMLs of myeloid lineage presenting with enlarged nuclei, are CD45+ and exhibit cytoplasmic staining by cytokeratin 8, 18 and 19 and epithelial cell adhesion molecule (EpCAM) (page 3515). Adams teaches that the CAMLs were identified as a single cell with an enlarged nuclear profile (14-64 m in diameter) (page 3518). Adams reports that the CAMLs have various shapes including amorphous, oblong, spindle-shaped, round, and tadpole shaped (Figure 1 page 3515). Adams further reports that CAMLs are CD14+/CD11c+, have multiple individual nuclei, and fused nucleoli are also common (page 3515).
Adams teaches that the detection of these cells in the peripheral blood of patients with advanced cancer may serve as an independent prognostic indicator of cancer progression (page 3515). Adams teaches that CAMLs provide a robust indicator of invasive cancer (page 3517). Adams teaches that peripheral blood samples from 79 cancer patients were collected and analyzed using the CellSieve low-flow microfiltration procedure to isolate CAMLs (pages 3517-3518). Adams teaches that patients examined were in stages I through IV and unknown stages, having breast, pancreatic and prostate cancer (page 3516).
Adams teaches that CAMLs contain engulfed material from the site of the tumor (page 3516). Adams further teaches that CAMLs interact with CTCs which originate at a tumor cite and circulate in the peripheral blood and have the ability to seed metastatic sites. (page 3516). Adams teaches that patients with metastatic disease have CAMLs bound to CTCs as well as CAMLs engulfed cells that appeared to have an epithelial phenotype (page 3517).
Thus, Adams teaches determining the presence of CAMLs in a biological sample from subjects having cancer.
Adams does not specifically teach predicting survival and progression free survival for over a period of at least 12 months based on the size of the CAMLs.
However, Adams teaches that in patients with metastatic disease and thus having poor prognostic outcomes, the CAMLs interact with CTCs and are engulfed cells that appeared to have an epithelial phenotype. Thus, based on the teachings of Adams, it is apparent that CAMLs in cancer patients with progressive disease are larger due to their attachment to CTCs and engulfed appearance. Thus prior to the effective filing date, it would have been obvious to a person of ordinary skill in the art that patients with larger CAMLs would have a poorer prognosis as compared to patients with smaller CAMLs since patients with metastatic disease and thus have poor prognosis have been found to have large CAMLs. Thus, predicting overall survival and progression free survival based on the size of CAMLs is rendered obvious in view of the teachings of Adams.
Claim 4 is rendered obvious since Adams teaches analysis of HER-2 by FISH Probe which will allow visualization of CEP17 dots associated with HER-2.
With respect to the limitation that the OS and/or PFS is over a period of at least 12 months or 24 months, one would reasonably expect patients lacking these CAMLs to have less aggressive and less invasive cancer that is treatable, resulting in a greater OS and PFS for an indefinite period of time. Therefore, in the absence of secondary considerations such as a demonstration of criticality, the time period as claimed, i.e. at least 12 months or at least 24 months is rendered obvious in view of the cited prior art teachings.
Thus, the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 2-4, 6-9, 11, 16, 17 and 19 are rejected. Claims 1, 5, 10, 12-15 and 18 are canceled. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
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, Adam C. Milligan can be reached on (571)270-7674. 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.
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM