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 .
Claim Status
Applicant’s amendment filed October 25, 2023 has been received and entered.
Claims 1, 4-7, and 9-11 have been amended.
Claims 2 and 8 have been canceled.
Claims 1, 3-7, and 9-11 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/EP2022/060970 filed April 26, 2022, which claims the benefit of foreign application EP 21305541.1 filed April 27, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 25, 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
Claims 1 and 9-11 are objected to because of the following informalities:
Claims 1 and 9-11 recite CD3+ cells and CD8+ cells, however, the claims should read CD3+ T cells and CD8+ T cells.
Claim 1 (line 5) - should read “in the center of the tumor (CT)”.
Claim 11 (lines 5-6) - should read “the density of CD3+ cells in the IM…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 4 and 9-11 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 4 recites the relative term “short time to recurrence” which renders the claim indefinite. The short time to recurrence is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree of short time to recurrence, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The instant specification does not define any length of time associated with recurrence, therefore one cannot ascertain whether time to recurrence is short or long.
Claims 9-11 recite the limitation “The method of claim 8”, however, the claim is incomplete as claim 8 has been canceled.
For the purposes of examination, the claims are interpreted as depending from claim 1 which recites implementing a scoring system.
Claims 9-11 recite the limitation “the tumor tissue sample”, however, the claims depend from claim 1 which only recites a “tumor sample”. Therefore, there is no antecedent basis for “tissue” in the claims.
Claim rejections - 101
35 USC 101 reads:
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.
For each rejection below, dependent claims are rejected similarly as not remedying the rejection, unless otherwise noted.
Judicial Exceptions to 101 Patentability
Claims 1, 3-7, and 9-11 are rejected under 35 USC 101 because the claimed inventions are not directed to patent eligible subject matter.
The claimed invention is directed to a correlation of prognosis of the survival time or responsiveness to an antitumoral treatment (i.e. endoscopic resection) without significantly more. The claim(s) recite(s) a correlation which is deemed a law of nature. Further, the claims recite an abstract idea of “calculating the arithmetic mean value”. This judicial exception is not integrated into a practical application because the claims only recite the natural correlation and steps of quantification and do not integrate the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps are considered general and routine knowledge in the prior art.
The claims are drawn to quantifying CD3+ and CD8+ T cells in T1 colorectal cancer patients, comparing, determining values, calculating and comparing.
Dependent claims set forth further limitations for additional markers and type of patient. These dependent claims do not provide anything more than the judicial exception because the claims merely limit types that are naturally occurring and are in the general population.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (1st & 2nd prongs) and 2B as follows:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter?
YES: The claims are directed to a process.
Step 2A, Prong one: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea?
YES: The claims recite a law of nature and an abstract idea.
The correlation of risk of metastasis and/or recurrence and the density of CD3+ and CD8+ T cells is considered a natural correlation.
The calculation of arithmetic mean value or median value of percentile is considered an abstract idea. This is considered a mental process.
Step 2A, Prong two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
NO: The steps require only routine and conventional steps and does not integrate the judicial exception to a practical application.
Step 2B: Does the claim recite additional elements that are significantly more than the judicial exceptions?
NO: Haasnoot et al. (2020; cited IDS 10/25/2023) teaches a method of predicting lymph node metastasis and/or recurrence in a patient suffering from a T1 gastrointestinal cancer comprising determining the density of CD3+ and CD8+ T cells and comparing with a predetermined reference and comprising arithmetic mean value to determine risk of metastasis and/or recurrence [pg. 2629, col. 2 - 2630, col. 3]. Furthermore, the additional element of “treating” does not add significantly more as radical surgery is routine in the art.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-7, and 9-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haasnoot et al. (Modern Pathol; 33:2626-2636; cited IDS 10/25/2023) (“Haasnoot”).
