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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/31/2026 has been entered.
Claims 1-3, 10-12, 15, 20, and 23-25 are now pending. Claims 1, 2, and 12 are amended. Claims 1-3, 10-12, 15, 20, and 23-25 are currently being examined.
Maintained Rejections
(Amendments addressed)
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 1-3, 10-12, 15, 20, and 23-25 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/ a natural phenomenon) without significantly more. The claim(s) recite(s) determining size and numbers of CAMLs in a blood sample and determining the progression of cancer. Thus, the claims are directed to the judicial exception of naturally occurring sizes and numbers of CAMLs as correlated to cancer progression. This judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures to detect and observe naturally occurring the size and numbers of CAMLs. The amended step of “wherein CAMLs are isolated from the biological sample using a microfilter having a pore size ranging from about 5 microns to about 20 microns, wherein the pores of the microfilter have a round, race-track shape, oval, square, and/or rectangular pore shape” fails to add significantly more to the judicial exception and fails to practically apply the judicial exception.
The steps of determining the size and numbers of CAMLs in a blood sample to determine the progression of cancer and isolating them based on size, are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception. For example, Adams et al (2014) (Circulating giant macrophages as a potential biomarker of solid tumors, Proceedings of the National Academy Sciences of the United States of America, Vol 9, 03/4/2014), Adams et al (Circulating Cancer-Associated Macrophages-Like Cells Differentiate Malignant Breast Cancer and Benign Breast Conditions, Cancer Epidemiol Biomarkers Prev. Vol 8, 07/2016), Tang et al (WO2016033103A1, Published: 03/03/2016), Adams (US20200003781A1, Priority Date: 02/16/2017), Zhu et al (2016) (Detection of tumor-associated cells in cryopreserved peripheral blood mononuclear cell samples for retrospective analysis, Journal of Translational Medicine, vol. 14, 07/2016), and Mu et al (2016) (Detection and Characterization of Circulating Tumor Associated Cells in Metastatic Breast Cancer, International Journal of Molecular Sciences, Vol.17, 2016) review known, established, and routine laboratory methods for detecting the number and size of CAMLs. Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
The step of “making a treatment decision based on predictions” is considered an abstract idea or mental decision. This decision can have two outcomes: (1) a decision to administer treatment or (2) a decision not to administer treatment. In outcome (2), there is no administration of treatment and no practical application of the judicial exception, and no steps recited that amount to significantly more than the judicial exception and abstract idea. In outcome (1), the claim recites administering a generic treatment or cancer treatment and fails to affect a particular therapy that provides a practical application of the judicial exception and amounts to significantly more. The recitation of “administering a treatment to the subject” is a generic instruction to apply the judicial exception. Generic treatment steps are no more than appending conventional steps specified at a high level of generality, are a generic direction to “apply it,” and fail to supply inventive concept to the judicial exception. The step of “administering a treatment to the subject” does not apply or use the judicial exception to affect a particular treatment for the subject (see MPEP 2106.04(d)(2)). The amended treatment step fails to amount to an element significantly more than the judicial exception.
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
Response to Arguments
Applicant amended claims 1 and 2 (the independent claims) to recite the use of blood as the biological sample. Applicant argues that the noted limitation of the independent claims should establish that the claims do not foreclose others from using the law of nature/natural phenomenon as defined the Examiner. Applicant argues that the invention being recited in the amended claim set now encompasses an additional element that uses the natural principle.
Applicant arguments have been considered but are not persuasive. Contrary to arguments, the claims are still directed to a judicial exception that is a correlation of naturally occurring sizes and numbers of CAMLs to cancer progression, without significantly more and without a practical application of the judicial exception and abstract idea, regardless of the source of the biological sample.
Maintained Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-3, 10-12, 15, 20, and 23-25 remain rejected under 35 U.S.C. 103 as being unpatentable over Tang et al (WO2016033103 A1, Published: 03/03/2016; of record), in view of Adams et al (Circulating Cancer-Associated Macrophages-Like Cells Differentiate Malignant Breast Cancer and Benign Breast Conditions, Cancer Epidemiol Biomarkers Prev. Vol 8, 07/2016; of record), and Adams et al (2014) (Circulating giant macrophages as a potential biomarker of solid tumors, Proceedings of the National Academy Sciences of the United States of America, Vol 9, 03/4/2014; of record).
Claim interpretation: Claims 1 recite that when a CAML size is less than about 50µm, the cancer is predicted to not progress or progress slowly, and when a CAML size is about 50µm or more, the cancer is predicted to progress or progress faster. It is note that the predicted outcomes of progression are reasonably interpreted to be overlapping in scope for each treatment decision, where cancer predicted to “progress slowly” is encompassed by cancer predicted to “progress”, given slow progression is a form of progression. Similarly with claim 2, the predicted outcomes of progression are overlapping for either result.
Tang teaches a method for detecting CAMLs in a blood sample from humans as a biological marker to provide diagnosis, early detection, cancer relapse or recurrence in the determination, and can also be used to determine effectiveness of chemotherapy and radiation therapy and treatment response. [0006, 0024, 00120] Tang also teaches monitoring efficacy of cancer treatment, comprising assaying the characteristics of CAMLs in a blood sample, including number and size of CAMLs, and assaying values at different timepoints during treatment (before, during or after completion), wherein a change in one or more assay values indicates efficacy of the cancer treatment in a subject. [0014, 00132-00136]. Humans inherently express at least one HLA allele. Tang teaches that based on the outcome of detecting CAMLs in a blood sample, a treatment decision is made, wherein the decision is to administer a cancer treatment to the subject. [0010] Tang teaches that the more aggressive the cancer is, the number of CAMLs increase. (Figure 33B) Tang also teaches a method for determining the size of CAMLS to determine cancer progression and that the cells can be used to determine the effectiveness of cancer therapy. [0006-0020]
Tang also teaches the characteristics of CAMLs, average size 20-300 µm, atypical nucleus having 14-64 µm in diameter, morphological shape (spindle, tadpole, round, oblong, two legs, more than two legs, thing legs, or amorphous, CD14 positive, CD45 expression, EpCAM expression, vimentin expression, PD-L1 expression, CD11 marker, CD146 marker, CD202b marker expression, CD31 marker expression. ([0015] [0086-0093] Figures 10-12)
Tang further teaches the methods for isolating CAMLs by size exclusion methodology, comprising using a microfilter, wherein the microfilter has a pore size ranging from about 5 microns to 20 microns, wherein the pores of the microfilter have a round, race-track shape, oval, square and/or rectangle pore shape. Tang further teaches that the microfilter has precision pore geometry and uniform pore distribution [0017, 0078, 00114] Tang also teaches that CAMLs are isolated via microfluidic chip based on physical size-based sorting, hydrodynamic size-based sorting, grouping, trapping, immunocapture, concentrating large cells, or eliminating small cells based on size, or the cells are isolated via low-pressure microfiltration assay. [0027]
Tang teaches that the biological sample obtained from the subject consists of peripheral blood, blood, lymph node, bone marrow, cerebral spinal fluid, and urine, and that the when it’s obtained from blood, the blood may be obtained from antecubital-vein blood, inferior-vena-cava blood, or jugular-vein blood. [0024] Tang teaches that the biological sample is between 5-15 mL. [00150] Tang teaches that the cancer is a solid tumor, and may be Stage -IIV, carcinoma, sarcoma, neuroblastoma, melanoma, epithelial cell cancer, or breast cancer. [0025] Tang further teaches that the subject is undergoing treatment, such as chemotherapy, radiation therapy, immunotherapy, vaccine therapy, targeted therapy, or a combination. [0026]
However, Tang does not explicitly teach that the treatment decision made is based on predictions of cancer progression determined by 50µm CAML size cutoff, changes in average CAML size between baseline and treatment samples, or by changes in CAML numbers between baseline and treatment samples.
Adams (2016) teaches a method for predicting cancer progression in a subject having cancer, comprising determining the size of circulating cancer associated macrophage-like cells (CAMLs) in a biological sample obtained from the subject, and making a prediction. Adams teaches that cancer associated cells are typically larger cells compared to the vast majority of the mononuclear cells found in circulation. Adams teaches the subject is undergoing treatment, such as chemotherapy. Adam teaches that the biological sample obtained from the subject is between 5 and 15 ml, and the source is blood, peripheral blood, tissue. Adams teaches that the cancer is a solid tumor, such as breast cancer. Adam teaches that the CAMLs have the following characteristics: a) multiple individual nuclei, b) cell size of about 20-300 µm, c) morphological shape such as spindle, round, oblong, amorphous, d) CD14+ phenotype and e) CD45 expression. Adams further teaches that the CAMLs are isolated from the biological sample using size exclusion methodology. (Introduction, Materials and Methods, Figure 2)
Adams (2014) teaches a method for predicting cancer progression in a subject having cancer, comprising determining the size of circulating cancer associated macrophage-like cells (CAMLs) in a biological sample obtained from the subject, and making a prediction. Adams teaches that this data can allow for future approach and will be useful in the selection and monitoring of standard systemic therapies or combined with more innovative immunotherapies. Adams teaches the subject is undergoing treatment, such as chemotherapy. Adam teaches that the biological sample obtained from the subject is between 5 and 15 ml, and the source is blood, peripheral blood, tissue. Adams teaches that the cancer is a solid tumor, such as breast cancer, prostate cancer, or pancreatic cancer. Adam teaches a method for predicting cancer progression by determining the size of CAMLs in a first and second biological sample, wherein the first sample is obtained prior to or during cancer treatment, and wherein the second sample is obtained after cancer treatment. Adam further teaches a method for predicting cancer progression comprising determining the number of CAMLs in a first and second biological sample, wherein the first sample is obtained from the subject prior to or during the cancer treatment and wherein the second sample are obtained from the subject after at least one cancer treatment. (Introduction, Results: CAMLs Are Found in a Broad Patient Population, and Chemotherapy Affects CAML Numbers; Materials and Methods: Testing Temporal Changes of CAMLs in Patient Blood & Testing Temporal Changes in CAMLs in Patient Blood Before and After Cancer Resection; Figures 2B, S5A)