The instant claims are drawn to a method of predicting the risk of lymph node metastasis and/or recurrence of a patient suffering from a T1 gastrointestinal cancer treated by endoscopic resection and treating the patient comprising, quantifying, in a tumor sample obtained from the patient, a density of CD3+ cells in the center of the tumor (CT), a density of CD8+ cells in the center of the tumor (CT), a density of CD3+ cells in an invasive margin (IM), and a density of CD8+ cells in the invasive margin; implementing a scoring system that inputs quantification values of the density of CD3+ cells in the CT, the density of CD8+ cells in the CT, the density of CD3+ cells in the IM, and the density of CD8+ cells in the IM, and outputs a score, identifying a patient having a low score, compared to a corresponding predetermined reference value, as at risk for lymph node metastasis and/or recurrence; and treating the patient by performing a radical surgery.
Haasnoot discloses methods to evaluate the prognosis of lymph node metastases (LNM) or cancer recurrence in patients with surgically removed T1 advanced colorectal cancer (CRC) using an immunoscore classification system [Abstract]. LNM and/or recurrence were measured in patients treated with an endoscopic resection (n=471) [pg. 2627, col. 2] as both LNM and recurrence are relevant outcomes to identify those patients who will benefit from a surgical resection [pg. 2628, col.1]. The patient immunoscore is determined by measuring the density (number of positive cells/surface area analyzed) of CD3 and CD8 expressing lymphocytes within the tumor center (TC) and the invasive margin (IM) [pg. 2629]. Haasnoot further discloses the therapeutic decision to perform additional oncologic surgery is based on conventional histological markers, but due to low specificity, this leads to unnecessary surgery for patients classified as high-risk but without actual lymph node metastasis (LNM) being present (false positives). The immunoscore classification system has potential to enable organ preservation in some patients [pg. 2627, col. 1] (instant claim 1).
Haasnoot evaluated hematoxylin-eosin (H&E) tumor tissue slides from the patients with T1 colorectal cancer for the conventional histologic risk factors (i.e., differentiation grade, lymphovascular invasion, invasion depth, and tumor budding), wherein deep invasion was defined as invasion depth ≥ 1000 mM. When the muscularis mucosae could not be identified, submucosal depth was measured from the surface of the tumor at the site of invasion [pg. 2628, col. 1] (instant claims 6-7).
The immunoscore was obtained by calculating the mean density per tumor region for each individual patient; CD3 IM, CD TC, CD8 IM, and CD8 TC. These four values are then averaged and used to categorize patients into immunoscore groups [pg. 2630, col. 1]. The formula used to calculate immunoscore in T1 CRCs: (((log(CD3 IM + 6.35) - 6.5185)/0.9117) + ((log(CD3 TC + 19.325) -6.4082)/0.8030) + ((log(CD8 IM + 0.3333) - 4.4885)/1.4498) + ((log(CD8 TC + 0.5) - 4.1358)/1.4636))/4 (instant claim 9). If the result is ≤ 0.64175 the patient is classified as I-Low. If the result is ≥ 0.64175 patient is classified as I-High [Fig. 2, pg 2629] (instant claim 10).
Haasnoot also divided patients into three groups (≤ 25th percentile: Low; 25th-70th percentile: Intermediate; ≥70th percentile: High) (instant claim 11) or the immunoscore was determined to range from I0 when low densities of both cell types were found in both the TC and IM, to I4 when high densities were found in both regions [pg. 2630, col. 1]. The instant specification explains a non-continuous scoring system inputs the cell densities as low, intermediate, or high [pg. 6, lines 25-30].
Lastly Haasnoot evaluated whether immunoscore was associated with adverse outcome of LNM and/or recurrence. A low immunoscore suggests an increased risk for an adverse outcome (LNM or recurrence) and is associated with shorter survival times. Alternative methods for determining the immunoscore did not result in an improved risk stratification, however, immunoscore as a continuous variable did show an increased risk for lower scores [Abstract, pg. 2632, col. 2] (claims 4-5). Therefore, absent a showing of any difference, the methods disclosed by the prior art are deemed to anticipate the claimed methods.