Adams further teaches that the average size of the CAML in the first sample is about 50 µm or more. Adam teaches that the CAMLs have the following characteristics: a) multiple individual nuclei, and/or one or more fused nuclei having a size of about 14-64 µm, b) cell size of about 20-300 µm, c) morphological shape such as spindle, tadpole, round, oblong, two legs, more than two legs, thin legs, and amorphous, d) CD14+ phenotype, e) CD45 expression, f) EpCAM expression, and g) monocytic CD11C marker expression. (Materials and Methods; Results: Defining CAMLs) Adams further teaches that the CAMLs are isolated from the biological sample using size exclusion methodology. Adams further teaches that CAMLs were found in 38 of 41 patients with invasive breast cancer but none in healthy controls. (Figure 3)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to make a treatment decision based on a prediction of cancer progression according after determining the size of CAMLs greater or less than 50µm, and determining changes in the number of CAMLs between baseline and treatment samples. One would have been motivated to, because: (1) Tang teaches baseline characteristics of CAML, including the number and sizes, and teaches making a prediction of cancer progression based on changes of baseline characteristics of CAMLs, and (2) Adams (2016) and Adams (2014) both teach baseline characteristics of CAMLs and teaches a method of predicting cancer progression by a change in the size of the CAMLs, and further teaches that cancer associated cells are larger cells. One of ordinary skill in the art would have a reasonable expectation of success, because: (1) Tang teaches based on the changes of CAMLs, such as increase in number of CAMLs or increase in size, a treatment decision is made, wherein the decision is to administer cancer therapy, (2) Adams demonstrates that the CAML size before cancer therapy is 50µm or more, and (3) Tang and Adams (2014) both teach measuring CAML size and/or number before and after cancer treatment to determine cancer progression. Given the known method of monitoring baseline CAMLs size and numbers and determining cancer progression and given the known method of administering cancer treatment based on these changes, and given the need to treat patients with cancer, one of skill in the art could have pursued making a treatment decision based on a prediction of cancer progression according after determining the size of CAMLs greater or less than 50µm, and determining changes in the number of CAMLs between baseline and treatment samples, with a reasonable expectation of success.
Response to Arguments
Applicant argues that the combination of the cited art fails to teach or suggest that the average size of CAMLs has any relevance to a method of predicting cancer progression. Applicant argues that the combined teachings of the cited art fails to recognize the criticality of 50 μm and thus fails to teach or suggest a predictive method based on this value.
Applicant’s arguments have been considered but are not persuasive for the following reasons: To re-iterate teachings of the prior art:
The primary reference used in the 103 rejection above is Tang and Tang teaches that the average size of CAMLS are 30-300 μm which includes 50 μm; see at least paragraphs 0015 and 0088. Adams 2014 does not teach that the average value is 43.5 μm, rather the median values for CAMLS were 43.5 μm [Figure 1] Adams 2014 teaches that the average diameter of a CAML is 51.3 μm. See p. 3518-Interacting CAMLS and CTS. Regardless, the instant claims recite “wherein when at least one CAML in the sample is about 50 μm or more in size”. The median value (or the “middle” number) of Adams 2014 was 43.5 μm, which is in line with the instant claims which states at least one CAML is greater than 50 μm in Figure 1 (see image below). Further, Tang also teaches that CAMLs in later stages have more CAMLs with larger sizes. [00101] Thus, with these teachings of Adams and Tang, one of ordinary skill in the art to look for CAMLs in larger sizes as indicators of cancer progression. Tang and Adams (2014) also both teach measuring CAML size and/or number before and after cancer treatment to determine cancer progression. Thus, the combination of the cited art renders obvious that the average size of CAMLs has direct relevance to predicting cancer progression.
PNG
media_image1.png
287
587
media_image1.png
Greyscale
PNG
media_image2.png
482
582
media_image2.png
Greyscale
Maintained Rejection
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-3, 10-12, 15, 20, and 23-25 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-3, 7-9,11, 12, 16, 17, and 19 of copending Application No. 16/486,303 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending application claims a method for predicting overall survival and progression free survival of a subject having cancer, comprising determining the size of circulating cells in the subject, and predicting that the overall survival and progression free survival of subjects with larger sized cells (>50 µm) will be less than subjects having smaller-sized cells (<50 µm).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant stated that the rejection has been considered and appropriate action will be taken once allowance has been achieved in one of the two applications.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 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, Gregory Emch can be reached at (571) 272-8149. 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.
/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600
Prosecution Insights