Nonstatutory Double Patenting
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-7, and 9-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-8, 11, 13, and 16 of US Patent No. 8,481,271, in view of Haasnoot et al. (Modern Pathol; 33:2626-2636; cited IDS 10/25/2023) (“Haasnoot”). Although the claims at issue are not identical, they are not patentably distinct from each other because they teach methods for the prognosis of survival time from a patient suffering from colorectal cancer, comprising quantifying CD8 and CD3 cells from both tumor center (CT) and invasive margin (IM) and comparing cell density quantification values with corresponding predetermined cut-off reference values and determining a prognosis for said patient. Further comprising identifying said patient as being at high risk for recurrence of said cancer and likely to benefit from adjuvant therapy when the results are for a poor prognosis.
The issued claims differ from the instant claims in that they do not teach the colorectal cancer is T1 CRC, that the patient has at least one histological criterion, the exact mathematical steps comprising continuous and non-continuous scoring systems as recited in the instant claims, or that those with high scores can be treated with radical surgery.
The teachings of Haasnoot are set forth above. Specifically, Haasnoot teaches methods to evaluate the prognosis of lymph node metastases (LNM) or cancer recurrence in patients with surgically removed T1 advanced colorectal cancer (CRC) using an immunoscore classification system. Haasnoot uses both continuous and non-continuous scoring systems to predict risk of LNM and/or recurrence. Those at high risk are candidates for surgical resection.
Given that Haasnoot teaches methods to evaluate the risk of lymph node metastases (LNM) or cancer recurrence in patients with surgically removed T1 advanced colorectal cancer (CRC), it would have been obvious to one of ordinary skill in the art to modify the issued claims to include immunoscore system as taught by Haasnoot. One would have a reasonable expectation in success in combining the protocols because Haasnoot found that the system predicted LNM and recurrence in T1 CRC patients, which provides an improved method to assess risk and prevent unnecessary surgery in patients. As such, the instant claims are an obvious modification of the issued claims in view of Haasnoot.
Claims 1, 3-7, and 9-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-10, and 15-18 of copending Application No. 18/003,999, in view of Haasnoot et al. (Modern Pathol; 33:2626-2636; cited IDS 10/25/2023) (“Haasnoot”). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims read on predicting recurrence of a colorectal cancer comprising quantifying the density of immune markers, a non-continuous scoring system and treating the patient with radical surgery. The claims of the copending application differ from the instant claims in that they do not teach the colorectal cancer is T1 CRC, or that the patient has at least one histological criterion.
The teachings of Haasnoot are set forth above, including methods to evaluate the risk of lymph node metastases (LNM) or cancer recurrence in patients with surgically removed T1 advanced colorectal cancer (CRC) presenting with the typical histological criteria using an immunoscore classification system.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings and apply to colorectal cancer to assess the immune responses to glean differences in clinicopathological characteristics before and after treatments, as well manage the data collected from the different measures to correlate with survival and/or responsiveness to treatments to determine whether radical surgery is necessary.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings of Haasnoot that quantify an immunoscore, given it is routine in the art to apply this method, and the immunoscore system based on CD3+ and CD8+ T cell densities is widely regarded as a reliable prognostic predictor for stage I-III colon cancer patients, and aids in predicting a patient's prognosis after a curative surgery [see Haasnoot in entirety].
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Additionally, claims 1, 3-7, and 9-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over one or more claims of the following copending applications, in view of Haasnoot.
Application No. 18/003,535 - claims 1-4, 8-10, and 15-18
Application No. 16/099,451 - claims 30 and 32-35
The copending applications have overlapping subject matter that renders obvious the claims of the instant invention. In the interest of compact prosecution, Applicant is invited to indicate whether or not the differences between the instant claims and the copending claims are obvious, as they are drawn to predicting recurrence of colorectal cancer comprising quantifying the density of immune markers and determining therapeutic options using an immunoscore classification system.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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